Closed-loop, Allostatic, Acoustic Stimulation Neurotechology for Military-related Traumatic Stress: The WFSM HIRREM Research Program

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Merry Horton
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Breaking the Stigma: Closed-loop, Allostatic, Acoustic Stimulation Neurotechology for Symptoms of Military-related Traumatic Stress Charles H.

1 Breaking the Stigma: Closed-loop, Allostatic, Acoustic Stimulation Neurotechology for Symptoms of Military-related Traumatic Stress Charles H. Tegeler, MD McKinney-Avant Professor of Neurology No conflicts to report Closed-loop, Allostatic, Acoustic Stimulation Neurotechology for Military-related Traumatic Stress: The WFSM HIRREM Research Program Selected concepts on brain management of stress/trauma The HIRREM method Selected highlights of HIRREM research to date: Insomnia studies Military-related traumatic stress Questions 1

2 Military Post-traumatic Stress (PTS) PTS/TBI are signature injuries of recent conflicts, with a host of associated symptoms (hyperarousal, insomnia, depression, re-experiencing traumatic events) PTS is stigmatized, ignored, but may lead to chronic symptoms, conditions, illnesses Evidence of brain imbalance, autonomic inflexibility, impaired autonomic cardiovascular regulation in PTS Substantial drop out rate for current therapies, many fail to benefit, and some risk of adverse events Need for additional effective, short term, noninvasive, non-drug approaches Wake Forest Baptist Medical Center Background Brain frequencies (Hertz) and amplitudes (microvolts) are usually fairly balanced Trauma of all types (physical and non-physical) may activate autonomic nervous system survival responses resulting in imbalance in frequencies and amplitudes Due to brain plasticity/ability to change, repeated or severe/persisting trauma/stress responses may become the new norm (accumulating allostatic load) If imbalance gets stuck/persists beyond time of need it may interfere with performance and resilience, or cