INTRODUCE THE FIRST KEY NOTE SPEAKER OF THE DAY DR. HUGO CRITCHLEY FROM BRIGHTON AND SUSSEX MEDICAL SCHOOL. HE IS CHAIR OF THE PSYCHIATRY THERE AND CONSCIOUSNESS AND HIS RESEARCH IS ON HUMAN NEUROSCIENCE FOCUSSED ON AUTONOMIC CONTROL AND INTEROSEPTI INTEROSEPTIVE PROCESSES WELCOME TO DISORDERS AND HE'LL GIVE HIS TALK. >> THANK YOU VERY MUCH TO THE ORGANIZERS FOR INVITING ME. IT'S QUITE TRICKY TO PICK WHAT TO TALK ABOUT HEARING HOW DIFFICULT IT IS WHEN YOU HAVE LOTS OF MATERIAL TO SELECT. AND WHICH IS MOST RELEVANT AND I THOUGHT I'D TALK ABOUT THE STUDIES THAT I DID 20 YEARS AGO THAT USED NEUROLOGICAL PATIENTS AS A MODEL TO TRY TO UNDERSTAND INTEROCEPTI INTEROCEPTIVE PROCESSES. WE KNOW IT REGULATES BLOOD PRESSURE AND DIFFUSION OF THE ORGANS AND IT'S FUNDAMENTAL TO WELL BEING. AND PERCEPTUAL SALIENCE AND HOW WE INTERACT WITH OTHER PEOPLE EVEN AND THE STATES CAN BE EMOTIONALLY LABELLED IF YOU LIKE. SALIENCE CAN FEED INTO ENHANCING MEMORY EMOTIONAL MEMORY IN PARTICULAR. WE HEARD YESTERDAY HOW THE CONTINUOUS FEEDBACK FROM THE BODY CAN GIVE RISE OR EVEN BE THE INVESTMENTAL BASIS TO SUBJECTIVE SELF AND INTERNAL SELF AND SELF INTEGRITY AND THE CONTINUITY OF THAT CAN BE THE PLATFORM THROUGH WHICH WE EXPLORE THE WORLD AS AN INDIVIDUAL SEPARATE FROM THE WORLD. I'M GOING TO TALK ABOUT INTEROCEPTION AND NOT TALK ABOUT THE MICROBIOME OR IMMUNOLOGICAL PROCESSES AND SOME FORMS OF NEURAL INTEROCEPTION. WE CAN RECOGNIZE LEVELS OF INTEROCEPTIVE PROCESSING AND THE INTERNAL MECHANISMS INTRINSIC AND THE SENSE WITHIN THE ORGANS THAT TRANSMIT SIGNALS TO THE C.N.S. THROUGH SMALL NERVES. AND HOMEOSTATIC REFLEXES THAT RELAY TO THE BRAIN STEM OR WITHIN THE SPINAL CORD AND BRAIN STEM WE HAVE THE CENTRAL REPRESENTATIONS OF THE VISCERA OR ABSENCE OF SIGNALLING. AND WE HAVE PSYCHOLOGICAL REPRESENTATIONS OF INTEROCEPTIVE PROCESSES THAT FEED INTO EMOTION. AND WE HAVE INCIDENTAL FUNCTIONS. A COUPLE GROUPS KEEN ON HOW WITHIN THE BRAIN THEY FACE REPRESENTATIONS FORM OTHER PROCESSES PARTICULARLY TO INCREASE THE EFFICIENCY OF THE PROCESSING OF INTEROCEPTIVE STIMULI AND IMBUE THAT WITH AN INTERNAL SENSE OF SELF. WTHIN THE HIERARCHY WE CAN LOOK AT INTEROCEPTIVE PROCESSES. THE WORK COMING UP AFTERWARDS WILL GET TO WHAT I WON'T GET TO AND WE CAN MEASURE AFFERENT SIGNALS MEASURES ACTIVITY IN THE BRAIN OR PERIPHERY AND LOOK AT THE WAY IN WHICH INTEROCEPTIVE SIGNALS IMPACT OTHER PROCESSES AND LOOK AT PSYCHOLOGICAL REPRESENTATIONS AND LOOK AT HEARTBEAT DETECTION OR SUBJECTIVE REPORTS ON CONFIDENCE RATE OF ACCURACY. AND THEN THE INTERACTION OR RATHER THE CORRESPONDENCE BETWEEN SUBJECTIVE AND OBJECTIVE MEASURES VIEWED AS MEASURES OF THE BODY AND THESE LEVELS FEED OR RELATE TO THE OTHER SUBJECTIVE MEASURES LIKE EMOTIONAL FEELINGS. SO WHAT DO WE SEE WHEN WE SEE DYSFUNCTION OF AUTONOMIC NERVES. WE SEE WHAT BLOCKS THE VISCERAL ORGANS AND SMALL MICRO NEUR NEUROPATHIES THAT IMPAIR SMALL FIBERS. AND THERE'S A NUMBER OF THINGS THAT GIVE WAY TO IMPAIRMENT WHICH AFFECT PHYSICAL HEALTH AND THE QUESTION IS TO THE EXTENT THEY DISRUPT INTEROCEPTION AND FIBROMYALGIA IS BECOMING PART OF THE RESEARCH WE'RE DOING. 20 OR SO YEARS AGO I WAS WORKING IN QUEEN SQUARE IN THE AUTONOMIC CONTROL FAILURE AND LOOKING AT THE GANGLIA PARASYMPATHETIC AND SYMPATHETIC AND LOOKING AT PARKINSON'S WHERE FAILURE HAS NO CENTRAL INVOLVEMENT AND NO OBVIOUS NEURODEGENERATION OF THE BRAIN. THERE'S SECONDARY CAUSES OF AUTONOMIC FAILURE AND THERE'S HEREDITARY AND AUTONOMIC DYSFUNCTION AND A PORTION OF PATIENTS HAVE COGNITIVE IMPAIRMENT. THE REST OF THEM I GUESS HAVE ATEN Y ATE ATTENUATED IMPAIRMENT AND DAMAGE TO THE SPINAL CORD CAN ACT AS MODELS FOR UNDERSTANDING NEURAL PATHWAYS BUT THE IMPACT ON THE MIND AND THIS WAS MENTIONED YESTERDAY IT'S NOT THAT IMPRESSIVE. MORE IMPRESSIVE ARE THE AUTONOMIC DYSFUNCTIONS AND YOU HAVE TACHYCARDIA SYNDROME AND COLLAGEN DYSFUNCTION AND ABOUT 20% OF THE POPULATION HAVE THESE DISORDERS BUT THE CONDITIONS ARE ASSOCIATED WITH VULNERABILITY TO ANXIETY AND PANIC DISORDERS AND NEUROPSYCHIATRIC SYNDROMES LIKE FIBROMYALGIA. SPINAL CORD DYSFUNCTION AND THIS IS AN AUTONOMIC DYSFUNCTION. THIS IS TAKEN FROM A PAPER AND PSYCHIATRIC DISORDERS HAVE INVOLVEMENT OF INTEROCEPTIVE PROCESSES AND THEY RELATE TO HYPERACTIVITY OR INTERPRETATION OF AUTONOMIC SIM BOWLS RATHER THAN A MAJOR DYSFUNCTION OF HOMEOSTASIS. SO WE CAN LOOK AT WORK I WAS DOING 20 YEARS AGO. SMALL NUMBERS OF PATIENTS AND IT ILLUSTRATES THE POINT AND THE WAY WE WERE APPROACHING THE SUBJECT. WE WERE LOOKING AT PATIENTS WITH PURE AUTONOMIC FAILURE AND SPINAL CORD TRANSSECTION. WE LOOKED AT PEOPLE OF VAGUS NERVE STIMULATION FOR BLOOD DYSFUNCTION AND MORE RECENTLY WE HAVE LOOKED AT THE HYPERACTIVITY SYNDROMES WHERE THERE'S AUTONOMIC DYSFUNCTION AND EXPRESSION OF ANXIETY AND RELATED PSYCHIATRIC DISORDERS. AND WE HAVE BEEN LOOKING AT PATIENTS WITH INTEROCEPTIVE FEATURES RELATED TO PSYCHOSIS. AND WE HAVE LOOKED AT DIFFICULT ISO METRIC EXERCISE INCREASE THE HEART RATE AND BLOOD PRESSURE WITH EFFORT AND AFFECTS THE CORTEX AND TO WHICH THE AREAS ARE ACTIVATED MEASURES WITH THE CARDIOVASCULAR SYSTEM SO BLOOD PRESSURE CHANGES MAPPED INTO THE RIGHT ANTERIOR CORTEX IN THE STUDY. WE REPLICATED THIS TYPE OF EXPERIMENT. LOOKING ACROSS DIFFICULT THINKING AND EXERCISES AND ISOLATING THE AUTONOMIC COMPONENTS. WE CAN SAY THIS TIME AND TIME AGAIN. FOR EXAMPLE, PEOPLE AGED 65 INCREASED IN BLOOD PRESSURE COINCIDE WITH THE ACTIVATION. WHEN WE LOOK AT PATIENTS WHO THEN TAP THE AUTONOMIC ACTIVITY BECAUSE THEY LACK AN AUTONOMIC PERCEPTION AND IT SHOWED ACTIVITY IN TWO REGIONS. FIRST IN THE AREA WHERE THERE'S DYSFUNCTION RELATIVE TO THE CONTROLS WHEN THEY'RE TRYING TO EXERT EFFORT INTO THEIR BODY WITH THE DEMANDS OF THE TASK WHETHER IT'S EXERCISE OR ARITHMETIC. WE ALSO SEE BRAIN STEM DIFFERENCES AND THEY'RE NOT DEPENDENT ON WHETHER ERTS ARE BEING EXERTED. AND IT'S CONSISTENT WITH THE SENSOR AND THIS IS THE SECOND OR THE REPRESENTATION WHERE THE BODY'S TRYING TO OR BRAIN IS TRYING TO INTEGRATE PHYSIOLOGICAL PROCESSES WITH TASK DEMANDS. SO DECREASES IN AREAS WHICH WE SEE ARE SENSORY CORTEX. THE EVIDENCE FOR THE SENSORY CORTEX AT LEAST IN MY WORK CAME FROM STUDIES OF PURE AUTONOMIC FAILURE PATIENTS AND USING TASKS WHERE HAVING AN ELECTRIC SHOCK TO A STIMULUS MAKES THE STIMULUS THREATENING AND IT TAKE PLACE IN THE AMYGDALA AND PEOPLE GET THE RESPONSE BUT DON'T GET THE AUTONOMIC COMPONENTS OF THE THREAT RESPONSE. IN THOSE PATIENTS IS ACTIVATION OF AMYGDALA WITH LEARNING AND IN RESPONSE TO THREAT STIMULI BUT THERE'S DIFFERENCES. THEY FAIL TO ACTIVATE TO THE CORTEX TO THE EXTENT OF THE CONTROL GROUP AND FAIL TO ACTIVATE REGIONS OF THE AMYGDALA AND DIFFERENT REGIONS OF THE AMYGDALA. CONSISTENT WITH BOTH AREAS BEING SENSORY SENSITIVE TO THE INTERNAL STATE OF THE BODY THAT NORMALLY ACCOMPANIES RESPONSE TO THREAT. WE PLAYED WITH PERCEPTUAL AWARENESS OF THE THREAT STIMULI WHICH SHOWS EMOTIONAL RESPONSES THAT ARE QUITE AUTOMATIC. EVEN WITH THE MASS THREAT STIMULUS. YOU FLASH THE THREAT STIMULUS AND MASK IT WITH A NEUTRAL STIMULUS THE PATIENTS IN THE CONTROL SHOWED A RESPONSE, THE OTHER PATIENTS DON'T SHOW THE AUTONOMIC COMPONENTS AND WE SEE AREAS WITH THE DORSAL AND INTERIOR INSULA AND THE PRESENCE OF AN AUTONOMIC RESPONSE AND THIS DEMANDS THIS KIND OF INTEGRATIVE MODE OF HAVING AWARENESS OF THE COURSE OF THE PHYSIOLOGICAL RESPONSE. SO THE AUTONOMIC FAILURE INDICATE THE WAY IN WHICH THE AUTONOMIC CONTROL IS INSTIGATED IN THE BRAIN AND THE SENSORY STIMULATION AND IN THIS AUTONOMIC FAILURE WE CAN IDENTIFY DEFICITS IN EMOTIONAL FUNCTIONING BUT THERE'S THINGS LIKE SOCIAL COGNITION TASKS. WHEN LOOKING AT PATIENTS WITH SPINAL CORD SENSATION. THE NEURAL INPUTS ARE IN THE BRAIN AND UP THE SPINAL CORD AND SMALL FIBERS TRACK ALONG THE SYMPATHETIC NERVES TO THE DORSAL ROOT GANGLION AND UP THROUGH THE SPINAL CORD AND THIS SEEMS ON THE ONE IN WHICH THEY'RE MORE ABLE TO LINK TO FEELING STATES AND WE HAVE INPUT IN THE MAJORITY OF PEOPLE THROUGH VAGUS. AND THEY CAN FEEL THE PAIN STIMULUS BECAUSE THE SHOT WAS ABOVE THE LESION AND WE LOOKED AT THE RESPONSE OF THE SPINAL CORD TRANSSECTION PATIENTS TO THE THREAT STIMULI NOT THE SHOCK. AND FOUND OTHER AREAS WE KNOW ARE INVOLVED IN OUGAUTONOMIC CONTROL. AND IT'S RELATIVE TO CONTROLS. DORSAL GRAY WERE HYPERREACTIVE IN THE GROUP TO THREAT AND OTHERS WE SEE ANTISYMPATHETIC IN THE PREFRONTAL CORTEX HAD AN OPPOSITE AFFECT AND ATTENUATION IN THE SPINAL CORD GROUP. WE CAN LOOK AT PATIENTS TO TRY TO UNDERSTAND A LITTLE BIT MORE ABOUT THE VAGUS ROOT. WE DID LOOK AT PATIENTS WITH DEPRESSION IN THE EARLY TRIAL OF VAGUS NERVE STIMULATION FOR DEPRESSION. WE WERE A LITTLE BIT OVER AMBITIOUS IN THIS STUDY. WE HAD PEOPLE DOING AN EMOTIONAL MEMORY TASK WITH A SERIES OF WORDS AND IF YOU TEND TO REMEMBER THE EMOTIVE WORDS AND FORGET THE WORDS AROUND THE EMOTIONAL WORD. SO YOU WON'T REMEMBER SOME WERE IN THE THERE BUT REMEMBER MURDER WAS AND THE NEXT OF THE PATIENTS PROGRAMMED IT IN 30-SECOND BURSTS. IT SHOWED THE PRESENCE OF ACTIVE VAGUS NERVE STIMULATION WAS SELECTIVE IN FOUR OF THE PATIENTS WE SAW. AND WE TRIED TO GET MORE IN AN M.R.I. SCAN AND THERE ARE WERE CHALLENGES TO BE OVERCOME. WE ABANDON THE STUDY AFTER SCANNING BECAUSE OF TECHNICAL ISSUES. THIS IS DATA FROM THE ONE PERSON LOOKING AT THE D.N.S. EFFECTS OF NEGATIVE WORDS AND SHOWING WHEN PEOPLE ARE SEEING NEGATIVE WORDS DURING D.N.S. VAGUS NERVE STIMULATION COMPARED TO OFF VAGUS NERVE STIMULATION IT GOES TO THE CORTEX AND BRAIN REGIONS AND PREFRONTAL CORTEX AND THE INSULA AND FRONTAL REGIONS SHOWED EFFECTS THAT CORRESPONDED TO THE VAGUS NERVE STIMULATION. SO AGAIN, WE'RE ABLE TO USE THE CHALLENGE TO UNDERSTAND A LITTLE BIT MORE ABOUT THE AFFERENT INTEROCEPTIVE PATHWAYS. AN ADDITIONAL GROUP WHERE WE LOOKED STIMULATION WHERE PATIENTS WITH RETENTION SO CONDITIONS WITH A SYNDROME AND IT AFFECTS YOUNG WOMEN WHO GET MASSIVELY OVER DILATED BLOOD AND/OR NERVE STIMULATION WHICH RETURNS THE URGE TO VOID. THAT APPEARS TO BE SOMETHING WRONG WITH THE NORMAL REFLEXIVE CONTROL AND THE ASSUMPTION THAT DRIVES FEELING STATES AND ALSO CONTROLS THE REFLEX WHICH IS GENERALLY CONTROLLED AT THE LEVEL OF THE BRAIN. SO SACRAL NERVE STIMULATION REDUCES THE AUTONOMY IN THE SPHINCTER AND THE THERE'S REGIONS OF CORTEX INCLUDING POSTERIOR SINGULETS AND YOU HAVE ADDITIONAL FRONTAL ENGAGEMENT AND LESS ENGAGEMENT AND POSTERIOR REGION BUT NO BRAIN STEM ACTIVITY AND WHEN THE STIMULATOR RESTORES THE FUNCTION OF THE BLOOD IN TERMS OF SIGNALLING FULLNESS, YOU GET AMP AND WE CONDUCTED A STUDY WHERE THE STIMULATION WAS DONE JUST BEFORE THEY WENT INTO ONE OF THE SESSIONS. AND WE SEE IT'S RELATED TO THE RETURN TO THE URGE TO VOID. AND THE STUDY OF THE TRANSSECTION THE PATIENTS TELL US ABOUT THE HYPERREACTION TEST OF THE CORTICES AND MID BRAIN IN THE ABSENCE OF THE SPINAL ROOTS OF THE INTEROCEPTIVE SIGNALLING AND SUGGEST THE INPUT FROM THE BODY GOING THROUGH THE SPINE IS IMPORTANT IN ASPECTS OF FUNCTIONING OF THE BRAIN REGIONS WHICH WE NO ARE IMPLICATED IN FUNCTIONS INCLUDING EMOTION. AND IT AFFECTS PROCESSING INCLUDING EMOTIONAL MEMORY. AND THERE'S THE CORTICAL CONTROL REGIONS REENGAGE THE SENSORS WITH THE ENGAGEMENTS INTO THE CORTEX AND THE RETURN OF THE URGE TO VOID. AND THERE WAS A STUDY WHERE THE BALANCE OF THE CLINICAL WORK WAS SHIFTING FROM AUTONOMIC FAILURE TO PEOPLE WHO FAVENT -- FAINT AND HAVE THE CONDITION WHERE IT'S TACHYCARDIA SYNDROME WHERE THERE'S SYMPTOMS LIKE FATIGUE, DIZZINESS AND ARRANGE OF THINGS LIKE PALPITATIONS AND THAT'S A BIG FEATURE IN THE PATIENT GROUP AND THAT CONDITION'S LINKED TO COLLAGEN DISORDERS. VERY PREVALENT. IN FACT ALL THE PATIENTS SEEN IN THE AUTONOMIC UNITS IN THE U.S. AND U.K. HAVE THIS. AND THERE'S AUTONOMIC SYNDROME AND THE VULNERABILITY TO ANXIETY AND PANIC DISORDER AND FIBROMYALGIA AND PAIN DISORDERS, IRRITABLE BOWEL SYNDROME AND OTHER DISORDERS. WE LOOKED AT PEOPLE WHO FAINTED COMPARED TO PEOPLE WHO DIDN'T AND I'M NOT SURE HOW LUCKY WE WERE BUT WE FOUND DIFFERENCES BETWEEN PEOPLE WHO FAINT AND PEOPLE WHO DON'T IN THE REGIONS OF MEDULLA AND MID BRAIN. WE LOOKED AT FAINTERS FOR CORRELATES WITH HOW FREQUENTLY THEY FAINTED. THEY'RE COMPONENTS OF FAINTING RESPONSE AND THEY'RE 15 TO 20 TIMES MORE VULNERABLE TO THESE DISORDERS IN PEOPLE THAT FAINTED AND THERE'S BEEN PREDICTED HOW FREQUENTLY PEOPLE FAINTED. AND THAT LEVEL OF HEART RATE AND THE EXPERIENCE OF ANXIETY. THE TACHYCARDIA PATIENTS WE SAW, AGAIN, THIS IS A SMALL NUMBER OF PATIENTS AND THE DISORDER IS RECOGNIZES MORE FREQUENTLY TO BIGGER STUDIES AND WE LOOKED AT BRAIN VOLUME DIFFERENCES AND WHAT WE SAW RELATIVE TO CONTROLS INCLUDES INSULA AND CINGULATE REGIONS AND FRONTAL LOBE AREAS AND FRONTAL PARIETAL REGIONS. AND THE SYMPTOMS WERE REPORTED FROM THE SYSTEMS INCLUDING THE VOL TOMB -- VOL TOMB PRE THE VOLUME PREDICTED WHETHER THEY WERE VULNERABLE TO ANXIETY AND WHAT YOU GET IN THE POSTURAL TACHYCARDIA AND THEY SEEM TO HAVE TO BE RESTRICT OND STANDING. BLOOD PRESSURE IS MAINTAINED BY ACCELERATING THE HEART. AND THE CLINICAL SIGNATURE OF POTS DUE TO LAXITY OF VESSELS IN THE LEGS BUT IT DOESN'T EXPLAIN THE FEATURES YOU GET IN TERMS OF NEUROPSYCHIATRIC VULNERABILITY. AND IT MIGHT EXPLAIN SOME OF THE ANXIETY SYMPTOMS. WE LOOK AT THAT WITH A FUNCTIONAL TASK WHERE PEOPLE WERE PROCESSING DIFFERENT AFFECTIVE STIMULI AND ANGER AND NEUTRALITY AND WHAT WE FOUND IN THE PATIENT GROUP WHILE LYING FLAT IN THE SCANNER WAS A HIETDENNED CARDIAC -- HEIGHTENED CARDIAC RESPONSE TO ANY STIMULATION AND THAT'S REFLECTED HEE WHENEVER THE STIMULUS CAME UP ON THE SCREEN AND THAT CARDIAC ACCELERATION ACROSS DIFFERENT EMOTIONAL CATEGORIES WAS ASSOCIATED WITH DIFFERENCES IN THE ACTIVATION OF THE FRONTAL CORTEX SO IF YOU LIKE, THIS IS A PARASYMPATHETIC AREA AND IT'S TAKEN OFF WHEN PEOPLE SEE EMOTIONAL STIMULUS. I MENTIONED THEY DON'T HAVE MOBILITY SYNDROME OR IN PEOPLE WITH POSTURAL TACHYCARDIA SYNDROME AND MY COLLEAGUE AND WE LOOKED AT LARGE DATABASES AND WE SEE THE SAME THING WHICH IS IN THE POPULATION THERE'S 20% AND THE PSYCHIATRIC POPULATIONS CAN GO UP TO 30%, 35%, 40% DEPENDING ON WHAT GROUP YOU SEE AND 50% IN ANXIETY GROUPS. IT'S A COMMON FEATURE ACROSS FEATURES AND DIFFERENT ACROSS DIFFERENT POPULATIONS. IN PEOPLE WITH HYPERMOBILITY SYNDROME WE FOUND DIFFERENCES IN THE AMYGDALA VOLUME THEY TENDED TO HAVE BIGGER AMYGDALA COMPARED TO PEOPLE WITHOUT HYPERMOBILITY FEATURES AND SCORED ON SUBJECTIVE RATINGS OF SENSITIVITY TO STATES HIGHER THAN PEOPLE WITHOUT HYPERMOBILITY. AND WE'VE LOOKED AT THE AUTONOMIC STATES AND LOOK AT AWARENESS OF AUTONOMIC FEATURES AND THERE SEEMS TO BE DISCREPANCIES TO THE EXTENT TO WHICH THEY PERCEIVE AUTONOMIC SYMPTOMS AND THE MEASURES IN THIS GROUP. FUNCTIONAL IMAGING STUDIES HAVE SHOWN DIFFERENCES IN THE AMYGDALA IN THESE GROUPS AND THESE INSIGHTS ARE NOW BEING TESTED IN CLINICAL TRIALS OR EXPLORATORY TRIALS OF TRAINING PEOPLE TO BETTER UNDERSTAND THEIR AUTONOMIC RESPONSES AND I WANTED TO MENTION SOME OTHER AVENUES INTO CLINICAL WORK WE'RE DOING NOW. WE HAVE BEEN LOOKING AT DIFFERENT LEVELS OF INTEROCEPTION. IT'S LONG BEEN NAMED THAT HEART BEATS OF SIGNALS OF CARDIOVASCULAR AROUSAL IF YOUR HEART BEATS FAST YOU GET AFFERENT SIGNALS THAT ARE QUICK AND STRONG AND IF IT'S BEATING IRREGULARLY IT CAN TAP INTO THE SIGNALLING OF CARDIOVASCULAR AROUSAL BY FINDING STIMULI BEFORE THE HEART BEATS OR ON THE HEART BEATS. AND LOOK AT THE WAY THE STIMULI ARE PROCESSED IN THE CONTEXT OF THE AFFERENT SIGNAL OR IN BETWEEN IN THE QUIET PHASE OF BIORECEPTOR SIGNALLING AND THE CARDIAC SIGNAL INHIBITS PROCESSES LIKE PAIN PROCESSING AND OTHER TYPES OF PERCEPTION. WE DID AN IMAGING STUDY YEARS AGO LOOKING AT REACTIONS TO PAIN STIMULI AND SHOWED WHEN PAIN STIMULI ARE PRESENTED AT CARDIAC SYSTOLE YOU GET DIFFERENCES IN ATTENUATION OF PROCESSING PAIN RECEPTION AND CARDIAC SYSTOLE OR IN THE STATE OF AROUSAL. AND THAT ATTENUATION BY VISCERAL AFFERENT SIGNALS IS ASSOCIATED WITH DISENGAGEMENT OF IN SULA CORTEX MID BRAIN AND ENGAGEMENT OF AMYGDALA AND THERE ARE OTHER FEATURESSULA CORTEX MID BRAIN AND ENGAGEMENT OF AMYGDALA AND THERE ARE OTHER FEATURES THAT INVOLVED THE RELATIONSHIP WITH OTHER MEASURES OF HEART RATE VARIABILITY. HOWEVER, WE FOUND AN OPPOSITE EFFECT TO THE PROCESSING OF THREAT. WHILE MOST STIMULI PARTICULARLY PAIN ATTENUATED BY THE CARDIAC SIGNALS THE PERCEPTION OF FEAR FACES AND THE DETECTION OF FEAR AND THE SUBJECTIVE RATINGS OF HOW STRONG THE PHASES ARE ENHANCED AT CARDIAC SIS TOYSTOLE SO BEFORE THE HEART BEATS COMPARED TO WHEN THE HEART'S BEATING, FEAR IS ENHANCED AND THAT RESPONSE IS ASSOCIATED WITH INCREASED AMYGDALA ENGAGEMENT AND THAT DEGREE TO WHICH THE AMYGDALA RESPONSE IS EXPRESSED AND THE STRENGTH OF THE SYSTOLIC ENHANCEMENTS OF FEAR PREDICTS INDIVIDUAL DIFFERENCES IN HEALTHY PEOPLE AND ANXIETY. THIS HAS BECOME AN -- OF INTEREST TRYING TO LOOK AT INDIVIDUAL DIFFERENCES IN PATIENTS.N -- OF INTEREST TRYING TO LOOK AT INDIVIDUAL DIFFERENCES IN PATIENTS. -- OF INTEREST TRYING TO LOOK AT INDIVIDUAL DIFFERENCES IN PATIENTS.-- OF INTEREST TRYING TO LOOK AT INDIVIDUAL DIFFERENCES IN PATIENTS.- OF INTEREST TRYING TO LOOK AT INDIVIDUAL DIFFERENCES IN PATIENTS.OF INTEREST TRYING TO LOOK AT INDIVIDUAL DIFFERENCES IN PATIENTS. IN PATIENT GROUPS WE GET THIS ENHANCEMENT IN ANXIETY GROUPS OF THIS CARDIAC DRIVE TO INCREASE FEAR PERCEPTION. SO SCREENING PATIENTS WITH ANXIETY DISORDER ON THIS CARDIAC-DRIVEN TASK, WE GET A BIGGER RESPONSE TO PATIENTS WITH ANXIETY AND YOU GET ATTENUATION ACROSS DIFFERENT GROUPS IN OPPOSITE DIRECTIONS TO NEUTRAL PHASES. THE STAND-OUT FINDINGS WAS SOMETHING DIFFERENT GOING ON IN PEOPLE WITH PSYCHOSIS WHICH IS NOW THE SUBJECT OF A LOT OF INTERESTING STUDIES. I'LL CONCLUDE PATIENT STUDIES CAN PROVIDE INSIGHT INTO INTEROCEPTIVE PROCESSES AND THE MECHANISMS THAT ENABLE PEOPLE WITH MASSIVE DYSFUNCTIONAL HOMEOSTATIC COMMUNICATION AND PEOPLE WITH PERIPHERAL LESIONS SEEM TO BE AFFECTED AND THAT WAS TOUCHED ON YESTERDAY. INTEROCEPTIVE PROCESSES PROVIDE A MORE COMPREHENSIVE UNDERSTANDING OF BOTH PHYSICAL DISORDERS AND PSYCHOLOGICAL DISORDERS. AND WE CAN HOPEFULLY IDENTIFY INTEROCEPTIVE TARGETS FOR INTERVENTION NOT ONLY FOR ANXIETY BUT DISINTEGRATED DISORDERS LIKE PSYCHOSIS AND PAIN CONTROL AND CONDITIONS LIKE CARDIAC DISORDERS AND PHYSICAL CONDITIONS AND CAN DEVELOP WHAT'S ALREADY IN PLACE AND TAP INTO OUR INCREASING KNOWLEDGE OF INTEROCEPTION. SO JUST TO ACKNOWLEDGE OUR FUNDERS AND THE RESEARCH COUNCIL FUNDED THE EARLY WORK AND CLINICAL TRIALS AND TO THOSE FOR ALL THEIR HARD WORK. THANK YOU VERY MUCH. >> IN THE INTEREST OF TIME I'M GOING TO MOVE ON TO THE NEXT SESSION. DR. CRITCHLEY WILL BE UP AT THE PANEL AT THE END OF THE SESSION FOUR FOR QUESTIONS. >> GOOD MORNING EVERYBODY. I'M VICTORIA SPRUANCE AND FELLOW AT NIDDK. FOR THOSE IN THE ACRONYM WORLD IS NATIONAL INSTITUTE OF THE DIGESTIVE AND KIDNEY DISORDERS AND WE'LL LOOK AT THERAPEUTICS FOR DISEASE INTERVENTION. AND WE HAVE A GREAT LINEUP OF SPEAKERS AND ALSO ALONG WITH ME CHAIRING THE SESSION IS DR. CYNTHIA PRICE AND DR. HELEN WENG AND WE HAVE AN INTRAMURAL RESEARCHER TALKING TO THE RETURN OF THE IDEA OF THE GUT-BRAIN ACCESS AND POTENTIAL NORMAL TARGETS FOR THE TREATMENT OF ADDICTIONS. WE'LL MOVE ON TO DR. JACK FELDMAN WHO WILL TALK ABOUT THE RESPIRATORY SYSTEM AND INTEROCEPTION. DR. JEANIE PARK IS GOING TO MOVE AND AND TALK ABOUT HOW WE CAN LEVERAGE INTEROCEPTION TO IMPROVE SYMPATHETIC FUNCTION AND TALK ABOUT HER WORK IN CHRONIC KIDNEY DISEASE AND I BELIEVE PTSD AND DR. NAPADOW WILL TALK ABOUT HOW TO USE RESPIRATORY VAGUS NERVE STIMULATION AS THERAPEUTIC TREATMENT IN PATHWAYS AND WE'LL TAKE A BREAK AND COME BACK FOR DR. PRICE'S DISCUSSION ON LEARNING HOW INTEROCEPTIVE AWARENESS SKILLS RELATE AND WITHOUT FURTHER ADO, DOCTOR. >> THANK YOU, VICTORIA FOR THE INTRODUCTION AND TO THE ORGANIZERS. AS WE ALL KNOW ADDICTION ARE LEADING CAUSES OF MORTALITY AND MORBIDITY. WE HAVE ROUGHLY 40,000 PEOPLE DYING EVERY YEAR IN THE UNITED STATES BECAUSE OF OPIOIDS. MORE THAN TWICE, ROUGHLY 89,000 PEOPLE DYING EVERY YEAR IN THE UNITED STATES. ADDICTION IS CLEARLY A CRITICAL PUBLIC HEALTH AND MEDICAL CONCERN. THE GOOD NEWS IS THAT NOW WE HAVE A MUCH BETTER UNDERSTANDING OF THE NEUROBIOLOGY OF ADDICTION AND KNOW THERE ARE PATHWAYS IN PARTICULAR NEUROCIRCUITRY OF THE BRAIN INCLUDING PATHWAYS RELATED TO REWARD PROCESSING AS WELL AS HOMEOSTASIS AND STRESSORS DO PLAY AN IMPORTANT ROLE IN THE DISORDERS. THE BAD NEWS IS WE STILL DON'T HAVE A GOOD AMOUNT OF TREATMENTS THAT CLINICIANS MAY USE TO HELP OUR PATIENTS. THE NUMBER OF MEDICATIONS WE HAVE IS VERY SMALL. SO THEY FEEL THE WAY WE ARE IN HUGE NEED TO TRY TO IDENTIFY NEW TARGETS TO DEVELOP NEW TREATMENT. WITH THAT IN MIND, THE ANGLE MY PROGRAM AND OTHER SCIENTISTS ARE TAKING AS TO LOOK AT PATHWAYS BEYOND THE USUAL SUSPECT TO TRY TO FIND NEW TARGETS IN DEVELOPING NEW TREATMENTS. WITH THIS IN MIND AND WE LOOK AT THE BRAIN TO IDENTIFY NEW TREATMENTS AND IT'S RELEVANT TO THE WORKSHOP AND WE'VE REVIEWED THE ROLE OF INTEROCEPTION AND THE TAKE-HOME MESSAGE IS THE IDEA THAT THERE'S ROLES INCLUDING STRESSORS AND HOW THIS MAY IN FACT PLAY A ROLE IN DEVELOPMENT IN MAINTENANCE OF ADDICTIVE DISORDERS. WE LOOKED AT THE BIG PICTURE FRAMEWORK. THE SPECIFIC ANGLE WE'RE TAKING IN OUR LAB IS TO LOOK AT HUNGER AS A POTENTIAL WAY AND PATHWAYS OF MECHANISMS OF ADDICTION AND OUR APPROACH IS AN ENDOCRINE PATHWAY AND THE GROWING NICKNAME IS THE HUNGER HORMONE IS A PEPTIDE WHICH DOES COME FROM THE STOMACH AND IS 80%, 90% COMES FROM THE STOMACH BUT IT PROCESSES INTO THE BRAIN AND IT'S RELATED TO FOOD REWARD. THE QUESTION IN OUR FIELD IS WHETHER IT'S ROLE IN REGULATING HUNGER ALSO PLAYS A ROLE IN ADDICTIVE DISORDERS AND IF YOU INJECT INTO A RODENT AND ANTAGONIST YOU GET THE OPPOSITE EFFECT MEANING THERE'S A PROXY FOR REWARD AND THESE OUTCOMES ARE BLOCKED AND OUR JOB AS PHYSICIAN SCIENTISTS HAVE BEEN TO TRY TO TRANSLATE THIS INFORMATION TO HUMANS. AND WE KNOW IN THE RECEPTOR WE HAVE A REDUCTION IN ALCOHOL DRINKING AND SO PROVIDING MORE EVIDENCE NOT ONLY THE PEPTIDE AND RECEPTOR ITSELF IS IMPLICATED IN THE MECHANISM OF ALCOHOL-SEEKING BEHAVIOR AND THE TINKING IS IF WE BLOCK THE RECEPTOR IT COULD BE A POTENTIAL WAY TO TREAT HUMANS. AND PATIENTS WITH ALCOHOL DISORDERS FEEL NOT LIKELY TO RELAX AND OTHERS ARE LESS LIKELY TO RELAX. NOW, WE'RE TRYING TO SHOW CORRELATION AND NOT CAUSATION LIKE IN THE ANIMAL WORKED AND WE LOOKED AT THE PLACEBO CONTROL AND WE SEE IF THE MANIPULATION IS CORRELATED TO CHANGE IN SCHO ALCOHOL-SEEKING BEHAVIOR AND IN THE STUDY WE SEE BY INJECTED WE HAVE AN INCREASE AND WE LOOK AT THE ALCOHOL CUES RATHER THAN FOR OUR CONTROL CUES. THEN WE GO TO THE NEXT STEP WHERE GHRELIN IS INJECTED AND WE INJECT THE DOUBLE-BLOCKED PLACEBO CONTROL AND THE SUBJECT HAS THE ABILITY TO USE THIS AND WHEN WE INJECT GHRELIN WE HAVE AN INCREASE IN ALCOHOL DEMONSTRATION AND IN THE SCAN THE PRESENCE OF ALCOHOL STIMULATION WE SEE AN INCREASE IN AMYGDALA AND SUGGESTING THE WAY WE MANIPULATE THE GHRELIN THERE'S A DIFFERENCE IN CHANGING BEHAVIOR AND NEUROCIRCUITRY AS IT RELATED TO AND EMOTIONALITY IN THE AMYGDALA. SO WHAT'S THE NEXT STEP? I STARTED TO TELL YOU WE WANTED TO DEVELOP NEW TREATMENTS AND WE HAVE SHOWN YOU DATA THAT WE INJECT GHRELIN AND WE MAKE THE SYMPTOMS WORSE. SO IT WAS IMPORTANT TO SHOW CAUSALITY IN HUMANS BUT NOW YEAR -- WE'RE COMMITTED TO MOVE TO A MEDICATION AND WE WERE ABLE TO HAVE ACCESS TO A COMPOUND DEVELOPED BY PFIZER WHICH IS A GHRELIN RECEPTOR BLOCKER AND THERE'S NO MEDICATION IN THE MARKET SO THIS ALLOWS US WITH IS THE UNIVERSITY OF RHODE ISLAND TO HAVE ACCESS TO THE COMPOUND. THE UNIQUENESS OF THIS COMPOUND IS IT'S BEEN THE ONLY COMPOUND SO FAR THAT HAS BEEN MOVED TO CLINICAL. IN FACT PFIZER HAD DONE A PHASE 1 STUDY WHERE THEY SHOWED IT IN HEALTHY CONTROLS. AND WHAT WE HAVE DONE SO FAR WE SHOWED IT WITH ALCOHOL AND WE SHOWED IN A PAPER WE SHOWED THE SAFETY IN ALCOHOL-DEPENDENT PATIENTS AND IN A SMALL GROUP WE SEE THE PF COMPOUND REDUCES THE CRAVING FOR ALCOHOL AND FOOD AND WE'RE CONDUCTING A STUDY TO SEE WHETHER IT MAY IN FACT BE A PROMISING NEW TREATMENT FOR ALCOHOL AND BEYOND ALCOHOL FOR ADDICTIVE DISORDERS. TO SUMMARIZE, WE AND OTHER PEOPLE HAVE PROVIDED EVIDENCE IN ANIMALS AND IN HUMANS INCLUDING THE POPULATION OF ALCOHOL USE DISORDER PATIENTS AND THE GHRELIN SEEMS TO PLAY A ROLE AND IN STUDIES WITH RODENTS INDICATE BY BLOCKING THE GHRELIN RECEPTOR IT COULD BE A PHARMACEUTICAL WAY TO TREAT ALCOHOL DISORDER AND WE HAVE INITIAL PRELIMINARY DATA IN HUMANS WHETHER IN HUMANS BLOCKING THE GHRELIN RECEPTOR MAY LEAD TO EFFECTIVE RESULT IN PATIENTS AND THEN FOR THE DISCUSSION, TWO OTHER QUESTIONS I WANT TO POSE TO THE AUDIENCE AND MYSELF IS WHETHER BEYOND GHRELIN DOES THE STAGE OF HUNGER PLAY A ROLE IN ADDICTION AND HOW IMPORTANT IS THE INTEROCEPTION HELPS US TO UNDERSTAND AND TREAT ADDICTION AND THANK YOU SO MUCH. >> THANK YOU VERY MUCH, COLLEAGUES AND CYNTHIA AND THANK YOU FOR ORGANIZING THIS AND GIVE ME AN OPPORTUNITY TO TALK. AND I'M GOING TALK ABOUT BREATHING AND I'M GOING TO ASK YOU ALL TO TAKE A DEEP BREATH AND EXHALE. SO YOU HAVE ESTABLISHED INTEROCEPTION OF BREATHING. WE ARE NOT AWARE OF BREATHING MOST THE TIME BUT ARE AWARE WHEN WE TAKE DEEP BREATHS OR BREATH HOLD OR MEDITATE AND WITH HEAVY EXERCISE WE'RE MOVING A LOT OF AIR AND WE'RE AWARE OF IT. THERE'S AN EMOTIONAL COMPONENT OF BREATHING AND WHEN WE LAUGH AND CRY WE MAY BE AWARE OF OUR BREATHING PLAYING A ROLE IN THAT AND WHEN WE HAVE DISCOMFORT LIKE BREATHLESSNESS WE'RE AWARE AND WE SEE IT IN DISEASES LIKE PANIC AND ANXIETY DISORDERS. NOW, THERE'S SYMPTOMS OF BREATHING BUT I WANT LOOK AT SLEEP APNEAS ARE COMMON AND I IMAGINE THERE'S MORE THAN A FEW PEOPLE HERE WHO HAVE SIGNIFICANT SLEEP APNEAS AND THAT'S AN AFFECT ON BREATHING YOU MAY NOT BE AWARE OF UNLESS YOU ARE FALL ASLEEP DURING MY TALK AND OPIOID OVERDOSE CAN CAUSE AN ARREST OF BREATHING AND CARDIAC FUNCTIONS AND COUGHING RELATED DISEASES. SUDDEN UNEXPLAINED DEATH DUE TO EPILEPSY I'LL TALK ABOUT PANIC AND ANXIETY DISORDERS. THIS IS AN ARTICLE IN THE NEW YORK TIMES THAT DISCUSSED THE PATHWAY IN WHICH BREATHING EXERCISES MAY HAVE POSITIVE INFLUENCE ON EMOTION. I'LL HIT ON THAT LATER. IN ORDER TO DISCUSS THIS I'LL FOCUS ON BREATHING AND WE'LL STIPULATE 35 YEARS WORTH OF WORK AND SAY IT'S A SMALL REGION IN THE BRAIN STEM AND IF WE LOOK AT THE HUMAN THE COMPLEX IS IN THE BRAIN STEM AND WE HAVE A GOOD IDEA WHERE IT IS IN HUMANS IT'S 5,000 TO 10,000 NEURONS. NOW WHAT AFFECTS BREATHING. AND THE VAGUS NERVE IS IMPORTANT AND THE COMPLEX MODULATES BREATHING PATTERN AND THERE'S A ROLE IN MODIFIED BREATHING. IF WE DETECT AN ORDER WE WILL SNIFF AND BREATHING IS NECESSARY TO BREATHE AND IT PROFSES OLFACTORY INFORMATION AND THAT WILL GIVE SIGNALS THROUGHOUT THE BRAIN. WE HAVE DESCENDING SIGNALS. I'M HERE ABLE TO SPEAK TO YOU BECAUSE I CONTROL MY EFFORTS AND WE TIME THOSE EFFORTS VERY PRECISELY FOR THE AMOUNT OF INFORMATION WE WANT TO CONVEY DURING THE NEXT EFFORT. WE HAVE EMOTIONAL CONTROL OF BREATHING. LAUGHING AND DRYING AND THAT HAS POWERFUL EFFECTS ON BREATHING. AND THERE'S ALL SORTS OF BREATHING MANIFESTS ITSELF. HERE'S AN EXAMPLE FROM MESH MEASUREMENTS A PERSON WITH EPILEPSY AND THEY MEASURE BREATHING AND THIS MAY UNDER LINE THE UNEXPLAINED DEATHS OF PATIENT WHO'S DIE OF THESE CAUSES FROM EPILEPSY. THE PUPILS DIAL DILATE WITH THE BREATHING. AND YOUR ACTION TIME IS SHORTEST ON THE INHALATION AND IF YOU'RE A BOXER OR MARTIAL ARTIST OR BASKETBALL PLAYER YOU MAY TYPE YOUR PUNCH OR FAKE WHEN YOU'RE OPPONENT IS EXPIRING AND THE RESPONSE TIME IS SLOWER. FEAR REACTION. WE HEARD ABOUT THIS EARLIER TODAY VARIES WITH THE CARDIAC CYCLE AND VARIES WITH THE CARDIAC CYCLE. YOU SHOW A FEARFUL STIMULUS AND THEIR RESPONSE WILL VARY BETWEEN INSPIRATION AND EXPIRATION. WE DON'T HAVE A SINGLE EXPLANATION AS TO WHY BUT IT'S THE FACT. BREATHING RHYTHMS WHEN YOU JUST LOOK FOR RHYTHMS THEY'RE FOUND WHERE EVER IN THE BRAIN. THIS IS FROM A REVIEW SO HERE IF WE LOOK AT RODENTS WE SEE THE OLFACTORY BULB AND BREATHING AND OSCILLATIONS NOT SURPRISING BECAUSE THE AIR FLOWS ACROSS THE NAVAL MUCOSA AND YOU SEE IT IN THE HIPPOCAMPUS AND THERE'S DATA THE EXHALATIONS PLAY A ROLE IN LEARNING AND MEMORY. IF WE LOOK AT THE SOMATOSENSORY CORTEX AND YOU CAN SEE THE OSCILLATIONS OF BREATHING AND THE ACTIVITY. PREFRONTAL CORTEX IMPORTANT IN EXECUTIVE FUNCTION. HAVE THE OSCILLATIONS. IF YOU DO THE MEASUREMENTS IN HUMANS AND HERE'S THE SUPER POSITION OF BREATHING AND THE GROSS ACTIVITY IN THE PERIPHERAL CORTEX AND HERE'S THE HIPPOCAMPUS AND THIS HAS PROBABLY NOTHING TO DO WITH NORMAL BLOOD GASES. I THINK THE BRAIN IS HIJACKED WITH HIGH OSCILLATION TO PLAY A ROLE IN BRAIN FUNCTION WHERE OSCILLATION SEEMS TO BE IMPORTANT IN INFORMATION PROCESSING AND BINDING AND BREATHING IS THERE 24 HOURS, SEVEN DAYS A WEEK, 24 HOURS A DAY. IT'S THERE ALL THE TIME AND THE BRAIN IS HIJACKED. AND THE INTERESTING THING THEY'RE -- THERAPEUTICALLY AND THIS IS A REVIEW WE WROTE ABOUT THE PREFRONTAL CORTEX AND WE SHOWED THE SYNAPSE PROJECTIONS AND YOU SEE THINGS IN THE MID BRAIN AND PROJECTIONS IN THE THALAMUS. THE SIGNALS ARE VERY IMPORTANT TO THE BRAIN AND WANTS DIRECT INPUT FROM THE COMPLEX AND THESE REGIONS WILL HAVE SECONDARY INPUTS CARRYING RESPIRATORY MODULATION. WE HEARD ABOUT ANOTHER NEURONS THAT GO TO THE AREA AND ONCE THERE THERE'S ACCESS TO EVERYTHING AND I'LL SHOW YOU DATA THAT IMPACTS THE ROLE IT PLAYS HERE. SO DEEP BREATH. NOW, THIS BENEFITS ME BECAUSE IT WILL PROVIDE A LITTLE BIT OF AROUSAL AND RELAX YOU A LITTLE BIT AND MAYBE PAY MORE ATTENTION TO WHAT FOLLOWS. SO I WANT TO TALK ABOUT SIZE OF DEEP BREATHS. WE DO THIS ALL THE TIME. WE ASSOCIATE THEM WITH STRESS AND WHATNOT. WE'RE OFTEN AWARE BUT WE TAKE SIGHS EVERY FIVE MINUTES AND THOSE WE'RE PROBABLY NOT AWARE OF AND THEY'RE IMPORTANT TO MAINTAINING LUNG FUNCTION BUT THEY'RE VERY CHARACTERISTIC DEEP BREATHS. WE MADE A DISCOVER THRIVE KEY ELEMENT ARE -- DISCOVERY OF THE KEY ELEMENTS OF SIZE BASED ON THE FACT THAT DURING STRESS THE SIGH RATE GOES UP AND THERE'S A RELEASE BY THE HYPOTHALAMUS OF PEP SIDES AND THEY GO UP. SO IN MY LAB WE SAID MAYBE THESE PEPTIDES ARE CAUSAL FOR INCREASING OR REGULATING SIGH RATE. SO THEY INJECTED RATS AND THE SIGH RATES WENT FROM 25 TO 250 PER HOUR AND WHEN WE DID THE EXPERIMENTS WHERE THESE ARE FIVE INDIVIDUAL RATS EACH ONE IS A SIGH WE INJECT THE PEPTIDES TO OVER 1,000 PER HOUR BY INJECTING THE PEP SIDES LOCALLY INTO THE COMPLEX. AND IF WE LOOKED AT THE SPONTANEOUS SIZE IT STOPPED. AND IF WE KILL THE CELLS THEY REPRESENT 10% OF THE CELLS IN THE PREBOT COMPLEX AND THE TOXIN TAKE FIVE DAYS AND THEN IT GOU DOWN AND AFTER FIVE DAYS THE RATS ARE BREATHING NORMALLY BUT NOT SIGHING AT ALL. THIS IS A KEY COMPONENT OF THE CIRCUIT FOR SIGHING AND WE KNOW SIGHS HAVE A POSITIVE EFFECT ON EMOTIONAL STATE AND SO ON. SO WE HAVE ABOUT 250 NEURONS. ANOTHER DEEP BREATH BECAUSE I'M GOING TO TALK ABOUT ONE MORE THING. I'LL TALK ABOUT THE PROJECTION. SO WE HAVE THE PROJECTION PERFECT PREBOT C UP TO AND THEY FOUND THERE WERE SPECIAL NEURONS THAT EXPRESS THE MARKERS CDH9. WHAT HE WAS ABLE TO DO WAS KILL THE CELLS. HERE YOU HAVE THEM AND INJECT THE VIRUS WHICH KILLS THE CELLS. SO WHAT HAPPENS? THE RAT CONTINUES TO BREATHE NORMALLY BUT BY ALL MEASURES THE ANIMAL'S A LOT CALMER. THAT'S THE ONLY THING THAT SEEMS TO CHANGE. IF WE LOOK AT THE BREATHING PATTERN, THIS IS THE DISTRIBUTION OF BREATHS OF THE NORMAL AWAKE RATS AND IF WE KILL SO THE ANIMALS THEMSELVES BECOME CALMER. I'M NOT RECOMMENDING THIS AS A THERAPEUTIC INTERVENTION BUT WE MAY BE ABLE TO TAKE ADVANTAGE AND NEED TO EXPLORE WHAT THE PROJECTIONS ARE DOING. SO THIS IS A 30,000 FOOT HIGH SUMMARY OF WHAT'S GOING ON. IT'S RATHER COMPLICATED BUT HAS POTENTIAL FOR EXPLORING THE AFFECTS OF BREATHING ON FUNCTION. SO THE PREBOTZINGER COMPLEX IS AN INTERCEPTION OF BREATHING AND LIKELY FOR THE AFFECTS OF BREATHING ON BEHAVIOR. I'M GOING SKIP THIS BECAUSE CYNTHIA AND VICTORIA ARE GOING TO DISCUSS THAT. I'D LIKE TO THANK MY FUNDERS INCLUDING MORE RECENTLY NCCIH AND ALL MY CLOLLABORATORS. THANK YOU VERY MUCH. >> I'D ALSO LIKE TO THANK THE ORGANIZERS. I'LL DISCUSS POTENTIAL METHODS FOR LEVERAGING INTEROCEPTION TO IMPROVE SITH SYMPATHETIC NERVOUS SYSTEM IN CHRONIC DISEASE STATES. IT'S THOUGHT TO BE RESPONSIBLE FOR THE FLIGHT OR FIGHT RESPONSE. SO WHEN THE SYMPATHETIC NERVOUS SYSTEM IS ACTIVATED THERE'S A RELEASE THAT BINDS TO RECEPTORS ON BLOOD VESSELS AND LEADS TO AN INCREASE IN BLOOD PRESSURE. THE MAJOR REGULATOR OF THE SYMPATHETIC NERVOUS SYSTEM IS FROM INPUT FROM THE BARR RECEPTOR INCLUDING THE ARTERIAL RECEPTORS THAT MODULATE SYMPATHETIC OUTPUT IN RESPONSE TO BLOOD PRESSURE AND THE PULMONARY RECEPTORS THAT MODULATE RESPONSE TO CHANGES IN BLOOD VOLUME ALL IN AN EFFORT TO KEEP BLOOD PRESSURE WITHIN A NARROW RANGE. IT TURNS OUT THERE'S ALSO CENTRAL TOP-DOWN SIGNALS THAT ARISE FROM WITHIN THE CENTRAL NERVOUS SYSTEM THAT ALSO MODULATE SYMPATHETIC TONE. CENTRAL COMMAND IS A VOLITIONAL SIGNAL THAT INCREASES SYMPATHETIC NERVES DURING ACTIVITY. THINK OF EXERCISE AND YOU'RE ABLE TO INCREASE YOUR SYMPATHETIC NERVE OUTPUT. SO IT'S CLEAR THE SYMPATHETIC NERVOUS SYSTEM IS IMPORTANT FOR MOMENT TO MOMENT CONTROL OF BLOOD PRESSURE AND MAINTENANCE OF PHYSIO LOGIC HOMO STASIS BUT IT ALSO PLAYS A MAJOR ROLE IN BLOOD PRESSURE REGULATION AND THERE'S A NUMBER OF HIGHLY PREVALENT CHRONIC CONDITIONS THAT ARE CHARACTERIZED BY OVERACTIVATION OF THE SYMPATHETIC NERVOUS SYSTEM THAT INCREASES RISK INCLUDING HYPERTENSION, HEART FAILURE, SLEEP APNEA, SMOKES, CHRONIC KIDNEY DISEASE AND POST-TRAUMATIC STRESS DISORDERS AND OTHERS. AND THE MECHANISMS BY WHICH SYMPATHETIC INCREASES CARDIOVASCULAR RISK IS THROUGH AN INCREASE IN BLOOD PRESSURE BUT THERE'S A NUMBER OF MECHANISMS INDEPENDENT FROM EFFECTS THAT INCLUDE CARDIOVASCULAR RISK LEADING TO VENTRICULAR STIFFNESS AND INCREASING THE RISK OF SUDDEN CARDIAC DEATH. NOREPINEPHRINE HAS A PRO-INFLAMMATORY EFFECT AND THERE'S CHANGES IN VASCULAR FUNCTION AND STRUCTURE INCLUDING REDUCING ARTERIAL COMPLIANCE AND ENDOTHELIAL DYSFUNCTION AND THIS LEADS TO VOLUME RETENTION AND PROGRESSION OF RENAL DISEASE INDEPENDENT OF ITS AFFECTS ON BLOOD PRESSURE. TO THE MUSCLE CONTRIBUTES TO INSULIN RESISTANCE AND IMPAIRED GLUCOSE CLEARANCE. AROUND AND CONDITIONS CONTRIBUTE TO CARDIOVASCULAR DISEASE RISK. THE PROBLEM IS THAT OUR CURRENT THERAPIES FOR COMBATTING SYMPATHETIC OVERACTIVATION ARE LIMITED TO PERIPHERAL AND SIM PATHIC MEDICATIONS WHICH THOSE OF US IN MEDICINE ARE LIMITED BY PHYSICAL AND METABOLIC SIDE EFFECTS AND OFTEN NOT WELL TOLERATED. THERE'S A CLINICAL NEED TO DEVELOP NEW TREATMENT STRATEGIES TARGETING SYMPATHETIC OVERACTIVATION IN CHRONIC DISEASES CHARACTERIZED BY INCREASED CARDIOVASCULAR DISEASE RISK. I'D LIKE TO PROPOSE THAT PERHAPS WE CAN LEVERAGE INTEROCEPTION AND INTEROCEPTIVE PROCESSES TO IMPROVE SYMPATHETIC NERVE REGULATION IN CARDIOVASCULAR DISEASE RISK AND FOLLOWING JACK'S NICE PRESENTATION I'D LIKE TO GIVE A COUPLE CLINICAL EXAMPLES BY WHICH INTEROCEPTION OF BREATHING MAY BE UTILIZED TO AMEALIORIZE SYMPATHETIC OVER ACTIVATION IN CARDIAC DISEASE AND ACTIVATING PULMONARY STRETCH RECEPTORS AND AS WELL AS POTENTIALLY HAVING DIRECT CENTRAL EFFECTS TO REDUCE SYMPATHETIC OUTPUT. THE FIRST IS IN POSTTRAUMATIC STRESS DISORDER THOUGH I'M A NEPHROLOGIST I TAKE CARE OF PATIENTS BECAUSE I WORK AT THE V.A. HOSPITAL. PTSD IS A DEBILITATING CONDITION MARKED BY PERSISTENT STRESS AFTER A TRAUMATIC EVENT. IT'S BECOME INCREASINGLY APPARENT THAT PTSD IS INDEPENDENTLY ASSOCIATED WITH AN INCREASED RISK OF DEVELOPING CARDIOVASCULAR DISEASE AND THERE'S BEEN LARGE, WELL CONTROLLED EPIDEMIOLOGICAL STUDIES THAT HAVE LOOKED AT THIS ASSOCIATION. THESE ARE DATA FROM META-ANALYSIS THAT SHOWS PATIENTS WITH PTSD HAVE A TWO- FOLD RISK AFTER OTHER MORBIDITY CONDITIONS AND WHAT UNDERLIES DISEASE RISK IN PTSD HAVE NOT BEEN FULLY ELUCIDATED BUT WE HAVE EVIDENCE THESE ARE PATIENTS WITH CHRONIC OVERACTIVATION OF THE SYMPATHETIC NERVE SYSTEM. WE MEASURE IT DIRECTLY USING INTERNEURAL MEASURES OF BLOOD VESSELS. AND SO WHEN WE USE THIS TECHNIQUE WE FOUND PTSD PATIENTS HAVE THIS AUGMENTED SYMPATHETIC NERVE RESPONSE DURING MENTAL STRESS. WE USED VIRTUAL REALITY COMBAT EXPOSURE AS THE MENTAL STRESS. THIS IS A STRESS RELATED TO THEIR PTSD SYMPTOMS. INTERESTINGLY, THIS INCREASED SYMPATHETIC REACTION AND THEY HAVE THIS NERVE REACTIVITY AND EXAGGERATED REACTIVITY IS ASSOCIATED WITH HYPERTENSION AND CARDIOVASCULAR DISEASE. AND WE HAVE EVIDENCE OF REGULATION IS IMPAIRED IN PTSD. SO WE USE THE MODIFIED OXFORD TECHNIQUE TO ASSESS REFLEX FUNCTION WHICH INVOLVES THE ADMINISTRATION TO FARM KOL LOGICALLY REGULATE BLOOD PRESSURE AND WE CAN QUANTIFY THE AND THERE'S A RESPONSE IN THE SYMPATHETIC RESPONSE AND CHANGES IN BLOOD PRESSURE DEMONSTRATING IMPAIRED REFLEX SENSITIVITY. SIMILARLY WE CAN QUANTIFY THE CARDIOVAGAL ARM AND LOOK AT CHANGES IN BLOOD PRESSURE AND AGAIN THE ARM IS ALSO BLUNTED IN PTSD. SO NOT ONLY IS SYMPATHETIC ACTIVITY AUGMENTED IN PTSD THERE'S ALSO IMPAIRED ARTERIAL BAROREFLEXIVITY AND THAT ITSELF IS ASSOCIATED WITH DISEASE. AND WE WONDERED IF THE SLOWING OF HYPERTENSION MAY IMPROVE SYMPATHETIC REGULATION THROUGH THE BAR REFLEXES IN PTSD. WE USED SLOW BREATHING WHICH INVOLVES A RESPIRATORY SENSOR BELT WHICH MONITORS BREATHING MOVEMENTS AND THROUGH BIOFEEDBACK THE DEVICE DELIVERS BREATHING GUIDING TONES WHICH INCREASE THE AWARENESS OF BREATHING AND EFFORTLESSLY SHOULD REDUCE THE RESPIRATORY RATE TO FIVE TO SIX BREATHS PER MINUTE AND THE PATIENT THEN SYNCHRONIZES THE BREATHING HOMES WITH THE GUIDING TONES. THE DEVICE IS F.D.A. APPROVED FOR THE ADDICTIONS OF RELAXATION. SO SLOWED BREATHING ENGAGING COMPONENTS OF INTEROCEPTION INCLUDING PULMONARY STRETCH RECEPTORS AND THE BODILY SENSATION OF BREATHING. WHAT DID WE FIND? WITH DEVICE GUIDED SLOW BREATHING THERE'S A GREATER REDUCTION IN MUSCLE SYMPATHETIC NERVE ACTIVITY COMPARED TO THE CONTROL INTERVETION WAS BREATHING WITH AN IDENTICAL DEVICE WITH THE SAME MUSICAL TONES BUT GUIDED REEGING RATES OF NORMAL -- BREATHING RATES NORMALLY OF 14 BREATHS A MINUTE AND WE OBSERVED THE GREATER REDUCTION IN SYSTOLIC HAIRED TO SHAM AND WE FOUND AN IMPROVEMENT IN THE SENSITIVITY WITH THE DEVICE THAT IS SLOW BREATHING OPPOSED TO THE SAM. SO WE HAVE A PERIPHERAL MECHANISM IN WHICH THE REDUCTION AND RESPIRATORY RATE LEADS TO COMPENSATORY INCREASE IN THE VOLUME TO MAINTAIN VENTILATION AND THAT LEADS TO A GREATER ACTIVATION OF PULMONARY STRETC RECEPTORS WHICH LEADS TO A DECREASE IN SYMPATHETIC NERVE ACTIVITY AND REDUCTION IN BLOOD PRESSURE. AND THERE MAY ALSO BE A COMPONENT CENTRAL FEED FORWARD COMPONENT WHERE THE INCREASED BREATHING AWARENESS MODULATES CLINICAL TONE AND THE NEXT EXAMPLE SUGGESTS BOTH COMPONENTS ARE NECESSARY TO OBSERVE THE PHYSIOLOGIC EFFECT ON AUTONOMIC FUNCTIONING AND A NEPHROLOGIST THIS IS A POPULATION NEAR AND DEAR TO ME THIS IS CHRONIC KIDNEY DISEASE. IT'S A DISEASE THAT AFFECTS 31 MILLION U.S. ADULTS. ABOUT 10% OF THE U.S. POPULATION AND THESE PATIENTS ARE FIVEFOLD OF CARDIOVASCULAR DISEASE AND THIS BEGINS EARLY ON IN THE COURSE OF KIDNEY DISEASE. EVEN MINIMAL DECREASES IN KIDNEY FUNCTION ARE ASSOCIATED WITH INCREASED RISK OF CARDIODISEASE. WE KNOW PATIENTS WITH DECREASED KIDNEY FUNCTION ARE OVERACT OVERACTIVATION OF CARDIOVASCULAR FUNCTION AND THERE'S BEEN MANY MARKERS SHOWING HERE ARE EXAMPLES OF CHRONIC KIDNEY PATIENT DISEASE AND CONTROLS AND YOU CAN HOPEFULLY APPRECIATE THE NUMBER OF THE FREQUENCY OF SYMPATHETIC NERVE BURSTS IN THE CHRONIC KIDNEY DISEASE PATIENT HIGHER THAN CONDITION -- CONTROLS AND WELL LOOKED AT A FOCUS ON BREATHING AWARENESS LOWERS SYMPATHETIC ACTIVITY IN PATIENTS WITH CHRONIC KIDNEY DISEASE AND WE ENROLLED MEN WITH VARIOUS STAGES OF CHRONIC KIDNEY DISEASE AND UNDERWENT MEDITATION VERSUS A CONTROL OF HEALTH RECORDING. WE FOUND A SIGNIFICANTLY GREATER REDUCTION IN MUSCLE SYMPATHETIC NERVE ACTIVITY WITH MINDFULNESS MEDITATION COMPARED TO THE CONTROL INTERVENTION. THIS WAS ACCOMPANIED BY LESS ARTERIAL PRESSURE AND REDUCTION IN HEART RATE. WE THEN ADDED A THIRD ARM IN WHICH PARTICIPANTS RETURNED FOR A CONTROLLED BREATHING INTERVENTION IN WHICH WE REDUCED THE RESPIRATORY RATE WITHOUT THE MINDFULNESS COMPONENT AND WE FOUND THERE'S A SIGNIFICANT REDUCTION IN SITH PATHETIC NERVE -- SYMPATHETIC NERVE ACTIVITY AND IT SUGGESTED SLOW BREATHING ALONE WAS NOT ENOUGH TO LOWER SYMPATHETIC TONE AND THE MINDFULNESS WAS NEEDED TO OBSERVE THE AFFECT ON SYMPATHETIC FUNCTION. HOPEFULLY I'VE BEEN ABLE TO CONVINCE YOU THAT PERHAPS THERE MAY BE SOME POTENTIAL BENEFITS FOR MANIPULATING RESPIRATORY RATE AND MAY HAVE ACUTE AFFECTS THAT MIGHT BE BENEFICIAL IN OUR PATIENT POPULATIONS THAT ARE AT INCREASED CARDIOVASCULAR RISK BY VIRTUE OF CHRONIC OVERACTIVATION OF THE SYMPATHETIC NERVOUS SYSTEM AND I HOPE TO ANSWER MORE QUESTIONS ON FUTURE DIRECTIONS AND DETERMINING THE MECHANISMS BY WHICH INTEROCEPTION OF BREATHING MAY IMPROVE SYMPATHETIC FUNCTION AND DETERMINING WHETHER THESE FUNCTIONS CAN HAVE SUSTAINED AFFECTS WHICH IS GOING TO BE NECESSARY FOR THEM TO BE CLINICALLY MEANINGFUL AS WELL AS LEADING TO IMPROVED CLINICAL OUTCOMES. THANK YOU. >> THANK YOU, IT'S NICE TO TALK TO YOU AND THERE'S NICE SEGUES BETWEEN RESPIRATORY MECHANISM AND I'LL TALK ABOUT RESPIRATORY RHYTHM FOR REGULATION. I'LL TALK ABOUT VAGUS NERVE STIMULATION. IT'S ACTUALLY A QUINTESSENTIAL MODULEARY APPROACH WITH SURGICAL STIMULATION THERE'S A PACE MAKER IMPLANTED AND ELECTRODES ARE TRACKED IN THE VAGUS AND STIMULATION HAS BEEN FOUND TO BE EFFECTIVE FOR A NUMBER OF DISORDERS AND HAS BEEN FDA APPROVED FOR EPILEPSY AND HAS BEEN PREVIOUSLY APPROVED FOR TREATMENT RESISTANT DEPRESSION AND OTHER CONDITIONS POTENTIALLY BENEFICIAL SUCH AS ARTHRITIS, G.I. DISORDERS AND PSYCHIATRIC DISORDERS AND MIGRAINE HEADACHE. INTERESTING, THE VAGUS NERVE IS 80% AFFERENT FIBERS. EVEN VISCERAL APPLICATIONS SUCH AS G.I. AND CARDIAC MANY RESEARCHERS CONSIDER THE AFFERENT PATHWAYS MAY BE MORE IMPORTANT AND THE THOUGHT THEY STIMULATE THE VAGUS IS INTERESTING. AND VAGUS NERVE STIMULATION IS ASSOCIATED WITH SIGNIFICANT SIDE EFFECTS HOARSENESS DUE TO THE NERVE FROM THE VAGUS TO THE LARYNX AND THERE'S COMORBIDITIES AND NON-INVASIVE APPLICATIONS IS IMPORTANT FOR BROADER ALTERNATIVES AND THERE'S THE BRANCH OF THE VAGUS NERVE THAT EXITS OUT TO THE EAR. AND WHEN WE LOOKED AT WHAT PORTION ARE AFFECTED BY THE VAGUS NERVE THEY LOCALIZED THIS TO A REGION SPECIFICALLY OF THIS PORTION OF THE EAR. THERE'S OTHER REGIONS AFFECTED BY THE VAGUS NERVE BUT THIS IS THE PERCENTAGE OF EARS THAT WERE INTERVATED. AND THE EAR LOBE IS 100% REGULATED BY THE NERVE AND I'LL LATER USE IT AS A CONTROL IN SOME STUDIES. AND IT GOES ACROSS THE ABVN TO AND ONTO THE PRIMARY SYNAPSE OF THE NERVE AND IN THE JUGULAR OR SP 5 OVER HERE. SO RESPIRATORY RIDGE AM -- RHYTHMS AND YOU CAN HAVE A DECREASE IN EFFERENT TONE AND EVERY TIME WE BREATHE IN THE HEART RATE INCREASES AND WHEN WE BREATHE OUT IT DECREASES AND IT'S MEDIATED BY BOTTOM UP AND TOP DOWN PATHWAYS AND THE BAR RECEPTOR WHICH IS THE PRIMARY SYNAPSE. AND THE NUCLEUS AMBIGUOUS IS THE NUCLEUS OF THE HEART WHICH THEN SLOWS DOWN THE HEART BOUGHT IT'S INHIBITORY YOU HAVE A DECREASE IN VAGAL TONE. THIS IS THE TOP DOWN, BOTTOM UP PATHWAYS. RESPIRATIONS ARE KNOWN TO BE INVOLVED IN STRESS REDUCTIONS. I WON'T GO INTO DETAIL BUT THE QUESTION IS CAN RESPIRATORY RIDGE AM CAN BE USED FOR NEUROLOGICAL RESPONSE. RESPIRATION AFFECTS MANY PROCESSES AND COGNITION AND WE SHOWED THE AFFECTS ON PROCESSING AND THEY LOOKED AT COGNITIVE PROCESSING AND THIS IT RETRIEVAL IS GREATEST WHEN THERE'S CYCLES AND RHYTHMS HAVE BEEN FOUND IN THE RAT AND IN HUMANS WITH INTERCRANIAL E.G. ELECTRODE. RESPIRATORY RIDHYTHMS CAN BE IMPORTANT AND THOSE ARE HYPOTHESIS. WE DEVELOPED IN A TVNS APPROACH THAT AND DEPENDING ON WHERE THEY ARE IN THE RESPIRATORY CYCLE WE CAN DELIVER NEUROMODULATORY CYCLES AND WE CAN HAVE A GATE THAT OPENS OR CLOSED WHEN WE WANT IT OPENED OR CLOSED. WE BASICALLY ARE TRYING TO OPEN AND CLOSE IT IN TUNE WITH THE RESPIRATORY RHYTHM. AND THE ADVANTAGE IS COMPARED TO CONTINUOUS TVNS IT PRODUCE AS A REGULAR STIMULATION WHICH MAY MITIGATE THE EFFECTS OF HA -- HABITUATION AND DURING THE RESPONSE WHICH MAY BE A PHASE WE WANT TO AVOID BECAUSE THERE'S COMPETING AFFERENTS AND THERE'S INHALATION AND NOT JUST ARRHYTHMIA AND WE MAY WANT AVOID THESE DURING CERTAIN PORTIONS SUCH AS DURING EXHALATION. THAT'S THE PREMISE BEHIND THE TECHNIQUE. AND FIRST WE RECENTLY PUBLISHED A STUDY OF FUNCTIONAL M.R.I.s WHICH ALLOWS US TO GET BETTER TEMPORAL AND SPACIAL RESOLUTION. WE FOCUSES OUR ACQUISITION ON A PORTION THAT INCLUDES THE BRAIN STEM BECAUSE WE WERE INTERESTED IN NTS TARGET. WE BASICALLY HAVE A SYSTEM BY WHICH TO DELIVER STIMULATION DURING EXHALATION AND INHALATION WHICH IS OVER HERE AND WE ALSO HAVE CONTROLLED CONDITIONS WHERE WE STIMULATED DURING EXHALATION BUT FOR A TARGETED ELECTRODE NOT ON CONTROLLED TERRITORY. IT'S NOT INTERVATED BY THE BRANCH OF THE VAGUS NERVE. WE FOUND NO DIFFERENCES IN THE NUMBER OF EVENTS IN THE CONDITIONS AND THAT'S GOOD FROM A CONTROL STANDPOINT. AND THERE WAS AN INTENSITY RATED BY THE SUBJECTS. THOSE WERE ALSO CONTROLLED HERE. AND WHAT WE FOUND WAS THAT DURING STIMULATION THERE WAS NICE ACTIVATION IN AREAS CONSISTENT BOTH WITH NUCLEUS AND NUCLEUS AMBIGUOUS AND THERE WAS NO RESPONSE WITH A CORRECTION METHOD FOR INHALEATED STIMULATION AND THIS IS TLURG EXHALATION WHERE WE SEE A RESPONSE BUT IT WAS MORE SUPERIOR AND LATERAL AND MORE CONSISTENT WHICH WE FOUND OVER HERE. AND IT'S NOT INVASIVELY IN HUMANS. WHEN WE DIRECTLY COMPARED THEM WE FOUND THIS NICE CLUSTER CNSISTENT IN THE PROXIMAL MEDULLA. WE TOOK REGIONS OF INTEREST THAT WERE CHOSEN FROM THE LITERATURE BASED ON EITHER M.R.I. STUDIES AND FROM LIGANDS STUDIES FOR THE NUCLEUS AND HERE WE FOUND THE RESPONSE IN THESE REGIONS OF INTEREST WAS GREATEST FOR EXHALATION. AND WHILE THERE WAS STIMULATION OF THE EAR LOBE THE GREATER NERVE CONTROL IT DID NOT TRANSLATE TO THE NUCLEUS OR THE SER COERULEUS AND EFFERENT PARTS OF THE BRAIN AND WE'VE DONE THIS IN PREVIOUS STUDIES AND WE FOUND IN PATIENTS THAT IF WE LOOK AT THE REGION IN THE PROXIMAL MEDULLA THAT WAS ACTIVATED AND WE LOOKED AT WHAT ELSE IN THE BRAIN IS CONNECTED TO THAT REGION DURING STIMULATION VERSUS A SHAM CONTROL WE FOUND GREATER CONNECTIVITY TO THE SALIENCE NETWORK AREAS SUCH AS THE ANTERIOR CINGULATE AND THAT WAS DEPENDENT ON THE PHASE OF THE MIGRAINE PATIENTS. SO EPISODIC MIGRAINE IS A CYCLICAL SYNDROME AND THE CLOSER THEY GET TO THEIR NEXT MIGRAINE ATTACK WHEN IT HAPPENED TO BE WE SCANNED THEM. WE DIDN'T CONTROL FOR THIS BUT ASSESSED WHEN THEY HAD THEIR NEXT MIGRAINE ATTACK VERSUS THE PREVIOUS WE FOUND THE ACTIVITY WAS GREATEST THE FURTHER AWAY THEY ARE FROM THEIR NEXT MIGRAINE THEY ARE AND AS THEY CLES CLOSER TO THE NEXT -- THEY GET CLOSER TO THE NEXT ATTACK THE ACTIVITY DECREASES AND THAI THIS MAY BE IMPORTANT TO WHEN WE STIMULATE AND TRY TO KEEP THE MIGRAINE PATIENTS AND THE CONNECTIVITY HIGH WITH STIMULATION. A STUDY CAME OUT THAT SHOWN PATIENTS WITH LESIONS IN THE ANCILLARY INSULA WAS CONSISTENT WITH REDUCED PERFORMANCE AND REDUCED ACCURACY ON IN THE INTEROCEPTIVE TASK WHICH WAS NOT THE CASE FOR CONTROL PATIENTS WHICH HAS LESIONS NOT IN THIS REGION OF THE INSULA. THAT IS INTERESTING. SO WE ALSO HAVE DONE WORK ON A STATISTICAL MODEL SHOWING HEART RATE VARIABILITY. WHAT WE FOUND IS DURING E RAVENS STIMULATION THERE'S AN INCREASED IN CARDIOVAGAL MODULATION WITH HEART RATE VARIABLE WHICH WAS NOT THE CASE FOR AMBULATORY GATED STIMULATION. WE HAVE DONE STUDIES WITH PAIN WITH OUTCOMES SUCH AS REDUCTION IN HYPERALGESIA AND TEMPORAL STIMULATION BEFORE AND AFTER STIMULATION AND EVEN 5 MINUTES AFTER STIMULATION AND REDUCTIONS IN ANXIETY AND CHRONIC PAIN PATIENTS. THIS WAS CHRONIC PELVIC PAIN AND THIS WAS THE FIRST STUDY WE PUBLISHED. AND SO I'M GOING TO TALK ABOUT ONGOING WORK AND FUTURE WORK WHERE WE'RE TRYING TO COMBINE RESPIRATORY GATED TNS WITH OTHER STRONG COMPONENTS SUCH AS MINDFULNESS MEDITATION TRAINING AND THERE MAY BE RATIONALE FOR DOING IT AND IT FOCUSES ATTENTION ON ONE'S OWN BREATHING WITH A CALM AND ALERT MIND PROMOTING RELAXATION. THE FOCUS ON BREATH IS A KEY COMPONENT OF MINDFULNESS TRAINING AND IT CAN AFFECT RAVEANS AND TNS. THE HYPOTHESIS IS THE INTEROCEPTIVE PATHWAYS FOR MINDFULNESS MECHANISMS ARE POTENTIATED BY THE CIRCUITRY. WE HAVE SIMILAR CIRCUITRIES AND THE LOCUS SER SER AND THIS IS A LARGE STUDY WE'RE EMBARKING ON SOON. IN THE MEANTIME IT WILL BE YEARS BEFORE WE CAN GET RESULTS BUT IN THE MEANTIME WE'RE RUNG -- RUNNING A STUDY ON PATIENTS ON OPIOIDED AND WE BROUGHT THEM BACK AND HAVE TWO SESSIONS CROSSED OVER WITH MINDFULNESS MEDICATION AND RAVEANS OR SHAM TNS AND WE FOUND THERE ARE IMPROVED PAIN OUTCOMES AND THIS IS A VERY PAINFUL PAIN OUTCOME. THIS IS DIPPING YOUR HAND INTO 4 DEGREES CELSIUS WATER AND COMPARED TO BASELINE IS DECREASING WHEN WE COULD MINDFULNESS MEDITATION WITH RAVE RAVENS AND THESE ARE HIGH LEVELS OF PAIN BY THE WAY AND 15 SECONDS THEY REMOVED THEIR HAND THE COLD WATER THEY STILL FEEL IT AND IT'S 50 OUT OF 100 PAIN AND WE HAVE REDUCTION IN THIS AS YOU GO COMPARED TO BASELINE TO POST STIMULATION AND EVEN 15 MINUTES AFTER WHEN WE HAVE THIS AUDIO GUIDED MINDFULNESS. AND IT'S SHOWING THOUGH IN A SMALL NUMBER OF PATIENTS. IN CONCLUSION, WE'VE SHOWN INTERORECEPTIVE STATES AND RAVENS COUPLED WITH MINDFULNESS AND MEDITATION TRAINING HAVE SHOWN CLINICAL BENEFIT. WHAT WE NEED IS MORE ANIMAL MODELS TO TRY TO BETTER UNDERSTAND THESE AFFECTS AND HOW RESPIRATORY RHYTHMS IN THE BRAIN MAYBE GATING NEUROMODULATORY RECEPTORS. AND SENSITIVITY HAS BEEN ASSOCIATED WITH ANXIETY DISORDERS SO THERE'S MANY RESEARCHERS THAT LOOK GREATER INTO INTEROCEPTION HAS A NEGATIVE THING BUT IN MINDFULNESS WE FOCUS ON THE BREATH. PERHAPS IT DEPENDS ON THE BASELINE DRIVE WHICH MAY BE ANALOGOUS TO BLOOD PRESSURE. IF YOU HAVE HYPERTENSION WE WANT TO REDUCE IF YOU HAVE HYPOTENSION YOU WANT TO INCREASE THE PRESSURE AND THE SAME THING MAY BE GOING ON WITH INTERORECEPTIVE DRIVE. THANK YOU FOR YOUR ATTENTION AND I WANT TO ACKNOWLEDGE BOTH OUR FUNDING SOURCES INCLUDING A COMPANY HELPING US DEVELOP A DEVICE WE CAN USE IN LONGITUDINAL THERAPIES. WE'VE NOT BEEN ABLE TO DO THAT WITH THE GARAGE-MADE DEVICE I CREATED IN THE LAB AND I WANT TO THANK RONALD GARCIA AND THE POST-DOCS AND JUNIOR FACULTY THAT HAVE BEEN CARDINAL IN DEVELOPING THESE IMAGING STUDIES. THANK YOU. [APPLAUSE] >> WE WERE GOING FOR A 10 MINUTE AND MOVE UP AROUND AND INTEROCEPTIVE BREAK AND I'LL HE SEE YOU BACK HERE AT 10:35. SO AGAIN I WANT TO THANK THE ORGANIZERS FROM NIH FOR INVITING ME AND ALL OF US WHO ARE SPEAKING TODAY AND YESTERDAY. . I'M GOING TO SHIFT THE CONVERSATION A LITTLE BIT AS WE TALK IN THIS PANEL ABOUT HOW WE LEVERAGE MANIPULATION OR MANIPULATE POTENTIALLY INTEROCEPTION FOR HELPING PEOPLE WHO HAVE VARIOUS DISORDERS OR CONDITIONS THAT MIGHT BENEFIT FROM INCREASING THEIR CAPACITY TO ATTEND TO INTEROCEPTION. I'M GOING TO BE TALKING ABOUT HOW WE ACTUALLY TEACH THIS AND HOW DO PEOPLE LEARN IT AND WHAT DO WE NEED TO PAY ATTENTION TO BASED ON THE RESEARCH I'VE BEEN DOING. AND THEN I'LL TALK A LITTLE BIT ABOUT A RECENT STUDY RELATED TO THIS WORK. YESTERDAY WHAT WAS MENTIONED IS PERHAPS WHAT WE NEED IS MORE TARGETED THERAPEUTIC APPROACHING TO INTEROCEPTION AND I HOPE THE WORK I'M DOING FITS THAT. THAT'S THE WAY I PERCEIVE IT. SO MANY MANY PEOPLE WHO NEED TO PERHAPS LEARN INTEROCEPTION OR INCREASE THEIR CAPACITY TO PAY ATTENTION TO THEIR BODIES HAVE PROBLEMS DOING SO. AND I SAY THAT FROM MY OWN CLINICAL EXPERIENCE AS A FOR 20 YEARS WORKING WITH PEOPLE WHO SOUGHT ME OUT BECAUSE AS A SOMATIC THERAPIST BECAUSE THEY WERE FEELING DISCONNECTED FROM THEIR BODIES. BODY AWARENESS AND WE'VE BEEN HEARING SPEAKERS ABOUT PAYING ATTENTION TO YOUR BREATHING. FOR MANY PEOPLE IT'S REALLY EASY. YOU JUST BRING YOUR ATTENTION INSIDE AND FOLLOW THE SENSATION OF INHALE AND EXHALE AND IT'S NOT TRUE FOR EVERYONE AND IT'S NOT TRUE FOR A LOT OF PEOPLE WITH MENTAL HEALTH DISORDERS. I WORKED A LOT WITH PEOPLE WITH CHRONIC PAIN AND PTSD AND ANXIETY DISORDERS OF MANY KINDS. THE BASIC WAYS IT SHOWS UP IS A LACK OF AWARENESS MUCH OF THE BODY OF BEING AWARE OF PHYSICAL TENSION AND A LACK OF A LINK BETWEEN PHYSICAL SENSATIONS AND EMOTIONAL SENSATIONS. SO IT WAS OUT OF WORKING WITH THIS POPULATION AND THEN COMING TO ME SAYING, I KNOW, THIS IS ME. I'M THIS PERSON FROM THE HEAD UP AND I'M NOT INSIDE HERE AND IT'S CAUSING ME QUITE A BIT OF DISTRESS. THE PTSD CONTINUE TO CAUSE TRAUMATIC EXPERIENCES PARTICULARLY FISCAL AND SEXUAL -- PHYSICAL AND SEXUAL ABUSE THAT WERE EXTENSIVE THEY MAY HAVE BEEN IN THERAPY FOR DECADES AND HIGH FUNCTIONING IN JOBS AND SO ON BUT STILL EXPERIENCING A LOT OF TRAUMATIC MEMORIES. A LOT OF DISRUPTED SLEEP. A LOT OF DIFFICULTY IN INTIMACY WITH THEIR PARTNER, THEY ASSOCIATE IT WITH A LACK OF BODY AWARENESS AND BEING IN BODY AND THEY WERE COMING TO ME AND SAYING HOW DO I DO THIS? I'M GOING TO TALK ABOUT HOW WE DO THIS BUT FIRST I'LL TALK ABOUT THE OVERLAP WITH MINDFULNESS AND INTEROCEPTION AND ONE OF THE FIRST THINGS YOU LEARN IS YOU'RE GUIDED TO INHALE AND EXHALE THE BREATH OR DO A BODY SCAN AS A WAY TO ENGAGE INTEROCEPTION AND MINDFULNESS I THINK IS FUNDAMENTAL FOR GAINING INTEROCEPTIVE SKILL AND IT'S A SKILL TO BRING THAT INTO YOUR BODY. IT'S A SKILL SOME OF US HAVE WITHOUT HAVING TO WORK AT IT BUT IT'S NOT TRUE FOR EVERYONE. SO LEARNING TO HAVE PRESENT MOMENT AWARENESS IN THE BODY WITHOUT HAVING A LOT OF THOUGHTS AND DISTRACTIONS GOING ON IS REALLY IMPORTANT AND THAT'S A MINDFULNESS SKILL. THEY'RE VERY CONNECTED. I STUDY AN APPROACH CALLED MINDFULNESS THERAPY AND A MODEL IS BY LEARNING EMOTION REGULATION AND IMPROVED HEALTH AND I'M GOING TAKE A FEW MINUTES TO TELL YOU ABOUT WHAT WE DO IN THIS APPROACH IN TERMS OF LEARNING THESE SKILLS PARTICULARLY IMPORTANT FOR PEOPLE FOR WHOM IT'S CHALLENGING TO DO SO. AND THE LETTERS IN BLUE, AWARENESS, ACCESS AND APPRAISAL OR EVALUATION HAVE BEEN IDENTIFIED AS COMPONENTS OF INTEROCEPTIVE AWARENESS SKILLS AND THE WORDS IN BLACK ARE THE COMPONENTS OF THE TRAINING WE DO WHERE WE INCREMENTALLY HELP PEOPLE DEVELOP FIRST THROUGH BODY LITERACY TRAINING WHICH IS THE CAPACITY TO ARTICULATE AND IDENTIFY SENSATION. I WAS TRAINED AS A MASSAGE THERAPIST AND THEN WENT ON TO PSYCH AND THEN WENT ON TO RESEARCH BUT WE USE OUR HANDS TO TEACH. WE USE TOUCH TO TEACH. AND THE REASON IT'S SO IMPORTANT IS THAT SO MANY PEOPLE FOR WHOM THIS IS DIFFICULT, I THEY DON'T KNW WHERE TO BRING THEIR ATTENTION AND IT'S HARD TO MAINTAIN ATTENTION ON THE BODY. WHEN YOU TOUCH SOMEONE AND SAY CAN YOU BRING YOUR ATTENTION TO THIS AREA AND HOW WOULD YOU DESCRIBE WHAT YOU FEEL YOU'D BE AMAZED HOW MANY PEOPLE HAVE DIFFICULTY DOING THAT. SO WE START THERE. WE START EXTERNALLY AND THEN MOVE INTO HELPING PEOPLE LEARN TO BRING THEIR AWARENESS INSIDE THE BODY OR ACCESSING THEIR BODY JUST IN THESE SIMPLE WAYS LIKE WITH BREATHING, BRINGING YOUR ATTENTION INSIDE AND WE GUIDE THEM IN LEARNING THE PROCESSES. THEN THE LAST HALF WITH INTERVENTION IS FOCUSSED ON SUSTAINED ATTENTION IN SPECIFIC AREAS OF THE BODY. IN MINDFULNESS MEDITATION PRACTICE OFTEN THE FOCUS IS ON THE BREATH BUT NOT OTHER PLACES IN THE BODY AND IN THIS APPROACH WE'RE HELPING PEOPLE BRING THEIR ATTENTION TO AREAS OF THE BODY ANYWHERE IN THE BODY. AND PARTICULARLY AREAS THAT ARE EITHER REGULATED FOR THEM SO IT COULD BE A RESOURCE FOR THEM, THEY FEEL MORE AT HOME IN THEIR BODY OR PLACES WHERE THEY MAY HAVE EMOTIONAL OR PHYSICAL OR BOTH DISCOMFORT AND LEARNING TO TOLERATE AND KIND OF COME IN TO THOSE SPACES IN THE BODY BIT BY BIT, CLOSER AND CLOSER. AND REALLY TAKING OVER TIME THEY LEARN HOW TO CHANGE THESE DISASSOCIATIVE PATTERNS THAT HAVE BECOME AUTOMATIC FOR THEM AND HAVE THEIR BODIES BE SOME PLACE WHERE THEY CAN GO AND STAY AND WE'RE FOCUSSING ON SUSTAINING ATTENTION IN THOSE AREAS OF THE BODY AND IT LEADS TO THE APPRAISAL PROCESS. WHAT ARE YOU AWARE OF IN YOURSELF AND THAT'S EXTREMELY IMPORTANT FOR THE PROCESSES THAT PEOPLE CONTINUE TO USE. IF IT DOESN'T HAVE MEANING TO YOU YOU CAN'T HAVE MEANING. IF YOU DON'T SEE THE AFFECT ON FEELING BETTER YOU WON'T USE IT BUT IF YOU'RE PAIN AND ANXIETY IS REDUCHD -- REDUCED AND HAVE SOMETHING YOU CAN USE WHEN YOU FEEL ESCALATED YOU'LL USE IT AND THAT'S WHAT WE'RE TEACHING AND IT'S CLINICALLY IMPORTANT. WHEN I STARTED DOING RESEARCH I REALIZED WE REALLY DIDN'T HAVE MEASURES FOR LOOKING AT THE KIND OF PROCESSES THAT WE WERE TEACHING IN THIS INTERVENTION. WE DEVELOPED A SKILL WHICH LOOKED AT BODY AWARENESS AND BODY DISASSOCIATION AND WENT ON TO WORK WITH OTHERS TO DEVELOP THE MULTIDIMENSIONAL ASSESSMENT CALLED THE MAYA. AND THAT'S GOING TO BE USED. I WANT TO TELL YOU ABOUT IT BRIEFLY. SO I'VE BEEN FUNDED BY NIIDA AND WHY DO WE WANT TO TEACH INTEROCEPTION? WE KNOW FROM OTHER PEOPLE HERE IN THIS ROOM THAT PEOPLE OF SUBSTANCE USE DISORDER MAY HAVE PROBLEMS PROCESSING INTEROCEPTION COMPARED TO HEALTHY CONTROLS AND WE KNOW IT'S RELEVANT TO SUBSTANCE DISORDER TREATMENT DUE TO RELAPSE AND NEGATIVE AFFECT AND THE IMPORTANCE OF INTEROCEPTION TO IMPROVE EFFECTIVE BEHAVIOR AND RELAPSE PREVENTION. THAT'S WHY WE WERE LOOKING AT WHETHER AN ADD ADJUNCTIVE TREATMENT WAS HELPFUL AND THERE WAS A DESIGN WITH AN ACTIVE CONTROL FOR TIME AND ATTENTION. AND THERE WAS RESPONSES. WHEN EVERY ONE OF THESE PEOPLE HAD A VERY EXTENSIVE HISTORY OF INTERPERSONAL TRAUMA OR PTSD WHICH IS COMMON IN THIS POPULATION. AND OVER TIME DO THESE INTERVENTIONS HAVE AN AFFECT? ONE OF THE FIRST QUESTIONS WHEN YOU DO A STUDY LIKE THIS IS ARE THEY LEARNING WHAT YOU'RE TEACHING THEM? THAT'S WHY WE USE THE MAYA TO LOOK AT THIS AND WE SEE THE INCREASE FOR THOSE WHO GOT MABT WITH SIGNIFICANTLY INCREASED ACROSS TIME COMPARED TO THE OTHER TWO GROUPS. SO THEY ARE LEARNING WHAT WE ARE TEACHING THEM IN A DISTRESSED POPULATION. THEN WE ASKED THEM WHAT DID YOU LEARN AND IT'S INCREASED AWARENESS OF BODILY SELF AND SENSATION, MORE REGULATORY SKILLS AND ACCEPTANCE OR EMBODIMENT EXPERIENCES. AND IN PRARENTHESES THEY RELATE TO THE SCORES ON THE MAYA AND WHAT THEY WERE TELLING US THEY WERE MATCHED. WE FOUND AT THREE MONTHS THE STUDY GROUPS WERE PRETTY MUCH IDENTICAL IN TERMS OF THEIR REPORTED DAYS OF ABSTINENCE FROM SUBSTANCE ABUSE OR FINISHING IT UP AT THAT TIME. AT SIX MONTHS THEY'RE STILL MOSTLY ALL IN TREATMENT. YOU CAN SEE TAU THE TREATMENT GROUP IS HAVING MORE USE AND THE TWO GROUPS GETTING TIME AND ATTENTION BOTH WERE SUSTAINED AND IT DID SHOW OVERALL OVER THE COURSE OF THE YEAR LESS SUBSTANCE USE THAN THE OTHER GROUPS. RELATIVELY THEY DIDN'T USE ALL THAT MUCH. THEY WERE MOTIVATED GROUPS BECAUSE THEY HAD CHILD PROTECTIVE SERVICES INVOLVED AND WE LOOKED AT ARRHYTHMIA WE HEARD ABOUT THAT AS A PSYCHO PHYSIOLOGICAL BIOMARKER AND WE SAW ASSAYS WAS MUCH IMPROVED FOR THOSE WHO GOT THIS AND WE LOOKED AT RESPONSE TO MEDICATION AND MEDITATION WAS SIMILAR TO WHAT THEY WERE LEARNING IN THE INTERVENTION. THIS WAS REGULATING FOR EVERYONE AT BASELINE. WE WROTE ABOUT THAT IN PSYCHO PHYSIOLOGY IN 2013 AND THOSE WHO GOT THE INTERVENTION IN THE FIRST THREE MONTHS THE FIRST UPPER DOT WERE MUCH MORE REGULATED IN RESPONSE TO THE INTERVENTION AND THAT CONTINUED FOR THEM AT EACH OF THE TIME POINTS WHICH I THINK JUST TELLS US HOW REGULATING IT IS TO ENGAGE IN INTEROCEPTIVE MEDICATION AND BODY AWARENESS THEY WERE LEARNING IN THE SKILLS. IN SUMMARY, THE RESULTS SUPPORTIVE MODELS AND RESEARCH-RELATED INTERCEPTION SUGGESTING THE IMPORTANCE OF TRAINING FOR INCREASED EMOTION REGULATION AND SUPPORTED RELAPSE AMONG THOSE WITH SUBSTANCE DISORDER TREATMENT AND THESE ARE SOME OF MY QUESTIONS. WHAT KINDS OF TRAINING WILL PROMOTE INTEROCEPTIVE SKILLS AND HOW IS TRAINING MOST HELPFUL. RSA HAS BEEN IDENTIFIED AS EMOTIONAL REGULATION AND WHAT PHYSIOLOGICAL METHODS CAN BE USED TO BETTER UNDERSTAND THE INTERNAL EXPERIENCE OR SHIFT OCCUR WITH SUSTAINED MEDITATIVE RECEPTION. IT'S AMAZING WHEN PEOPLE ARE REALLY ATTENDED TO THEIR INTERNAL EXPERIENCE IN A VERY SPECIFIC PART OF THE BODY, WHAT CHANGES FOR THEM EXPERIENTIALLY AND IT WOULD BE GREAT IF SOMEONE COULD FIGURE THIS OUT AND WE'RE DOING OUR FIRST STUDY COLLABORATING AND WE DON'T HAVE THE RESULTS YET SO IF THE PANEL MEMBERS COULD ALL COME UP AND DR. CRITCHLEY AS WELL NOW THESE WERE SOME OF THE BROAD QUESTIONS THAT THE PANEL MEMBERS IDENTIFIED. CAN YOU ALL COME DOWN AND SIT HERE? WHAT ARE THE KEY QUESTIONS WE NEED TO ASK OF ANIMAL MODELS TO INFORM NOVEL INTERVENTIONS FOR HUMANS. HOW CAN STUDIES GUIDE DEVELOPMENT AND LEVERAGING INTERCEPTION TO REDUCE HYPERACTIVITY. IS TRAINING INTEROCEPTION A GOOD THING AND FOR WHOM? WHAT ARE THE BIGGEST GAPS THAT LINK SKILLS WITH CLINICAL CONDITIONS. WITH THAT I'LL CLOSE. [APPLAUSE] >> SO WE HAVE THESE BIG QUESTIONS ABOVE US AND SOME OF YOU HAVE ADDITIONAL QUESTIONS ON YOUR SLIDE. DO WE WANT TO START WITH QUESTIONS FOR EACH OTHER AND THEN MOVE TO QUESTIONS FROM THE AUDIENCE? I'D LIKE TO POSE THE QUESTION TO LORENZO WHAT IS THE IMPACT ON THE FEEDING BEHAVIORS OF THE PATIENTS RECOVERING FROM ALCOHOL ABUSE? >> I DIDN'T SHOW THE DATA BECAUSE OF TIME BUT IN THE PHASE I SUDDENY -- STUDY, WE SEE THE PF COMPOUND AN NIFT -- ANTAGONIST REDUCE THE ALCOHOL CRAVING AND REDUCING FOOD CRAVING AS WELL. SO IT DOES SEEM TO HAVE AN IMPACT ON THAT PARADIGM BUT NOW WE ARE CURRENTLY CONDUCTING A PHASE II WHERE WE'RE LOOKING AT THE FURTHER ON THE COMPOUND OF THE FEEDING BEHAVIORS. WITH SMALL SAMPLES THERE'S ALWAYS THE RISK OF FALSE POSITIVE AND WE HAVE NOT GIVEN THE MEDICATION CHRONICALLY. ON ONE HAND CLINICALLY WE SEE MANY PATIENTS WITH ALCOHOL USE DISORDER WHO ALSO HAVE OBESITY. ONE THOUGHT COULD BE SUCH A DRUG COULD KILL TWO BIRDS WITH ONE STONE. ON THE OTHER SIDE, THERE'S THE POTENTIAL THAT THE AFFECT ON FEEDING COULD BE A SIDE EFFECT IF PEOPLE DON'T NEED TO LOSE WEIGHT. IT'S A BALANCE THAT HAS TO BE TREATED CLINICALLY. >> I WONDER IF THE DRUG WOULD BE SEEN AS A POTENTIALLY A WEIGHT LOSS CURE RATHER THAN TREATMENT FOR ALCOHOLISM? >> IT COULD. THAT WOULD BE GREAT. WE HAVEN'T PUBLISHED THE DATA. IT'S AN EXPERIMENT WITH RATS WHERE WE SEE WHEN WE KNOCK OUT THE GERLIN -- GHRELIN RECEPTOR IT AFFECTS THE RATS AND WE SHOWED IT IN MICE WE ARE NOW SHOWING THAT IN RATS. AND IT DOESN'T MEAN SUCH A DRUG OR SUCH A TARGET WILL BE NECESSARILY EFFECTIVE FOR OBESITY. IN FACT, THEY WANT TO PURSUE THE GHRELIN AS A TARGET FOR OBESITY. IN MY MIND I THINK WE'RE STILL LOOKING AT THAT AND THE RECENT POTENTIAL OF GHRELIN IN OBESITY MAY BE MORE EFFECTIVE THAN IN ALCOHOL BUT THESE ARE ALL OF OUR QUESTIONS. >> THE CLINICAL TRIAL USING GHRELIN IN PARIS WHICH IS A HUGE STUDY AND [INDISCERNIBLE]. >> I MISSED THE WORD. >> GHRELIN IS USED IN CLINICAL TRIAL FOR PATIENT WITH [INDISCERNIBLE]. WHICH IS A BIG PROBLEM WE HAVE IN CLINICAL PRACTICE. IF YOU BREAK GHRELIN YOU WILL CREATE ANOTHER PROBLEM. YOU'RE NOT AFRAID ABOUT THAT? >> I DON'T THINK WE CAN CLOSE THE LOOP. YOU'RE RIGHT, GHRELIN IS UNDER INVESTIGATION AS A POTENTIAL TREATMENT FOR GASTRIAL PARESIS AND YOU COULD HAVE CONSTIPATION BUT YOU'RE NOT INDUCING IT BECAUSE THE OTHER SYSTEMS WILL OVERCOME THE PHARMACOLOGIC BLOCKING. THIS HAS NOT BEEN SEEN AS A POTENTIAL CONCER EITHER IN RODENTS OR IN PATIENTS. NOW, YOUR POINT IS STILL WELL TAKEN MEANING WE'RE NOT GIVING THE DRUG CHRONICALLY. AND THE COMPROMISE BETWEEN MY PERSPECTIVE AND MY PERSPECTIVE I'M NOT CLINICALLY CONCERNED BUT YOU'RE POINT IS TAKEN THAT THE MEDICATION IF MOVED FORWARD THERE IS THAT AN ASPECT TO PAY ATTENTION TO. >> AND THERE'S AN INFLAMMATORY EFFECT. >> WE HAVE EVIDENCE OF INFLAMMATION OF SOME ENCYTOKINES BUT IT GOES BACK TO THE BALANCE OF ALSO THE BLOOD PRESSURE IS AN EXAMPLE. IT MAY HAVE AN EFFECT BUT BY BLOCK THE GHRELIN RECEPTOR YOU WON'T HAVE THE AFFECTS NECESSARILY. SO AGAIN, I THINK IT'S SOMETHING TO MONITOR AND I THINK THE SAME MAY BE SAFE FOR MANY MEDICATIONS THAT ARE ALWAYS UNDER TREATMENT OR UNDER INVESTIGATION IN THE MARKET. >> I HAVE A QUESTION FOR THE PANEL. THIS QUESTION WAS STIMULATED BY REMARKS BY DR. PRICE AND CRITCHLEY AND OTHERS. THAT IS SEX DIFFERENCES. DO YOU OBSERVE DIFFERENCES IN PARASYMPATHETIC DISORDERS IN THE INTEROCEPTIVE AWARENESS AND THINGS OF THAT NATURE? CAN THE PANEL SPEAK BROADLY ABOUT THE POTENTIAL INFLUENCE OF SEX DIFFERENCES ON INTEROCEPTIVE AWARENESS? >> THERE'S GREATER ACCURACY. SOME OF THAT IS RELATED TO THE THORAX. IT'S A PARADOX TO AN EXTENT IF YOU THINK THE INTEROCEPTIVE SENSITIVITY IS MEASURED AND THE EXPRESSION OF THE ANXIETY DISORDERS IN WOMEN COMPARED TO MEN. >> IN TERMS OF LEARNING THESE SKILLS AND WANTING TO AND USING THEM, I CAN'T TOTALLY ANSWER THAT QUESTION BECAUSE MOST MY RESEARCH HAS BEEN WITH WOMEN. HOWEVER, I HAVE DONE A STUDY WITH PEOPLE LIVING WITH HIV WITH MEN AND MEN AND WOMEN WHO HAVE OPIOID USE DISORDER AND ARE TAKING MEDICATIONS AND TREATMENT AND IT DOESN'T APPEAR THERE IS ANY REASON TO THINK THAT THERE WOULDN'T BE SIMILAR IN THIS WAY. >> THERE'S CONDITIONS MORE COMMON IN WOMEN COMPARED TO MEN WITH ANXIETY DISORDERS. >> I'M TRAINED AS A NEUROSCIENTIST AND CLINICAL PSY PSYCHOLOGIST AND TAUGHT MANY PATIENTS MINDFULNESS AND I'D SAY THERE'S GENDER DIFFERENCES IN WAY PEOPLE ARE SOCIALIZED TO UNDERSTAND OR EXPRESS THEIR EMOTION. WITH MEN, THEY'RE MORE RETICENT TO DO THAT AND WE HAVE TO TALK THROUGH WHY THEY FEEL THIS WAY AND ONCE THEY UNDERSTAND IT'S FOR YOUR OWN SELF KNOWLEDGE YOU DON'T HAVE TO EXPRESS THEM TO ME OR ANYONE ELSE BUT THIS IS FOR YOUR OWN SELF UNDERSTANDING AND FOR WOMEN THERE'S A LOT OF MESSAGES HOW WE SHOULD FEEL, HOW WE SHOULD LOOK AND THERE'S SYSTEMIC OPPRESSION OF WOMEN AND ONE CASE THAT PARTICULARLY COMES UP IS A WOMAN AT WORK FELT LIKE SHE ALWAYS FELT SHE HAD TO SMILE WITH PEOPLE AND DISCONNECTED WITH HOW SHE FELT INSIDE AND WE DID MINDFULNESS OF THE SENSATION OF THE FACE AND I WAS SURPRISED NO ONE MENTIONED THE FACE BECAUSE WE EXPRESS SO MUCH IN OUR FACE AND EXPRESS TO EACH OTHER AND SO SHE TUNED INTO THE SENSATION OF HER FACE AND PRACTICED THE EMOTIONAL EXPRESSIONS SHE SHOWED INSIDE AND HAVING MORE OF A MATCH. I THINK THAT'S WHAT I'LL SAY ABOUT THAT. SO IF THERE ARE SEX DIFFERENCES IN BEING AWARE AND THEIR FEELINGS AREN'T VALIDATED AND THE PEOPLE AROUND THEM AREN'T ACKNOWLEDGING THEM OR TELLING THEM TO FEEL A DIFFERENT WAY THERE'S GOING TO BE A MISMATCH BETWEEN WHAT THE BODY SAYS AND WHAT'S EFFECTIVE IN BEHAVIOR. I THINK THAT CAUSES A LOT OF DISTRESS. THAT MAY LEAD TO WHY THERE ARE SEX DIFFERENCES IN SOME OF THE CONDITIONS WE'RE SEEING AND THEY'RE ACTUALLY PSYCHO THERAPEUTIC TREATMENTS AND PSYCHO THERAPY FROM SOCIAL JUSTICE FRAME WORKS THAT ACKNOWLEDGE THE LARGER SYSTEMIC SOCIETAL DIFFERENCES IN THE WAY PEOPLE ARE TREAT AND HOW IT IMPACTS MENTAL HEALTH. >> I HAVE TWO QUESTIONS HERE. MOSTLY TO JACK AND HUGO. IN BOTH THE TALKS YOU BROUGHT UP IN JACK'S TALK THE SLIDE WAS NOT HIGHLIGHTED BUT MENTIONED NEURODISEASES AND WHAT'S THE BREATHING CONNECTED TO THE DISEASES AND HUGO, YOU SKIPPED OVER AUTISM. CAN YOU CLARIFY THE INTEROCEPTIVE ISSUES IN AUTISM PATIENTS? >> I THINK MY COLLEAGUE WILL BRING THE STUDIES IN AUTISM IN HER TALK LATER TODAY. >> IT WAS A COMMENT TO A TOPIC WE TALKED ABOUT YESTERDAY AND IT WAS BROUGHT UP AND LIKE IF YOU TAKE PANIC ATTACKS OR LIKE THERE'S AN ENHANCED AWARENESS OF RESPIRATORY ACTIVITY CAN PLAY A ROLE AND THERE'S EXTENSIVE RESEARCH ON THIS. ONE IS INTEROCEPTIVE INPUT AND THE OTHER IS A SALIENT ASSESSMENT OF WHAT THAT MEANS TO THE BRAEN -- BRAIN AND IT'S THERAPEUTIC. IF YOU DO ALL THESE FUNCTIONAL PATIENTS WHO HAVE TREMENDOUSLY ENHANCED INTEROCEPTIVE SENSITIVITY BUT ASSOCIATED WITH A THREATENING OR NEGATIVE SYMBOL DO YOU THINK IT'S A POSSIBILITY TO EXPLAIN THAT AND WITH YOUR STUDY YOU ENHANCE INTEROCEPTIVE THERAPEUTIC AFFECTS AS IN OTHER PEOPLE YOU WANT TO DO THE OPPOSITE OR REFRAME THE INTERPRETATION BY THE PATIENT. >> I THINK WE'LL SEE BECAUSE WE'RE JUST STARTING SOME STUDIES. I THINK IT MAY BE SIMILAR TO EXPOSURE THERAPY WHERE YOU HAVE SOME PANIC DISORDER OR SOMETHING LIKE THAT WHERE YOU HAVE SOMETHING THAT ELICITS A NEGATIVE PSYCHIATRICAL RESPONSE AND YOU PROVIDE THE STIMULUS BUT WITH THE PROPER FRAMING ASSOCIATED WITH IT AND IT'S THAT COUPLING. SO IF YOU CAN PROVIDE THE INTEROCEPTIVE AFERENCE IN A WAY THAT REFRAINS THE SENSATIONS YOU'RE FEELING THAT MAY LEAD TO A BETTER OUTCOME. SO IF WE LOOK AT MINDFULNESS MEDITATION IT'S NOT SIMPLY BREATH AWARENESS OR FOCUSSING TONE BREATH BUT YOU DO THAT AND HOW YOU REFRAME THE SENSATIONS YOU FEEL AND YOU WORK WITH THE SENSATION MAY BE IMPORTANT. >> I'LL ANSWER YOUR QUESTION, IN SEVERAL DEGENERATIVE DISEASES LIKE PARKINSON'S AND ATROPHY, THESE INDIVIDUALS AT THE LATE STAGES CAN BREATHE FAIRLY WELL DURING WAKEFULNESS BUT HAVE PROBLEMS DURING SLEEP. THEY HAVE SERIOUS SLEEP APNEAS WE SPECULATE IT'S A PRINCIPLE CAUSE OF DEATH. AND WHEN YOU LOOK AT THE BRAIN STEM FOR PEOPLE WHO HAVE DIED FROM LATE STAGES PARKINSON'S, THERE'S 50% TO 90% OF NEURONS IN THE PRE-BOTZINGER COMPLEX AND THE BREATHING CAN CAUSE -- I'M NOT SURE YOU LUMP THEM AS NEURODEGENERATIVE DISEASE BUT SLEEP APNEAS HAVE BEEN ASSOCIATED WITH DEGENERATION OF BOTH GRAY AND WHITE MATTER. THAT HAS SERIOUS CONSEQUENCES AND I DON'T KNOW TO THE DEGREE WHERE INFANTS CAN BE CONSIDERED INTEROCEPTIVE BUT THE PROXIMAL CAUSE OF DEATH IS THEY STOP BREATHING AND THE THEORY IS THERE'S A PROBLEM IN THE MATURATION OF THEIR BREATHING CIRCUITS THAT THEY REACH A CRITICAL POINT IF THEY BECOME SLIGHTLY HYPOXIC DURING SLEEP INSTEAD OF AROUSED AND THEY BECOME FURTHER HYPOXIC AND SUCCUMB. >> TO EXPAND ON THE TOPIC OF SLEEP DEPRIVATION AND SLEEP WE TALKED ABOUT BREATHING AND THE COMMENT THAT IT'S NOT REALLY ABOUT BREATHING IT'S THIS CONNECTION OR INTEROCEPTIVE. WHAT I'M MOSTLY INTERESTED IN IS YOU TOUCHED A BIT ON SLEEP APNEA BUT WHAT ABOUT GENERAL SLEEPINESS WHICH MOST OF THE POPULATION HAS. IF YOU'RE SAYING SIZE AND THINGS CAN HAVE TO DO WITH POSITIVE EMOTION AND REGULATION AND WE KNOW WITH SLEEP REGULATION YOU CAN'T REGULATION EMOTION AND HAS NEGATI NEGATIVE CONSEQUENCES I WANTED TO HEAR MORE ABOUT A DISEASE OR DISORDER OR GENERAL SLEEP DEPRIVATION. >> AS YOU KNOW, SLEEP IS NOT REALLY MY AREA OF EXPERTISE AND IT'S CLEAR SLEEP IS FUNDAMENTAL TO BODY AND BRAIN HEALTH. AND WHEN YOU DON'T REGULAT YOUR BREATHING PROPERLY DURING SLEEP YOU GET SLEEP DISRUPTION. YOU CAN GET SOME COMPENSATION FOR SLEEPINESS BY MEDITATING. I MYSELF VERY OFTEN IN THE MIDDLE OF THE DAY IF I FIND MYSELF FADING, AS CAN OFTEN HAPPEN, IF I TAKE 10 MINUTES OUT AND MEDITATE I FEEL TOTALLY REGENERATED AND I DON'T KNOW HOW THAT INTERACTS WITH SLEEP BUT PARTICULARLY AFTER LUNCH WHERE THERE'S THAT DEPRESSION AND I'M NOT SURE WHAT YOU'RE LOOKING FOR. >> I SAW OTHER MICS GO ON BUT I WAS INTERESTED IN BECAUSE THIS IS THE FIRST I'M HEARING ABOUT INTEROCEPTION IN THE TALKS YOU GUYS GAVE ABOUT BREATHING AND MINDFULNESS I THINK I WAS THINKING AS YOU WERE GOING THROUGH THOUGH THIS IS IN THE CONTEXT OF DISORDERS THAT THERE'S ANOTHER BURDEN OR ISSUE THAT IS SLEEP DEPRIVATION WHICH IS NOT A DISORDER BUT CAN ALSO FIT INTO THE SPACE. >> SO THERE HAVE BEEN STUDIES DONE FOR SURE THOUGH SLEEP DEPRIVATION IS NOT A DISEASE THERE'S DELETERIOUS AUTONOMIC ISSUES AND WOMEN HAD MORE ACTIVATION IN RESPONSE TO SLEEP DEPRIVATION. IT'S NOT HEALTHY TO BE SLEEP DEPRIVED. WHETHER THESE TYPES OF INTERVENTIONS AND PART OF THE PATHOLOGY IS THE HEIGHTENED SYMPATHETIC RESPONSE. IF THERE'S A WAY TO USE THE PRACTICES, BREATHING PRACTICES TO LOWER SYMPATHETIC TONE AND IMPROVE SLEEP HYGIENE, THOSE KINDS OF STUDIES I DON'T THINK HAVE BEEN DONE YET. >> YOU DESCRIBED MINDFUL MEDITATION AS INTERVENTION AND I'M WONDERING IF THE TECHNIQUE OR DOSE IS STANDARD IEFTD YOU -- STANDARDIZED, IF THERE'S AN EFFECT ONCE A MONTH OR SIX MONTHS AND IN GOING FORWARD AND IF EVERYBODY'S DOING THIS IN A SLIGHTLY DIFFERENT WAY I'M NOT SURE WE'LL LEARN A LOT. >> I THINK OTHER MEMBERS OF THE PANEL HAVE A LOT OF EXPERTISE ON THIS AS WELL. I THINK THAT'S A VERY IMPORTANT QUESTION AND WE DON'T KNOW. IN TERMS OF BLOOD PRESSURE THERE'S QUITE A BIT OF PRESSURE WITH THE EIGHT-WEEK PROGRAM WITH MBSR SHOWED SUSTAINED AFFECTS ON LOWERING BLOOD PRESSURE. AND WE HAD UNTRAINED INDIVIDUALS WHICH WAS SURPRISING TO SOME EXPERTS IN THE FIELD BECAUSE IT'S THOUGHT TO BE THIS THING THAT TAKE TIME TO LEARN ETCETERA. WE SAW SIS -- PHYSIOLOGIC AFFECTS ACUTELY AND TO BE CLINICAL WE NEED TO FIGURE OUT THE DOSE, METHOD, DURATION THAT IS GOING TO CHANGE CLINICAL OUTCOMES. >> I'LL ADD TO THAT THERE'S BEEN RESEARCH DONE IN RECENT YEARS AS PROBABLY MANY OF YOU KNOW. IT DOES SHOW AFFECTS BUT OFTEN TIMES THERE'S BEEN LITTLE DONE LOOKING AT INCREASES AT INTERCEPTION PER SE WHETHER IT'S LOOKING AT RSA OR USING IMAGING OR INTERCEPTIVE SELF-REPORT SCALES. THERE'S MORE OF THAT HAPPENING BUT WE DON'T KNOW THE DOSE THAT IS NEEDED TO HAVE THE BEST AFFECT AND FOR DIFFERENT POPULATIONS. AND I'M VERY AWARE OF THAT WITH THE WORK I DO WHERE IT'S BEEN AN EIGHT-WEEK INTERVENTION JUST LIKE MOST THE MBSR INTERVENTIONS HAVE BEEN DESIGNED TO BE AND WE SEE AN AFFECT A YEAR OUT BUT THE LEVEL OF WHEN IT'S SUSTAINED AND MEASURING A SELF-REPORT. IT'S SUSTAINED BUT NOT GOING UP AND THESE ARE VERY DISTRESSED PEOPLE AND THEY NEED MORE SUPPORT THAN THEY GET ON ALL SORTS OF LEVELS. HOW MUCH MORE CAN WE INCREASE IT, WHAT DO WE NEED TO DO IN TERMS OF DOSE. WE DON'T KNOW AND THERE'S SO MANY QUESTIONS LIKE THAT THAT NEED ATTENTION. >> I'D LIKE TO SAY WITH THE VARIOUS PEOPLE HERE WITH OPPORTUNITIES THAT REVIEW PAPERS THAT HAVE METHOD SECTIONS WE PAY FAR MORE ATTENTION TO ASKING THE WRITERS OF VARIOUS PAPERS TO STEP UP TO THE PLATE AND BE EXPLICIT IN THE METHODS THEY USED SO THINGS CAN BE COMPARED IN THE FUTURE. >> AND PEOPLE HAVE MODIFIED RESEARCH HAS SHOWN TO CYNTHIA'S POINT NOT ONLY DOSE BUT PRACTICE OF THE SKILLS CORRELATES WITH OUTCOME. THERE'S A BIT OF WORK OUT THERE IN TERMS OF DOSE AND FREQUENCY OF PROTOCOLS OF EXPANDED TO 12 WEEKS. AND LONGER PERIODS AND WE FOUND ARE IMPORTANT FOR WEIGHT-RELATED CHANGES AND A GROUP HAS SHOWN THAT MINDFULNESS BASED INTERVENTIONS CAN HAVE AN EFFECT ON METABOLIC OUTCOMES IN EIGHT WEEKS. THERE'S QUITE A BIT ON DOSE AS WELL AS THE IMPORTANCE OF PRACTICE. >> ALSO A SHOUT OUT TO STUDIES JUST STARTING TO LOOK AT THE DOSING EFFECT AND IT'S MOSTLY DO WE NEED ONE CLASS A WEEK OR TWO OR THREE AND ALSO DO WE NEED SUSTAINED AFFECTS BEFORE MEDICATIONS AT HOME. >> I'LL JUST MENTION THERE'S A BRIEF MINDFULNESS BASED INTERVENTIONS THAT ARE ONE-TIME DOSE. THERE'S A REVIEW OF 20 PAPERS OF A ONE-TIME INTERVENTION OF MINDFULNESS APPEARS TO HAVE AN AFFECT. >> THERE'S A BOOK BY TIMOTHY McCALL WHICH SUMMARIZES MANY STUDIES DONE ON YOGA AND MINDFULNESS RESEARCH A BOOK OF OVER 200 STUDIES LOOKED AT METHODOLOGY, DOSE AND FREQUENCY. >> THE QUESTION IS ON THE AFFECT FOUND BECAUSE OF LESS COMPETITIVE INPUTS. I WANTED TO RELATE AND WE COULD HAVE LIKE DOCTORS TALKING ABOUT THIS AND THE LAST COMMENT IS ABOUT HOW FOR EXAMPLE, RESPIRATION CAN BE USED TO IMPROVE COGNITIVE PERFORMANCE BUT HOW DOES THE TASK HAVE AN AFFECT, FOR EXAMPLE, I WILL HOLD MY BREATH TO HEAR BETTER THE GUNSHOT WHERE IF I HAVE A PREDICTIONS OF WHERE THE STIMULUS WILL ARRIVE I SYNCHRONIZE TO THE INPUT. >> THERE'S A LOT TO UNPACK THERE. I'M SORRY, THE MIDDLE QUESTION -- >> THE RELATION OF THE NEUR NEUROPLASTICITY WE HAVE THROUGH PRACTICE VERSUS THE VAGUS STIMULATION PAIRED WITH MINDFULNESS. >> I WANT TO LOOP HUGO INTO THESE BECAUSE HE TALKED INTO THE RHYTHMS. I THINK THAT'S A GREAT WAY TO THINK ABOUT IT THERE'S A PHYSIOLOGIC RHYTHM WITH CARDIAC AND HEARTBEAT RHYTHMS AND BARORECEPTOR RIDHYTHMS AND THERE MAY BE UP AND DOWN STATES IN TERMS OF MIND WANDERING AND SALIENCE PROCESSING AND THINGS LIKE THAT WHERE YOU MIGHT WANT TO LOOK AT TARGETING STIMULI DURING THE UP AND DOWN STATES AND YOU MIGHT GET BETTER EF EFFECTS AND A REGION OF THE BRAIN WAS MONITORED AND THEY DELIVERED STIMULI THAT ARE AROUND THRESHOLD AT DIFFERENT UP AND DOWN STATES AND NETWORK OSCILLATIONS AND FOUND DIFFERENCES IN PERCEPTION WHEN YOU'RE APPLYING THE STIMULUS DURING DOWN VERSUS UP STATES AND WE KNOW THERE'S RHYTHMS IN THE BRAIN. SOME ARE LINKED TO RESPIRATORY AND CARDIAC RHYTHMS. I THINK WE NEED MORE RESEARCH TO UNPACK YOUR QUESTION WHICH IS HOW THESE ARE LINKED TOGETHER. >> THERE'S INSPIRATION YOU MOVE AIR IN AND OUT AND IF YOU LOOK AT WHAT'S GOING ON IN THE BRAIN AND MUSCULATURE INSPIRATION IS AN ACTIVE PROCESS AT REST AND YOU CONTRACT THE DIAPHRAGM AND EXPIRATION YOU JUST RELAX. IF YOU LOOK AT THE DIFFERENCES BETWEEN INSPIRATION AND EXPIRATION IT COULD BE DUE TO AN ACTIVE NEUROMUSCULAR ACTION VERSUS A PASSIVE ONE. NOW THAT CHANGES WHEN THE VENTILATION GOES UP AND YOU HAVE TO ACTIVELY EXPIRE. THE STUDIES WERE DONE AT REST AND WHETHER THEY REMAIN THE SAME WHEN YOU BEGIN TO ACTIVELY USE YOUR MUSCLES IS IN QUESTION. THE SECOND THING IS IN LOOKING WE DISCOVERED A DIFFERENT OSCILLATOR THAT DRIVES EXHALATION PHYSICALLY DIFFERENT AND UNDER NORMAL CONDITIONS IT'S INHIBITED SO YOU DON'T HAVE ACTIVE EXPIRATION AND WHEN YOU NEED IT YOU LIFT THAT. NORMALLY THEY'RE EXTREMELY TIGHTLY COUPLED SO THEY LOOK LIKE ONE SYSTEM BUT EXPERIMENTALLY YOU CAN DECOUPLE THEM AND SEE THERE ARE TWO OSCILLATORS. THAT JUST GOES TO WE DON'T KNOW ENOUGH RIGHT NOW. >> YOU USED STIMULATION AT 25 HERTZ DID YOU TRY 5 OR 10 HERTZ. >> WE RECENTLY COMPLETED A STUDY WITH 30 INDIVIDUALS WITH FOUR DIFFERENT FREQUENCIES WHERE WE DID A FREQUENCY MODULATION AND SURPRISINGLY WE FOUND 25 HERTZ THE DATA I SHOWED YOU THERE WAS NOT THE MOST EFFICIENT FREQUENCY TO STIMULATE WITH AND THERE WAS A HIGHER FREQUENCY AND 100 HERTZ WAS MORE AFFECT IN AFFECTING THE NUCLEUS AND WE GOT SOME ACTIVATION IN THE IPSLATERAL MEDULLA. WITH NEURAL MODULATION THERE'S DEFINITIONS THAT NEED TO BE CONSIDERED. AND FREQUENCY IS ONE OF THEM. RESPIRATORY RHYTHM COULD BE AN IMPORTANT ONE AS WELL. IT'S THE SAME WAY YOU'D MODULATE FREQUENCY IS LOOKING AT RESPIRATORY PHASE AS AN IMPORTANT PARAMETER TO MODULATE. IT'S A GREAT QUESTION. >> I THINK THE VAGUS NERVE WITH STIMULATION IF YOU -- >> 8 HERTZ WAS OPTIMAL. IN STUDIES THEY USE 8 HERTZ FOR ANTI-INFLAMMATORY EFFECTS AND THEY HAVE BRIEF SIMULATIONS. AND TO ME IT'S SURPRISING BUT THAT'S WHAT THE ANIMAL WORK HAS SHOWN AND THEY'VE CARRIED THAT OVER INTO THE HUMAN WORK. I THINK ANTI-INFLAMMATORY EFFECTS MIGHT BE OPTIMIZED AT A DIFFERENT FREQUENCY THAN OTHER EFFECTS AND COGNITIVE PROCESSING OR ANTI-DEPRESSIVE AFFECT IT NEEDS TO BE MAPPED BASED ON THE DISORDER YOU'RE TRYING TO ATTACK. >> I THINK 20 HERTZ IS A GOOD FOR BOTH. >> WE STARTED WITH THAT BECAUSE OF THE RECEPTOR WE LOOKED AT THE RECEPTORS BUT WHEN YOU PROVIDE ELECTRICAL STIMULATION SUBCUTANEOUSLY YOU MAY BE DIRECTLY DEPOLARIZING AXONS AND THAT MAY BE THE CRITICAL FEATURE SO GETTING AWAY FROM THE RECEPTOR SENSITIVITIES MAY NOT BE A BAD THING. >> AND PEOPLE WORKING ON THIS LOOK AT SIDE EFFECTS BUT WE HAVE PATIENTS WITH CROHN'S DISEASE HAVE YOU NO DRUGS TO TAKE. YOU HAVE NOTHING DO TO DO AND IN INFLAMMATORY CONDITIONS IBD WE HAVE BIG PROBLEM OF COMPLIANCE OF DRUGS IN 40 TO 50 PERSON. I THINK IT'S STILL IT'S A GOOD TECHNIQUE. >> WE HAVE TIME FOR ONE MORE QUESTION AND REEL BREAK FOR LUNCH. >> GOING BACK TO THE DISCUSSION HOW HUMAN AND ANIMAL STUDIES INFORM EACH OTHER, FROM YESTERDAY'S DISCUSSION THERE WAS QUITE A BIT OF SKEPTICISM ONLY BOTH SIDES. TO ME IT'S QUITE CLEAR WE COULD DO EXPERIMENTS IN ANIMALS IN PLACES WHERE WE CANNOT REACH IN HUMANS. ON THE OTHER HAND HIGH CORTOID FUNCTIONS AND EXCEPTIONS CAN BE EASILY MEASURED IN HUMANS AND TRANSLATED BACK TO ANIMALS, MAYBE. I'M JUST ASKING THE PANEL TO COMMENT. >> THE NEUROAMAT MY -- NEUROANATOMY MAY BE A GREAT PLACE TO START AND COULD BE A STARTING POINT FOR ANIMAL MODEL RESEARCH. >> WITH THAT I THINK WE WILL END THIS SESSION. AND WE'LL BREAK FOR LUNCH AND BE BACK HERE BY 12:30. WE'LL START WITH SESSION FIVE. >> SO IT IS 12:32 AND WE'LL GET STARTED WIN OUR SESSION FIVE. -- WITH OUR SESSION FIVE. HELLO, EVERYBODY. MY ROLE IS TO JUST INTRODUCE OUR SPEAKERS AND GET OUT OF THE WAY OF THE EXPERTS. SO I'M ONE OF THE CO-CHAIRS AND RAPPORTEUR IS HERE AND WE HAVE SARAH GARFINKEL FROM THE SUNRISE OF SUSSEX. WE'LL FOLLOW THE SAME MODEL AND TRY TO KEEP THE FORMAL TALKS TO AN HOUR OR A LITTLE OVER AN HOUR TO HAVE PLENTY OF DISCUSSIONS FOR QUESTIONS AFTER YARDS. THE TITLE IS TECHNOLOGIES AND METHODOLOGIES FOR BIORECEPTION NETWORK. WE'LL TALK ABOUT THE TOOLS AND BIOMARKERS THEY USE IN THEIR RESEARCH AS WELL AS GAPS AND NEEDS AND METHODS AND TECHNIQUES IN THE FIELD. AND THREE OF OUR TALKS ARE ON SENSORIMOTOR ISSUES AND AND AN INTRODUCTION TO THE GLAD BLADER FUNCTION AND ROB WILL FOLLOW ON TECHNOLOGY ON FREELY BEHAVING ANIMALS AND THEN WE WILL HAVE A TALK ON SENSORY AND MOTOR IN THE ACTIONS AND SARAH WILL TALK ABOUT CARDIOSENSING AND DIMENSIONS OF INTEROCEPTION AND WE TURNED OUR RAPPORTEUR AS ONE OF OUR SPEAKERS AND SHE WAS GOING TO START QUESTIONS WITH SUMMARIES AND QUESTIONS BUT SHE'S PREPARED A NICE TALK OF HER OWN SO WE'RE GOING TO TURN HER INTO OUR FIFTH SPEAKER AND THEN AFTER THAT CHRISTOPH WILL DO SUMMARY ANDINSPIRATIONAL TALKS AND WE'LL GET INTO IT WITH OUR FIRST SPEAKER. LISA. >> I ALSO WANT TO THANK THE ORGANIZERS. IT'S BEEN VERY INTERESTING. MY LAB IS FOCUSSED ON STUDYING HOW SENSORY SIGNALS ARE TRANSFORMED INTO BEHAVIOR. OVER THE LAST FEW YEARS WE'VE BEEN FOCUSSING ON USING URINATION AS A STUDY. AS HUMANS WE DO TWO DO TWO KINDS OF URINATION, REFLEXIVE AND ONE IS BASED ON PHYSIOLOGICAL NEED IT'S FULL AND REFLEXIVELY ELIMINATES BUT BY THE TIME WE'RE ABOUT 3 OR 4, WE LEARN TO CONTROL THIS WITH OUR BRAIN AND INVOLUNTARY MEANS YOU GO WHEN YOU HAVE TO GO AND VOLUNTARY YOU GO WHEN YOU HAVE THE URGE TO ELIMINATE. UNLIKE OTHER PROCESSES WE WERE DEBATING YESTERDAY WHETHER HAVE YOU CONSCIOUSNESS AWARENESS AND WHETHER YOU CAN BE AWARE OF THE INTEROCEPTION THIS IS THE TYPE OF THING WHERE YOU'RE EXTREMELY AWARE OF THE STATE OF YOUR BLADDER. THIS IS WHERE WE HAVE EASY ACCESS TO IT BUT THE PROCESS IS A LOT OF THE ACCESSES AREN'T KNOWN AND TELLS YOU IT'S A BLENDING OF INTERNAL AND EXTERNAL CUES SO WHEN YOU'RE VOLUNTARILY EUROPE URINATING YOU USE SENSORY AND SOCIAL CUES TO MAKE THAT JUDGMENT. SO WE KNOW A LOT ABOUT REFLEXIVE EUROPE -- URINATION IN HUMANS AND ONE REASON WE DON'T KNOW ABOUT THE MORE VOLUNTARY URINATION IS WE DON'T HAVE A GOOD ANIMAL MODEL TO GET TO THE MECHANISTIC ANALYSIS AND IT'S HARD TO DO A TACH OR RODENT STUDY AND MOTIVATE THE ANIMAL TO PEE. YOU DON'T KNOW WHEN TIME ZERO IS. ARE THEY DOING IT BECAUSE IT'S REFLEXIVE OR MOTIVATED ONE AND A STUDENT DEVELOPED AN ASSAY AND THAT IS MALE MICE I'LL SHOW YOU HERE. MALE MICE ARE MOTIVATED AND HAVE PHEROMONES IN THEIR URINE AND THE FEMALE MICE GETS THE MALE MICE TO IN TURN SEND HIS PHEROMONES AND YOU SEE THE PATTERNS THE FEMALE PHEROMONES TRIGGER. AND WA WE'D LIKE TO YOU AGREE WITH US ON IS THE MOTIVATED URINATION IS WHAT WE DO AND IN THE FIRST TWO MINUTES OF THE ASSAY WHEN WE HAVE THE CONTROL AND THERE'S LITTLE URGE OF THE ANIMALS TO GO TIMED WITH THE PRESENTATION OF THE FEMALE ODOR CUES THE MALE NOW HAS THE MOTIVATION AND ALL THE ANIMALS YOU CAN SEE THERE'S URINATION CONTROLS AND WE LOOK AT WHAT THE BRAIN IS SENSING AND HOW'S IT CONTROLLING IT. THE TARGET OUTPUT OF THIS IS THE URINARY SYSTEM IS QUITE SIMPLE. THERE'S TWO MUSCLES THE BLADDER NEEDS TO CONTRACT AND SPHINCTER STAYS CONSTRICTED AND ONLY RELAXES OCCASIONALLY TO URINATE AND YOU CAN PUSH ON YOUR DIAPHRAGM BUT YOU CANNOT SQUEEZ YOUR BLADDER. THE SPHINCTER IS A SOMATICALLY CONTROLLED AND YOUR TIGHTENING OR RELAXING THE SPHINCTER. IN ORDER TO STUDY HOW THE BRAIN'S CONTROLLING THIS BEHAVIOR WE WENT ON A SEARCH FOR THIS SO CELLS IN THE BRAIN THAT ARE RELAX THE SPHINCTER AND WHAT WAS KNOWN WAS A STUDY OU THE SPINAL CORD CONTROLS URINATION BUT LITTLE WAS KNOWN ABOUT THE CELLS AND YOU HEARD ABOUT A REGION CALLED BARRINGTON'S NUCLEUS AND AT THE TIME WE BEGAN THE STUDIES THIS IS THE PMC AND THE ONLY MARKER FOR CELLS IN THE REGION IS THIS RED MARKER, C.R.H. WHEN WE TEST HAD WE COULDN'T FIND A ROLE FOR THE LARGE POPULATIONS OF NEURONS AND WE USED THE TOOLS AVAILABLE IN THE MOUSE AND WELL DEFINED IN THE BRAIN. WE USED THE ALLEN BRAIN ATLAS AND MOLECULAR SCREENING AND STARTING TO SEQUENCE WHEN WE RAN UPON THIS NOVEL MARKER THAT MARKS A NOVEL POPULATION. THIS WAS KEY FOR US TO HAVE THE MARKERS AND IT HAPPENS TO BE ESTROGEN RECEPTOR BUT WE DON'T KNOW IF IT HAS A BIOLOGICAL FUNCTION IN THE PROCESS. WE HAVE A MARKER AND NOW WE CAN MANIPULATE THE CELLS IN INDEPENDENTLY OF THE OTHER CELLS. THE FIRST THING WE WANTED TO DO WAS STUDY THE ANATOMY AND IT'S IMPORTANT IN UNDERSTANDING HOW THE BRAIN IS WORK WITH THE PERIPHERAL PROCESSES. WE CAN LABEL THE SPHINCTER AND THE BLADDER AND IN THIS EXPERIMENT WE CAN USE A CONDITIONAL VIRUS WHERE WE INJECT IT INTO THE BARRINGTON'S NUCLEUS IN ANIMALS EXPRESSING THIS IN THE GREEN POPULATION OF NEURONS OR THE RED POPULATION OF NEURONS AND IF WE HAVE THE TWO DIFFERENT DRIVERS YOU SEE THE ANATOMICAL PROJECTIONS AND THIS PATTERN IS ACROSS THE G.D.C. IS CONSISTENT OR HAVING A ROLE IN REGULATING THE SPHINCTER. OR THE POPULATIONS ARE INTERMINGLED THEY HAVE ENTIRELY DIFFERENT ANATOMICAL PROJECTIONS AS REVEALED BY THIS TOOL. THE NEXT TOOL WE CAN USE WITH THE CONDITIONAL DRIVERS IS TO PUT FLUORESCENCE ACTIVE MARKERS IN THE NEURONS. WE USED THIS SPECIFICITY OF THE MARKER AND CAN PUT IT IN THE POPULATION OF NEURONS AND PUT IN A RECORDING ELECTRODE TO RECORD THE EMISSIONS OF FLUORESCENCE OF THE NEURONS SHOWN IN GREEN AND YOU SEE THE UPTICKS INDICATING THE FLUORESCENCE AS A PROXY FOR NEURAL ACTIVITY AND THIS IS RECORDING TO THE BEHAVIOR LIKE I SHOWED YOU BEFORE, WE COULD TIME THIS WITH THE RECORDING OF THE FLUORESCENCE ACTIVITIES. YOU CAN SEE THE NEURAL ACTIVITY LARGELY CORRELATES WITH THE BEHAVIOR. THAT TOLD US WE WERE ON THE RIGHT TRACK BUT DURING NORMAL URINATION BEHAVIOR THE NEURONS ARE NORMALLY ACTIVE. WE CAN MANIPULATE THEM. WE USE THE SAME TRICK OF USING THE ARTIFICIAL MARKER THAT WILL ACTIVATE NEURONS ON THE BASIS OF LIGHT. NORMALLY THERE'S NO LIGHT IN THE BRAIN SO WE USE THE CANNULA TO DELIVER LIGHT AND YOU CAN SEE THERE WAS IMMEDIATELY A URINE DR DROPLET AND WE CAN DO THIS BY ADDING MORE AND MORE LIGHT YOU CAN SEE WE BIG BIGGER URINE SPOTS. THESE ARE NICELY TIME LAPPED WITH THE LIGHT AND THE MORE NEURAL ACTIVITY WE HAVE THE MORE URINE WE GET OUT. THE NEURONS WERE CORRELATED AND THEY WERE SUFFICIENT TO DRIVE THE BEHAVIOR. WE COULD ALSO DO THIS BECAUSE IT'S A SIMPLE BEHAVIOR THAT REQUIRES JUST THESE MULS MUSCLES. HERE WE HAVE THE CHANNEL EXPRESSED IN THE BRAIN OF THE ANIMALS AND CAN STIMULATE WITH LIGHT AND WE HAVE A TUBE GOING IN THAT IS REPLENISHING THE BLADDER WITH FLUIDS SO WE CAN DO THIS OVER AND OVER AGAIN AND YOU CAN SEE AS THE LIGHT GOES ON SALINE AT THIS POINT COME OUT AND WE CAN USE RECORDING DEVICES AND YOU CAN SEE AS THE LIGHT COMES UP THE BLADDER PRESSURE RISES AND THE SPHINCTER IS DOING CONSTRICTIONS AN RELAXATION AND THE PROCESS IS LIKE A PUMP. IT'S A LONG URETHRA SO THIS IS A PROCESS. WE CAN LOOK AT THE TIMING AND CONTRACTION OF THE MUSCLES AND HOW THE BRAIN IS TALKING TO THE ACTUAL OUTPUT IN THIS ASSAY. FINALLY, WE COULD ASK, IS IT INVOLVED IN THE MOTIVATED BEHAVIOR. WE WANT TO KNOW IF THE BRAIN IS BEING ENGAGED IN THIS IF IT HAS ANY CONTROL OVER THIS. SO TO USE THAT WE CAN USE THE SAME TOOLS OF THE SPECIFIC DRIVERS AND THE VIRUSES AND THIS TIME WE'RE INJECTING A SYNTHETIC CHANNEL IF WE INJECT A DRUG IT WILL BLOCK NEURAL ACTIVITY. THE DRUG IS CALLED CNL. IF WE PUT IT WHERE THEY'RE STIMULATED AND MOTIVATED TO URINATE YOU SEE THE PRESENCE OR ABSENCE OF THE DRUG WE'RE USING TO ACTIVATE THE INHIBITORY CHANNEL HAS NO EFFECT BUT IF WE PUT IT JUST ON THE SPECIFIC NEURONS, THE GREEN NEURONS THAT TALK TO THE SPHINCTER WE GET LITTLE GENERATION EVEN IN THE PRESENCE OF THE FEMALE ODOR. I CAN SHOW THIS ON A DIFFERENT TIME SWALE. WE HAVE OTHER -- SCALE. WE HAVE OTHER TOOLS AND THE INHIBITORY LIGHT MODULE AND INSTEAD OF ACTIVATING THEM THIS TIME WE INHIBIT THE NEURONS WE'LL DO THE SAME EXPERIMENT BUT THIS TIME WITH LIGHTS ON SO THE ANIMAL DOESN'T EMPTY THE BLADDER FROM THE REFLEX OF PEEING. WE'RE STOPPING THE GREEN NEURONS FROM BEING ACTIVATED ON BOTH SIDES OF THE BRAIN. WHAT YOU SEE HERE IS HE'S SPENDING A LOT OF TIME SNIFFING. THAT TELLS US HIS OLFACTORY SYSTEM IS NOT IMPAIRED BY DOING THIS BUT IF YOU'RE CLOSE YOU CAN SEE A LITTLE BIT OF URINE BUT NOTHING LIKE THE VIDEO I SHOWED BEFORE AND JASON TURNS OFFER THE LIGHT. I DON'T HAVE THE CAMERA UNDERNEATH BUT YOU SEE IT START TO GLOW AND HE RESUMES THE MARKING PATTERN AND BEHAVIOR. THIS TELLS US YES, THE NEURONS ARE INVOLVED IN THE MOTIVATED CONTROL. IT TELLS US THE NEURONS ARE DROWN STREAM OF THE COMMAND AND HE SMELLED A FEMALE ODOR AND HE WAS MOTIVATE AND ALL THE ANIMALS DO THIS AND YOU SENSE THE CIRCUIT WAS PRIMED AND THAT INFORMATION WAS THERE AND HE WAS SLIGHTLY AROUSED BECAUSE WHEN WE TURNED OUT THE LIGHT THE MOTOR RESPONSE STARTED BACK UP AGAIN. FOR A CODING POINT OF VIEW IT SUGGESTS THE NEURONS ARE THERE. AUTO SO FOR THIS PARTICULAR BEHAVIOR HAVING A GOOD AS IS A A -- ASSAY ALLOWS US TO SEE WHAT THE ANIMAL WAS DOING AND BIOMARKERS WERE IMPORTANT AND IF YOU DO THIS BROADLY IN BARRINGTON YOU GET DIFFERENT RESULTS SO BEING ABLE TO SEPARATE THIS CELL POPULATION IS IMPORTANT. IN THE MOUSE WE HAVE NICE VIRAL TOOL KITS TO BE ABLE TO DO THIS IN LOTS OF NEURAL POPULATIONS THROUGHOUT THE BRAIN. THEN THE TOOLS I JUST SHOWED YOU THAT ARE WIDELY AVAILABLE AND EASY FOR EVERYBODY TO USE. WHAT WE DON'T HAVE IN THE SYSTEM IS A REAL KNOWLEDGE OF HOW THE SPHINCTER AND BLADDER ARE TALKING TO THE BRAIN. WE DON'T KNOW THE SENSORS OR HAVE A WAY TO INFECT THE SPINAL CORD OR THE PERIPHERAL SENSORS AND NEURONS AND A REPERTOIRE OF THOSE WOULD BE SUPER HELPFUL THEN WE CAN ASK THE OTHER MORE INTERESTING QUESTIONS HOW THE BRAIN IS RECEIVING THE INFORMATION AND HOW IT'S RESPONDING TO IT. SO THANK YOU VERY MUCH. >> AFTER THAT EXCELLENT TALK I'LL START WITH AN INTRODUCTION OF THINGS I'LL DISCUSS TODAY AND A BRIEF DISCLOSURE. A LOT OF THE WORK WE JUST TALKED ABOUT RELIES HEAVILY ON NEW TOOLS THAT HAVE COME ONTO THE SCENE IN NEUROSCIENCE IN THE PAST COUPLE YEARS. INDEED, SOME OF THE WORK IS FUNDED BY THE BRAIN INITIATIVE WHICH IS DESCRIBED HERE AND THE BRAIN INITIATIVE DID SOME SMART THINGS FIRST AND FOREMOST TO ACKNOWLEDGE TECHNOLOGICAL HURDLES WHICH WERE PREVENTING ADVANCES IN SCIENCE AND DEVELOPED NEW TOOLS TO HACK THE BRAIN AND FIGURE OUT WHAT NEURONS ARE DOING AND HOW THEY TALK TO EACH OTHER AND LISA TALKED ABOUT THESE COOLS -- TOOLS AND INTERVENTIONAL TOOLS IS ONE OF THE FIRST THINGS THE BRAIN INITIATIVE DID AND IN THIS MEETING IN THINKING ABOUT INTEROCEPTION AND SENSORY INPUT IN THE BRAIN IT HAS UNIQUE ADVANTAGES THERE'S A BONY ANCHOR POINT NEARBY AND YOU CAN PUT PROBE BY THE BRAIN AND KNOW THEY WON'T CAUSE A LOT OF DAMAGE AND THERE'S PROMOTERS THAT DRIVE INDEPENDENT POPULATIONS OF NEURONS. WHERE HAVE YOU TISSUES THAT ARE SOFTER AND A PLACE TO ANCHOR HARDWARE TO DO THESE TYPES OF MANIPULATIONS AND A LOT OF RELATIVE MOTION, YOU ENCOUNTER UNIQUE ENGINEERING PROBLEMS THAT PREVENT THINGS LIKE OPT GENETICS AND PHYTOPHOTOMETRY AND YOU CAN STIMULATE PERIPHERAL ACTIVITY TO RELIEF CONDITIONS AND THAT HAS SPURRED TECHNOLOGICAL DEVELOPMENT WITH PERIPHERAL NERVES AND MY LAB HAS WORKED WITH MANIPULATING AND STUDYING ACTIVITY OF CELLS IN THE PERIPHERY. SO CONTINUING WITH OUR SYMPOSIUM ON URINATION AND BLADDER BEHAVIOR, I WAS MOTIVATED TO GET STARTED AND THIS QUESTION BY -- I'M THE PROFESSOR AT PAIN AT WASHINGTON UNIVERSITY AND WE HAVE PATIENTS WITH CHRONIC PELVIC PAIN SYNDROMES AND IT'S ONE OF THE PROMINENT COMPONENTS AND THESE PATIENTS HAVE SEVERE PAIN AND FILLING OF THE BLADDER AND EXTREME URGENCY AND FREQUENCY AND IT'S HIGHLY REFACTI REFACTIVE --REFRACTIVE AND WE LOOKED AT THE INSTALLATION OF LOCAL CATHETERIZATION AND IT CAN RELIEVE SYMPTOMS TEMPORARILY ALLOWING THEM TO RUN ANNERAND. IT'S ERRAND AND IT'S INCONVENIENT SO WE WERE MOTIVATED TO THINK ABOUT HOW WE IMAGINE LOCAL NERVE BLOCKS AS A WAY TO PROVIDE A LONGER TERM TREATMENT FOR THIS. IN THINKING ABOUT INTEROCEPTION AND THE PROBLEM OF THE DYSFUNCTIONAL INTEROCEPTION NERVOUS SYSTEM. THE PROBLEM WE HAD WAS CAN WE USE OPTIGENETICS AS A WAY TO ACTIVATE OR INHIBIT THE INTEROCEPTIVE INFERENCE FROM TE BLADDER TO GET AT THE PROBLEMS I JUST SHOWED YOU OF URGENCY, FREQUENCY AND PAIN ASSOCIATED WITH CHRONIC PELVIC PAIN SYNDROMES? IN GENERAL, IT WORKS WELL. THIS IS A RECORD FROM AN ISOLATED NEURON AND WE PUT TRACES IN THE BLADDER AND LOOKED AT THE DORSAL ROOT GANGLY -- GANGLIA AND YOU CAN SEE A CELL THAT IS RAPIDLY FIRING STOPS FIRES OR IF YOU PRODUCE A GENERATOR THAT MAY BE HAPPENING AS THE BLADDER IS STRETCHING AND YOU GET A GRADUAL DEPOLARIZATION CAN YOU REPEAT THAT WITH THE CELL THAT'S INHIBITED AND NOW THE CELL DOESN'T FIRE. IN PRINCIPLE YOU SHOULD BE ABLE TO OPTOGENETICS AND YOU SMUD BE -- SHOULD BE ABLE TO STUDY THIS IN MICE. IN THE CASE OF THE BLADDER IT PRESENTS A PROBLEM. THIS IS AN EXAMPLE OF DIFFERENT ASPECTS OF THE CIRCUIT. THE PERIPHERAL TERMINALS OF THE SENSORY NEURONS ARE HERE IN THE BLADDER WALL. THE CELL BODIES OF THE GANGLIA AND YOU SEE THE CENTRAL TERMINALS ARE HERE AND YOU SEE ANY OF THESE PLACES WOULD BE A FINE PLACE TO PROVIDE A LIGHT SOURCE TO BE ABLE TO ACTIVATE OR INHIBIT THE CELLS. THE PROBLEM ARE NONE OF THESE ARE AMENABLE TO PUTTING A FIBER OPTIC THERE WITHOUT A GIANT BLOCK OF GLUE OR CREMENT -- CEMENT AND THAT WILL IMPEDE THE ANIMALS. THIS IS AN EXAMPLE OF THE FIBER OPTIC IMPLANTED IN THE BRAIN LIKE THIS, THIS IS ANCHORED TO THE SKULL FOR STUDYING SENSORY BIOLOGY IF YOU CAN CHASE THE ANIMAL AROUND AND STIMULATE THE PAWS OR USE THE DISCO FLOOR APPROACH OF LED ILLUMINATED FLOORS AND STIMULATE THEM INTO THE CHAMBER BUT THIS WON'T WORK WELL FOR US TO STUDY INTEROCEPTIVE REFLEXES IN THE BLADDER. WE HAVE USED THE SAME PREP YOU JUST SAW AND INSERTING THE CABLE TO INHIBIT THE SENSORY NEURONS IN THE BLADDER. AND WHAT WE WERE ABLE TO SHOW AND WE CAN DO THIS IN CONJUNCTION WITH DISTENSION OF THE BLADDER AND MEASURE THE TRACE IN THE ABDOMINAL WALL. IT'S A SURROGATE FOR DISTENSION-INDUCED PAIN BEHAVIOR AND IF WE AVE THE INHIBITORY EXPRESSED IN THE BLADDER YOU CAN SEE IT BLOCKS THIS ACTIVATION OF THIS VISCERAL MOTOR REFLEX. THAT TOLD US IT'S POSSIBLE TO REALLY ILLUMINATE THE PAIN ASPECT ASSOCIATED WITH THE BLADDER INFLAMMATION. WHEN YOU LOOK AT THE WAY WE HAVE TO DO THIS EXPERIMENT, THIS IS NOT THE MOST PHYSIOLOGICAL PREP. WANT TO DO THIS IN AN ANIMAL FREELY BEHAVING AND MOVING AROUND AND ENGAGING IN NORMAL BEHAVIORS AND EVEN WHEN CABLES ARE ATTACHED TO THE HEAD OR EVEN IN THE BRAIN, THE CABLES AND ALL THIS CAN PROVIDE SERIOUS RESTRICTIONS ON THE ANIMALS. SO WE'VE BEEN WORKING INITIALLY FROM FUND FROM THE TRANSFORMATIVE RESEARCH AWARD AND BRAIN INITIATIVE FUNDING ON DEVELOPING LIGHT SOURCE RATHER THAN SHINING THEM INTO THE BRAIN ARE TINY LIGHT SOURCE ARE BIOCOMPATIBLE YOU INTEGRATE IN THE NEUROCIRCUIT. THIS IS DONE WITH JOHN RODGERS AT NORTHWESTERN WHO IS GOOD AT DEVELOPING TINY BIOCOMPATIBLE ELECTRONICS AND THIS IS THE SIZE OF THE CELLS TO GIVE YOU A SENSE OF THE SCALE. THOSE LIGHTS MAY PROVIDE A WAY TO PUT THOSE IN CONJUNCTION WITH SOFT MATERIALS TO ALLOW IS TO DO THIS. WE'VE MOVE FORD -- FORWARD IN ARE IMPLANTABLE SUBCUTANEOUSLY AND WE MADE PROGRESS IN THAT AREA BUT IT REQUIRES ANCHORING TO THE SKULL. IN ORDER TO WHERE WE CAN DO THINGS LIKE THIS FOR THE BLADDER WE NEED TO WORK WITH ALL THE RELATIVE MOTION THE ANIMALS ARE GOING THROUGH AND THE DELICATE SOFT TISSUES THAT ARE MOVING AROUND. IN DEVELOPING A FULLY IMPLANTABLE VERSION IT'S A RADIO FREQUENCY HARVESTING ANTENNA AND THERE'S NO BATTERIES IN THE ELECTRONICS THAT HARVEST THAT ENERGY AND THIS IS A SOFT STRETCHABLE MATERIAL THEY COULD BE INTERFACED WITH ALL KINDS OF PARTS OF THE BODY AND THIS IS AN EXAMPLE OF ONE OF THESE THAT HAS A DEVICE IMPLANTED AND YOU CAN SEE HE'S ABLE TO RUN JUST FINE AND THERE'S A LOT OF RELATIVE MOTION IN THAT REGION BUT WE DON'T HAVE DETECTABLE DAMAGE IN NERVES OR ANYTHING LIKE THAT SO IT SEEMS TO BE A GOOD ADAPTATION OF THE TECHNOLOGY. WE'VE BEEN ABLE TO DEVELOP THIS IN MULTIPLE FORM FACTORS FOR ACTIVATING OR INHIBITING DIFFERENT TYPES OF CELLS AND INTEGRATED WITH THE PERIPHERAL NERVE AND A CATHETER TYPE OF LED FOR STIMULATING SPINAL CORD AND THIS DEVICE IS THE ONE WE USED TO STUDY BLADDER PAIN AND JUST TO SAY WE ARE ABLE TO INHIBIT BLADDER PAIN. THERE'S MORE GOING ON THAN JUST THIS PAIN OUTPUT. AND WE LOOKED AT URGENCY AND FREQUENCY AND IN ORDER TO STUDY THIS IN A FREELY MOVING ANIMAL WE NEEDED A WAY TO MEASURE THE BLADDER IN REAL TIME AND INHIBIT THE SENSORY NEURONS. THIS IS A STRAIN GAUGE AND INTEGRATED INTO THAT ARE MICRO LEDs ATTACHED TO THE STATION THAT PROVIDES INFORMATION AND THIS GOES SUB CUTANEOUSLY AND THAT WAY YOU CAN MEASURE FILLING AND EMPTYING OF THE BLADDER IN REAL TIME. AND PROVIDE DATA FEEDBACK. WE'RE ALLOWED TO MEASURE THESE EVENTS IN REAL TIME AND LOOK AT ACTUATORS AND YOU SEE EACH TICK IS A VOIDING EVENT. EACH ROW IS A DIFFERENT RAT. AT BASELINE YOU GET ONE VOID EVERY TWO OR THREE HOURS. IF WE INFLAME THE BLADDER YOU GET AN INCREASE IN THE VOIDS. IF AND WE CAN DECREASE THE VOID. IT SUGGESTS YOU SHOULD BE ABLE TO GET FEEDBACK CONTROL. WHAT WE THEN SOUGHT TO DO IS INCORPORATE THIS INTO A CLOSED LOOP SESSION TO MEASURE EVENTS IN REAL TIME AND UNDERSTAND WHEN THE BEHAVIOR BECOMES PATHOLOGICAL AND DELIVER THE CORRECT STIMULUS. THERE'S A LOT MORE MOTION ARTIFACTS INVOLVED. THERE'S SMOOTHING ALGORITHMS AND FALSE VOID DETECTION AND WE CAN COME DOWN TO THE WAY THE SYSTEM DETECTS REAL VOIDS AND WE CAN INHIBIT THE SENSORY INFORMATION COMING FROM THE BLADDER. IF YOU HAVE A CONTROL ANIMAL HERE'S BASELINE VOIDING. IF YOU PUT THIS IN THE ANIMAL TO CAUSE BLADDER INFLAMMATION YOU GET HIGH FREQUENCY VOIDING AND'S ONE, TWO, THREE VOID IN AN HOUR AND IT KEEPS VOIDING BECAUSE THIS IS A CONTROL ANIMAL. AND HERE'S THE INCREASED VOIDING. IF YOU TURN IT ON THE VOIDING TURNS OFF AND THEN RETURNS. YOU CAN ADAPT THESE AND THIS WORKS WITH THE ANIMALS AND WORKS FOR MONTHS AND YOU CAN MONITOR THE PHYSIOLOGY IN REAL TIME. >> WE HAVE DATA COMMUNICATION AND REAL TIME ANALYTICS THAT ALLOW US TO DETECT THE PATHOLOGICAL BEHAVIOR AND ACTUATOR. IN GENERAL THAT PLATFORM CAN BE RE-IMAGINED TO HAVE AC SHOE WAITERS TO -- AC ACTUATORS AND YOU CAN HAVE CHANNELS THAT CAN GO THROUGH LONG PROCESS AND DELIVER A DRUG LOCALLY. THIS IS A CUFF TO HAVE PHARMACOLOGIC AND OPT OWE OPT OWE OPTOGENETIC MODULATORS AND HERE'S AN EXAMPLE WHERE WE'VE BEEN WORKING TO ADAPT THIS TO ANOTHER WIRELESS APPROACH AND THIS IS THE RECORDING WE SHOWED AND HERE'S A WIRELESS DEVICE THAT CAN BASICALLY DO THE SAME THING. A LOT OF THIS RELATES WELL WITH WHAT LISA SAID. WE HAVE TOOLS THAT CAN ACTIVATE AND INHIBIT NEURAL ACTIVITY. WE REALLY NEED TO HAVE ADDITIONAL TOOLS VALIDATED FOR MEASUREMENT MANIPULATION OF SIGNALLING AND OTHER CELL TYPES AND EPITHELIAL CELLS AND OTHERS WE HEARD AT THIS MEETING. WE HAVE SOME VIRAL VECTOR TOOLS THAT WORK WELL IN COMBINATION WITH ANIMALS AND WE NEED CELL-TYPE SPECIFIC TOOLS THAT ALLOW US TO TARGET INDIVIDUAL CELL TYPES IN THE VARIOUS TISSUES WE'RE LOOKING AT. THAT'S A BIG ADVANTAGE RIGHT NOW. WE NEED PATIENTS OF IMAGING MODALITIES FOR THE STRUCTURES WHERE RELATIVE MOTION SAY PROBLEM. I THINK BEING ABLE TO MONITOR CELL ACTIVITY IN REAL TIME. A BIG FOCUS OF THE SPARK INITIATIVE IS ADDITIONAL TOOLS FOR STABLE CHRONIC ELECTROPHYSIOLOGY TO MONITOR IN REAL TIME WITHOUT CAUSING INJURY TO NERVES AND EXPANDED TOOL KITS AND I THINK AS WE SEE THE TALKS WE CAN START TO THINK ABOUT HOW THESE CAN ALL WORK TOGETHER TO PROVIDE OPPORTUNITIES IN STUDYING INTEROCEPTION. THANK YOU. >> THANKS VERY MUCH. I'M GOING IT TALK ABOUT LOWER URINARY TRACT FUNCTION BUT OPPOSITE OF WHAT DR. GERREAU TALKED ABOUT AND WHAT'S AN ESSENTIAL PART OF THE BLADDER EMPTYING. AND THE LACK OF THE PROPER FEEDBACK LEADS TO TOO LITTLE ACTIVITY IN THE BLADDER. BEFORE I GET STARTED I'M REQUIRED TO MAKE A FINANCIAL DISCLOSURE I'M AN INVENTOR ON SOME PATENTS I'LL TALK ABOUT TODAY. THE CLINICAL CONDITION I'LL TALK ABOUT AND COME BACK TO IN THE END WITH TRANSLATIONAL WORK IN HUMANS AND THE CONTRACTOR MUSCLE OF THE BLADDER AND THERE'S INDIVIDUALS ACROSS A RANGE OF DISORDERS THAT HAVE A LACK OF CONTRACTION OF THE BLADDER. AND WE UNDERSTAND VERY LITTLE ABOUT THE PATH OF PHYSIOLOGICAL BASIS FOR THE ACTIVITY. I'LL DESCRIBE TO YOU TODAY, FIRST A SERIES OF STUDIES WHERE WE ESTABLISH A ROLE FOR YOU'RE EITH EITHER -- URETHRA ACTIVITY AND TAKE THE FEEDBACK TO TREAT THE ACTIVITY. SO THIS A BRIEF OUTLINE OF WHAT I'LL GO THROUGH. FIRST THE FEEDBACK THAT COMES FROM THE URETHRA THAT IS RESPONSIVE TO FLOW. AND WHEN THE FEEDBACK IS DISRUPTED EITHER BY ANESTHESIA OR NERVE DAMAGE A WAY TO RESTORE THE FUNCTION FOR BLADDER EMPTYING. THIS IS DATA IN AN ANESS A ANESTHETIZED RAT AND DATA ON THE RIGHT STILL MAKES THE POINT. WE SHOW THE AVERAGE SIGNAL OF THE NERVE ACTIVITY AS A FUNCTION OF TIME. AND AS WE'RE FLOWING FLUID THROUGH THE URETHRA AT LOW FLOW RATES. AS WE INCREASE THE FLOW RATE AS THE COLORS GET HOTTER, YOU GET A LARGER AND LARGER RESPONSE. WE HAVE A FLOW THROUGH THE URETHRA. WE'VE DONE A SIMILAR EXPERIMENTS IN CAT. HERE'S THE RAW RECORDING. AND THE FLOW RESPONDS. IF WE ANESTHETIZE THE AFERENCE YOU NO LONGER GET A NEURAL RESPONSE AND IF WE FILL THE BLADDER SO THE ANNAL -- ANIMAL VOIDS REFLEXIVELY AND THIS IS THE VOIDED VOLUME AS A FUNCTION OF TIME. AT THIS POINT THE ANIMAL IS VOIDING, THERE'S ACTIVITY IN THE SAME NERVE. SO THE NERVE IS RESPONDING TO THOSE FLOW THROUGH THE URETHRA THAT'S OCCURRING DURING A VOIDING CONTRACT. THIS SHOWS THE DISTAL URETHRA IN THE CAT AND YOU CAN SEE THE VAST ARRAY OF INNERVATION ALONG THE YOU' URETHRA AND WE SEE THIS ALONG THE WALL AND IF YOU LOOK AT CROSS SECTION THEY LOOK LIKE GIGANTIC CORPUSCLES. WE DON'T KNOW WHAT THEY ARE BUT THAT'S WHAT THEY LOOK LIKE SO THERE'S A SUBSTRATE TO REGULATE THE FLOW RATE SIGNALS. SO FEEDBACK FROM THE SIGNALS FLOW. NEXT, WE WANTED TO ESTABLISH THE FLOW SIGNAL'S ACTUALLY IMPORTANT. SO WHAT WE DID IS A SERIES OF EXPERIMENTS WHERE WE DISRUPTED FLOW BY TRANSSECTION IN THIS EXPERIMENT OR BY URETHRA ANESTHESIA. AND IF YOU SLOWLY FILL THE BLADDER IT CONTRACTS AND EMPTIES AND WE CAN MEASURE HOW MUCH COMES OUT AND IS THERE AND IT GIVES A MEASURE HOW EFFICIENTLY THE ANIMAL IS VOIDING. THEN WE SIMPLY TRANS SECTED THIS NERVE AND NOW YOU SEE THE BLADDER CONTRACTIONS ARE MORE PALTRY AND CLOSELY SPACED SO YOU REACH THE THRESHOLD SOONER. YOU CAN LOOK AT THE CONTROLLED CONDITIONS UNDER ANESS SHEESH YA YOU GET ABOUT -- A AESTHESIA YOU GET ABOUT 75% AND IF YOU DO A BILATERAL TRI SECTION YOU GET A LOWER AMOUNT AND THIS IS FOR EFFICIENT VOIDING. THIS IS THE SAME KIND OF EXPERIMENT EXCEPT WEIN SPILLED LOCAL -- EXCEPT WE INSTILLED ANESTHESIA AND AVOIDING EFFICIENCY OF 75% AND FOLLOWING THE ADMINISTRATION OF THIS CONFIRMED THE FLOW RESPONSIVE AFFERENTS ARE IMPORTANT TO EFFICIENT VOIDING. SO WE'RE INTERESTED IN TRYING TO UNDERSTAND WHAT MIGHT WE BE ABLE TO DO ABOUT THIS BECAUSE OUR CLINICAL COLLEAGUES EXPRESSED A GREAT DEAL OF FRUSTRATION WHEN THEY HAVE A PATIENT WITH UNDER ACTIVITY THERE'S NO THERAPY THEY CAN OFFER TO THAT PATIENT. SO WE WANTED TO DETERMINE WHETHER PERHAPS WE COULD USE PERIPHERAL NERVE STIMULATION BY AMPLIFYING THE FEEDBACK COMING FROM THE URETHRA. SO THE IDEA WAS TO ELECTRICALLY STIMULATE THE AFFERENTS AND ACTIVATE THE AUGMENTING REFLEX WHERE THE FEEDBACK SIGNAL WOULD FURTHER EXHIBIT THE SPHINCTER TO FACILITATE BLADDER EMPTYING. WE USED THE SAME ANESS THETTIZED ANESTHETIZED RAT MODEL AND THEN WE DO A UNILATERAL SENSORY NERVE TRANSSECTION. YOU GET THE PALTRY BLADDER CONTRACTIONS MORE CLOSELY SPAFD BECAUSE THEY'RE NOT -- SPACED BECAUSE THEY'RE NOT VOIDING EFFICIENTLY AND WE'RE REPLACING THE FEEDBACK WE DISRUPTED BY NERVE TRANSSECTION. IF WE CHANGED THE PARAMETERS WE CAN TRUNCATE THE VOIDING CONTRACTIONS RATHER THAN PROLONG THEM. WHAT'S ILLUSTRATED HERE IS THE PROPORTION OF VOLUME THE ANIMAL VOIDED UNDER CONTROL CONDITIONS FOLLOWING UNILATERAL TRANSSECTION AND WITH STIMULATION AND WE CAN DOUBLE THE VOIDING EFFICIENCY THAT WAS THERE. THIS APPEARS THAT ELECTRICAL STIMULATION OF THE FLOW RECEPTIVE AFFERENTS MAYBE A WAY TO AMPLIFY BLADDER CONTRACTIONS AN INCREASE VOIDING EFFICIENCY WITH THOSE INDIVIDUALS WITH UNDERACTIVITY. AND GIVEN THE APPROACH, THE YOU'RE -- URETHRA IS ACCESSIBLE AND WE TOOK A SERIES OF ELECTRODES AND WE DEMONSTRATE THROUGH A SERIES OF PRE-CLINICAL EXPERIMENTS WHERE WE CAN VALIDATE WE CAN PASS THIS INTO THE URETHRA AND ELECTRICALLY ACTIVATE THE AFFERENTS. IT'S A MINIMALLY INVASIVE WAY TO TRANSLATE TO HUMANS. FOLLOWING THE IRB REVIEW AND INFORMED CONSENT THE WOMAN WITH THE UNDER ACTIVITY ONLY VOID ABOUT 150CCs AND MOST OF YOU IF YOU'RE IN A NORMAL PLACE YOU COULD VOID 400 OR 500CCs AND IS VOIDING INEFFICIENTLY AND SHE'S ON PROPHYLACTIC ANTIBODIES BECAUSE THE CONTINUOUS VOLUME OF URINE IS A CONTRIBUTOR TO FREQUENT URINARY TRACT INFECTIONS. AND THIS IS WHERE ON THE TRIAL WE HAPPEN TO DELIVER STIMULATION DURING VOIDING AND ON THIS TRIAL WE DID NOT AND IF WE DID THIS IN A RANDOM ORDER WE MEASURED THE AREA UNDER THE CURVES DURING THE VOIDING BLADDER CONTRACTIONS. THAT'S WHAT'S ILLUSTRATED UNDER HERE WITH FOUR TRIALS UNDER CONTROLLED CONDITIONS AND DURING STIMULATION. YOU SEE IN EVERY CASE WE CAN AMPLIFY THE AREA UNDER THE BLADDER CONTRACTION CURVE LIKE WE SAW IN THE PRE-CLINICAL EXPERIMENTS IN RATS. BUT IT HAS VARIABLE AFFECTS ON HER VOIDING EFFICIENCY. AND THESE ARE FOUR TRIALS. IN THESE TWO SHE'S VOIDING LESS THAN 10% OF THE VOLUME IN HER BLADDER. IN ONE CASE STIMULATION HAS NO EFFECT. HERE IT HELP. HERE SHE VOIDED ABOUT 40%. NO AFFECT OF STIMULATION AND HERE SHE'S VOIDING EFFICIENTLY WITH NO STIMULATION. IT'S A CLEAR CHALLENGE OF TRYING TO STUDY AN INTERVENTION WHERE THIS MUCH VARIANCE OF TRIAL TO TRIAL. IF YOU WERE TO PARTICIPATE YOU HAVE ALL THE SCIENTISTS STANDING AROUND WATCHING YOU. THERE'S CLEARLY AN OPPORTUNITY TO PERHAPS USING SOME IMPLANTABLE DEVICES TO PERHAPS REDUCE THE EXTRA RECEPTIVE WAYS TO VOIDING. AND HERE'S THE COMPONENTS I TOLD YOU ABOUT. THERE'S THE URETHRA FLOW SIGNALS AND I'VE ADDED QUESTIONS THAT HAVE COME UP. WHAT AND ARE THE AFFERENTS? ARE THEY RESPONSIVE TO FLOW OR DISTENSION OF THE URETHRA? DO THE CHANGE IN HUMANS WITH VOIDING DYSFUNCTION? IS THERE A ROLE OF SIMILAR FEEDBACK. WE HAVE ALL A REFLEX WHERE YOU COUGH OR JUMP AND YOU HAVE A CONTRACTION OF THE SPHINCTER SO YOU DON'T VOID. MIGHT THE SAME RECEPTORS BEING INVOLVED AND IS THERE A ROLE FOR VOIDING DYSFUNCTION AND IN TERMS OF TRANSLATION, WHAT ARE THE APPROPRIATE PARAMETERS FOR STIMULATION AND THINKING ABOUT BEYOND THE SIMPLE CATHETER APPROACH IN THE LAB HOW MIGHT WE INVESTIGATE THIS IN HUMANS. THANK YOU. >> HI. THANK YOU TO THE ORGANIZERS FOR THE INVITATION. IT'S A REL -- HEAL -- REAL HONOR AND AS SOMEONE WHO STUDIES INTERSECTION IN HUMANS, MY PARTICULAR CHALLENGE IS HOW BEST TO CHARACTERIZE INDIVIDUAL DIFFERENCES IN INTEROCEPTION. IN ORDER TO DO THIS COMPREHENSIVELY I TOGETHER WITH OTHERS DELINEATED AN INTEROCEPTION ACROSS DIFFERENT DIMENSIONS. THESE RANGE FROM THE AFFERENT SIGNALS TO THE SIGNAL AND HOW IT CAN CHANGE STIMULUS PROCESSING TO THE ACCURACY WITH WHICH THE SIGNALS CAN BE DETECTED. THE BELIEF ON THE ACCURACY AND A MEASURE ON HOW ACCURATE THAT IS AND HOW HIGHER ORDER MEASURES LIGHT, EXECUTION AND ATTRIBUTION OF THE SIGNALS. WE CAN TEST ALL THESE IN THE LAB AND THEY'RE IMPORTANT BECAUSE THEY ARE IN INDIVIDUALS AND LATCH ON TO COGNITIVE AND EFFECTIVE PROCESSING AND WE NEED MORE TECHNOLOGY TO GUIDE US IN THE CONCEPTUAL DISTINCTIONS BETWEEN THESE THINGS AND I'D LIKE TO TALK ABOUT THE WORK LEADING THE WAY IN THE INTEROCEPTION ROAD MAP PAPER DEVELOPING A TAXONOMY OF INTERSECTION. AND IN LOOKING AT THE DIFFERENT DIMENSIONS, WE LOOKED AT BEHAVIORAL MEASURES AND WE MONITOR HEARTS AND/OR BREATHING AND SEE HOW ACCURATELY THEY CAN DETECT WHEN THEY'RE HEART IS BREATHING AND A BEHAVIORAL MEASURE OF BEING INTERCEPTIVELY ACCURATE AND WHEN WE LOOK AT THE PROCESSES. IT DOESN'T MAP ON TO HOW ACCURATE THEY ARE. THE OTHER IS SUBJECTIVE BELIEF RELATIVE TO ACCURACY AND WE CAN SEE HOW THEY MAP TOGETHER. AND FORGIVE THE MESSY DATA BUT THIS IS DATA IN 80 INDIVIDUALS AND WHEN YOU LOOK AT THEM TOGETHER IT DOESN'T CORRESPOND TO SELF-REPORT WHICH DOESN'T CORRESPOND TO MEDICAL INSIGHT. ONLY WHEN YOU DIVE DIVIDE THEM IN HIGH ACCURACY DO YOU SEE THE DIMENSIONS ALIGNED AND EVEN THEN ALIGNMENT ISN'T ABSOLUTE. THAT'S WHAT'S INTERESTING ABOUT INTERTR INTEROCEPTIVE INSIGHT. AND WE CAN LOOK AT BODILY ACCESS AND WE LOOKED AT CARDIOVASCULAR PERCEPTION AND TIMING WITH HEART BEATS AND YOU CAN GET PEOPLE TO COUNT THE HEART BEATS. IT'S SIMILAR BUT WITHOUT INTERFERENCE AND YOU CAN ALSO DO JUDGMENT WHERE PEOPLE HAVE TO MAKE JUDGMENTS ABOUT WHETHER THEY'RE HEART IS SYNCHRONIZED AND LOOKED AT PAIR DIMES WHERE WE GET PEOPLE TO BREATHE AND WE HAVE FILTERS ON TO THE TUBE AND WE CAN SEE THE ACCURACY OF WHICH THEY CAN DETECT THE PRESENCE OF HIDDEN FILTERS. WE CAN THAN LOOK AT THE CORRESPONDENCE OF AXISES AND WE CAN LOOK AT CARDIAC RELATED TO OTHERS AND WE DID NOT FIND CARDIAC TOCK -- TO BE RELATED TO OTHERS AND WE CAN TAKE THE TESTS INTO PATIENT SAMPLES. THIS IS INDIVIDUALS WITH AUTISTIC SPECTRUM CONDITIONS AND AUTISTIC INDIVIDUALS RELATIVE TO A CONTROL GROUP. WE FIND THE AUTISTIC INDIVIDUALS HAVE THE CAPACITY TO BE INTEROCEPTIVELY ACCURATE AND IF YOU ASK THEM HOW GOOD DO YOU THINK YOU ARE AT DOING THE TASKS AND HOW FREQUENTLY ARE YOU AWARE THEM THERE'S HIGH SELF-REPORT MEASURES AND THERE'S A LOOK AT THE ACCURACY AND BELIEF. AND THE INTEROCEPTIVE ACCURACY IN AUTISM HAS BEEN REPLICATED IN CHILDREN AGED 6 TO 18 INDICATING SOMETHING HAPPENS EARLY ON. THE AUTISM LITERATURE I'D BE HAPPY TO TALK ABOUT IN THE SESSION IF IT COMES UP. WHAT WE'D LIKE TO SAY IS WHEN YOU LOOK AT THESE MEASURES OF ACCURACY BY DISBELIEF YOU CAN GET AN ERROR SCORE. HOW GOOD PEOPLE THINK THEY DID THE TEST RELATIVE TO THE ABILITY AND YOU CAN SEE THE DIFFERENCE YOU CAN SEE THIS IS AN INCREASE IN PERCEPTION THAT YOU'RE GOOD AT THIS AND PREDICTS ANXIETY. IF YOU'RE HEART IS POUNDING YOU'RE GETTING THE SIGNALS BUT NOT ABLE WITH CORRECTLY WITH PRECISION DETECT THE SIGNALS AND THIS GETS MISDIRECTED AS ANXIETY AND THERE'S A HYPOTHESIS WHERE INTEROCEPTIVE ACCURACY CAN REDUCE ANXIETY. USING THE SIMPLE CARDIAC INTEROCEPTIVE TESTS AND WE'RE INTERESTED IN THE GOLD STANDARD OF THE HEARTBEAT DISCRIMINATION TESTS AND LOOKING AT INTERNAL, EXTERNAL INTEGRATION TASK AND PEOPLE TEND TO LOOK AT THIS MEASURE. SO THAT'S OUR MEASURE OF INCREASED INTERCEPTIVE ACCURACY. IN ORDER TO SEE WHETHER WE COULD CHANGE INDIVIDUAL'S INTEROCEPTIVE ACCURACY AND WE DID A STUDY IN HEALTHY CONTROLS WHERE WE TAKE BASELINE ANXIETY AND SELF-REPORTS SCALE AND WE DO INTEROCEPTIVE FEEDBACK TRAINING WITH THESE INDIVIDUALS. HERE WE DID SIMPLE MANIPULATIONS WHERE WE GET THEM TO DO EXERCISE AND YOU ALL FEEL THE HEARTBEAT MORE STRONGLY I PRESUME IF YOU'VE DONE EXERCISE AND WE GET PEOPLE TO DO STAR JUMPS OR RUNNING AND THEN THEY FILL THEIR HEART BETTER. WE THEN DO THE INTERCEPTIVE TASKS AND GET FEEDBACK WHETHER THEY'RE CORRECT OR INCORRECT AS THE HEART RATE COMES BACK DOWN TO BASELINE AND THE SIGNAL GETS BIGGER. IT REMAINS IN THE INTERCEPTIVE CHANNEL AND AFTER YOU'VE REPEATED THIS A FEW TIMES YOU DON'T NEED TO DO ANYTHING TO HEIGHTEN THE HEART RATES. THEY CAN JUST REST AT BASELINE AND ARE ABLE TO TAP INTO THIS. AND WE FIND THAT IN THIS GROUP THAT THE HEARTBEAT TRACKING IS SIGNIFICANTLY ENHANCED AND HEARTBEAT DISCRIMINATION SO THE SYNCHRONICITY JUDGMENT IS INCREASED. WE SEE REDUCTIONS IN ANXIETY AND FIND THEY'RE COUPLED TO IMPROVEMENTS IN BOTH THE TRACKING AND DISCRIMINATION. SO INCREMENTAL ACCURACY INCREASES ARE COUPLED TO [INDISCERNIBLE] IN ANXIETY AND I'D LIKE TO HIGHLIGHT WHEN WE GIVE A SELF-REPORT MEASURE WE ALSO FIND NOT WORRYING AND ATTENTION REGULATION COMPONENTS ARE RELATED TO THE DROP IN ANXIETY AND THIS HAS BEEN RAISED ALREADY WHICH IS IF YOU PERCEIVE YOUR HEARTBEATING, YOU DON'T WANT TO WORRY ABOUT IT. HAVING HEIGHTENED INTEROCEPTIVE ACCURACY INTO THAT CHANNEL BUT NOT HAVING AN ATTRIBUTION WHERE YOU WANT TO PANIC ABOUT IT IS NECESSARY. ALSO TENSION REGULATION. YOU DON'T WANT PEOPLE OVERLY ATTUNED TO THE BODY. ANXIETY IS OFTEN COUPLE WITH A SELF-DIRECTED FOCUS AND YOU NEED THEM TO REFLEXIVELY BETWEEN THE TWO AND WHEN I RUN IT IN A CLINICAL TRIAL WITH AUTISM WITH BRAIN SCANS BEFORE AND AFTER TO LOOK AT INTERCEPTIVE ACCURACY AND HOW IT'S COUPLED TO BRAIN ACTIVITY IN PARTICULAR THE INTERIOR AND INSULAR. WHILE IT'S NOT YET COMPLETED WE HAD REPORTS FROM PEOPLE WITH AUTISM WHO COMPLETED IT AND THE CHANNEL GETS CLEARER AND THE OUT CHANNEL GET MORE QUIET AND WHEN I NOTICE THE IMPACT OF ANXIETY I'M ABLE TO ASSURE MYSELF IT'S JUST A PHYSICAL REACTION AND ABLE TO SLEEP DEEP BREATHS INSTEAD OF LETTING ARE THE SPIRAL AND ARE ABLE TO ENGAGE IN REGULATION STRATEGIES. THERE'S A SUGGESTION THIS MAY EX EXTRAPOLATE TO KNOW WHEN THEY'RE HUNGRY. WE CAN LOOK AT AFFERENT SIGNALS EXPRESSED IN BRAIN. THIS IS ANOTHER MEASURE OF INTERCEPTION BY COUPLING THE BRAIN ACTIVITY WITH BODILY SIGNATURES. AND THERE'S WONDERFUL WORK IN PARIS LOOKING AT STOMACH/BRAIN SYNCHRONY AND LOOK AT AFFERENT SIGNALS EXPRESSED IN BRAIN AND I'M RUNNING OUT OF TIME AND YOU CAN ALSO FOR EXAMPLE LOOK AT STIMULATION SUCH AS RECTAL STIMULATION RELATIVE TO ANAL AND LOOK TO STIMULATION IN THE BRAIN AND THERE ARE WAYS OF LOOKING AT THE NEUROCORRELATES OF INTERCEPTION. ONE MAY BE MORE ANALOGOUS TO MINDFULNESS WHERE YOU GET PEOPLE TO FOCUS ON BODILY SENSATIONS. I WANT TO MAKE THE DISTINCTION IT'S NOT JU-- AND THE ACCURACY IS FOCUSSED WITH ACTIVE IN THE RIGHT INSULAR AND GRAY MATTER AND THAT REGION SO GETTING PEOPLE TO FOCUS ON THE BODY DOESN'T NECESSARILY TELL YOU WHETHER THEY'RE DOING IT ACCURATELY OR NOT. AND WE NEED TO BE ABLE TO MEASURE BOTH. IF YOU LOOK AT THE IMPACT AND YOU HAVE COVERED SOME OF THE STUDIES EARLIER IN THE KEY NOTES IF YOU TIME STIMULI TO PRECISE POINTS OF THE CARDIAC CYCLE, YOU CAN MAKE THEM COINCIDE WITH THE RECEPTOR ACTIVITY AND THIS ACTIVE HEART-BRAIN CHANNEL. AND PAIN PERCEPTION IS KNOWN TO BE REDUCED WHEN THE HEART IS BEATING. I EXTENDED THAT TO SHOW MEMORY IS ALSO IMPACTED. IF YOU SEE A WORD WHEN THE HEART IS BEATING RELATIVE TO INBETWEEN HEART BEATS YOU'RE LIKELY TO FORGET IT AND IT'S ALL PART OF THE PRESUMED INHIBITORY OF INTERFERING AFFECTS OF HEART BEATS IT'S CONTRASTED BY HEIGHTENED FEAR PERCEPTION WHICH CAN HAPPEN WHEN THE HEART IS BEATING AND THIS CAN MANIFEST IN TERMS OF NEUROMODULATION IN THE BRAIN. THIS IS WHEN YOU GET NEURAL ACTIVITY AND PROCESSING DIFFERING AS A FUNCTION OF THE TYPE OF STIMULUS YOUR PROCESSING AND IT'S REFLECTED IN NEURAL ACTIVITY MODULATIONS SPECIFICALLY IN THE INSULAR. LOOKING AT THE ACTIVE HEART/BRAIN CHANNEL AND THE DYNAMIC INTERACTION FOR IT TO CHANGE THE WAY THE STIMULUS PROCESSES, THEN YOU CAN TAKE THIS TO PATIENT POPULATIONS AND SEE HOW THESE AFFERENT SIGNALS ARE EXPRESSED IN THE BRAIN ALL TO STIMULUS PROCESSING SHOWING DIFFERENT PATTERNS GIVING US INSIGHT INTO MECHANISTIC ALTERATIONS IN THESE PATIENT POPULATIONS. SO INTEROCEPTION CAN BE DELINEATED ACROSS DIFFERENT LEVELS WITH OR WITHOUT CONSCIOUS AWARENESS AND THEY NEED TO BE MAPPED OUT AND UNDERSTOOD. SOME CORRESPOND AND OTHERS ARE DISASSOCIATED AND YOU CAN SEE GREATER DISASSOCIATIONS IN PATIENT POPULATIONS, FOR EXAMPLE, SUCH AS AUTISM. INTEROCEPTIVE INFORMATION CAN AFFECT BEHAVIOR AND NOT NECESSARILY AWARENESS AND MAPPING OUT HOW THEY MAP ON TO EMOTION AND COGNITIVE PROCESSING IS SOMETHING WE NEED TO UNDERSTAND IN A MORE SYSTEMATIC WAY. AND MEASURES ARE NEEDED IN THE LAB WITH THOUGHT TO WHAT THEY ARE ACTUALLY TESTING. ARE WE LOOKING AT THE INTEROCEPTIVE SYSTEM AND ALSO THE SIGNALS EXPRESSED IN THE BRAIN. AND COMPREHENSIVE NORMATIVE UNDERSTANDING OF INFECTION WILL ALLOW US TO LOOK AT ALTERATIONS ASSOCIATED WITH PHYSICAL AND MENTAL ILLNESS. I WOULD LIKE TO THANK MY MENTOR AND MAIN COLLABORATOR AND OTHER PEOPLE IN THE LAB AND THANK YOU SO MUCH. >> THANK YOU FOR HAVING ME HERE AND THANK YOU FOR LETTING ME SPEAK. THEY DECIDED I SHOULD ADD A COUPLE WORDS TO OTHER TECHNOLOGIES THAT WE USE IN pI WORK WITH HUMANS AND ALSO MENTION SOME OF THE COMPUTATIONAL METHODS BEING DEVELOPED I ALSO THOUGHT IT MADE SENSE BECAUSE I'M THE RAPPORTEUR AND I WANT TO REMIND US OF THE OBJECTIVES OF THE WORKSHOP. ONE OF THE OBJECTIVES IS TO IDENTIFY THE GAPS IN THE RESEARCH RELATED TO INTEROCEPTION AND TO DEVELOP NEW STRATEGIES AND RECOMMENDATIONS. I THINK WE'VE BEEN QUITE GOOD AT IDENTIFYING GAPS AND I WANT TO TALK A LITTLE BIT ABOUT THAT. WE HAVEN'T QUITE GOTTEN TO DEVELOPING STRATEGIES AND RECOMMENDATIONS AND IT'S SOMETHING MAYBE THE SESSION IS A GOOD WAY TO FOCUS ON THAT IN THAT IN PARTICULAR. THIS IS SESSION FIVE AND IT'S ABOUT METHODOLOGY AND TECHNOLOGY AND BIOMARKERS. WHEN I THOUGHT ABOUT AS A TOPIC THE FIRST QUESTION IS WHAT THE EXISTING OR THE NOVEL METHODOLOGIES AND TECHNOLOGIES WE HAVE IN INTEROCEPTION RESEARCH? AND WHAT'S AN OVERVIEW OF THAT BECAUSE WE ALL COME FROM A DIFFERENT ANGLE. THE SECOND QUESTION IS WHAT ARE THE METHODOLOGIES WE NEED IN ORDER TO CONTINUE THE TYPE OF WORK WE WANT TO DO TO ADVANCE WHAT WE'VE BEEN DOING SO FAR. AND FINALLY, WE KNOW ONCE WE IDENTIFIED THE GAP, WHAT WE WANT TO DO IS COME UP WITH A RECOMMENDATION OF STRATEGY TO BRIDGE THE GAP. SO I'M TRYING TO PUT SOME OF THE WORK WE DO INTO THE CONTEXT OF THE QUESTION. AS A FIRST QUESTION WHAT ARE EXISTING METHODOLOGIES AND TECHNOLOGIES. THEY'RE VERY DIFFERENT DIMENSIONAL APPROACHES YOU CAN TAKE. YOU CAN SAY THERE'S NON-HUMAN WORK AND WITH YOU HEARD ABOUT THIS IN THIS PARTICULAR SESSION BUT THERE'S RESEARCH ON HUMANS. YOU COULD DIFFERENTIATE METHODOLOGIES OR TECHNOLOGIES ON THE BASIS OF THAT AND THERE'S PURELY READOUTS OF MEASUREMENTS AND WE CAN USE MANIPULATIONS IN THE SYSTEM. WE ALSO NEED PERIPHERAL MEASUREMENTS AND IT MAKES THIS RESEARCH DISTINCT PERFECT -- FROM WHERE WE HAVE IMAGES AND IF YOU PUT THIS TO FRAMING THE APPROACHES AND IT GIVES AN OVERVIEW OF THE TECHNIQUES WE HAVE IN THE FIELD THAT WE SHOULD BE TALKING ABOUT. SO WE ARE BEHAVIORAL ASSESS MANIES WHICH ARE MEASUREMENTS IN ANIMALS AND WE HAVE MEASUREMENTS IN HUMANS WHICH SOMETHING SARAH JUST ALLUDED TO AND WE'LL TALK ABOUT E.G. AND I.E.G. THESE ARE THE READ OUTS BUT THEN ALSO HAVE MANIPULATIONS. ANIMAL RESEARCH IS SO MUCH MORE ADVANCED IN TERMS OF DEVELOPING MANIPULATIONS AND THERE'S GOOD REASON FOR THIS AND WE HAVE TO THINK ABOUT HOW WE CAN GET FROM THE REALLY INTERESTING TOOLS LIKE OPTOGENETICS LIKE WE HAVE IN ANIMALS TO GETTING TO UNDERSTANDING HUMANS BETTER. THE WAY WE TEND TO MANIPULATE IS USING THINGS LIKE T.M.S. AND WE HAVE PHARMACOLOGICAL STIMULATION AND THAT MAKES IT SPECIFIC TO INTEROCEPTION. AND NOW WE ALSO HAVE MEASUREMENTS OF THE PERIPHERY AND IT TURNS OUT WE HAVE MEASUREMENTS OF THE CARDIAC SYSTEM AND WE USED SKIN CONDUCTANTS AND ON THE OTHER HAND WE CAN MANIPULATE THE SYSTEM AND THERE ARE WAYS TO DO THIS. WE HAD A NICE PRESENTATION ABOUT USING VAGAL NERVE STIMULATION IN HUMANS TO MANIPULATE THE PERIPHERY AND VAGAL STIMULATION WE HADN'T HEARD ABOUT BUT IS AN INTERESTING TOOL AND BREATHING ASSISTANCE. THERE'S THE OVERVIEW OF THE PLAYGROUND WE HAVE AND SO THE QUESTION IS WHERE ARE THE GAPS IF WE THINK ABOUT METHODOLOGIES AND TECHNOLOGIES? THE GAP I THINK IS TRANS PLACE AND WHY DO WE NEED TRANSLATION? WELL ONE THING YOU CAN THINK OF TRANSLATION IS WE WANT TO TRANSLATE NON-HUMAN RESEARCH TO HUMAN RESEARCH BECAUSE THEN IT GETS INTO CLINICAL APPLICATIONS. SO WE ALREADY HAVE DISCUSSIONS AT THE PODIUM THERE ARE ANATOMICAL DIFFERENCES IN THE FUNCTIONALITY OF THE CIRCUITS. HOW DO WE BRIDGE THE GAPS BETWEEN DIFFERENT ANIMAL MODELS AND ONCE WE GO TO HUMAN RESEARCH. AND SIMILARLY THERE'S DIFFERENT METHODS A -- ALLUDED TO IN THE QUEUE AND WHEN WE LOOK AT REWARD LEARNING WE USE SIMILAR PARADIGMS ACROSS DIFFERENT MODELS. THIS COULD BE A GAP YOU CAN IDENTIFY AND BRIDGE IN FUTURE RESEARCH. ANOTHER THING I WANT TO ALLUDE TO AND SOMETHING MENTIONED AGAIN YESTERDAY IS WE ALSO NEED A GAP THAT YOU USUALLY DON'T HAVE TO DO IN NEUROSCIENCE BECAUSE YOU IGNORE THE BODY BUT HERE WE WANT TO BRIDGE THE GAP BETWEEN BRAIN AND BODY INTERACTIONS AND IT'S BILATERAL. WE SAID PERCEPTIONS SHAPE ACTION AND ACTION SHAPE PERCEPTION. WHAT WE WANT TO UNDERSTAND IS EFFECTS WE HAVE IN THE BODY CAUSES CHANGES AND WE HAVE LIMITED MEASUREMENT TOOLS IN THE PERIPHE PERIPHERY AND AT THE LEVEL OF THE BRAIN AND LIMITED TOOLS FOR MANIPULATION AND THE PROBLEM IS IF YOU LOOK AT THE CIRCUIT, IF YOU WANT TO UNDERSTAND THE INTERACTIONS WITHIN THE CIRCUITRY MANIPULATION IS KEY HOW ONE SYSTEM AFFECTS THE OTHER. I THINK THIS IS ONE OF THE GREATEST LIMITATIONS WE HAVE CURRENTLY AND WE HAD A CONVERSATION ABOUT CONSCIOUS AND SUBCONSCIOUS I WON'T GET INTO HERE. THERE'S ANOTHER GAP IN TRANSLATION WHERE WE GO FROM HEALTH TO DISEASE. EVEN IF WE UNDERSTAND THE SYSTEM AND A HEALTHY ANIMAL OR HUMAN, THE NEXT QUESTION IS HOW CAN WE IDENTIFY DYSFUNCTION AND MAKE THIS CLINICALLY USEFUL? FOR THAT, THAT FIRST OF ALL MEANS WE HAVE TO HAVE APPROPRIATE ANIMAL MODELS WHERE YOU CAN LOOK AT DISORDERS OR DYSFUNCTIONS RELEVANT TO HUMANS. ANOTHER IS ONCE WE GO TO LARGE-SCALE MEASUREMENTS THE SAMPLE SIZES TEND TO BE TOO LOW AND THAT'S NOT A PROBLEM OF INTEROCEPTION RESEARCH AND WE DON'T DO LONGITUDINAL LOOKS AND WE KNOW THE BODY FLUCTUATES AND IF WE DON'T REPEAT IT WE DON'T KNOW HOW RELIABLE THE MEASUREMENT IS AND ARE WE ASSESSING THINGS STABLE OVER TIME OR MEASURING A STATE RATHER THAN A FUNCTION AND IT'S SOMETHING WE NEED TO THINK ABOUT IN THE FUTURE. ALSO TO GO TRANSDIAGNOSTIC AND THE LABELS WE'RE USING IS NOT AS RELIABLE AS WE WANT THEM TO BE. WE WANT TO GO TRANS SECTIONAL AND LOOK AT SYMPTOMS BUT MAYBE NOT AT SPECIFIC DISORDERS BUT GO BEYOND THE DISORDER AND UNDERSTANDING THE INTERACTIONS IN GENERAL. THESE ARE THE GAPS I'VE IDENTIFIED AND HERE'S EXAMPLES HOW WE TRIED TO BRIDGE THE GAP IN THE WORK WE DO AND TO GIVE AN INDICATION OF THIS FROM A HUMAN PERSPECTIVE. ONE EXAMPLE I THINK ARE QUITE INTERESTING IS WE HAD A DISCUSSION ABOUT A LOT OF SIGNALS THAT HUMANS ARE NOT AWARE OF. FOR EXAMPLE, I'M NOT AWARE OF MY HEART UNLESS IT STARTS RACING AND THAT'S PROBABLY THE CASE FOR MOST OF YOU AND YOU PROBABLY ARE NOT AWARE OF THE BLADDER UNLESS YOU HAVE TO URINATE. IF YOU WANT TO MEASURE THESE THINGS MAYBE WE NEED READ OUTS THAT GO BEYOND SELF-REPORT. ONE IDEA IS TO LOOK AT SENSORY INPUTS AND HOW WE PERCEIVE THEM AND REGULATE THE BODY AND MEASURE THE SYSTEM OF THE BODY AND WE MEASURE SINGLE HEART BEATS. THEN INSTEAD OF ASKING PEOPLE WE USE THE BRAIN ACTIVITY OF A METRIC HOW YOU PERCEIVE YOUR OWN HEART. THERE IS A RESPONSE ASSOCIATED WITH THE PROCESS OF SINGLE HEART BEATS. AND WHAT IS INTERESTING IS HOW DO WE INTEGRATE THE INTEROCEPTIVE STIMULI ON A SUBCONSCIOUS LEVEL NOT CONSCIOUS LEVEL? WE LOOK AT HOW DO YOU COMBINE INTERNAL AND EXTERNAL STIMULUS AND YOU HEAR A TONE AND YOU SEE A SURPRISE SIGNAL IN THE CARDIAC DOMAIN. WE CAN USE TONES TO PREDICT THE NEXT HEARTBEAT AND USE HEARTBEATS TO PREDICT TONE AND YOU CAN USE E.E.G. ALL YOU NEED TO DO IS PASSIVE PROCESSING OF DIFFERENT TYPES OF INFORMATION. THIS IS ONE WAY TO GO FORWARD WITHOUT LOOKING AT SELF-REPORTS. IF YOU TRY TO INTEGRATE THIS YOU CAN WRITE DOWN FORMAL EQUATIONS OF THE AUDITORY VERSUS THE CARDIAC INFORMATION WHEN WE LOOK AT PEOPLE COMBINING THE INFORMATION AND YOU CAN USE COMPUTATIONAL MODELLING WHICH IS HOW WE USE THE INFORMATION IN THE BODY. THIS IS A BUSY SLIDE AND ALL TO SHOW YOU THERE IS YET ANOTHER WAY TO USE COMPUTATIONAL MODELS AND YOU CAN SAY THERE'S VARIABILITY IN THE NORMAL HEART RATE AND WE HAVE A LOT OF RESTING STATE DATA AND IF YOU THINK OF EVERY HEARTBEAT AS A STIMULUS EVENTS BUT SOMETIMES HEARTBEATS ARE VERY LONG AND WE SKIP A BEAT OR SOMETIMES THEY'RE SHORT. WE USE LEARNING MODELS ABOUT LOOKING INTEROCEPTIVE INFORMATION AND APPLY IT TO BRAIN DATA, IN THIS CASE E.E.G. DATA TO GET READ OUTS HOW MUCH YOU USE INTEROCEPTIVE INFORMATION. THIS IS DONE IN RESTING STATES. YOU CAN USE A RESTING STATE AND USE IT IN THE TASK IN THE INTEROCEPTIVE DOMAIN. AISLE TIMES IT'S -- A LOT OF TIMES WE CAN USE THE PHYSIOLOGY IN REACTIONS TO MODEL OUR DATA. ONE LAST THICK -- THING WE WANT TO LOOK AT BIOMARKERS AND THIS COMES FROM COMPUTATIONAL PSYCHIATRY AND THE IDEA IS HOW DO WE GET FROM HAVING THESE VERY SIMPLE ASSESSMENTS TO DEVELOPING BIOMARKERS. ONE IS WE HAVE COMPUTATIONAL ASSAYS AND THEY CAN BE ALGORITHMIC AND THEN I THINK THE NEXT STEP IS WE NEED TO DETECT SUBGROUPS AND DIMENSIONS THAT ARE DIFFERENT IN TERMS OF THEIR MECHANISM IN THE MECHANISM THAT WAS DEFINED BY US. ON THE BASIS OF THAT THEN THE BIOMARKER LOOKS AT INDIVIDUAL TREATMENTS OR PREDICTING INDIVIDUAL DEVELOPMENT AND SO FORTH. THIS IS WHERE WE WANT TO GO AND I THINK WE'RE FAR FROM THAT. SO TO END THIS, ONE OTHER RECOMMENDATION IN STRATEGY I THINK THIS IS ALL UP TO DISCUSSION THAT'S WHY I'M PUTTING IT OUT THERE BECAUSE THIS IS WHERE WE'RE STARTING NOW BUT I THINK WE FEED TO THINK ABOUT A COMBINATION OF BRAIN IMAGING PERIPHERAL MEASUREMENTS AND POTENTIALLY TO GET AT THING THAT ARE SUBCONSCIOUS IN HUMANS IF YOU WANT TO DO RESEARCH IN THIS AREA. AND USE COMPUTATIONAL MODELS AND THERE'LL BE A WORKSHOP TOMORROW ON COMPUTATIONAL MODELING AND HOW TO BRIDGE THE GAP BETWEEN HUMANS AND ANIMALS. FOR SOME INTERESTED YOU MAY WANT TO STAY ON A COUPLE DAYS. IN TERMS OF BIOMARKER RESEARCH WE NEED TO LOOK AT ASSESSMENTS AND CONDUCT LARGE-SCALE STUDIES THAT POTENTIALLY SPAN ACROSS MULTIPLE CENTERS. AND FINALLY I THINK WE NEED APPROPRIATE MANIPULATIONS AND ADD THE END WE'LL TALK ABOUT THE WAYS TO DO THIS IN HUMANS. THANK YOU. >> I'LL ASK THE SPEAKERS TO COME AND SIT IN THE FRONT TO GO STRAIGHT TO QUESTIONS. AFTER CHRISTOPH IS THROUGH. >> I DON'T HAVE SLIDES. I'LL JUST MAKE A FEW REMARKS. THANK YOU VERY MUCH TO MY CO-CHAIR, JIM, AND TO LISA AND OTHERS FOR THEIR BEAUTIFUL TALKS. I WANTED TO ADD FOUR COMMENTS FROM ANY PERSPECTIVE. I'M A SCHOLAR INTERESTED IN CONSCIOUSNESS AND HOW IT ORIGINATES FROM THE MOST COMPLEX PIECE OF HIGHLY EXCITABLE MATTER IN THE UNIVERSE, THE BRAIN AND HOW TO MEASURE IT AND TRACK THE FOOT PRINTS IN THE BRAIN OF HUMANS AND ANIMALS AND I'M THE HEAD OF A LARGE INSTITUTE WITH A LARGE PROJECT AROUND CELL TYPES WHERE WE TRY TO LOOK AT CONNECTIONAL ATLAS OF ALL CELL TYPES IN THE BRAIN OF THOSE MICE AND HUMANS USING POST MORTEM TISSUES AS WELL AS A SAMPLE. IT LEADS ME TO MY FIRST POINT. THERE'S EXCITEMENT IN THE COMMUNITY AND WE NOW HAVE A TECHNIQUE OR SERIES OF TECHNIQUES THAT ALLOWS US TO SEQUENCE A HIGH SCALE RELATIVELY INEXPENSIVELY USING A VARIANT OF TEN X AND USING SEQUENCE TECHNOLOGY USING MILLIONS OF NEURONS AND IDENTIFY SUBSETS OF NEURONS AND LOCATE THEM TO SPECIFIC PARTS OF THE BRAIN. THIS IS NOT ONLY INTERESTING FOR THE BASIC SCIENCE QUESTION FOR HUME CELL TYPES THERE ARE IN THE MOUSE AND HUMAN AND YOU SAW IN THE FIRST TWO TALKS IN OUR SESSION BY LISA AND BOB AND SAW FROM OTHER TALKS USING MOUSE MODELS, EVERY AREA OF THE BRAIN MAYBE EXCEPT THE THALAMUS BUT CERTAINLY IN THE BRAIN STEM AND HYPERTHALAMUS AND MEDULLA AND CORTEX CONTAINS 50 TO 100 CELL TYPES AND IT'S PHYSIOLOGICAL CELL TYPING AND MORPHOLOGICAL CELL TYPING AND THIS IS NOT DISTINGUISHING BECAUSE THE TECHNOLOGY IS STILL IN THE INFANCY. IF YOU DO THE CONSTRUCTION OF SINGLE NEURONS WHERE THEY SEEM TO BE TRANSCRIPTIONAL IDENTICAL MAY HAVE DIFFERENT CELL TYPES. SO IF IT'S TRUE WE HAVE A BRAIN THAT CONSISTS OF 1,000 OR 2,000 CELL TYPES IT'S OF THE VASTLY MORE MAN THE ELEMENTS THAT MAKE UP THE VISIBLE MATTER. IT'S DAUNTING. ON THE OTHER HAND IT GIVES US POWERFUL TOOLS BECAUSE WE'RE GOOD AT A COMMUNITY IN THE MOUSE AND OTHER ANIMALS LIKE THE RAT AND NON-HUMAN PRIMATES TO BUILD TOOLS AND WE CAN BUILD TOOLS AND WE CAN IDENTIFY SPECIFIC SUBSETS OF NEURONS AND ONCE WE CAN IDENTIFY THEM WE CAN LABEL THEM AND LABEL THEM LONG TERM OR LABEL THEIR POST-SYNAPTIC OUTPUT AND TURN THEM ON OR OFF WITH PRECISION OR USING OPTOGENETICS OR USING CHEMO GENETICS. AND SO WE NEED TO DO THE SAME THING. THIS IS ALL DONE FOR THE C.NS. AND WE SHOULD DO THE SAME THING THROUGHOUT THE ENTIRE BODY DOING A GENERAL ATLAS SO WE KNOW HOW MANY CELL TYPES ARE THERE IN THE GUT USING SOME COMMON STANDARDS AND THEN BUILD TOOLS AROUND THOSE AS WELL AS A LARGE-SCALE CONNECTION AND WE HAVE MEASUREMENTS IN PLACE IN THE BODY WITH ALL IS THE ORGANS SO WE CAN SEE IN FULL THE ENTIRE WIRING IN THE BODY NOT JUST THE BRAIN ITSELF. I THINK IT'S IMPORTANT WE TAKE ADVANTAGE AS A COMMUNITY OF THESE POWERFUL TOOLS THE BRAIN INITIATIVE IS MAKING AVAILABLE. SO WE HAVE PEOPLE THESE VERY POWERFUL TOOLS TO HOPE US UNDERSTAND WHAT NEURONS ARE INVOLVED AND TURN THEM ON AND OFF WITH HIGH PRECISION. THERE WAS ONE SLIDE ON NON-HUMAN P PRIMATES AND WE HAVE LOOKED AT CIRCUIT AND CELL TYPES INVOLVED IN SPECIFIC BEHAVIORS BUT WE'RE NOT JUST OVERGROWN MICE. IT'S NOT JUST TRUE OUR BRAIN IS BIGGER SO WE TAKE THE MOUSE BRAIN AND AMPLIFY IT AND WE GET A HUMAN BRAIN. AS PETER POINTED OUT THERE'S MANY STRUCTURES THAT THAT ARE VERY DIFFICULT TO IDENTIFY OR ARE NOT PRESENT IN RODENTS. I THINK WHAT'S CRITICAL AND I CAN SAY THIS UNBIASSED WE NEED TO PUT MORE EMPHASIS ON NON-HUMAN PRIMATES THE NEW WORLD OR OLD WORLD MONKEY AND THE DIFFERENCE BETWEEN US AND THEM IS LESS THAN US AND MICE. AND THERE WAS A WONDERFUL SUMMARY OF THE TECHNOLOGY WE NEED AND TECHNOLOGY FOR ANIMALS IN THE PERIPHERY WHERE IT'S DIFFICULT TO RECALL BECAUSE OF ALL THE MOTION AND IT'S A GREAT CHALLENGE TO DO ELECTRICAL RECORDING WITH NEWER PIXELS. THE LAST THING I WANTED TO EPHASIZE COMES FROM 150 YEARS OF PSYCHOLOGY. SINCE THE PSYCHO PHYSICS WAS DEVELOPED FIRST IN THE MID TO LATE 19th CENTURY IN GERMANY AND SO FOR THE LAST 50 YEARS WE'VE NOW DEVELOPED A POWERFUL TOOLS AND METHODS AROUND SIGNAL DETECTION AND IT ALLOWS US TO MANIPULATE WIRTH GREAT PRECISION -- WITH GREAT PRECISION STIMULI AND VISUAL AND AUDITORY STIMULUS. AND WE CAN MAP. WE HAVE A WHOLE SLEW OF MEASURES AND OBJECTIVE AND SUBJECTIVE MEASURES AND THEY MAP NICELY AND REDUCIBLE ONTO EACH OTHER AND WE HAVE AWARENESS SCALES AND CONFIDENCE MEASURES AND METACONFIDENCE MEASURES, TASKS. THERE'S A LARGE SET OF ILLUSIONS WE CAN TAKE ADVANTAGE AND NEGATIVITY PARADIGM AND IT'S IMPORTANT WE BEGIN TO USE THOSE TECHNIQUES IN RESEARCH BECAUSE THEY'RE POWERFUL. FOR EXAMPLE, THE VISUAL DOMAIN, I CAN SHOW YOU THINGS THAT ARE PERFECTLY VISIBLE TO THE RIGHT EYE BUT IF YOU PRN -- OPEN BONG EYES AND IT CAN BE INVISIBLE FOR MINUTES AT A TIME AND THERE'S VISUALLY LUTIONS. I THINK WE AVAIL OURSELVES OF THE VISUAL ILLUSIONS IN THE RECEPTIVE DOMAIN. KNOW ONE VISUAL ILLUSION. YOU WANT TO KNOW WHAT IT IS? IF YOU GO TO THE MUSEUM OF SCIENCE IN JAPAN THERE'S BEEN SET UP A POWERFUL PERFORMANCE ART SO WHEN YOU GO TO THE MEN'S BATHROOM, THE USUAL URINALS WHERE YOU PEE AND THEN THERE'S THIS WINDOW AND IT LOOKS LIKE IT'S A CLEVER SET OF WINDOWS AND IT LOOKS LIKE PEOPLE ARE DIRECTLY LOOKING DOWN AT YOU. YOU KNOW THIS IS AN ILLUSION BUT IT'S IMPOSSIBLE TO OVERCOME AND YOU HAVE TO CLOSE YOUR EYES AND FORGET THAT BEFORE YOU CAN VOID. IT WOULD BE WONDERFUL IF WE CAN USE MORE OF THOSE TECHNIQUES. AND IT ALLOWS US TO HAVE SELECTI SELECTIVE ATTENTION. I CAN PAY ATTENTION TO SOMETHING OVER THERE WHILE MY EYES SEE SOMETHING OVER THERE. I CAN DISASSOCIATE FROM WHERE I LOOK TO WHERE I PAY ATTENTION AND IT'S WIDELY ACCEPTED THAT PAYING ATTENTION TO SOMETHING HAS POWERFUL EFFECTS IN THE BRAIN AND THE SIGNAL BECOMES TONE AND THE SIGNAL BECOMES ENHANCED AND IT'S DIFFERENT FROM BECOMING CONSCIOUS. YOU CAN DISASSOCIATE AWARENESS AND ATTENTION AND THIS IS IMPORTANT IN ADDRESSING THE CONSCIOUS AND IT'S IMPORTANT WE TAKE THOSE TECHNIQUES FROM OTHER AREAS THAT HAVE BENEFIT FROM 150 YEARS OF STUDIES. WITH THAT, LET'S START OUR DISCUSSION OR DEBATE. >> ANY OTHER DELUSIONS WE CAN TALK ABOUT? >> WE CAN MANIPULATE IT DYNAMICALLY. IN THE KYOTO MUSEUM YOU EXPECT PEOPLE CAN SEE YOU AND IN THE EXPERIMENTS WE USE WE DO PLACEBO CONTROLS AND YOU CAN LOOK AT THE DIFFERENCE BETWEEN A PRESENTATION OF A KNOWN SIGNAL OR KNOWN STIMULUS WITH A KNOWN IMPACT ON VISCERAL SIGNALS RATHER THAN VISUAL AND SEE THE DIFFERENCE DURING THE PLACEBO OR INSERT EXPERIENCE AND WE HAVE SEEN NERVOSA AND THEY CAN FEEL SOMETHING AND IT PROBABLY HAS TO DO WITH THE EXPECTATION. >> WE'VE LOOKED AT PROCESSING AND AFFECT. >> AND SARAH YOU TALKED ABOUT INTEROCEPTIVE ACCURACY VERSUS SELF-REPORT WHERE THEY GO OPPOSITE. WOULD THAT BE HELPFUL AS A WAY TO EVEN PINPOINT WHAT THE PROBLEM MAY BE? MAYBE IT'S NOT IN THE PERIPHERAL SENSORY BUT MAYBE MORE OF A BRAIN PROBLEM? >> TO ME IT'S ABOUT UNACCOUNTED FOR SIGNALS. YOU HAVE A BELIEF YOU'RE GOOD AT IT BUT NOT ABLE TO DETECT THE SIGNALS FOR POSITION YOU HAVE UNACCOUNTED FOR SENSORY SURPRISE. >> SO IT'S IN THE A CENTRAL PROBLEM? >> IT MAY BE REPRESENTED CENTRALLY BUT FOR ME IT'S MAPPING OUT THE LEVEL, BELIEF AND ACCURACY AND SEEING WHEN THEY ALIGN OR WHEN THEY'RE DIFFERENT. >> I GUESS I'M TRYING TO TRANSLATE THAT TO CIRCUITRY PROBLEMS. IT'S OKAY. I HAVE A QUESTION WHERE I DON'T KNOW IF YOU'RE AWARE OF A 2017 PAPER IN JAMA DEMONSTRATED ACUPUNCTURE COULD BE EFFECTIVE FOR URINARY INCONTINENCE AND I'VE BEEN INTRIGUED WHY ACUPUNCTURE WOULD BE USEFUL FOR THAT AND I'M CURIOUS WHY IT MAY BE TAPPING INTO PATHWAYS YOUR STIMULATION DEVICES MAY BE GOING FOR. >> WE'RE FOCUSSED ON THE OPPOSITE PROBLEM, NOT INCONTINENCE BUT RETENTION. IN THIS CASE WE KNOW WELL THE AFFERENTS WE'RE STIMULATING. I THINK IT'S QUITE DISTINCT FROM AN APPROACH LIKE THAT FROM WHAT YOU ARE INFLUENCING IN THE NERVOUS SYSTEM IS UNCERTAIN WHEREAS WITH THIS APPROACH WE KNOW WITH CERTAINTY WHAT WE ARE INFLUENCING. >> I WONDER IF THEY COULD CONVERGE. >> A QUESTION FOR SARAH. SO YOU TALKED ABOUT THE AFFECT OF STIMULI ON COGNITION AND EMOTION AND SO FORTH AND YOU ALSO DISCUSSED IMPROVING INTEROCEPTIVE ACCURACY. I WONDER IF THERE'S A LINK. FOR EXAMPLE, IF YOU HAVE IMPROVED INTEROCEPTIVE ACCURACY, DOES THAT MUTE THE FEAR RESPONSE THE ENHANCEMENT OF THE FEAR RESPONSE OR SOMETHING LIKE THAT. >> THESE ARE ABOUT THE DIFFERENT LEVELS OF INTERCEPTIVE AND I THINK IMPROVING THE ACCURACY WILL MAP MORE TO EMOTION PROCESSING. SO WHAT YOU CAN SEE IN PEOPLE WITH INDIVIDUALS WHO HAVE DIFFICULTY UNDERSTANDING THEIR OWN EMOTION THEY SEPT -- TEND TO HAVE THE ABILITY TO DETECT THE SIGNALS SO ENHANCING THESE SHOULD SEE A REDUCTION IN EMOTIONAL UNDERSTANDING OF SELF AND OTHER. WE REPRESENT THE EMOTIONS OF OTHERS AS WELL. WITHIN OUR AUTISTIC SAMPLE AS WELL AS MAPPING ANXIETY CHANGE WE'RE LOOKING AT CHANGES AND WE'RE ALSO DOING EMOTION PROCESSING ON AND OFF THE HEARTBEAT AND HOW THE CARDIAC SIGNAL MAY CHANGE. >> A QUESTION AND AFTER THE PANEL I HAVE TO ASK TO SARAH OR CHRISTOPH, SO THE INTEROCEPTION ALL THE SIGNALS COME FROM THE BODY TO THE BRAIN. I LIKE TO COMPARE THIS TO A SELF-DRIVING CAR WHICH GETS MASSIVE AMOUNTS OF INFORMATION FROM SENSORS AND CAMERAS AND RADAR AND WHATEVER. BUT ULTIMATELY THE INTERPRETATION OF THE INFORMATION IS MADE IN THE CAR'S COMPUTER IN THE SALIENT SYSTEM SO IT DOESN'T BRAKE EVERY TIME IT SEES SOMETHING BUT UNDER CERTAIN CONDITIONS. IF THE SETTING IS PERMANENTLY BIASSED IN A NEGATIVE WAY, THEY'D PUT ON THE BRAKES CONTINUOUSLY BECAUSE THEY SENSE TOO MUCH. IF YOU TAKE THE EXAMPLE OF PANIC DISORDERS AS A FORM OF ANXIETY THERE'S AN EXPLANATION OF THEORY AND EXPERIMENTS THAT SUPPORTS THE INCREASED AWARENESS OF SENSORY SIGNALS IS ONE OF THE TRIGGERS AND IT'S IN THE CONTEXT OF EMOTIONS ABOUT THE SENSATIONS THAT THEY'RE NEGATIVE. IF YOU DO THE SAME THING IN MINDFULNESS YOU HAVE THE IMAGE OF THE BUDDHA AND YOU'RE SAFE AND RELAXED AND IF THE BRAIN TAKE THE SAME INFORMATION BUT DOES NOT PUT ON THE BRAKES OR CUE THE ALARM BELLS. I DIDN'T HEAR IN THE PRESENTATIONS HOW MUCH IMPORTANCE THOSE CENTRAL FACTORS COULD BE EMOTION, SELECTIVE ATTENTION, MEMORIES, TRAUMATIC MEMORIES, HOW MUCH OF A ROLE THEY PLAY OPPOSED TO THE INFORMATION FROM THE BODY FROM THE PERIPHERY. THAT'S SOMETHING I'VE BEEN STRUGGLING WITH AND HASN'T BEEN ADDRESSED DIRECTLY IN THE DISCUSSIONS. >> SO WE CAN ASK THE QUESTIONS AND OF THE CELLS WE TRACED BACKWARDS TO GET A WHOLE SKELETAL CIRCUIT AND WE CAN LOOK AT IT AND MANIPULATE THE EXPERIENCE OR ENVIRONMENT OF THE MOUSE AND MAKE THEM LESS OR MORE STRESSED AND ASK HOW DOES THE ACTIVITY ACROSS THE CIRCUIT CHANGE. FROM WHAT WE LEARNED SO FAR FROM WHAT I SHOWED YOU IN THE BRAIN STEM DOWN NONE OF THOSE THINGS IMPACTED. ALL THE MODULATIONS YOU TALKED ABOUT WHICH ARE THE THINGS WE WORRY ABOUT AND AFFECT OUR HEALTH AND BEHAVIOR EVERY DAY, THOSE ARE ALL OCCURRING DEEPER IN THE BRAIN. TO LOOK FOR THEM IN THE MOUSE WE COULD MAYBE HAVE A MODEL OF WHERE TO LOOK AT THEM MORE SPECIFICALLY AND HOW WE CAN FOCUS IN ON THOSE THINGS IN HUMANS WHEN WE'RE IMAGINING BY DOING THE BASIC RESEARCH LIKE THAT WE CAN GET TO THE MORE COMPLICATED QUESTIONS OF HAVING THE COOL THINGS THAT BIND THE MIND WITH THE BODY. >> WE LOOKED AT THE EXPERIMENTS THAT CAN BE DONE IN THE MOUSE AND HUMANS IT'S A VISCERAL SIMULATION THAT IS NOT IN A PLEASANT, RELAXED CONTENT. IT'S NOT MEDITATING OVER YOUR STOMACH CONTRACTIONS OR WHATEVER. IT'S PERCEIVED AS NEGATIVE AND THIS HIGHLY RELATED BY PATIENTS WHO WE HAVE THAT ENHANCED SENSITIVITY AND YOU SEE GREATER ACTIVATION OF THE INSULA. YOU CAN SAY THEY HAVE AN INCREASED AWARENESS OF THEIR INTESTINE BUT IT'S A COMPROMISING THING FOR THEIR WELL BEING TO FEEL BLOATED ALL THE TIME AND HAVE SYMPTOMS. AS IT A CONDITION AND RESEARCH I FIND IT'S DIFFICULT TO PUT THE TWO THINGS TOGETHER. >> AND TO WHAT EXTENT THE INTEROCEPTION IS A BENEFIT TO PATIENTS AND YOU'RE SAYING VERY OFT OFTEN IT IS TO THEIR DETRIMENT? >> IN INDIVIDUALS 50% OF THE POPULATION WHO HAVE THE DISORDERS OF GENERALIZED HYPERSENSITIVITY TO VISCERAL AND SOMATIC EVENTS IT'S A BIG NEGATIVE THING. BUT ALSO THE IMPORTANCE OF THIS INTERPRETATION. AND IT'S ONCE IT COMES UP TO THE PREFRONTAL CORTEX THAT THAT INFORMATION IS NOT WHAT'S DETERMINED NECESSARILY FROM THE PATHWAYS THAT COME UP TO THE BRAIN. >> HOW IMPORTANT IS THAT FOR A CLINICAL SETTING? IS IT MORE IMPORTANT THAT YOU KNOW WHAT COMES UP TO THE THALAMUS OR IS IT MORE IMPORTANT WHAT AFFECTS US IN OUR EMOTIONAL STATE, ANXIETY, WELL BEING. >> I HAVE A SIMILAR QUESTION TO GIVE OF THOSE. IT SOUNDS LIKE WITH TRAINING THE ACCURACY OF DETECTION AND COGNITIVE AWARENESS DOESN'T. IT MEANS TO ME AND THERE'S MANY OTHER EXAMPLES OF SIMILAR TRAINING LIKE COGNITIVE OR SOCIAL SKILLS AND OTHER DISORDERS. YOU TRAIN THEM FOR THE SPECIFIC SKILLS BUT IT DOESN'T GENERALIZE IN CLINICAL OUTCOMES OR MAY GET WORSE. SO DO YOU HAVE COMMENTS ABOUT IT? >> SO I THINK A LOT OF IT IS ABOUT COMBINING THE QUESTIONS TOGETHER I THINK A LOT OF WHAT YOU MAY BE TALKING ABOUT IS ABOUT SELF-REPORT AND THE FEELING OF BEING HYPERSENSITIVE AND IT'S ALSO ABOUT HOW WE REFERENCE THE TERMINOLOGY. I THINK IF YOU LOOK AT THE PRECISION WITH WHICH THEY CAN DETECT THAT'S DIMINISHED. SO SENSITIVITY CAN BE LOOKED AT IN DIFFERENT WAYS. I THINK IT WOULD BE MOST DAMAGING WHERE WE SEE THE BELIEF OF BEING HYPERSENSITIVE IN THE ABSENCE OF ACCURACY IN POSITION TO THOSE. >> IF YOU ASK THEM LIKE ANXIETY YOU SEE HYPERACTIVATION OF THE INS LA -- INSULA AND YOU SEE HIRE REPORTS. >> MY QUESTION IS CONCERNING INTEROCEPTIVE SENSITIVITY AND SO FORTH. THIS MAY BE MORE A GAP IN MY OWN KNOWLEDGE THAN THE FIELD BUT TO WHAT EXTENT DO WE UNDERSTAND THE VISCERAL TUBIC MAP IN THE BRAIN AND TO WHAT EXTENT IS THEIR INDIVIDUAL VARIABILITY. IS THERE VISCERAL TOPEE -- AND DOES IT VARY BY EXPERIENCE. IF YOU PAY ATTENTION TO YOUR HEARTBEAT AND LEARN TO COUNT THE BEATS EFFECTIVELY CAN THE MAP OF THE HEART, IF THERE IS ONE, ACTUALLY ENLARGE? >> PETER, I DON'T KNOW IF YOU HAVE ANYTHING TO SAY ABOUT THIS. >> I'M AWARE OF STUDIES THAT HAVE MAPPED DIFFERENT VISCERAL ORGAN SYSTEMS TO DIFFERENT PARTS OF THE INSULA. I THINK MOST THE WORK HAS BEEN ON CARDIAC INTEROCEPTION OR RESPIRATORY BECAUSE IT'S VERY CONVENIENT. I DO REMEMBER THERE IS AT LEAST ONE STUDY THAT HAS A VISCERAL TOPIC MAP IN THE INSULA AND I THINK IT ALSO GOES INTO THE THALAMUS. >> AND THERE'S BEEN AMAZING WORK ON MAPPING DIFFERENT ORGANS ON THE INSULA. I KNOW IT'S NOT PUBLISHED YET BUT IT'S IN MONKEYS, NOT IN HUMANS. >> THERE'S BEEN A LOOK AT THE SYMPATHETIC OUTPUT IN THE KIDNEY AND STOMACH AND WE HAVE TO REMEMBER SYMPATHETIC OUTPUT LIES IN THE SPINAL CORD AND THERE'S A TOPOGRAPHY OF OUTPUT JUST LIKE THE TOPOGRAPHY OF MUSCLE OUTPUT. SO THERE'S A SHIFT IN THE LOCATION WITHIN M1 AND EVEN WITHIN M2 OF THE RAT WITH DIFFERENT SEGMENTAL LEVELS. >> I WANTED TO COME BACK TO THE IDEA OF UNDERSTANDING THE PERIPHERAL NERVOUS SYSTEM LESS AND WHAT THE MEETING HIGHLIGHTED TO ME WAS THE VAST INCREDIBLE INFORMATION INTEROCEPTION PAYS ATTENTION TO. I COME BACK TO THE IDEA THAT IT'S ALL STARTING FROM A FEW THOUSAND NEURONS AND D.R.G.s PROBABLY CONTRIBUTE MORE BUT IT'S AMAZING HOW LITTLE WE KNOW ABOUT THE NEURONS AND CHRISTOPH I THINK MENTIONED ALREADY THE KIND OF STUFF YOU GUYS ARE DOING WITH NOT JUST SINGLE-CELL RNA SEQ AND GETTING AN IDEA OF WHAT THE GROUP OF NEURONS WILL SENSE THINGS RELATIVE TO THIRST, EATING, WE KNOW LITTLE ABOUT THIS. THERE'S A COUPLE RNA SEQ PUBLICATIONS OUT THERE BUT NONE OF THEM MATCH TO WHAT ORGANS THEY'RE COMING FROM AND YOU WOULD THINK NODALS INTERVATING THE STOMACH ARE DIFFERENT THAN INNERVATING THE BLADDER. I THINK IT'S A QUESTION TO ANSWER WITH MEDIUM EFFORT. ONE LAB LIKE US WE THOUGHT DOING IT BUT I THINK IT'S A BIT OF A JOINT EFFORT WOULD BE TRANSFORMATIVE WITH RESPECT TO AND IT'S A MUCH SIMPLER SYSTEM THAN THE WHOLE BRAIN OF COURSE. IT MIGHT BE A GOOD STEPPING STONE WHERE IT'S IN THE PERIPHERAL NERVOUS SYSTEM THAN THE C.N.S. >> YOU WANT TO DO AN ATLAS IN THE FRAMEWORK SYSTEM FOR THE BODY. >> IT'S A LITTLE BIT OF AN EFFORT BUT IT'S NOT UNDOABLE. >> IT CAN BE DONE. >> [INDISCERNIBLE]. >> I THINK THAT'S WHY ONE WOULD START. ONE COULD ADD DIFFERENT SPECIES. >> THERE'S AN INTERNATIONAL EFFORT ON HUMAN ATLAS INCLUDING HEART, LIVER, LUNG AND OTHER ORGAN SYSTEMS. IS THERE PROGRESS FOR THAT PROGRAM? IT STARTED ABOUT TWO YEARS AGO >> IT'S FOCUSSED ON FOUR ORGANS INCLUDING THE SKIN BUT THERE'S NO PLANS TO DO P.N.S. OR MAP FROM THE HEART HEAR THE TO THE BRAIN BUT HEART AND BRAIN IN ISOLATION. >> WHO IS SUPPORTING THE EFFORT? >> C.C.I. >> SO I WANTED TO MAKE A COMMENT AND THEN A QUESTION FOR DISCUSSION. SO THE COMMENT IS THAT I'VE DONE SOME WORK MEASURING WITH INTEROCEPTIVE ACCURACY LIKE HERPES DETECTION AND TE -- THE TASK SO DIFFICULT TO DO AND YOU GET PEOPLE WITH AN AFFECT OR COUNTING AND TAPPING TASK YOU GET A CEILING AFFECT. THE COMMENT IS THE TASKS ARE NOT APPROPRIATE SOMETIMES PSYCHOMETRICCALLY AND I STARTED DOING THE TASKS WITH PATIENTS IN CHEMO AND IT'S HARD FOR THEM AND THERE'S NO WAY TO ASSESS INDIVIDUAL DIFFERENCES. THAT'S THE COMMENT. WE NEED TO MOVE TOWARDS BETTER ASSESSMENT METHODS OF INTEROCEPTIVE ACCURACY AND THE OTHER METHODS THAT MEASURE INTEROCEPTIVE ACCURACY YOU HAVE TO HAVE AN ACCURATE MEASURE OF ACCURACY IF YOU'RE GOING TO COMPARE ACCURACY TO CONFIDENCE. IT KIND OF RUINS TWO OF THE MEASURES. I THINK WE NEED TO MOVE TOWARDS BETTER MEASUREMENT TOOLS AND MY QUESTION IS IF PEOPLE COULD DISCUSS WHAT ARE SOME OTHER OPTIONS? I KNOW THERE WAS TALK ABOUT AN INJECTION THAT WAS A CARDIAC MEASURE BUT SIT APPROPRIATE AND SCALEABLE AND SOMETHING WE CAN DO IN A REASONABLE TIME PERIOD AND IN DIFFERENT POPULATIONS LIKE WITH OLDER ADULTS OR CHILDREN AND PATIENTS WITH LESS COGNITIVE RESOURCES OR ENERGY, FRANKLY, TO DO THE TESTS WHICH ARE VERY BORING ALSO. >> I DO THINK WE NEED MORE S SO I AM IN AGREEMENT. I WANT TO POINT OUT CONFIDENCE AND ACCURACY DOES ALIGN IN HIGH ACCURACY PEOPLE. THERE WAS A LINE OF PEOPLE THAT WERE VERY GOOD. BUT I DO TAKE YOUR POINT THAT ESPECIALLY IN CANCER PATIENTS, I CAN SEE WE DO NEED BETTER METRICS SENSITIVE FOR A POPULATION AND THAT'S ONE OF THE CHALLENGES IN THE FIELD THAT WE DO NEED TO DO AND I CAN ASK ANYONE TO EXPAND. >> I DIDN'T GET INTO DETAIL BUT THE TOOLS WE USE TRY TO GET AT THAT. IF YOU USE E.E.G. BUT TREAT IT LIKE A TASK YOU ACTUALLY GET THE MEASURE OF PRECISION OF THE INTEROCEPTIVE SENSITIVITY BUT IT'S A DIFFERENT KIND OF METRIC BECAUSE YOU USE COMPUTATIONAL MODELS IN WEIGHING THE SENSORY INFORMATION COMING FROM THE BODY AND SAME IS TRUE FOR THE IDEA OF CLASSICAL PSYCHO PHYSICS AND COMBINING HEARTBEAT INFORMATION WITH TONES. SO YOU CAN ANALYZE IT IN AN E.E.G. AND WE STARTED TO DO BEHAVIOR METRICS WITH YOU COMBINE TONES WITH HEARTBEATS TO GET AT A PSYCHOMETRIC FUNCTION AND GET TO THE PRECISION OF SENSORY INFORMATION COMING FROM THE BODY AND WE AGREE IT IS AN ISSUE. >> TO CONTINUE THAT THEME A BIT. YOU TOUCHED ON THE COMMENTARY ON THE TASK DON'T REQUIRE REPORT. THE FIRST IS THE MAJORITY OF INTEROCEPTIVE SIGNALS AND INPUT AND BEHAVIORAL OUTPUT IS FOR THE MOST PART NOT CONSCIOUS FOR GOOD ADAPTIVE REASONS. AND SO IT IS NOT UNLIKE INTEROCEPTIVE SENSING IN RESPONDING AND IF YOU THINK ABOUT A WELL TUNED SYSTEM IS THAT THAT DOESN'T USE UP THE COGNITIVE RESOURCES AREN'T USED UP CONSTANTLY AND YOU BECOME AWARE USUALLY DURING A PATHOLOGICAL STATE. SO IF YOU WANT TO LOOK AT NORMAL FUNCTION, THE TASK YOU USE THAT DON'T REQUIRE REPORT ARE OBSERVING TO WHICH THEY WORK WITHOUT COGNITIVE RESOURCES. IT'S ALSO GOT A LOT OF UTILITY IN USING IN ANIMALS WHO CAN'T REALLY REPORT IN THE WAY YOU'RE ASKING TO HUMANS DO TO DO AND CAN BE USED IN INFANTS. WE'RE ONLY USING THAT AS A BASE AND ON TOP OF THAT ADDING MEASURES OF COMPETENCE OR INSIGHT AS A SEPARATE THING AND NOT CONFOUNDING THE TWO. IT SEEMS LIKE MOST THE TIME THE BODY DOES THESE THINGS WITHOUT COGNITIVE EFFORT AND THAT REPRESENTS THE COGNITIVE STATE. >> I WANTED TO COME BACK TO THE ISSUE OF WHETHER MORE INTEROCEPTION IS BETTER. IT SEEMS TO ME THIS IS A QUESTION WHERE WE CAN PRODUCTIVE BRING IN CHRISTOPH'S ADVICE AND THINK OF INTEROCEPTION. IF YOU THINK OF THE PEOPLE HYPERSENSITIVE AND FEEL LIKE THEY HAVE A LOT OF INFORMATION ABOUT INTEROCEPTION, YET, NOT ACCURATE, YOU CAN THINK OF LIKE A RADIO WHERE YOU'RE TRYING TO LISTEN TO A CHANNEL AND YOU CAN'T HEAR WHAT'S GOING ON SO YOU TURN UP THE VOLUME. WHAT I THINK SARAH'S TECHNIQUES TRY TO GET THEM TO DO IS LOOK AT NOISE RATIO AND WE CAN MEASURE THE SIGNAL TO NOY -- TO NOISE RATIO AND THINK MORE PRODUCTIVELY ABOUT THESE ISSUES. >> I LIKE THE IDEA OF TURNING DOWN THE VOLUME FOR THE INTEROCEPTIVE FEELINGS WE DON'T WANT TO EXPERIENCE. ALSO GOING BACK TO APPROACHES GOING FROM HUMANS TO ANIMALS AND THE RESEARCH IN HUMANS THAT HAVE ELECTRODES IMPLANTED IN THE BRAIN GO TO HOW WE CAN TURN UP OR DOWN THE VOLUME. >> I DIDN'T SHOW THIS BUT I WAS SHOWN DISTINCT TRENDS AND RESPONSES NOTICE BRAIN THE BRAIN RESPOND TO THE HEARTBEAT WHICH IS THE POTENTIAL IN THE DATA. AND WE WERE GETTING I.E.G. DATA WHERE WE RUN THE MODELS TO LOOK AT THE RESPONSES. SO THE RECORDINGS ARE ALSO BASED IN THE INSULA. THERE'S POTENTIAL FOR TRANSLATIONAL RESEARCH FOR SURE. ANDLIKE TURNING DOWN THE RADIO. I LIKE THAT ANALOGY. WE HAVE TO BE CAREFUL IN TALKING ABOUT SENSATION VERSUS PERCEPTION. IF YOU THINK ABOUT THE SENSORY CHANNEL THERE'S INFORMATION AND IT'S ALSO NOISY AND THAT'S THE PRECISION OF THE CHANNEL AND IN ADDITION TO THAT WE COMBINE DIFFERENT SENSORY CHANNELS WITH DIFFERENT PRECISIONS AND WE KNOW OFTEN TIMES PROCESSING IS MORE RELIABLE THAN AUDITORY PROCESSING SO WE TEND TO TRUST MORE WHAT WE SEE THAN WHAT WE HEAR. THE SAME IS TRUE FOR INTERNAL SENSORS. WHEN WE ARE OVERLY PRECISE, WE RELY ON NOISE INFORMATION AND THAT'S ONE PROBLEM BUT IF WE TREAT THEM AS UNRELIABLE WHAT HAPPENS IF WE IGNORE THE SENSOR AND PLACE OUR PERCEPTION ON OUR BELIEFS OR OTHER SENSORY CHANNELS? IT'S A BALANCE. WE SHOULD START TO TALK ABOUT INFORMATION CONTENT VERSUS PRECISION RATIO BETWEEN THE DIFFERENT TYPES OF INFORMATION. I THINK THAT'S WHERE WE FIND WHAT IS HEALTHY VERSUS WHAT IS DYSFUNCTIONAL. >> I'M GOING TO TAKE A SPEAKER'S PREROGATIVE TO ASK THE LAST QUESTION. ROB AND WARREN YOU GAVE EXAMPLES OF PRE-CLINICAL DEVELOPMENT OF INVASIVE TECHNOLOGIES AND CAN YOU TALK ABOUT THE CHALLENGES OF TRANSLATING FROM THE CLINICAL TO THE APPLICATION? >> THAT'S A BIG PROBLEM FOR SOME OF THE TECHNOLOGIES I WAS DESCRIBING. IT'S LESS PROBLEMATIC IN THE CONTEXT OF USING THINGS LIKE OPTOGENETICS THAT REQUIRES TWO TYPES OF DEVELOPMENT BY WHICH ONE IS THE DEVICE DEVELOPMENT SIDE AND THE OTHER IS THERE'S A GENE THERAPY COMPONENT. NEITHER ARE INSURMOUNTABLE BUT COMBINING THEM TOGETHER RAISE THE CHALLENGES IN TERMS OF F.D.A. APPROVAL OF THAT APPLICATION. HAVING SAID THAT, THERE ARE CURRENTLY ONGOING CLINICAL TRIALS FOR OPTOGENETICS FOR CLINICAL DEVICES AND WE'RE GETTING EXPERIMENTS IN HUMANS NOW WITH THOSE. IT'S A REAL ADVANTAGE. THAT'S WHY THE BAR'S LOWER THERE. THERE'S ALSO BEEN GENE THERAPY APPROACHES IN EXPRESSING OPIOID PEPTIDE AND THINGS LIKE THAT. THERE ARE EXAMPLES WHERE IT WAS DONE INDIVIDUALLY AND THINGS WE DON'T KNOW ARE WITH OPTOGENETICS CAN THEY BE EXPRESSED OVER THE LONG TERM SAFELY AND WHAT IS THE AFFECT OF JUST EXPRESSION OF THE PROTEIN AND WHAT'S THE EFFECT OF SILENCING OF THE NEURAL POPULATION. DO YOU GET PLASTICITY. THE PROOF OF PRINCIPLE EXPERIMENTS I DIDN'T SHOW A LOT IN THE WORK TODAY BUT THERE'S CLEAR EVIDENCE SILENCING THE PATHWAY CAUSES RELIEF OF ONGOING PAIN WHICH IS DIFFICULT TO SHOW. AT LEAST IN THE ANIMAL AND RODENT STUDIES WE HAVE GOTTEN PAST THAT AND THE TIME NOW FOR THAT TYPE OF WORK WE'RE DOING THERE IS TO MOVE INTO A BETTER PREDICTIVE LARGE ANIMAL PIG AND ULTIMATELY NOT EVEN PRIMATES AND WHAT IT'S WORKING ON HAS A QUICKER PATH. >> I THINK IN BOTH CASES YOU WANT TO THINK ABOUT CAN YOU DO EXPERIMENTS IN HUMANS EARLY TO ASSESS WHETHER OR NOT WHAT WE'RE LEARNING IN AN ANIMAL MODEL MIGHT ACTUALLY WORK IN THE HUMAN. AND IF THE ANSWER IS NO, YOU NEED TO SNIFF UNDER A DIFFERENT TREE. I THINK IN YOUR CASE, ROB, YOU HAVE THE ADVANTAGE OF YOU CAN INSTILL ATHES -- ANESTHESIA INTO THE BLADDER AND IT PARALLELS WHAT YOU HAVE SHOWN WITH OPTOGENETIC INHIBITION AND THINKING ALONG THOSE KINDS OF LINES, MINIMALLY INVASIVE INTERVENTIONS TO ASSESS MIGHT THIS WORK BEFORE YOU BUILD A MODERN MEDICAL DEVICE AND TAKE IT INTO THE CLINICAL IT'S PROBABLY A $100 MILLION EXERCISE AND YOU DON'T WANT TO FAIL AT THAT POINT. THE ORIGINAL EXPERIMENT WAS DONE IN THE HUMAN WHICH IS THE LOCAL NERVE BLOCK SO THE EXTENSION OF OPTOGENETICS WAS STRAIGHTFORWARD. ONE THING I DIDN'T SHOW IN TERMS OF GETTING IT TO HUMANS QUICKLY WE CAN SHOW AT THE SINGLE CELL LEVEL THE OPTOGENETIC SILENCING OF NEURONS WORK AND WE CAN TAKE THEM FROM ORGAN DONORS AND WE GET THE SILENCING WE SAW IN THE RAT STUDIES. >> DON'T YOU HAVE TO REPLACE THE BACTERIAL WITH MAMMALIAN DERIVED INTO A HUMAN BODY? >> I THINK THAT MAKES SENSE. THERE'S A WHOLE UNIVERSE OF POSSIBILITIES AND YOU WANT SOMETHING HUMANIZED AT LEAST NOT HUMAN TO BEGIN WITH, IF NOT. BUT THERE'S A TON OF OPTIONS THERE. I DON'T THINK IT'S BEEN DONE IN THE CASE BUT THAT'S TO THE ENVIRONMENT. >> IT IS TIME FOR OUR BREAK AND IF WE CAN GIVE OUR SPEAKERS AND PANELISTS A HAND. [APPLAUSE] AND THIS IS OUR LAST SESSION. FUTURE DISCRETIONS AND RECOMMENDATIONS CHAIR BY MYSELF AND ANGELA BUT WE'LL BEGIN WITH ONE LAST TALK WITH DR. ARENSDORF WILL TALK TO US ABOUT ANSCH -- INTEROCEPTION SUMMIT TWO YEARS AGO AND YOU CAN READ HIS BIO SKETCH AND HE'S A PSYCHIATRIST AND NEUROSCIENTIST. HE'S CURRENTLY AT THE LAUREATE INSTITUTE FOR BRAIN RESEARCH AND WILL TALK ABOUT WHAT HAPPENED AT THE INTEROCEPTION SUMMIT AND IDEAS ON WHAT HAS COME SINCE THEN AND MAYBE MAKE HIS RECOMMENDATIONS WELL. DR. KHALSA. >> SO I WANT TO THINK FOR INVITE MEG AND -- INVITING ME AND THE ORGANIZERS. IT'S BEEN A SUPERB MEETING AND LOOKING FORWARD TO SHARING MY THOUGHT. THIS WORD CLOUD WAS GENERATED FROM THE DISCUSSIONS THAT HAPPENED THE THE INTEROCEPTION SUMMIT MEETING I'LL TALK ABOUT NEXT. IT WILL BE INTERESTING TO SEE WHAT KIND OF UPDATE THERE IS IN RELATIONSHIP TO THE DISCUSSION THAT'S HAPPENED AT THIS MEETING. THIS THE LAUREATE INSTITUTE IN TULSA, OKLAHOMA. SO IN 2016, THE SUMMIT WAS AN INTERDISCIPLINARY MEETING TO GET EXPERTS TOGETHER TO DISCUSS VARIOUS TOPICS OF INTEREST TO INTEROCEPTION WITH A FOCUS ON HOW IT COULD POTENTIALLY LEAD TO IMPROVEMENTS IN UNDERSTANDING AND TREATMENT OF MENTAL HEALTH. WE TALKED ABOUT PSYCHOPATHOLOGY AND A SESSION FOCUSSING ON A ROAD MAP. WHAT YOU CAN SEE FROM THIS MEETING IS IT WAS A TRANS CONTINENTAL GROUP AND SEVERAL INDIVIDUAL WHO'S PARTICIPATED IN THIS MEETING WERE ALSO AT THE MEETING AS WELL. THE FORMATS WERE A LITTLE BIT DIFFERENT. WE HAD PANELISTS AND PRESENTATIONS AND WHAT WE DID WAS AFTER EVERY PRESENTATION WE BROKE THE CONFERENCE UP INTO INDIVIDUAL GROUPS WHERE WE COULD GET REFLECTIONS AND WE HAD NOTE TAKERS WHO ACTUALLY COLLECTED THE RESPONSES THAT WERE RELAYED TO BE SHARED AND DISCUSSED OVER ALL IN A GROUP DISCUSSION. AND THERE WERE SEVERAL KINDS OF QUESTIONS EVERYONE WAS POSED AND YOU CAN VOTE AND THE ENTIRE WORKSHOP OUTPUT IS AVAILABLE AT THE WEB LINK IF YOU WANT TO TAKE A LOOK. IT WAS A NICE WAY TO GET A SENSE OF WHAT EVERYBODY THOUGHT IN PARTICULAR THIS MEETING I'VE BEEN IMPRESSED BY THE QUESTION THE AUDIENCE MEMBERS HAVE BEEN ASKING. THE PRIMARY OUTPUT WAS THIS WHITE PAPER ACCOMPANIED BY A SPECIAL ISSUE IN CNNI. AND ONE THINGS I'D LIKE TO POINT OUT IS A DEFINITION OF INTEROCEPTION THAT WAS DERIVED IN A CONSENSUS MANNER. NOT SAYING THIS IS THE ONLY DEFINITION BUT LISA AT OTHERS IT'S BEEN A RECURRING THEME WE NEED TO HAVE PRECISE DEFINITIONS FOR TERMS THAT WE'RE USING. MAKE SURE WE'RE NOT USING THE SAME WORDS WHEN WE MEAN THE SAME THING. THIS IS ONE DEFINITION OF INTERCEPTION SUGGESTING IT REFERS TO THE PROCESS BY WHICH THE NERVOUS SYSTEM INTERPRETS AND INTEGRATES SIGNALS ORIGINATE FROM INSIDE THE BODY TO PROVIDE A MOMENT BY MOMENT MAPPING OF THE INTERNAL LANDSCAPE ACROSS CONSCIOUS AND UNCONSCIOUS LEVELS. I'M NOT GOING TO GET IN THE DISTINCTION BETWEEN CONSCIOUSNESS AND AWARENESS AND WE CAN DISCUSS IT MORE BUT AGAIN IT'S IMPORTANT TO EMPHASIZE THIS IS THE NERVOUS SYSTEM AND CENTRAL AND PERIPHERAL BEING INVOLVED. WHEN YOU LOOK AT THE HISTORY OF INTEROCEPTION RESEARCH THIS IS ALL THE ARTICLES I COULD FIND PUBLISHED THAT DIRECTLY REFERENCE INTEROCEPTION TIME LINES GOING BACK TO DARWIN AND THE DEFINITIONS-BUT. BUT YOU CAN SEE IT'S HAD A FLUCTUATING COURSE AND IN THE '80s THERE WAS A SLOW INCREASE IN INTEROCEPTION AND IT WASN'T UNTIL PEOPLE LIKE BUD CRAIG AND OL VI VER CAMERON AND OTHERS STARTED PUBLISHING INFLUENTIAL BOOKS AND REVIEWS AND FINDINGS THAT YOU CAN MAP CORTICAL CIRCUITS AND HAVE AN INTEGRATED NEUROPHYSIOLOGICAL FRAMEWORK AND THERE'S BEEN AN EXPLOSION OF STUDIES IN THE PAST 15, 20 YEARS ON INTEROCEPTION. AND WE TALKED ABOUT THINGS THAT HAVE CHANGED. WE SEE ARTICLES DIRECTLY REFERENCING THE TERM INTEROCEPTION HAVE INCREASED. AND WHEN YOU LOOK, THIS IS A WEB OF SCIENCE AT THE DISCIPLINES AND JUST IN THE LAST THREE YEARS THAT ARE ACTUALLY MOST HEAVILY REFERENCING THIS TERM, NEUROSCIENCE IS NUMBER ONE FOLLOWED BY PSYCHOLOGY AND IF YOU AGGREGATE THE SUBDISCIPLINES IT WOULD OVERTAKE THE OTHER TWO. THEN THERE'S A BROAD INTERDISCIPLINARY MIX, GASTROINTEROOLOGY, NEUROIMAGING AND PHILOSOPHY. IT'S A RICH LITERATURE. OF COURSE WHEN YOU LOOK AT WORLD OF ANIMAL RESEARCH AND RESEARCHERS WHO CARE NOTHING ABOUT THE TERM INTEROCEPTION BUT STUDY VARIOUS FEATURES OF IT, YOU GET A DIFFERENT PICTURE. SO THIS ACTUALLY SHOWS THAT OVER THE LAST 40 YEARS, THERE'S BEEN ALMOST AN ORDER MAGNITUDE HIGHER OF LOOKING AT VISCERAL PROCESSES AND A LOT OF THESE ARE IN ANIMA ANIMALS WITHOUT DIRECTLY REFERENCING THE TERM INTEROCEPTION. ONE POINT IS THAT INTEROCEPTION DFFERS FROM OTHER BECAUSE IT'S CRITICAL FOR ENSURING BODILY HOMEOSTASIS. THERE'S A LOT OF DISCUSSION ABOUT WHAT IS AND ISN'T AN IN TER -- INTEROCEPTIVE SIGNAL OR SYSTEM AND THERE'S A CONVERSATION ON WHAT CONSTITUTES OUT OR NOT. THESE ARE BASIC ATTEMPTS TO CORRAL VARIOUS SYMPTOMS AND SIGNALS INTO PAINFUL VERSUS NON PAINFUL BUT WHAT YOU CAN SEE IS THERE'S AN INCREDIBLE VARIETY OF SIGNALS TO BE PROCESSED. FAR MORE THAN SOMETHING LIKE VISION OR HEARING OR ORAL FACTION. AND ONE THING THAT DIDN'T GET ANY DISCUSSION WAS THE ROLE OF THE MICROBIME. IN A WAY IT'S A WORLD WITHIN A WORLD WITHIN A WORLD. AND THERE'S AN INCREDIBLE AMOUNT OF COMPLEXITY THAT WAS DESCRIBED AND IN TERMS OF CHARACTERIZING THE PHYSIOLOGICAL SYSTEMS AND GASTROINTESTINAL AND LOOKING AT THE ROLE OF THE MICROBIOME THE GUT/BRAIN LINK IS COMPLEX AND INCREDIBLY FRUITFUL. IT'S ANOTHER WAY OF LOOKING AT THE VARIOUS SIGNALS THE BRAIN HAS ACCESS TO THAT COULD BE CONCEPTUALIZED AND IT'S POTENTIALLY HAPPENING ALL THE TIME AND YOUR BRAIN HAS A HARD TIME FIGURING OUT WHAT'S HAPPENING WHEN. WE DON'T ALL HAVE AN AWARENESS OF WHAT'S HAPPENING WITH OUR KIDNEYS AND BLOOD GLUCOSE AND BREATH ALL THE TIME BUT AS RESEARCH WE'D LIKE TO GET A SENSE OF THE SENSORY CHANNELS BY WHICH PARTICULAR SIGNALS ACCESS THE PERIPHERY AND BRAIN AND INFLUENCE PERCEPTION AND SYMPTOMS AND INFLUENCE DISORDERS. A LOT OF TIMES THERE'S PERCEPTUAL PROCESSING. A QUICK SHOW OF HANDS. HOW MANY PEOPLE IN THE AUDIENCE THINK THEY CAN FEEL THEIR HEART BRATE RIGHT NOW? -- HEARTBEAT RIGHT NOW? THIS IS AN INTEROCEPTIVELY ATTUNE AUDIENCE. MOST ARE WRONG. AND WE FIND ONLY ONE OF THREE INDIVIDUALS UNDER RESTING CONDITIONS CAN FEEL THEIR HEARTBEAT. WE DID A STUDY 10 YEARS AGO FINDING EXPERIENCED MEDITATORS THERE WAS NOT AN ACTUAL INCREASE IN THE ABILITY TO DETECT HEARTBEAT SENSATIONS BUT THERE WERE DIFFERENT DIMENSIONS OF INTEROCEPTIVE PROCESSING. AND I THINK ABOUT INTEROCEPTION IN TERMS OF AN ICEBERG. AND TRYING TO EMPHASIZE IN THE WHITE PAPER WE HAD A LOT OF DISCUSSIONS ABOUT THE DIFFERENCE BETWEEN INTEROCEPTION AND AWARENESS AND WHAT CAN BE FELT AND PERCEIVED AND REPORTED. WE CAME UP WITH A TABLE BASED ON WORK TRYING TO DELINEATE WHAT ARE THE FEATURES AND HOW CAN YOU DEFINE THESE. SO ATTENTION BEING THE OBSERVATION OF AN INTERNAL BODY SENSATION TO START TO BE USING THE SAME NOMENCLATURE OR AT LEAST UNDERSTAND WHAT WE MEAN WHEN WE SAY EACH TERM. YOU CAN ATTEND TO AN OBJECT BUT NOT NECESSARILY FEEL IT. YOU CAN DETECT OR NOT DETECT IT OR REPORT ON THE PERCEIVED INTENSITY OF THE STIMULUS OR LOCALIZE T AND ACCURACY HAS GOTTEN THE MOST INTEREST. I WOULD ARGUE THEY'RE ALL IMPORTANT. SELF-REPORT SCALES ON THE BOTTOM FROM THE ANGLE OF CLINICAL WORK IS THE MOST UNDERDEVELOPED AREA. THERE'S LOTS OF SCALES BUT WE DON'T HAVE A CLEAR IDEA HOW THEY MAP ONTO THE NERVOUS SYSTEM. THIS IS ONE ATTEMPT TO TRY TO PARCEL AND LOOKING AT ATTENTION TO HEARTBEAT AND IT DOESN'T MEASURE A LOT OF FEATURES. THERE'S DIFFERENT TASKS FOR MODULATING AND MEASURING VARIOUS FEATURES. IN MY LAB I'VE YOU'D LOOKING AT THE INTENSE OF THE SIGNAL BUT I THINK OTHER MINIMALISTIC TASK LIKE HEARTBEAT TAPPING AND SARAH REFERENCED IT CAN YOU WILL BE USEFUL BUT THEY JUST DON'T ALL MEASURE THE SAME THING NECESSARILY. AND YOU HAVE THIS SPACE OF SYSTEMS AND YOU HAVE LOTS OF DIFFERENT SIGNALS AND SO FOR EACH SIGNAL WHETHER IT'S RESPIRATORY YOU HAVE DIFFERENT TASKS THAT LOAD AND MEASURE THE FEATURES OF INTERCEPTIVE AWARENESS SLIGHTLY DIFFERENTLY. THEN HAVE YOU THE ADDED PROBLEM THE SIGNALS THEMSELVES VARY CROSS THE DIFFERENT SYMPTOMS IN TERMS OF AMPLITUDE AND FREQUENCY AND ALL OF THAT IS HAPPENING IN REAL TIME. SO THE QUESTION IS HOW CAN WE MAKE SENSE OF THE COMMUNICATION AND THE LINK BETWEEN THESE SIGNALS IN THE BODY AND ACTIVITY IN THE BRAIN? AS WE SAW IN THE LAST TWO DAYS, THERE'S A RICHNESS OF METHODOLOGICAL TOOLS FOR DISCREETLY MAPPING DIFFERENT CELL TYPES AND PROCESSES BY WHICH INTEROCEPTIVE SYSTEMS COMMUNICATE WITH THE BRAIN. BUT IF YOU LOOK AT EACH OF THESE PAPERS, WHAT IS CLER TO ME FROM A -- CLOR TO ME FROM A CLEAR TO ME FROM A HUMAN PERSPECTIVE EVERYTHING STOPS AT THE BRAIN STEM AND AS SOMEBODY INTERESTED IN THE CONSCIOUS ASPECT OF INTEROCEPTIVE SYMPTOMS WE NEED TO ADVANCE OUR ABILITY TO CONNECT THE TWO. AT THE PREVIOUS INTEROCEPTION MEETING THERE WAS THE POSSIBILITY OF ANIMAL MODELS AND HIGHLIGHT THE OCTOPUS AS A POTENTIAL MODEL SYSTEM FOR STUDYING INTEROCEPTION. THE OCTOPUS HAS NO BRAIN, THREE HEARTS AND IT ACTUALLY HAS 500 MILLION NEURONS. MORE THAN THE HONEY BEE BUT IT'S AN INVERTEBRATE AND THERE WAS A PAPER DESCRIBING FOR SOCIAL BEHAVIOR IN THE OCTOPUS AND THE PRESS SAID ANTISOCIAL OCTOPUS IS INTO CUDDLE BUNNIES. NORMALLY THE OCTOPUS DON'T LIKE TO HANG OUT NEXT TO EACH OTHER BUT WHEN INFUSED WITH AN AGONIST YOU CAN SEE THE OCTOPUS JUST WANTS TO HANG OUT WITH HIS BUDDY. HOW MIGHT HE HAVE A SIMILAR RESPONSE TO A MAMMAL? IN TERMS OF REVERSE TRANSLATION DESCRIBED IN THE FIELD OF PSYCHIATRY THERE'S A LOT OF REVERSE TRANSLATION CURRENTLY WITHIN THERAPEUTICS. THERE'S LOTS OF NEUROACTIVE DRUGS THAT ARE BEING INVESTIGATED BECAUSE OF THEIR POTENT AFFECTS AND THEY'RE FINDING BENEFITS FOR TREATMENT-RESISTANT DEPRESSION AND POSTTRAUMATIC DISORDER AND SO ON. AND WE ARE LOOKED AT MODELS FOR INTERVENING IN THE HUMAN AND IF YOU WANT TO READ MORE REFERENCES HERE, YOU CAN MODULATE SIGNALS WITH GREAT SPECIFICITY USING EACH OF THESE DOMAINS. SO THERE'S A VARIETY OF TOOLS FOR MODULATING RESPIRATION. IN MY LAB WE MODULATE THE EPI NEUROGIC STATES AND WE LOOKED AT AFFECTS OF INJECTING SOMEBODY WITH AN ENDOTOXIN AND THERE'S BEEN STUDIES SHOWING HEATING THE BODY INCREASING THE CORE BODY TEMPERATURE BY 2 DEGREES CELSIUS CAN HAVE AN ANTIDEPRESSANT AFFECT AND WE CAN LOOK AT THE VAGUE -- VAGUS NERVE STIMULATION AND A COLLEAGUE IS LOOKING BY ATTENUATING INPUT FROM SPEECH AND SIGNALS USING FLOATATION THERAPY IS ANOTHER WAY TO THEN SEE WHETHER INTEROCEPTIVE SIGNALS HAVE A PREDOMINANCE AND I'LL DESCRIBE A FINDING WITH THAT. CHRISTOPH MENTIONED THE VISUAL SOMETIME COULD BE A GOOD THING TO LOOK AT AND HERE'S AN EXAMPLE OF A VISUAL OBJECT THAT PROBABLY DOESN'T LOOK LIKE ANYTHING BUT WHAT'S CLEAR TO UNDERSTAND VISUAL SIGNALS THERE'S FEATURE BINDING THAT HAPPENS AND YOUR BRAIN FILLS IN A LOT OF GAPS. IF I SHOW THIS SIGNAL RIGHT HERE, CAN EVERYBODY SEE THE BEES NOW? SO YOUR BRAIN JUST FILLED IN THE GAPS BUT IT COULDN'T DO IT WITHOUT THE ADDITIONAL INFORMATION. SIMILARLY, THIS LOOKS TO ME LIKE A BOWL OF VEGETABLES. IF YOU CHANGE THE PERSPECTIVE, DO YOU GUYS SEE THE FACE? THIS IS AN ARTIST IN THE 1500s THAT LIKED TO EMBED THE IMAGES. THERE'S ANOTHER ILLUSION FOR EXAMPLE, YOU SEE THE DIFFERENCE IN THE EYES NOW? THE IDEA IS MAYBE THERE'S SOMETHING SIMILAR HAPPENING WEDGE THE INTEROCEPTIVE SYSTEM AND IT'S IMPORTANT TO SPEND TIME THINKING ABOUT AND DEVELOPING AND TESTING MODELS AND THEORIES THAT HAVE A COMPUTATIONAL BASIS BECAUSE THEY POSIT SENSORY THINKING AND SOMETHING HAPPENS AND THE BRAIN TRIES TO FILL IN THE GAPS AND THERE'S A PREDICTION THAT HAPPENS AND THAT PREDICTION IS BASED AND INFLUENCED BY WHAT HAPPENED TO YOU IN THE PAST. IT'S ALSO INFLUENCED BY YOUR MODEL OF YOUR BODY AND OF THE WORLD. THINGS THAT YOU ARE SORT OF BORN BECAUSE OF YOUR BIOLOGY HAVING. THERE'S A PROCESS WHERE YOU OFTEN TRY TO CONSIDER WHAT YOUR OPTIMAL MODEL MIGHT BE. AND THEN HAVE YOU THIS METACOGNITIVE ELEMENT WHERE YOU'RE EXPERIENCING YOUR MODEL AND SIGNALS CHANGING IN REAL TIME AND IMPORTANTLY, WHEN PREDICTION LEADS TO ACTION YOU GET A PREDICTION ERROR. SO YOU SEE WHAT THE IMPACT OF ALL THESE VARIOUS LEVELS OF PROCESSING IS ON BOTH SENSATION AND THEN THE ENSUING ACTIONS. SO THERE'S A VARIETY OF IMPORTANT BRAINS INVOLVED AND MANY HAVE TALKED ABOUT THIS. I THINK IT'S WORTH HIGHLIGHTING. THE OTHER THING IS WE HAVE WAY TOO MANY MODELS IN SOME WAYS. THERE'S AN EXPLOSION OF MODELS AND WHAT WE NEED IS TO BE ABLE TO TEST THEM AND KEEP IN MIND ULTIMATELY WHAT NIH AND ALL OF US CLINICIANS ARE INTERESTED IN IS HOW CAN WE IMPROVE OUR INFORMATION OF HOW TO TREAT MENTAL DISORDERS. THE ONLY POINT I WANT TO MAKE IS IN PSYCHIATRIC DISORDERS IT'S NOT JUST ONE OF THESE SYMPTOMS PATIENTS ARE PERCEIVING AT AN EXAGGERATED LEVEL. IT'S A COMPLICATED PROBLEM. IN RELATION TO THE RESPIRATORY SYSTEM EVEN AS SIMPLE AS HOLDING A BREATH, ELICITS A MODULATION OF AUTONOMIC STATE AND PEOPLE WITH ANXIETY AND DEPRESSION SEEMED TO HAVE HEIGHTENED FEELINGS OF SUFFOCATION THAT CORRELATE WITH A SCALE THAT MEASURES YOUR FEARS OF ANXIETY-RELATED SYMPTOMS AND INTEROCEPTION IS INVOLVED IN MEDICALLY UNEXPLAINED AND GASTROINTESTINAL, ETCETERA. HERE'S A FEW EXAMPLES. THERE ARE INTERVENTIONS IN THE CLINICAL ALREADY THAT FOCUS ON INTEROCEPTIVE TESTING BOTH IN TERMS OF COGNITIVE BEHAVIORALS AND THERE'S BEEN THERAPY IN CHILDREN AND CYNTHIA PRICE IS DOING TRAINING IN FINDING AFFECTS ON REDUCING DRUG USE. MY COLLEAGUE FOUND CARDIORESPIRATORY INTEROCEPTION INCREAS INCREASES WHEN PEOPLE ARE FLOATING AND ANG DECIDE CHANGE S -- ANXIETY CHANGES AND THIS ARE ALL THE ARTICLES I'VE EVER BEEN ABLE TO FIND ON INTEROCEPTION. YOU CAN DOWNLOAD THEM FOR FREE. IN TERMS OF OUTPUT, THERE WAS POTENTIAL MOTOR PATHWAYS TO THE ADRENAL MEDULLA. WE USE AN ADRENALINE ANALOG IT'S WHEN THE ADRENAL MEDULLA RELEASES ADRENALINE AND WE MAPPED IT WITH HIGH FIDELITY INTO THE INSULATE CORTEX AND A STUDY THAT LOOKED AT CONNECTIVITY BETWEEN THE SAME REGIONS IN HUMANS FOUND THAT THIS AREA SEEMS TO BE CONNECTED TO HUMAN ANALOG THAT RESEMBLES SHOWING ACTIVITY IN THE SPECIES AND IT RESPONDS TO A LOT OF INPUTS. YOU CAN SEE AREAS WHERE STIMULATION DOESN'T PROVIDE CONSCIOUSLY PERCEIVED SENSATION. I'M GOING SKIP MY REFLECTIONS BECAUSE I'M OUT OF TIME. AND FOR CHARTING A PATH FORWARD WE NEED TO START WITH CONCEPTUAL DISTINCTIONS AND WHAT IS IT AND WHAT IS IT NOT AND AGREE ON THE TERMINOLOGY OR STATE IT IN PAPERS AND MAP CONCEPTS TO MEASURES TO SPECIFIC MODELS AND APPROACHES AND REVISE THE CONCEPTS AS NECESSARY WITH NEW DATA AND DO REPRODUCIBLE SCIENCE. FINALLY, IN TERMS OF THE DISCUSSION WE'LL HAVE MOVING FORWARD, IF YOU THINK ABOUT THE INDEPENDENCE DAY MOVIE BEFORE WHERE THE AIL CENTSES ARE FIGURING -- ALIENS ARE FIGURING OUT WHERE THE MOST IMPORTANT PLACE TO START DESTROYING AND THEY START BY BLOWING UP THE WHITE HOUSE. WE ALL HAVE ASSUMPTIONS WHAT WE MAKE ON WHAT INTEROCEPTION IS BUT IN REALITY IT MAY LOOK LIKE THIS. THIS MAY BE WHERE THE ALIENS MAY START AND IN UNDERSTANDING THE PERSPECTIVE WE ALL CARRY IF WE COMMUNICATE AND USE CLEAR LANGUAGE AND WORK TOGETHER AND ARE PATIENT, WE'LL BE ABLE TO MAKE REAL PROGRESS IN THIS AREA. SO WITH THAT I'D LIKE TO THANK ALL MY COLLABORATORS AND THANK YOU FOR YOUR ATTENTION. >> WE'LL HAVE ALL THE COMMENTS.RS COMING UP AND HAVE - >> I'M NOT GARY. AIM A CELL BIOLOGIST ABOUT TO SPEAK FOR NEUROSCIENTISTS SO BE PATIENT. GARY HAS THE FLU. HE CAN'T BE HERE. HE HAD TWO BROAD PERSPECTIVES HE WANTED TO BRING TO THE DISCUSSION. MOSTLY FROM YESTERDAY'S CONVERSATION. HIS FIRST BIG POINT GOES BACK TO WHAT WE WERE TALKING ABOUT YESTERDAY ON THE DISTINCTION BETWEEN INTEROCEPTION AND EXETE INFORMATION AND IT'S RELATIVE AND AT WORSE OBSTRUCTIVE. HE WANTS TO POSE THREE EXAMPLES FOR YOU TO CONSIDER. THE FIRST HAS TO DO WITH HEARING AND RAISES THE POINT THE EIGHTH CRANIAL NERVE, FOR EXAMPLE, DOES NOT ENTAIL JUST THE AUDITORY NERVE BUT WHICH MEDIATES HEARING AND ALSO CARRIES SPECIAL SENSORY AFFERENTS MEDIATING VESTIBULAR SENSES. THE QUESTION IS THIS ANOTHER SOMATIC SENSE BEYOND THE TRADITIONAL FIVE SENSES? YOU HAVE -- I CAN'T SAY IT. THEY BOTH INVOLVE TRANSDUCTION PROCESSES ARISING FROM THE PHYSICAL STRAIN ON INTERNALAL STRUCTURES AND IS THIS INTEROCEPTIVE OR EXTERO CEPTIVE AND THE OTHER EXAMPLE HAS TO DO WITH OLOFACTION AND PHEROMONES. WITH THE MOUSE STUDY AND HE SAID IT'S FROM A CRANIAL NERVE 1 AND IT FOLLOWS LOCAL CHEMICAL INTERACTIONS IN THE OLFACTORY EPITHELIUM AND ORDER STIMULUS COMES FROM THE ENVIRONMENT HE PROPOSES WE MAY NEED TO ADD AN ADDITIONAL CRANIAL NERVE ZERO WHICH IS NOW WELL ESTABLISHED IN HUMANS. THIS IS DISTINCT FROM THE OLFACTORY NERVE AND INVOLVES A SEPARATE SET OF RECEPTORS THAT BIND PHEROMONES THAT LEADS TO THE RELEASE OF GONAD TROPINES WHICH THEN ALTERS HORMONAL AND BEHAVIORAL PROCESSES THAT MAY OR MAY NOT RAISE TO THE LEVEL OF CONSCIOUSNESS. AGAIN, HE SAYS IS THIS AN EXAMPLE OF A SENSE OR WHICH DOES NOT RISE TO THE LEVEL OF CONSCIOUS AWARENESS AND GOES ON TO RAISE ANOTHER EXAMPLE ABOUT PROPRIORRECEPTION AND HIS FIND POINT ON THIS TOPIC IS HE DOESN'T WANT TO SUGGEST THERE'S NOT AN IMPORTANT DISTINCTION TO DRAW FOR INWARD AND OUTWARD ATTENTION AND SOMETHING TO BE AWARE OF AND HIS OTHER POINT HAS TO DO WITH THE TOP DOWN, BOTTOM UP VIEW OF INTERCEPTION. HE BELIEVES THAT ANY MEANINGFUL PROGRESS IN THIS AREA WILL REQUIRE THE INTEGRATION OF TOP DOWN AND BOTTOM-UP APPROACHES AND THIS WILL BRING INTERACTIONS TO DIRECTIONAL AND WITH THAT I WILL MOVE ON. >> I'M SAY A FEW THINGS THAT OVERLAP AND WE HAVE COMMONALITY DESPITE THE FACT MANY OF US TAKE DIFFERENT PERSPECTIVES. FIRST OF ALL, WASN'T TO SAY I'M GOING REPEAT SOMETHING THAT'S BEEN SAID A NUMBER OF TIMES ABOUT THE FACT THAT WE NEED AN ONTOLOGY. AND I THINK IN PARTICULAR IT'S IMPORTANT BECAUSE WHERE WE COMMUNITY WITH ONE ANOTHER WE'LL PASS EACH OTHER IN USING THE SAME TERMS BUT MEANING DIFFERENT THINGS AND AN IMPORTANT PIECE IS THAT WE HAVE TO DISTINGUISH WA WHAT WE MEAN BY A CONSTRUCT AND MEASURE. THIS IS THIS IDEA OF INTEROCEPTIVE ACCURACY. I'LL CHOOSE TO USE THE TERM INTEROCEPTIVE SENSITIVITY. LET'S SAY WE MEAN THE INTERCEPTIVE SIGNALS THE BRAIN IS TRACK FROM THE PERIPHERY. AND THAT SOMEONE CAN REPORT UPON BY MOVING TO THE TASK LEVEL AND I'M NOT TALKING ABOUT A MEASURE. WHAT WE NEED TO DO IS BEGIN TO MAP THE TASK AND MEASURES THAT COME FROM THE TASKS TO THE CONSTRUCT WE MEAN. THERE'S BEEN LOOSENESS IN THAT AND WE HAVE THE HEARTBEAT TRACKING TASK AND OTHER TASKS I THINK THAT TASK REDUCES MEASURES THAT ARE MIXED WITH RESPECT TO THE CONSTRUCT IT RELATES TO. SO WE KNOW PEOPLE CAN HAVE KNOWLEDGE OF THE HEART RATE AND IT CAN IMPACT THE OUTCOME VARIABLE AND IF YOU THEN MAP THAT TO THE CONSTRUCT OF ACCURACY, I THINK YOU CAN VARY BY PERSON. SO THE MAPPING FOR A GIVEN PERSON MAY BE VERY DIFFERENT THAN THE MAPPING FOR ANOTHER PERSON. IT SUGGESTS THE TASK NEEDS RETHINKING PERHAPS OR AT LEAST THE WAY IN WHICH IT'S INTERPRETED NEEDS TO BE RETHOUGHT. SECOND OF ALL AND THIS CAME UP STRONGLY IN OUR SESSION SO WE TALKED ABOUT THE IMPORTANCE OF DOING CROSS PIECES ANATOMY AND BEING CAREFUL ABOUT THE HOMEOLOGIES DRAWN AND CHOOSING ANIMAL MODELS WISELY. I THINK THAT MEANS WE HAVE TO THINK ABOUT WHAT'S THE PHENOMENON BEING COMPARED AND ARE WE TALKING ABOUT INSULAR ANATOMY AND WHAT I SEE AS A PSYCHOLOGICAL VARIABLE. DEPENDING WHAT YOU'RE TRYING TO MODEL, YOU NEED A DIFFERENT MODEL TO DO THAT. SOME WORK BETTER WITH ANIMAL MODELS AND SOME PERHAPS LESS EASILY WITH ANIMAL MODELS. THE OTHER THING I'D LIKE TO DO IS APPLAUD PEOPLE DOING COMPUTATIONAL MODELS. I THINK IT'S IMPORTANT FOR A PARTICULAR REASON. THEY FORCE US TO MAKE OUR ASSUMPTIONS OR WHAT PHILOSOPHERS CALLED ONTO LOGICAL COMMITMENTS CLEAR AND IT'S EASIER TO COMPARE WHAT WE'RE SEEING WITH OUR MODEL WITH SOMEONE ELSE IS SEEING WITH THEIR MODEL AND WHEN WE TIE DOWN THE ELEMENTS OF THE COMPUTATIONAL MODEL IT POPS OUT IN RELIEF AND I THINK THAT'S IMPORTANT TO MAKE HEADWAY AND COMPARING MODELS. IT'S FUNNY THE NUT DOESN'T FALL FAR FROM THE TREE AND GARY BENSOM WAS MY ADVISER AND WE HAD NO CHANCE TO TALK. SO THE IDEA THERE BE ISSUES RAISED. WE NEED TO BE CLEAR THAT WHAT THEY ARE IS ORGANIZING PRINCIPLES FOR US AS THINKING SCIENTISTS WHO USE CATEGORIZATION LIKE ANY OTHER HUMAN BEING DOES BUT WE HAVE TO BE CAREFUL NOT TO ASSUME THEY'RE REAL. . I THINK EVERYBODY WOULD AGREE WITH ME THERE'S NO BIG DIFFERENCE BETWEEN THE CENTRAL NERVOUS SYSTEM AND THE PERIPHERAL NERVOUS SYSTEM AND WE HAVE TO ACT AS THOUGH IT'S NOT REAL IN SOME INHERENT SENSE AND I THINK INTEROCEPTION AND EXTEROCEPTION WILL DISSOLVE FOR THE SAME REASONS GARY POINTS OUT. AND WE NEED TO UNDERSTAND SOMETHING ABOUT WHETHER SENSITIVITY OR THE TRACKING OF INTERCEPTIVE SIGNALS FROM THE BRAIN IS DIFFERENT ACROSS SYSTEMS. THIS WAS ALLUDED TO AND I THINK IT'S IMPORTANT AND THERE'S BEEN VERY LITTLE WORK ON THIS SO WITHIN SUBJECTS USING SENSITIVITY TASKS PSYCHOPHYSICALLY BASED AND SHOWING COMPARISONS. SOMETIMES PEOPLE MATCH WITH ONE TASK AND NOT THE OTHER AND SOMETIMES THEY DON'T. THAT RAISES THE QUESTION, SIT THAT INDIVIDUALS -- IS IT THAT INDIVIDUALS HAVE DIFFERENT FOLLIES OF INTEROCEPTIVE INPUT INTO THE BRAIN THAT ARE MORE INTENSE UNDER SOME CIRCUMSTANCES AND LESS INTENSE UNDER OTHERS AND THAT'S BEING TAKEN IN BY THE BRAIN AND THAT'S PART OF WHAT THAT BRAIN IS ATTENDING TO OR PAYING ATTENTION TO AND USING IN ITS PROCESSING. THE NEXT PIECE IS HOW DOES INTEROCEPTION PLAY A ROLL OVER THE LIFE SPAN AND WA I WANTED TO SAY IS THAT TO THE EXTENT INTERNET -- INTEROCEPTIVE AND EXTEROCEPTIVE INPUTS AND FROM PAGE FROM INFANCY WHERE THE FIN FANT IS LEARNING TO MAKE SENSE ALL THE UPCOMING INPUT, CONSTRUCTING AN INTERNAL MODEL THAT GROWS AND CHANGES OVER TIME AND THEN IN AGING, WHERE WE THINK THERE'S A LOSS OF THE INTEROCEPTIVE INPUT AND DOESN'T SEEM TO ALTER THE PSYCHOLOGICAL LEVEL PHENOMENON SUGGEST THE IN PERSONAL MODEL AT SOME POINT MAY NO LONGER NEED THAT INFORMATION OR IT STARTS TO DISCOUNT THAT INFORMATION AS IT BECOMES MESSY, NOISY, ETCETERA. I THINK TAKING A MORE DEVELOPMENT APPROACH WILL BE CRITICALLY IMPORTANT. AND I THINK I'M PROBABLY OUT OF TIME SO I'LL LEAVE IT THERE AS SOME EXAMPLES. >> AND SESSION THREE'S RA -- RAPPORTEUR. >> SO I PUT THIS BASED ON MY CLINICAL AND EXPERIMENTAL WORK AND WORKING IN DISORDERS WITH DISEASE AND PATIENTS WITH DISEASE AND SENSITIVITY AND CONVINCED IN THESE PATIENT EVEN IF YOU'RE IN FRONT OF ORGANIC OR POTENTIAL PATIENTS I DON'T LIKE THE WORD FUNCTION BECAUSE THE PATIENTS ARE ORGANIC FOR ME. SO WHAT I SENSE FROM THIS MEETING WHICH IS VERY INTERESTING AND AT THE SAME TIME IS COMPLICATED BECAUSE IT SEEMS THERE'S A LOT OF THINGS NOT STILL WELL KNOWN OR WELL DEFINED. HAVE THESE COMMENTS. WHAT IS IMPORTANT FOR ME IS PRIOR EXPERIENCES LIKE EARLIER LIFE TRAUMA. IN MEDICAL STUDIES YOU DON'T ASK PATIENT DID YOU HAVE SEXUAL ABUSE, EMOTIONAL ABUSE AND SO ON AND WHEN YOU LOOK AT THE TRAUMA YOU FIND IT IN THE PATIENTS IN 30 TO 50% OF DISORDERS AND I'M CONVINCE THE TRAUMA ARE SUPPOSED TO FAVOR A STATE AND INDUCING THE MODEL OF I.B.S. OR IN THE ANIMALS IF YOU INDUCE COLITIS THEY HAVE MORE THAN OTHERS. THE OTHER POINT IS COMPLIMENTARY MEDICINE WHICH IS VERY IMPORTANT AT THE TIME. IN FRANCE MORE AND MORE PATIENTS HAVE MORE AND MORE FOR COMPLIMENTARY MEDICINE. PHYSICIANS ARE NOT OPEN TO THIS ENOUGH. WE SPOKE ABOUT C.B.T., MINDFULNESS BUT I'M INTERESTED IN THE HYPNOSIS IN MY PATIENTS WITH THIS AND WHAT IS INTERESTING IS AFTER SEVEN TO EIGHT SESSIONS IN FACT THE PATIENT THEY DON'T FEEL THE SYMPTOMS ANYMORE BUT THE INTEROCEPTION IS DOWN. I THINK THE COMPLIMENTARY MEDICINE IS IMPORTANT. AND WE'RE INVOLVED IN AN EXPERT AND I REALLY THINK >> I THINK IT'S IMPORTANT TO LOOK AT THIS TIME OF NEUROMODULATION AND YOU HAVE T.M.S. AND OPT OWE OPTOGENETIC STIMULATION AND YOU PRESENTED DATA AND THE BRAIN AXIS IS IMPORTANT, OF COURSE. WE KNOW FOR EXAMPLE, IF YOU MAKE A TRANSPLANTATION FROM A RAT WHICH IS DEPRESSED TO A NORMAL RAT YOU INDUCE MODIFICATION BUT IN RATS IT'S NOT IN HUMANS. WE HAVE MORE AND MORE DATA ON TRANSPLANTATION AND OF COURSE YOU HAVE PROBIOTICS AND NUTRITION. MOST OF OUR PATIENTS HAVE A GLUTEN-FREE DIET AND FOR EXAMPLE YOU HAVE A STUDY SHOWING 50% OF THE PATIENTS ARE THOSE WHO HAVE SOMATIZATION AND THE EMOTION IS IMPORTANT AT FIRST. OF COURSE THE BIG PROBLEM SEEMS TO BE BIOLOGICAL MARKER. PERHAPS WE CAN LOOK BRAIN IMAGING AND E.E.G. AND I KNOW MAIA IS A KNOWN QUESTIONNAIRE BUT YOU NEED TO LOOK AT THE COPING STRATEGIES AND DEPRESSION AND SO ON. IT SEEMS TO ME THE IMPRESS -- IMPRESSION I HAVE FROM THE MEETING YOU CAN HAVE THERAPIES BUT EACH PATIENT IS SPECIAL. NOW YOU NEED TO LOOK AT PERSONALIZED PATIENTS. I THINK WE NEED TO FOCUS ON THAT POINT. THANK YOU. >> THEN SESSION FOUR'S RAPPORTEUR. >> I'M GLAD YOU ENDED WITH PERSONALIZED INTEROCEPTION BECAUSE THAT'S A BIG THEME IN MY WORK AND I'M GOING GO FROM THERE. I'M A NEUROSCIENTIST THAT STUDIES MEDITATION AND A CLINICAL PSYCHOLOGIST AND PERSONAL MEDITATION PRACTITIONER AND I HAVE TO TEACH PEOPLE MEDITATION AND THE MORE I PERSONALIZE IT TO THEM. PEOPLE ARE ASKING IS IT BAD TO HAVE PEOPLE PAY ATTENTION WHEN THEY ARE FREAKING OUT. YOU DON'T BRING PEOPLE IN UNLESS THERE'S AN ISSUE AND WITH MINDFULNESS WE'VE BEEN USING THE BLANKET TERM BUT TO FLUSH THAT OUT MORE ONE DEFINITION IS PAYING ATTENTION TO THE PRESENT MOMENT IN AN INTENTIONAL WAY BECAUSE OUR ATTENTION TENDS TO FLUCTUATE. WHATEVER YOU WANT. WE OFTEN TRAIN PEOPLE TO THE BODY BUT IT'S ALSO NON-JUDGMENTAL, KIND, OPEN, CURIOUS, AS ONE OF MY PATIENT SAID, YOU MEAN I HAVE TO BE PERFECT. IT'S KIND OF A TALL ORDER BUT THE REALLY IMPORTANT PART IS THE NON-JUDGMENTAL ASPECT OF AWARENESS WE CONTINUOUSLY CULTIVATE ESPECIALLY IF THE FEELING IS UNCOMFORTABLE WE TEND TO PUSH IT AWAY. WE PUSH IT AWAY AND DON'T WANT TO FEEL IT. THE BODY IS ALWAYS SENDING US SIGNALS AND GET LOUDER SO THEY'RE IMPORTANT. WE NEED OTHER WAYS OF INTERACTING WITH THE SENSATIONS. IF WE JUDGE IT AND TRY TO PUSH IT AWAY OR OVER AMPLIFY IT OR FEEL DISTRESSED WE'RE NOT HEARING THE MESSAGE IT'S TRYING TO SEND. WE NEED TO MAKE THAT RADIO DIAL RIGHT ON THE RIGHT FREQUENCY TO UNDERSTAND THE MESSAGE COMING THROUGH. THE NON-JUDGMENTAL COMPONENT INCREASES THE REACTION TEST TO THE SENSATION AND HELP PEOPLE BE WITH IT AND FEEL IT AND IT'S UNCOMFORTABLE FOR A WHILE AND AS A CLINICIAN, WHEN YOU HELP PEOPLE SETTLE IN THE MESSAGES COME THROUGH. IT'S NOT A ONE TO ONE MAPPING. YOU CAN'T FORCE IT AND CYNTHIA DESCRIBED HER BEAUTIFUL INTERVENTION TO HELP PEOPLE SETTLE INTO THEIR BODIES. OUR FACE SENDS SIGNALS TO OTHER PEOPLE AND TO OURSELVES. IF YOU BLOCK THE FACIAL MUSCLES IT INTERRUPTS OUR OWN INFORMATION OF OURSELVES. THE VOCAL CORDS AND WE HOLD TENSION IN THE BACK AND SHOULDERS AND ALWAYS BRING PATIENTS TO THE HEART AND STOMACH. THE HEART THERE'S LOTS OF SOCIAL PSYCHOLOGY SHOWING CHANGES IN HEART RATE VARIABLES SHOWING ON SOCIAL SITUATIONS AND WITH ANXIETY SYMPTOMS GO TO STOMACH. PEOPLE TEND TO WANT TO ESCAPE IT SO YOU GENTLY BRING THEM IN BECAUSE IT'S TRYING TO TELL YOU SOMETHING. SOMETHING'S NOT RIGHT WITH YOUR BODILY HOMEOSTASIS AND THIS IS OFTEN RELATIONAL HOMEOSTASIS. PEOPLE NOT BEING TREATED WITH RESPECT IS THE BASIC THING. IT COMES IN ALL SORTS OF FORMS LIKE ABUSE OR STRUGGLING WITH A BOSS OR HAVING ROMANTIC PARTNER ISSUES. THE NOT FEELING RESPECTED OR HEARD OR KNOWING HOW TO PUT WORDS TO YOUR EXPERIENCES AND EXPRESS WHAT YOU NEED SO A LOT OF THE SKILLS I END UP TEACHING PEOPLE IS WHAT DOES THE BODY TELL YOU AND SAY YOU NEED NOR YOUR HOMEOSTASIS OR YOUR RELATIONAL HOMEOSTASIS AND HOW DO YOU EXPRESS WHAT YOU NEED AND HOW DO YOU DEAL WITH THE RESPONSE AND PEOPLE TEND TO FIGHT BACK. THEY WANT THE OLD HOMEOSTASIS AND THIS IS ALL TO SAY SUBJECTIVE EXPERIENCE I FEEL LIKE DID NOT GET NENOUGH AIR TIME HERE AND IT CAN BE SCARY BECAUSE IT'S DIFFERENT FOR EACH PERSON. I SAW HOW PEOPLE'S SUBJECTIVE EXPERIENCES WERE AND I LEANED INTO IT INSTEAD OF PULLED AWAY. IN SCIENCE WE WANT TO MAKE THINGS STABLE AND ALIVE AND ALL THESE THINGS AND THERE MUST BE A WAY BECAUSE THE MORE I EMBRACE THE UNIQUENESS OF EACH PERSON IN THE ROOM WITH ME THE BETTER THEY GOT AND IT HAD TO TRANSLATE TO RESEARCH. I FOUND PATTERN RECOGNITION LEARNING FOR DATA THAT LET'S EACH PERSON'S BRAIN BE ITS OWN UNIQUE ENVIRONMENT. IT'S NOT FORCED TO LOOK LIKE EVERYONE ELSE'S BECAUSE OUR MINDS AND BRAINS ARE DIFFERENT AND I MEASURE MENTAL STATES DURING MEDICATION. WE GET AN INDIVIDUALIZED BRAIN SIGNAL FOR WHAT BRUNO'S BRAIN LOOK LIKE WHEN HE'S FOCUSSING ON HIS BREATH LOOKS DIFFERENT THAN WHAT OTHERS PEOPLE LOOK LIKE AND WE GET INDIVIDUALIZED BRAIN SIGNALS AND NOW WE CAN TRACK MOMENT BY MOMENT WHICH MENTAL STATES ARE BEING REPRESENTED DURING MEDICATION -- MEDITATION AND TRYING TO FIGURE OUT HOW THE PRACTICES ARE HELPING PEOPLE. HOW MUCH TIME DO I HAVE IN >> YOU'RE ABOUT OUT. SAY YOUR CLOSING STATEMENT. >> I ENCOURAGE SCIENTISTS TO ENGAGE PEOPLE WITH ONE MORE SUBJECTIVE EXPERIENCES OF THE PATIENTS THEY WANT TO HELP. WHEN LORENZO WAS SPEAKING ABOUT ADDICTION, THE INTEROCEPTIVE SIGNALS PEOPLE ARE ESCAPING ARE OFTEN MEMORIES, DIFFICULT RELATIONSHIPS AND HELPING PEOPLE TWO IN TO UNDERSTAND WHAT THEIR BODIES ARE TELLING THEM AND LEARNING TO TOLERATE THE FEELING OF CRAVING WITHOUT ACTING ON IT. I'M INTERESTED ON THE METRICS CORRELATED WITH THE SUBJECTIVE EXPERIENCES. I THINK THERE'S AN INTERSECTION BETWEEN BIOLOGICAL MEASURES AND SUBJECTIVE EXPERIENCES BUT THE PEOPLE WHO HAVE EXPERTISE IN BOTH ARE NOT COMMUNICATING AND I HAVE THE CONVERSATION IN MY HEAD ALL THE TIME AND I FEEL CRAZY SO PLEASE, IF YOU WANT TO TALK TO ME MORE ABOUT THIS. IT'S SO HARD TO WRAP UP. I WANT TO SAY THAT I REALLY APPRECIATE JEANIE'S WORK SHE STUDIED AFRICAN AMERICAN MEN. THE OTHER POINT I WANTED TO MAKE IS WITH THE RELATION SHAN HOMEOSTASIS WE HAVE CO-LINKAGE IN E.E.G. SIGNALS AND IN CROSS-RACIAL INTERACTIONS AFRICAN AMERICAN PARTICIPANTS THEIR PHYSIOLOGICAL SIGNALS START TO MATCH THE CAUCASIAN SIGNALS AND THERE'S SO MANY IDENTITY DYNAMICS PEOPLE AREN'T AWARE OF BECAUSE RESEARCH IS NOT DIVERSE ENOUGH. IF YOU WANT TO TALK TO ME LATER, LET ME KNOW. >> AND OUR SESSION FIVE RAPPORTEUR. >> THE WERE SUPPOSED TO BRING IT DOWN IT THREE QUESTIONS AND I USED SOME BULLET POINTS TO HIDE MY OTHER QUESTIONS. WHAT CAME UP IS WHAT'S THE DIFFERENCE BETWEEN ACTION AND PERCEPTION. WE HAVE TO BE CAREFUL WITH OUR TERMINOLOGY HERE. THERE ARE SIMILARITIES BETWEEN INTERCEPTION AND EXTEROCEPTION AND WE RECEIVED INPUTS AND WE LOOK AT THE INPUTS. THAT'S WHAT WE CALL PERCEPTION. WE INTERPRET THEM IN THE CONTEXT OF THINGS WE EXPERIENCED IN LIFE AND APPRAISAL REALLY MEANS ASSESSMENT OF HOW I VALUE THAT WHAT I'M EXPERIENCING WHICH IS I THINK DISTINCT FROM PERCEPTION ITSELF. SO WE HAVE THAT AND BASICALLY REACT TO THE APPRAISAL AND WE HAVE DIFFERENT TYPES OF REACTIONS THAT CAN BE MOTOR EXECUTIONS. WHEN I'M THIRSTY I HAVE A DRINK AND IT COULD BE AN AUTONOMIC RESPONSE AND THIS IS WHERE WE HAVE TO BECOME EXPLICIT IN THE INTEREST OF THE DOMAIN. THERE'S DIFFERENCES IN MOTOR CONTROL IF I LIFT THIS UP I HAVE A SIGNAL THAT TELLS ME HOW HEAVY IT WILL BE AND WHAT STRUCTURE IT WILL HAVE AND I CAN ELICIT A MOTOR REACTION THAT'S TARGETED BUT IF I REALIZE MY HEART RATE IS INCREASING I HAVE A HARD TIME REGULATING. THERE'S DIFFERENT WAYS I CAN ACCESS THE INTEROCEPTIVE SYSTEM FROM AN EXTEROCEPTIVE SYSTEM AND THEY'RE REGULATING AUTONOMIC FUNCTIONS AND MANY AT THE SAME TIME AND IT THE CHANGE YOUR BREATHING AND SO FORTH. IT'S VERY DIFFERENT IN THE WAY IN TERMS OF THE ACTIONS WE CAN EXECUTE IN THE BODILY DOMAIN COMPARED TO THE EXTEROCEPTIVE DOMAIN AND WE HAVE TO BE EXPLICIT IN LOOKING AT THE SYSTEMS AND IN EMOTIONS IT INVOLVES BREATHING AND CARDIAC SYSTEM AND DIGESTION AND GIVES A SENSE OF THE BODY AND IS DIFFERENT FROM SAYING THE VISUAL SYSTEM AND THE AUDITORY SYSTEM WHERE YOU CAN MAKE THESE DISTINCTIONS THOUGH THEY'RE VERY MUCH LINKED BECAUSE VISION COME TOGETHER. THAT'S ONE OF THE THINGS I WANT TO MAKE A STRONG POINT ON IS WE HAVE TO BE MORE EXPLICIT. AND ANOTHER ONE I WOULD BE INTERESTED IN IS WE'VE BEEN TALKING ABOUT BIOMARKERS BUT I DON'T KNOW IF ANY ONE OF YOU THINKS THERE'S AN EXISTING BIOMARKER THAT IS INTERCEPTIVE AND IF NOT, WHY NOT. I THINK MAYBE ONE OF THE THINGS WE CAN DISCUSS IS WHAT ARE PROMPTING CANDIDATES AND WHAT ARE LOW-HANGING FRUITS AND WHAT SHOULD OF STUDIES SHOULD WE CONDUCT TO GET A BIOMARK DEVELOPMENT GIVEN WE HAVEN'T GOT GOTTEN THERE YET. AND THE LAST ONE IS HOW DOES IT LINK TO MENTAL HEALTH. WE'VE BEEN TALKING ABOUT THIS QUITE A BIT BIT THERE'S A LEAP FROM SAYING THERE'S A DIFFERENCE FROM STAGES TO MENTAL ISSUES AND FROM HAVING A REPRESENTATION IN THE BODY AND EMOTION AND THAT'S ONE WE HAVEN'T CLARIFIED YET AND ONE THING I STARTED TO THINK ABOUT EIGHT -- A LOT RECENTLY AND WHEN WE LEARN THAT ARE DEPENDENT ON THE PHYSICAL STATE. FOOD AND THIRST ARE EASY. WE KNOW IT CAN BE REWARDING IF I'M HUNGRY AND ATE BUT EVERY REWARD MAY BE INFLUENCED BY THE CURRENT STATE OF YOUR BODY. IF YOU HAVE A GOOD CONVERSATION AND SUDDENLY YOU GET DIGESTIVE PROBLEMS OTHER THINGS BECOME SALIENT AND REMOVE THE VALUE OF A SPECIFIC REWARD WE'RE FACED WITH AND IN TERMS OF LIKE OTHER SIDE OF WORK I DO IS COMPUTATIONAL MODELING OF LEARNING AND WE NEED TO INTEGRATE INTERCEPTION INTO LEARNING AND COGNITION. AND WE NEED TO TRY TO SEE HOW THAT HAS INFLUENCES AND IT GETS TO THE LAST POINT WHEN WE TALK ABOUT LEARNING AND WE TALK ABOUT TRAINING AND WE HAD A COUPLE OF REALLY NICE EXAMPLES WHERE PEOPLE USE FEEDBACK AND ONE OF THE KEY QUESTIONS IS HOW LONG ARE THE AFFECTS AND WHAT ARE THEY ACTUALLY CHANGING? ARE THEY CHANGING INTEROCEPTIVE PERCEPTION OR HOW THEY CHANGE SIGNALS OR CHANGING THE WAY WE EVALUATE SIGNALS AND AS LONG AS WE DON'T KNOW WE CANNOT SAY FEEDBACK IS GOING TO BE SERVING TREATMENT AND THAT'S A QUESTION WE NEED TO DEVELOP IN THERAPIES. >> THANK YOU. THANK YOU FOR YOUR COMMENTS. I THINK IN THE NEXT HOUR OR 55 MINUTES OR SO WHAT WE'D LIKE TO DO IS I'M TRYING TO REALLY GO TO THE RECOMMENDATION STAGE OF THE WORKSHOP. WE DESIGNED THE FIVE SESSIONS TO ADDRESS PARTICULAR ISSUES. I HAVE COLLECTED SOME THOUGHTS FOR EACH OF THOSE SESSIONS AND CERTAINLY MAYBE AS I MENTIONED THEM, I'LL ASK THE AUDIENCE AND SPEAKERS TO CHIME IN. BUT BEFORE WE DO GO TO THE SESSIONS THERE WAS A MENTION ON DEFINITION AND WE SHOULD HAVE A GOOD DEFINITION. WHEN WE HAD PRE-CONFERENCE CALLS I WAS WORRIED ABOUT COMING TO A CONSENSUS ABOUT IT BUT ANY OBJECTIONS ON WHAT WAS PROPOSED IN THE INTEROCEPTION SUMMIT AS A DEFINITION FOR INTEROCEPTION IN AND WOULD YOU LIKE TO STATE THAT DEFINITION AGAIN OR AT LEAST GET A PRELIMINARY SENSE FROM THE AUDIENCE WHETHER ANYBODY HAS A DIFFERENT OPINION ABOUT IT? >> I'LL READ IT SO I DON'T GET ANYTHING WRONG. ALSO I'LL ADD THAT WASN'T SPECIFICALLY MY DEFINITION IT WAS DEVELOPED THROUGH CONSENSUS IN THE PROCESS OF HAVING THE MEETING AND THEN ENGAGING WITH EVERYBODY WHO WAS INVOLVED. I THINK THAT COMMUNICATES SOME OF THE VALUES. THE PROCESS BY WHICH THE NERVOUS SYSTEM SENSES, INTERPRETS AND INTEGRATES SIGNALS ORIGINATING FROM WITHIN THE BODY PROVIDE MOMENT BY MOMENT MAPPING OF THE INTERNAL LANDSCAPE ACROSS CONSCIOUS AND UNCONSCIOUS LEVELS. >> I ALWAYS SAY TO THE PATIENT IF I AM DEPRESSED OR SOME WITH SENSITIVITY ARE DIFFERENT WITH THE PATIENT AND A PATIENT WITH GLUTEN SENSITIVITY IS NOT THE SAME. AND I'M CONVINCED THESE PATIENTS FEEL SOMETHING FROM THE BODY BECAUSE THE BRAIN IS THE CAUSE. THIS IS MY INTERPRETATION. IF YOU PUT THE BRAIN TO THE BODY. >> THE NERVOUS SYSTEM IS SO IN TUNE WITH WHAT'S HAPPENING IN THE BODY THE PROCESSING AND WHATEVER IS HAPPENING IN THE ORGAN SYSTEM IS BEING RELAID AND TRANSMITTED AND COMMUNICATED IN A BI-DIRECTIONAL WAY. FOR THAT SPECIFIC EXAMPLE IT SOUNDS LIKE YOU'RE DISCRIMINATING BETWEEN SOMEBODY WHO HAS A PROBLEM WITH A SPECIFIC ORGAN SYSTEM WHERE YOU CAN SEE A PATHOLOGY AND HAS A SYMPTOM VERSUS SOMEBODY WHO DOESN'T. IN BOTH CASES THE REPRESENTATION OF THAT INFORMATION IS IN THE NERVOUS SYSTEM. >> ANYBODY FROM THE AUDIENCE? AND >> I'D LIKE TO CALL TO ATTENTION THE ROLE OF OR THE EXISTENCE OF PRIOCEPTION. >> I WAS GOING ASK WHERE DOES TE -- THE BOUNDARY END. GARY BROUGHT THIS UP ABOUT THE VESTIBULAR SYSTEM. AND WE TEND TO THINK IT WOULD BE. >> IF WE LOOK AT WHAT IS INSIDE THE BODY VERSUS OUTSIDE AND INCLUDE PROPRI CEPTION AND HEAT WHAT'S THE DIFFERENCE IN SENSORY PERCEPTION AND AFFERENT INPUT IN GENERAL . >> ONE THING IS INTEROCEPTION IS CRITICAL FOR SENSING THE STATE OF THE BODY AND MAINTAINING THIS AND IF I CAN'T SENSE THIRST I HAVE ABOUT THREE DAYS IF I DON'T DRINK WATER BEFORE I'M OUT. SO THERE'S A STRONGER LINK TO THE SENSE OF THE INTEGRITY OF THE BODY BUT IF SOMEBODY THROWS THIS AT ME I NEED TO DETECT IT OR I COULD BE ENDED. >> IS THE THE IMPORTANCE OF THE SIGNAL TO HOMEOSTASIS? IT SEEMS HARD TO DRAW A DEFINITION BASED ON THAT. >> I AGREE. AT THE LAST CONFERENCE THERE WAS A LOT OF DEBATE ON WHAT IS INTEROCEPTION AND THERE WAS A BROAD DEFINITION THAT INCLUDED P PROPRICEPTION AND YOU HAVE FIBERS INTERVATING VAST SWATHS OF TISSUES INCLUDING THE SKIN. AND IN 20 YEARS THE TERM MAY NOT EXIST BUT WE NEED DIFFERENTIATION. >> WE HAVE A LOT OF HANDS. >> I WANT TO GO ON TO OTHER TOPICS SO GO AHEAD. >> THE DIFFERENCE BETWEEN SENSORY AFFERENT INPUT AND INTEROCEPTION, INTEROCEPTION IS THE BRAIN'S REPRESENTATION OF THE STATE OF THE BODY WHICH MEANS IT'S RUNNING AN INTERNAL MODEL AND COMBINING TWO THAT'S THE ISSUE OF TOP DOWN AND BOTTOM UP PREDICTION. AND FEDDERIQUE LET YOU ANSWER THE QUESTION HOW MUCH IS THE BRAIN USING AFFERENT IN PUT. INTEROCEPTION IS THE BRAIN'S REPRESENTATION TO SCAN THE BODY AND USING MULTIPLE SOURCES INCLUDING PAST EXPERIENCE AND AFFERENT INPUT IS THE MOST REASONABLE THING TO SAY AT THIS POINT AND REGARDING THE DEFINITION OF INTEROEPTION AND HOW IT'S DIFFERENT FROM EXTEROCEPTION WHEN SCIENTISTS ASK QUESTIONS FOR 150 YEARS AND DEBATE THEM AND CAN'T ANSWER THEM IT MAY BE A CLUE IT'S THE WRONG QUESTION. I THINK THERE ARE EITHER THINGS AND CERTAIN TYPES OF SENSORY INPUT LIKE TOUCH FROM THINGS LIKE THE INFORMATION FROM VISCERA AND OLAFACTION AND WHETHER THERE'S SENSORY FOCUS. MAY MAY HAVE IMPLICATIONS WE'RE IGNORING BECAUSE WE'RE TWIRLING OUR PENS AROUND WHETHER OR NOT SOMETHING SHOULD OR NOT BE DEFINED AS INTEROCEPTION. IF WE WERE GOING TO STICK WITH THAT WE'D WANT TO GO WITH THE DISTINCTION ABOUT THE LARGE MYELINNATED FIBERS AND HE'S USING EMBURIOLOGY NOT DISTINCTION. IF WE'RE GOING TO MAKE THAT DISTINCTION WE HAVE TO GOOD OUTSIDE OF OUR OWN INTERPRETATIONS AND USE SOMETHING MORE PRINCIPLED. >> WHEN I TEACH I GET A SIMPLE DEFINITION I GET FROM WIKIPEDIA AND IT'S AN INTERNAL STATE OF THE BODY. IT SEEMS SIMPLE AND TO MOST PEOPLE QUICKLY COMPREHENSIBLE. MOST SCIENTISTS WILL GET IT. >> THAT DEFINITION WAS WRITTEN BY AN UNDERGRAD IN MY LAB TWO YEARS AGO. [LAUGHTER] >> I AGREE WITH THAT TOO AND YOU MAKE THE DISTINCTION BETWEEN INTEROCEPTION AND EXTEROCEPTION AND YOU CAN USE THE EXAMPLE OF VISUAL AND I AGREE WITH LISA. IT'S ABOUT THE BRAIN'S REPRESENTATION OR THE NERVOUS SYSTEM'S REPRESENTATION OF THE BODY AND THINK OF SOMETHING LIKE VISION IT'S MAKING AN IN FERENCE ABOUT SOMETHING OUTSIDE THE BODY WHEN YOU THINK YOU SEE THE FLAG OVER THERE BUT IT'S A PHOTON THAT'S IN YOUR EYE. IT'S YOUR INFERENCE IT CAME FROM OVER THE OVER THERE WHEREAS THE NEURON IS INSIDE THE BODY WHEN HAVE YOU TEMPERATURE AND SAY IT'S COLD OUTSIDE. IT'S YOU GETTING COLD BECAUSE ARE OUTSIDE. IT'S STILL ABOUT YOU. IT'S ALWAYS IN YOUR BODY AND IN YOUR NERVOUS SYSTEM. IT'S THE INFERENCE ABOUT SOMETHING YOU'RE MAKING AND FURTHER SOLIDIFIES THE REPRESENTATION PART AND NOT IT CAME FROM OUTSIDE. >> I'LL GIVE YOU ONE MINUTE TO STATE YOUR PERSPECTIVE AND THEN IT'S GONE FOREVER. >> I WANT TO SEE WHETHER YOU WHY THIS THE BRAIN PART OF THE INTERSEFTIVE SYSTEM. WE HAVE INTEROCEPTIVE SYSTEM AND WE HAVE BREATHING AND THE BRAIN MODULATES ALL THE RECEPTOR FUNCTIONS. SO WHERE WE MIGHT SAY THE PERCEPTION IS MODIFIED BY THE BRAIN. WE HAVE THE HYPOTHALAMUS WITH ITS OWN SET OF SENSORS. WHERE DO WE DRAW THE LINE? IT SEEMS TO ME IF IT'S IN THE BODY AND THE BRAIN IS DOING INTERACTION WITH THE PERIPHERY, YOU HAVE TO INCLUDE THE BRAIN. >> DOESN'T THE NERVOUS SYSTEM INCLUDE THE BRAIN? >> THE CARDIOVASCULAR SYSTEM INCLUDES THE HEART, ARTERIES AND VEINS AND IF YOU SAY THE COGNITIVE YOU SAY THE BRAIN. AND THE NERVOUS SYSTEM. >> AND WHAT ABOUT THE CELLS? >> YES. >> THEN I'M WRONG. >> AND TO TALK ABOUT THE GASTROINTESTINAL TRACT IF YOU STRETCH IT IT'S THE SIZE OF A BASKETBALL COURT AND WE INCORPORATE THINGS ONTO THE SURFACE SO A SPACIAL CHANGE FROM THE EXTEROENVIRONMENT AND YOU CAN MAKE THE CASE IT'S NOT THAT DIFFERENT OR IT HAS TWO COMPONENTS, INTERCEPTIVE AND OTHERS IS AN EXTEROCEPTIVE. IT'S DIFFERENT FROM ANY OF THE OTHER VISCERA. >> ONE COMMENT AND HOPEFULLY NO MORE. >> I'LL TRY TO SAY THIS IN A NICER TONE. I APOLOGIZE. I'LL NOT SPEAK TO THE SCIENCE BUT THE ONTOLOGY OR DEFINITION ISSUE. I'VE BEEN WORKING WITH THE OFFICE OF BEHAVIORAL AND SOCIAL SCIENCE RESEARCH FOR THE LEAST THREE YEARS THINKING ABOUT ONTOLOGY DEVELOPMENT AND BEHAVIOR. BUT I THINK ONE OF THE THINGS I LEARNED IS RELEVANT WHICH IS WHEN YOU'RE BUILDING AN ONTOLOGY OR BUILDING TERMINOLOGY YOU DON'T WANT TO RECREATE THE WHEEL YOU WANT TO LINK ON TO OTHER ONTO LOGICAL SYSTEMS AND WHAT'S EXCITING TO ME ABOUT THIS CONFERENCE IS WE'RE AT THE TIPPING POINT. YOU SEE THIS VERY STRONG INCREASE OF INTEREST IN THIS FIELD WHICH MEANS IT'S STILL A VERY YOUNG FIELD WHICH MEANS. RECOGNIZING THERE'S HUNDREDS OF YEARS OF RESEARCH ON THIS BUT IN TERMS OF THE NEUROSCIENCE. THAT MEANS WE HAVE AN OPPORTUNITY TO NOT MESS IT UP. WE HAVE AN OPPORTUNITY FROM THE BEGINNING TO BE CLEAR ABOUT OUR TERMINOLOGY AND TO TRY AND AGREE ON THE TERMINOLOGY SO WE'RE NOT ALL BATTLING EACH OTHER ALL THE TIME FOR ACADEMIC PRECEDENCE BECAUSE WE CAME UP WITH A NEW TERM. NOW, WHERE WE BATTLING EACH OTHER BECAUSE IF WE DON'T DEFINE INTEROCEPTION THEY WON'T FIND IT IS NOT THE ISSUE. IF WE HAVE A DEFINITION OUT THERE AGREED ON AT A MEETING WHERE THE LEADERS IN THE FIELD AND NOW WE HAVE ANOTHER MEETING WITH LEADERS IN THIS FIELD, IF WE CAN AGREE ON THE SAME DEFINITION, THAT WOULD BE A HUGE ACCOMPLISHMENT. >> THANK YOU. ANGELA. >> THIS WILL BE A NICE TRANSITION TO ANOTHER TOPIC THAT WAS RAISED EARLIER ABOUT PRIOCEPTION. GARY RAISE THE POINT THAT THE FIRST DISTINGUISHED PERSON IN 1906 DISTINGUISHED THE DIFFERENCE BETWEEN INTERCEPTION AND EXETERO CEPTION AND HAD A THIRD DOMAIN AND SOME HAVE ALIGNED IT WITH EXTEROCEPTION OR INTEROCEPTION. ONE DISTINCTION IS THAT WITH PRI PROCEPTION WE CAN PRECISELY SPES TIE BODY LIMB POSITION BUT CAN'T SAY WHAT STIMULI WE'RE UTILIZING. AND PRI PROCEPTIONS IN MANY CASES ARE IN VAL YOU'LL. >> INVALUABLE. TO GET THE GROUP TO TRY TO REACH A CONSENSUS TODAY. I THINK THAT WILL BE A TALL ORDER. WE WILL HOPEFULLY PUBLICATIONS COMING FROM THE MEETING AND MAYBE THE AUTHORS CAN AT LEAST DEBATE WITH SOME CONSENSUS AT THAT POINT AND IT WILL BE REVIEWED AND CLARIFIED WITH NIH LEADERSHIP. MAYBE THAT WILL CARRY SOME WEIGHT. I WANT EVERYBODY TO HAVE A CHANCE TO AIR THEIR OPINIONS SO WE CAN CAPTURE YOUR THOUGHTS AND AS WE MOVE FORWARD. >> I HAD A QUESTION. I WANTED TO SEE FROM THE BEGINNING OF WORKING ON THE WORKSHOP, ONE QUESTION HAS COME UP TO ME AND ONE OF MY COLLEAGUES. IT WAS THE ROLE OF SLEEP AND CIRCADIAN RHYTHMS AND INTEROCEPTION. WHAT'S THE ROLE OF THAT? IS THAT SENSING FATIGUE? THE ENERGY BALANCE? ALSO WITH ALL THE INTERVENTIONS WE HEARD ABOUT WITH SESSION FIVE. A LOT OF THOSE FACTORS THAT YOU'RE MEASURING CAN BE ALTERED BY SLEEP PATTERNS AND SLEEP DE DEFICIENCY AND WHAT HAVE YOU AND I WANT INSIDER CLARIFICATION FROM ALL YOU WONDERFUL EXPERTS? >> ANYBODY WANT TO TAKE ON THAT QUESTION? >> I DON'T STUDY SLEEP BUT WE HAVE A MODEL WITH DEPRESSION AND FATIGUE. IF YOU'RE IN THE CONFINES OF CHRONIC STRESS, BECAUSE WE'RE IN THE USED TO HAVING CHRONIC STRESSES AND SO THE INTERPRETATION IS IT'S A SICKNESS BECAUSE YEAR NOT USED TO HAVE CONSTANT CHRONIC EXTERNAL STRESSES. THAT COULD EXPLAIN A SUBSET AND AND AFTER THAT IMMUNE RESPONSE ONE OF THE THINGS THAT CAN HAPPEN IS YOU ARE NOT ABLE TO FIGHT THE SICKNESS BECAUSE IT'S NOT INTERNAL. IT'S EXTERNAL. IT'S A MISINTERPRETATION OF THE SIGNAL. ONE STEP WOULD BE TO GO INTO AN ENERGY SAVING MODES AND THAT COULD BE THINGS LIKE APATHY OR RESULT IN FATIGUE. THAT'S WHAT YOU SEE IN PATIENTS THAT CAN BURN OUT AND THAT CAN LEAD TO CHRONIC FATIGUE SYMPTOMS AND THAT'S ONE POTENTIAL PATHWAY AND ONE OF THE THINGS WE'RE DISCUSSING IS THAT THAT IS A MEDICAL INTERPRETATION OF SIGNALS YOU'RE RECEIVING THAT ARE INTERPRETED AS INTEROCEPTIVE AND WE TRIED TO DISSECT WHETHER YOU CAN MEASURE IF THAT'S ONE OF THE POTENTIAL CAUSES FOR FATIGUE IN A SPECIFIC GROUP OF PATIENTS AND WE JUST STARTED TO WORK WITH M.S. PATIENTS BECAUSE THEY'RE FATIGUE IS QUITE COMMON BUT WE HAVE TWO PATIENTS. >> WE SKIPPED OVERRAN WE SKIPPED OVER JANINE'S REQUEST. OVER HAPPY WITH THE DEFINITION OF GIVEN AND MOST PEOPLE ARE HAPPY AND MY NOTION IS WE SHOULD MOVE ON. WE HAVE MORE IMPORTANT THINGS TO TALK ABOUT AND WE HAVE INTRINSIC GANGLION CELLS IN THE FORMATION OF IMAGES AND THEY PROJECT TO REACH INTO THE BRAIN THAT ARE INVOLVED IN COGNITION AND AFFECT AND HAVE PRETTY PROFOUND FUNCTIONS ABOUT THE WAY WE FEEL. I THINK IT'S ONE OF THE PLACES WHERE IF YOU GET TO A BORDER IT'S NOT INTEROCEPTION. THEY'RE SENSING LIGHT. SO MAYBE I'M NOT INVOLVED IN IMAGE FORMATION BUT THIS IS EXTERNAL INPUT AND I THINK YOU'RE THROWING OUT SOME OF THE BABY WITH THE BATH WATER. >> SLEEPINESS IS A SENSATION AND SLEEPINESS IS INDICATIVE SOMETHING IS AWRY BUT NOT DIAGNOSTIC OF WHAT IT IS BUT MAIN IS DIAGNOSTIC AND THE BODY TRIES TO TAKE A NAP FOR FIGHT THROUGH IT AND IF WE DON'T DEAL WITH IT WE HAVE DIRE CONSEQUENCES. >> THIS IS NOT INCLUDED IN THE WORKSHOP. THERE WAS A LITTLE BIT OF -- >> THE TOPICS NOT INCLUDED IN THE WORKSHOP AND THERE'S TOPICS FOR THE BANQUET NO BECAUSE OF OUR FAULT BUT THE SPEAKER COULDN'T COME. THANK YOU. I THINK WE SHOULD CLOSE THIS PARTICULAR DISCUSSION. LET'S TRY TO MOVE ON TO THE ISSUES OF THE SENSORS. AND I THINK WE SEEM TO HAVE A LOT OF GAPS IN THAT AREA. ONE THING I WOULD STRUCK BY AND WE ROOK AT SENSE WE WANTED TO LOOK AT SENSORY RESEPERS AND WASN'T TO SEE -- RECEPTORS AND I WANTED TO SEE IF THERE'S SPECIFIC COMMENTS OR RECOMMENDATIONS FOR THAT AREA OF RESEARCH RELATED TO CIRCUITS PER SE. YOU FEEL WE HAVE NOT COVERED. >> THERE'S A DIVERSITY OF SPEAKERS. I NOTICED THE VET -- VERTEBRATE AND INVERTEBRATES DON'T HAVE INTEROCEPTION OR THEY HAVE DESCENDING AND ASCENDING MODULATION AND CONTROL OF THE HOMEOSTASIS SO. >> I DON'T KNOW WHY IT WOULDN'T BE. AGAIN, IT'S NOT BECAUSE WE HAVE ONLY TWO DAYS TO TALK ABOUT THIS. IS THERE ANY OBJECTION TO INVERTEBRATES NOT BE INCLUDED? >> THERE'S NO MENTIONING OF ANY SPECIES. IT DOESN'T SAY IT'S SPECIFIC TO HUMANS OR NON-HUMAN ANIMALS. >> IN FACT, TWO COMMENTS. FIRST, THERE'S THE DISCUSSION OF HOW CAN YOU STUDY INTEROCEPTIVE AWARENESS IN ANIMALS AND YESTERDAY THERE WAS A BEAUTIFUL CIRCUITRY IN THE MAPPING AND I REMEMBER IN GRADUATE SCHOOL HEARING A SPEAKER TALK ABOUT THE NOTION THAT THERE'S A REDUCTION IN SENSITIVITY TO EXTEROCEPTIVE RECEPTORS IN MAMMALS AND THE CONNECTIVITY TO THE BARRINGTON NUCLEUS IS MODULATED AND YOU CAN DO BEAUTIFUL ANIMAL STUDIES WHERE YOU LOOK AT CONDITIONED PLACE PREFERENCE OR POSSIBLE KANSAS IN RESPONSE TO CUES TO SEEING IF THE ANIMAL CAN SENSE SALIENT INFORMATION AND YOU CAN POTENTIALLY DO THE SAME APPROACHES IN INVERTEBRATES I JUST DON'T KNOW WHAT WOULD BE THE RIGHT HOMOLOG. IN CIRCUITS, WHEN YOU LOOK AT CORTIC CAL CIRCUITRY IN HUMANS WHEN IT COMES TO GASTROINTESTINAL SENSATIONS IT'S NOT JUST IS THE INSULA YOU GET CORTEX S1 AND S2 AND YOU GET THE CEREBELLUM AND RESTRICTING YOU'RE THINKING TO ONE CORTICAL REPLAY STRUCTURE IS ALSO -- RELAY STRUCTURE IS NARROW. WE LOOKED AT A PATIENT WITH A LESION AND WE PREDICTED HE WOULDN'T FEEL IT WHEN HE KNOCKED HIM OUT AND THIS PATIENT HAD SELF AWARENESS AND FEEL HIS HEARTBEAT AND MODULATIONS. IT WILL WASN'T UNTIL WE ATTENUATED SENSORY IN THE CHEST WITH LIDOCAINE WE KNOCKED OUT HIS ABILITY TO FEEL HIS HEARTBEAT. AND IT CHANGED MY VIEW OF INTEROCEPTION IT'S NOT IN THE CLASSIC VIEW A SINGLE RECEPTOR TO A SINGLE RELAY AND THERE'S REDUNDANCY IN THE BRAIN AND A PATIENT WITH A UNILATERAL LESION IS USUALLY INCON -- INCONTINENT AND THERE'S PLASTICITY IN THE NERVOUS SYSTEM AND CIRCUITRY SO THE DEFINITION NEEDS TO BE APPROPRIATELY BROAD. >> THAT'S WHY I'M USING INDIVIDUALIZED BRAIN PATTERN TO FIND A DIFFERENT SIGNAL FOR DIFFERENT MENTAL STATES THAT ACCOUNTS FOR ANY VOXAL IN THE BRAIN. I CAN'T SAY THERE'S A CONSISTENT SIGNAL PAPERS ONLINE. >> IF HE WANT TO LOOK AT WHAT INTEROCEPTION IS DOING IT'S PROVIDING A SENSE OF THE ENERGY NEEDS OF THE BODY AND SENDING THAT INFORMATION BACK TO THE BRAIN. YO CAN SEE THAT EVEN IN VERY VERY LOW-LEVEL ORGANISMS, SINGLE-CELL ORGANISMS. IF THEY'RE MOBILE THEY CAN MOVE TO WHERE THERE'S MORE GLUCOSE OR LESS LESS GLUCOSE. I THINK AT LEAST IN THE WAY I'M THINK OF IT COUNTS AS INTEROCEPTION IN A BROAD SENSE BECAUSE IT HAS TO DO WITH HEART WITH ENERGY REGULATION AND ALL THE THINGS THAT ORGANISMS NEED TO TAKE IN, FIND, FORGE FOR AND IN SOME CASES ALSO DUMP OUT AS WASTE. >> I HEARD FOR A CALL OF MAPS BETWEEN THE BRAIN AND BODY. ARE THERE OTHER SPECIFIC RECOMMENDATIONS? >> ONE COMMENT ABOUT THE INVERTEBRATES. WE ALSO WORK WITH MARINE INVERTEBRATES AND THE CHALLENGES THE BRAIN AND BODY BECAUSE THEY OFTEN DON'T HAVE BRANINS AND THERE'S NO DIFFERENCE BETWEEN EXTEROCEPTION AND INTEROCEPTION AND THEY'RE IN AN ENVIRONMENT THAT REPRESENTS THEIR INTERNAL ENVIRONMENT AND ON THE OTHER HAND THIS BRINGS US TO THE IDEA THAT SOMETIMES WHEN YOU FORAY INTO WORKING WITH ANOTHER ANIMAL MODEL IT CAN TURN THE INTERNIZATION OF THE MODEL ON ITS HEAD. WE CAN DO THIS IN INVERTEBRATES AND IT'S ABOUT BRAIN BODY CONNECTION BUT THERE'S A LOT OF ORGANISMS WITHOUT BRAINS AND WE NEED TO BE GENERAL ENOUGH IF WE'RE LOOKING FOR A MULTISPECIES COMPARISON AND TO CAPITALIZE ON THE DECADES OF RESEARCH AND SPECIESES NA -- THAT ARE BRAINLESS WE NEED TO RETHINK OUR LANGUAGE. >> YES, JACK. >> SO YOU GET LARGE OR SMALL AREAS OF THE BRAINS WITH TENS OF THOUSANDS OF NEURONS AND IT'S IN MUCH SMALLER CIRCUITS. ULTIMATELY WE'LL HAVE TO BRIDGE THE GAP. WE DON'T HAVE THE TECHNOLOGY TO DO IT. I THINK IT HAS TO BE RECOGNIZED THAT WHEN YOU DO THESE BRAIN IMAGES, YOU ARE ARE GETTING LARGE AREAS AND IT DOESN'T REALLY GIVE YOU TERRIBLY MUCH INFORMATION ABOUT HOW THE SIGNALS ARE PROCESSED. AND I THINK IN TERMS OF TRYING TO UNDERSTAND HOW THEY'RE CONTROLLED BY THE NERVOUS SYSTEM THAT LEVEL OF RESOLUTION WON'T WORK BUT WE HAVE TO FIND SOME WAY TO DRILL DOWN FURTHER AND RIGHT NOW WE DON'T HAVE THE TECHNOLOGY TO DO THAT. >> GOING BACK TO THE IDENTITY OF THE SENSORS. FINDING PSO2 AS INVOLVED IN PRIOCEPTION AND REMOVING THE ONE MOLECULE ALLOWED US TO BRIDGE THE GAP BETWEEN MICE AND HUMANS NICELY. IT'S VERY INSTRUCTIVE THAT FINDING THE SENSORS THROUGHOUT THE BODY AND THROUGHOUT THE GUT, I THINK IT'S GOING TO EXPAND OUR INFORMATION OF MECHANISTICALLY WHAT THE BRAIN IS INTERPRETING AND A LOT OF THAT'S MISSING NOW. >> ONE MORE AND WE'LL HAVE TO MOVE ON. >> ANOTHER IDEA, AND IT GETS BACK TO THE INTEROCEPTION AND EX-T EXTEROCEPTION AND YOU HAVE TO NERVE CAN CARRY BOTH SIGNALS. THAT WAY YOU DON'T IGNORE SENSORY SYSTEM WHEN LOOKING FOR INTEROCEPTION. THE VISUAL SYSTEMS CAN COME UP THE SAME NERVE AND GO TO THE CENTRAL THALAMUS OR THE SENSORY CORTEX AND PART OF THE WAY THEY'RE CARRYING INTERCEPTIVE AND EXTEROCEPTIVE PERCEPTION AND WE LOOK FOR CLUES IN THE EXTEROCEPTIVE SYSTEMS FOR INTEROCEPTIVE MOLECULES AND OPENS NEW TOOLS. >> NEXT, I WANT US TO THINK MORE ABOUT THE DYNAMICS AND FUNCTION OF INTEROCEPTION. >> IT MAY SHAPE THE PROCESS AND IT'S SHORT DEPENDING ON WHAT YOU'RE LOOKING AT. I KEEP HEARING THE DIFFERENT MEASURES, OUTCOME MEASURES OF PROCESS AND CLINICAL OUTCOME OR BEHAVIORAL. THERE SEEMS TO BE -- I DON'T HAVE A LOT OF DISCUSSION ABOUT IT BUT I WONDER IF WE CAN GO INTO WHERE ARE WE IN TERMS OF THE MEASURES, FUNCTIONAL MEASURES FOR INTEROCEPTION. I ASSUME IT'S CRITICAL TO REALLY ASSESS THE IMPACT OF INTEROCEPTION FOR OUR FEASIBILITY. >> I WOULD LIKE TO TACKLE THE DYNAMICS QUESTION. YOU PUSHED IT IN A LONGITUDINAL QUESTION AND THERE'S NO QUESTION WE SHOULD TIKE A LIFE SPAN APPROACH BUT THERE'S A PURPOSE ON NOT TREATING AN INDIVIDUAL'S TEST PERSON WHETHER IT'S A PERSON DOING A HEARTBEAT TASK OR A MONKEY DOING AN AUTONOMIC TASK AND I DON'T THINK WE HAVE HISTORICALLY TREATED AS IMPORTANT THE VARIANCE IN TIME OVER THE SESSIONS. PARTICULARLY IN NON-HUMAN ANIMAL WORK. WE TRACK A RESPONSE IN A LIMITED WINDOW AND DON'T FOL IT OVER -- FOLLOW IT OVERTIME AND DON'T TRACK IT TO TRACK THE MAN OFFLINE. >> WE LOOKED AT WHAT INTEROCEPTIVE INFORMATION IS INVOLVED AND THAT'S A DIFFERENT QUESTION. >> I THINK SEX DIFFERENCES WAS RAISED AND THERE WAS THE QUESTION RAISED OF VASO BLUSHING AND THERE'S THE DEVELOPMENT OF PUBERTY AND IN PSYCHIATRIC DISORDERS AND MOOD AND ANXIETY AND EATING DISORDERS. IN TERMS OF MEASUREMENT WE MANIPULATE SIGNALS IN REAL TIME. THERE WAS INTESTINAL BALLOON DISTENSION WHICH IS A GREAT METHOD TO HAVE CONTROL OVER MODULATING A SET OF SIGNALS BUT WE KNOW BEYOND RERECEPTORS IT'S A MEGA STIMULUS THAT CAN HAVE A ROLE FOR SENSORY THAT IS PAINFUL AND NON-PAINFUL. >> I WANTED TO DISTINGUISH THE MEASURES VERSUS THE IMPACT OF INTERCEPTION. I DON'T SEE ANYTHING WANTING TO TALK ABOUT THIS. AND DID YOU GET EVERYTHING YOU WANTED TO GET OUT? >> I WANT TO POINT OUT EARLY LIFE ADD VERSUS TI. YOU DON'T KNOW WHETHER THE ADVERSITY HAPPENED WITH THE SEVERITY AND THERE'S BEEN A SYNDROME OF THING AND LIKELIHOOD TO REPORT ADVERSITY AND SENSITIVITY TO PAIN AND INTERNALAL SYMPTOMS. IT COMES UP IN THE CONTEXT OF LOOKING AT THIS FROM A LIFE COURSE PERSPECTIVE BUT HOW DO WE LOOK AT THE LIFE COURSE EXPERIENCES IN THE CONTEXT OF PEOPLE REPORTING THE PHENOMENON. THAT'S TO THE LIFE COURSE QUESTION AND TO THE FUNCTIONAL QUESTION I THINK WHEN WE TALKED AT THE DIFFERENT FUNCTIONAL ROLES OF INTEROCEPTION AND IN TERMS OF HOW INTEROCEPTION PLAYS A ROLE IN THE MORE COMPLEX PHENOMENON AND HOW IT MAY PLAY A ROLE IN COGNITION, I THINK THEY'RE PROVOCATIVE EARLY REPORTS OF THE COGNITIVE FUNCTIONS FROM THE NATIONAL INSTITUTE ON AGING PERSPECTIVE IT WOULD BE INTERESTING TO SEE GREATER WORK LOOKING AT HOW PROCESSES MAY CONTRIBUTE TO COGNITIVE CHANGES IN AGING AND IT'S A GAP NOT JUST A LACK OF INTEREST. >> AND ONE ELEMENT THAT WAS HIGHLIGHTED A LITTLE BIT AND I THINK THERE'S MORE WORK THAT NEEDS TO BE DONE AND THERE'S IMPACT ON INTEROCEPTIVE STATES WHETHER IT'S INSTRUMENTAL CONDITIONING AND THESE ARE EXPERIMENTS THAT CAN BE FOUND IN HUMANS AND ANIMALS. FOR EXAMPLE, IF YOU WERE TO DO A CONDITION PARADIGM AND PURELY PRESENT THE U.S. AND C.S. DURING A PERIOD DOES IT LEAD TO A DIFFERENT CONDITIONING PATTERNS AND EXTINCTION PATTERNS THAN IF YOU PRESENT IT DURING AN EXTEROCEPTIVE STATE OR OTHER CONDITIONS. THESE THE KINDS OF THINGS WHERE WE CAN BEGIN TO LOOK AT THE IMPACT OF COGNITIVE STATES AND THEY CAN BE DONE IN ANIMALS AND HUMANS. >> I HAVE A QUESTION. I DON'T STUDY INTEROCEPTION. I STUDY OTHER THING. I KNOW WHY THE FOCUS HAS BEEN ON GROUPS THAT HAVE TROUBLE WITH IT. AND HAS ANYONE STUDIED OR FOUND ANY GROUPS IN ANIMAL, HUMAN, ANYTHING. THAT'S GOOD AT SENSING THEIR INTERNAL STATE BECAUSE IF YOU COULD -- I KNOW THE MEASURES. I UNDERSTAND THE MEASURES AREN'T TERRIFIC BUT IF YOU COULD FIND THAT GROUP THEN YOU MIGHT BE ABLE TO SORT OF REVERSE ENGINEER THINGS. >> ANYBODY KNOW? >> I STARTED OUT IN THE MORNING ASKING WHY WE HAVEN'T LOOKED AT THE WORK OF PEOPLE IN OTHER SOCIETIES THAT DO YOGA WHERE THERE'S A LOT OF INTEROCEPTION AND OTHER CULTURES. I MENTIONED I JUST DID A Ph.D. IN AYURVEDA. PEOPLE THERE ARE VERY INTERCEPTIVELILY AWARE AND I DON'T KNOW HOW MANY WORK WAS DONE ON ACCURACY AND PRECISION AND THAT SIXTH SENSE IS THERE BUT THERE'S ALSO A SENSE OF WHAT'S GOING ON IN THE BODY. IF YOU CAN'T CONTROL YOUR DIGESTION YOU DON'T HAVE THAT SKILL AWAKE SO YOU BETTER GO FIX IT BECAUSE YOU SHOULD KNOW HOW TO DO THIS OR YOU SHOULD BE ABLE TO CONTROL YOUR HEARD RATE. >> IT'S A GAP. IT'S NOT THAT WE DON'T CARE ABOUT IT BUT WE HAVEN'T BEEN ABLE TO STUDY IT. AND THERE'S A CENTER FOR COMPLEMENTARY AND INTEGRATIVE HEALTH AND IT'S ONE OF THE REASONS. >> THEY WERE INTERESTED IN THE WORKSHOP. >> THERE WAS WORK BY ELMER GREEN WHO LOOKED AT A SWAMI WHO HAD INCREDIBLE INTERCEPTIVE ABILITIES AND THIS WAS RECORDED IN THE '70s AND I TRIED TO LOOK FROM HERE AND IT BLOCKED THE WEBSITE SO MAYBE THEY DON'T CONSIDER IT REAL SCIENCE. THERE'S CULTURES WHERE IT'S NORMAL AND IT ISN'T IN AMERICA AND WONDERING WHY DE WE DON'T ACCESS THOSE PEOPLE IN YOGA. >> WE HAVE FOUND WORK ON MEDICATION AND I THINK THE CHALLENGE IS DOING CROSS-SECTIONAL COMPARISON AND IT'S HARD TO DETERMINE CAUSAL IMPACT WHICH IS WHAT WE ARE TRYING TO PUSH HERE IN SOME WAYS BUT IT IS CHALLENGING. WE'VE SEEN ABILITIES AN BENEFITS FROM THOSE EXPERIENCED MEDITATORS BUT -- >> I DON'T THINK MEDITATION IS INTEROCEPTION. I THINK IT'S ONE OF THE TOOLS USED BY PEOPLE TO GO INSIDE FOR PEOPLE WOULD DON'T KNOW HOW TO GO INSIDE. THEY SAY MEDITATION. BUT THE ABILITY TO JUST BE AWARE WHICH HAS A WORD IN SANSKRIT, THAT'S THERE AND SOME PEOPLE MEDICATE TO GET THERE. SOME PEOPLE USE OTHER TOOLS. >>. >> MAY I SAY SOMETHING. I'VE BEEN DOING ACUPUNCTURE 30 YEARS AND EASTERN LEXICON HAS A WHOLE HOST OF VERBIAGE FOR THIS. AND I'M KIND OF PUSHING THE EDGES WITH SITTING WITH A WONDERFUL GROUP OF SCIENTISTS BUT I DO THINK WE NEED TO OPEN UP A CONVERSATION HAVING TO DO WITH. EASTERN MEDICINE HAS LEXICON FOR THIS. IT'S CHALLENGING TO REINTERPRET IT IN A SCIENTIFIC MODEL. I'M CURRENTLY TO BE WORKING WITH THIS WITH A PHYSIOLOGIST AND HOPING TO WRITE SOMETHING IN AN INTEGRATIVE ASPECT. WHETHER IT GETS PUBLISHED OR LOOKED AT IS ANOTHER TOPIC MATTER. I'M VERY EXCITED TO BE HERE AND TO DEEPEN MY KNOWLEDGE AROUND THE SCIENCE BUT I DO THINK WE NEED TO START RECOGNIZING THAT THE HUMAN BEING HAS A WHOLE HOST OF CAPACITIES. AND SCIENCE IS ONE WAY TO SEE IT BUT WE STILL NEED TO LOOK AT THE EIGHT LIMBS OF EASTERN MEDICINE AND THE HOMEOSTAT IC PROCESSES THAT GO ON WITHIN EACH INDIVIDUAL PERSON. >> WE HAVE TO MOVE ON OR WE WON'T GET OTHER ISSUES ADDRESSED. I WANT TO GET INTO THE DISEASE NERVOUS SYSTEM DISORDER BECAUSE IT'S A CRITICAL SECTION FOR US. I GOT THE IDEA THAT SOMETIMES CENTRAL INFORMATION IMPACT -- THE CENTRAL NERVOUS SYSTEM CAN HAVE ISSUES ON THE DISORDERS AND COMORBID ISSUES MAYBE WHEN IT'S A COMMON MECHANISM ACROSS THE BODY. SO WHAT I KIND OF DIDN'T QUITE COMPLETE GET A GOOD GRASP ABOUT IS WE TALKED ABOUT IT WHAT IS THE HEALTHY LEVEL OF INTEROCEPTION AND WHAT'S THE RECOMMENDATION BECAUSE IF YOU DON'T HAVE A HEALTHY LEVEL YOU DON'T KNOW WHAT THE STATES MAY BE. >> TOE TRULY UNDERSTAND THE MECHANISMS OF DISEASES ASSOCIATED WITH DISRUPTION OF THE INTERCEPTION, WE NEED TO STUDY THE CIRCUITRY AND PUT IT IN THE CONTEXT OF BRAIN NETWORK. AT THE BEGINNING, PEOPLE TEND TO STUDY ONE PARTICULAR SECTORRY OR ONE PARTICULAR RECEPTORS. IT MAY LOOK AT THE DISEASE STATE BUT WE LEFT OUT THE ENTIRE OTHER DOMAINS. THE NETWORK. TO TRULY UNDERSTAND HOW THE HUME ANBODY IS LOOKING AT THE DISEASE WE NEED TO PUT THE NETWORK TO THE PARTICULAR PATHWAYS IN THE ENTIRE NETWORK. >> ANYBODY ASK. >> I THINK THERE'S NOT A WRONG INTEROCEPTION BUT THERE'S AN ACTION. IF YOU OVERACT TO IT IT'S OVER A CONTROL AND IF YOU LOOK AT OTHER CONTROLS BECAUSE WE'RE TRYING TO DO IS KEEP THE SYSTEM IN BALANCE IN WHICH WE CAN SURVIVE. AND WHEN WE REGULATE THE SYSTEM IT GETS OUT OF BALANCE AND I'M NOT SAYING MONETARY BUT BASICALLY OVER OTHER PERIOD OF TIME. WE CAN TALK ABOUT SOMETHING WHICH IS CALLED CHRONIC STASIS AND THAT'S >> THE WAY WE DIAGNOSE PATIENTS IS THROUGH SYMPTOMS. WE DON'T HAVE DIAGNOSTIC TESTS OR BIOMARKERS AND WHAT THE PATIENT EXPERIENCES AND REPORTS TO US IS CRITICAL. SUBJECTI SUBJECTIST -- SUBJECTIVITY AT THE FINEST AND IF SOMEONE DOESN'T A COMPLAINT THAT DRIVES THEM TO THEIR OFFICE THEY COULD BE WELL OR NOT WELL. WOMEN HAVE A TENDENCY NOT TO SENSE WHEN THEY'VE HAD A HEART ATTACK AND HIGHER RISK OF DYING. THAT'S A FAILURE OF INTEROCEPTION THAT'S CRITICAL AND THERE'S EXAMPLES OF INSENSITIVE TO GLUCOSE DROPS WHEN THEY'RE GIVEN INSULIN. YOU WANT PEOPLE WHO HAVE A SYMPTOM THAT IS MAGNIFIED AND DISTRESSING YOU WANT TO ATTENUATE THE UNPLEASANT ASPECTS. MAYBE YOU RECALIBRATE THEIR COGNITIVE SENSE OF WHAT IT MEANS TO THEM AND YOU WANT PEOPLE WHO SHOULD BE FEELING SOMETHING AND AREN'T TO BE ABLE TO RISE TO THAT LEVEL AND FIGURING OUT HOW TO DO THAT IS HARD. AND WHEN I LOOK AT IT IN THE CONTEXT OF COGNITIVE FUNCTIONING MY CONCLUSION WAS YOU WANT ACCURACY. I THINK THAT'S A GIVEN. THE MORE ACCURATELY YOU CAN PERCEIVE YOUR BRAIN OR NERVOUS SYSTEM CAN REPRESENT WHAT IS HAPPENING THE BETTER. THERE'S NO GOLDILOCKS. I THINK YOU WANT TO KNOW WHEN YOU'RE RIGHT AND WHEN YOU'RE WRONG. I THINK HIGHER ABILITY DESCRIBED IN TERMS OF THAT AWARENESS OF WHEN YOU'RE CORRECT OR NOT. AND MORE IS BETTER AND I THINK ONE OF THE OTHER THINGS IS YOU WANT SENSITIVITY TO THE REL VAVENT DINE RELEVANT DYNAMIC RANGE WHICH IS THE GOLDILOCKS NOT TOO MUCH OR TOO LITTLE. IN THE SENSE THAT LIKE DR. CALLS TALKED ABOUT YOU WANT TO -- YOU DON'T WANT YOUR HEART RATE TO SKYROCKET BEFORE YOU NOTICE IT'S GETTING AB NORMALLY HIGH FOR IT TO BECOME SALIENT. WHEN I THOUGHT ABOUT THIS IN THE CONTEXT OF BODY FUNCTIONING AND YOU'RE ABLE TO DETECT YOUR BODY SENSATIONS AND IT CAN ENCODE THE BODY SENSATIONS OR STATE, YOU'LL HAVE BETTER MEMORY PERFORMANCE WHICH HAS BEEN SHOWN IN MULTIPLE STUDIES. EVEN IF THE BODILY STATES IS AT A LOW AROUSAL THE MULTIDIMENSIONAL FEATURES CAN BE ACCURATELY ENCODED AND RETRIEVED AS PART OF THE MEMORY. AND I THINK YOU CAN MAKE SIMILAR ARGUMENTS FOR OTHER FACULTIES INCLUDING EMOTION, FUNCTION, MEMORY, DECISION MAKING AND SO FORTH. I THINK YOU WANT HIGH ACCURACY. I THINK YOU WANT HIGH ABILITY TO KNOW WHEN YOU'RE RIGHT AND WRONG AND I THINK YOU WANT SENSITIVITY TO THE CORRECT DYNAMIC RANGE AND I THINK IN THE FUTURE, WE COULD UNDERSTAND BETTER WHAT IS THAT DYNAMIC RANGE AND WHEN IS IT ADAPTIVE AND MALADAPTIVE. THAT WAS MY THINKING AT THE TIME. >> THANK YOU. I'M GOING TO MOVE ON TO THE NEXT SESSION. SO THE NEXT SESSION WE'RE TALKING ABOUT MANIPULATIONS AND I HEARD WE DISCUSSED AND PRESENTED MANY MODES OF MANIPULATIONS, PHARMACOLOGIC AND PEOPLE MENTIONED DIET AND SUPPLEMENTS AND NON-PHARMACOLOGICAL DEVICES AND DISCUSSIONS ON TALKING ABOUT COMPLEMENTARY APPROACHES LIKE HYPNOSIS AND MEDITATION AND COMBINING MEDITATIVE APPROACHES. WOULD IT BE USEFUL TO FIGURE OUT WHAT IS GOOD FOR INTERCEPTIVE PROBLEMS. WITH THE DIET TYPE OF APPROACHES BE BETTER FOR THE GUT/BRAIN ISSUES VERSUS IF THE PROBLEM COMING FROM THE NERVOUS CENTRAL SYSTEM AND THE BRAIN-FOCUSSED TREATMENT IS MORE USEFUL FOR BEHAVIORAL APPROACHES. THAT'S MY COMMENTS HERE AND I WANTED TO GET A SENSE FROM EVERYBODY ELSE ABOUT IN TERMS OF INTERVENTIONS AND MANIPULATIONS WHAT ELSE WE SHOULD FOCUS ON. >> SO AGAIN I'M GOING GO TO PERSONALIZED ROUTE DEPENDING ON WHAT PEOPLE'S ISSUES ARE THAT SHOULD DETERMINE THE INTERVENTION, RIGHT. I WANTED TO PIGGY BACK ON THE LAST COMMENT WHERE TAUGHT SOME MEDICAL STUDENTS BASE BODY AWARENESS MEDITATION, MAYBE 10 TO 15 MINUTES AND ONE OF THE MEDICAL STUDENTS HAD CROHN'S DISEASE AND SAID THIS IS THE FIRST TIME I REALIZED I COULD PAY ATTENTION TO MY STOMACH AND WOULD ONLY ADDRESS THINGS WHEN IT GOT EXTREME. FOR SOMEONE WITH A CERTAIN CONDITION THE STOMACH WOULDN'T BE APPROPRIATE BUT THE IDEA WE HAVE THE CAPABILITY OF TUNE INNING AND THEY START TO TALK TO US. AND IT'S ON US TO BE ABLE TO -- RELIVE IN THE INSTRUMENTS OF OUR BODIES AND WE NEED TO LEARN HOW TO TUNE OUR INSTRUMENTS AND PLAY OUR INSTRUMENTS. CULTURALLY, LIKE WHY IS A MEDICAL STUDENT THEN GOING TO BE RESPONSIBLE FOR OTHER PEOPLE'S HEALTH ONLY LEARNING SHE HAS THE ABILITY TO TUNE INTO HER SYSTEM AND THIS REFLECT AS A CULTURAL ISSUE WHERE IT NED TO BE PART OF THE -- NEEDS TO BE PART OF THE EDUCATION SOONER AND EARLIER. WE NATURALLY LEARN THIS THROUGH TOUR FAMILIES BUT OUR FAMILIES ARE NOT PERFECT. THEY DICTATE WHEN THEY THINK WE'RE HUNGRY OR THIRSTY AND MAY NOT BE ACCURATE AND WE MAY OR MY NOT LEARN AN ACCURATE PERCEPTION OF OUR NEEDS, PHYSICAL AND EMOTIONAL. >> YOU SEE PATIENT TRY THINGS THAT WORK OR DOESN'T WORK. IT'S PERSONAL. I PRACTICE [INDISCERNIBLE] ABOUT TWO-THIRDS OF THE PATIENT ARE IMPROVED BY DIAGNOSIS IT DEPENDS ON THE PERSON AND THE THERAPIST OR SO. >> I'M NOTE SURE. -- I'M NOT SURE. SOMETIMES THE PATIENT FIND A DIFFERENT PERSON AND THEY FIND A GOOD ONE. I SAY YOU CAN SWIM -- >> SO RESEARCH WISE HOW CAN WE ADDRESS THAT AND MAKE THAT MORE WITH PEOPLE WILLING TO ADAPT THE MORE USING APPROACHES IF WE CAN DEMONSTRATE THEM. >> THIS IS ONE OF THE CHALLENGES. ACUPUNCTURE HAS BEEN SHOWN TO BE EFFECTIVE FOR QUITE A LONG TIME. THERE ARE SUBJECTIVE OPPORTUNITIES. EVERYBODY DOES NOT RESPOND. THAT'S WELL KNOWN IT SHOULDN'T DISMISS MORE SOLID RESEARCHES. THAT'S WHY I WOULD END. >> JUST TO ANSWER THE QUESTION. I DON'T THINK INTERVENTIONS SHOULD BE LIMITED TO DISORDERS OF INTEROCEPTION. HAVE YOU DIFFERENT THERAPIES. TREATMENT-RESISTANT DEPRESSION ANY DISORDER COULD BE DEFINED AS INTEROCEPTION, MAYBE. THERE'S DISORDERS AND THOSE SHOULD NOT BE THE ONES JUST APPROACHED BY INTERVENTIONS. >> AND IN THE INTEREST OF TIME WE'LL GET KICKED OUT IN A MINUTE OR SO. ABOUT TECHNOLOGY, I WAS VERY THRILLED WHEN CHRISTOPH MENTIONED THE INTEREST IN THE DOING THE MAPPING. IS THAT TRUE. >> IN CONCEPT, YES. >> I THINK FOR THOSE WHO DID A GREAT JOB OF SUMMARIZING I DON'T WANT TO REPEAT AND THE ONE QUESTION I HAVE WAS WITH ROB BUT I DON'T KNOW IF HE'S STILL HERE. THE ANIMAL MODEL MEASUREMENTS WERE WONDERFUL AND CURIOUS WHETHER THEY COULD BE APPLIED TO OTHER ANALYSIS AND I THINK THAT WOULD BE NICE. OTHER THAN THAT, I DON'T KNOW IF ANYBODY ELSE WANTED TO MAKE MORE COMMENTS ABOUT THAT PARTICULAR SESSION IN TERMS OF RECOMMENDING STRATEGIES RESEARCH STRATEGIES? WE DID THAT WELL, YES? OKAY. THANK YOU. I WANTED TO FIRST OF ALL THANK DANA. SHE'S BEEN A GREAT TROOPER TO KEEP US ON TIME. [APPLAUSE] AND ALSO ANGELA AND ALSO THE ENTIRE PLANNING COMMITTEE. I WISH I COULD READ IT BUT YOU CAN'T READ THE NAMES THERE AND THEY'RE VERY IMPORTANT PEOPLE FOR YOU. AND THE PARTICIPATING I.C.s AND THE INSTITUTES AND CENTERS AND IT'S BEEN INSTRUMENTAL IN SHAPING THE FRAMEWORK IN THE CHAIRS AND ALSO WITH THE NON-NIH SPEAKERS I WANT TO THANK THEM FOR THEIR WITH WISDOM AND TIME AND THANK YOU VERY MUCH. >> I WANTED TO SAY TWO QUICK THINGS. ONE, AGAIN, THANK TO SPEAKERS. WE GAVE YOU A VERY DIFFICULT TASK TO PUT ALL THAT STUFF IN A TINY AMOUNT AND WE REALLY APPRECIATE ALL YOUR HARD WORK TO COMPLY. I THINK THIS WENT REALLY GREAT. THE HOTEL SHUTTLE IS OUTSIDE FOR ANYBODY WHO NEEDS TO CATCH THAT. IF ANYBODY HAS FURTHER COMMENTS OR THOUGHTS E-MAIL WEN CHEN OR MYSELF. HAVE A GREAT DAY.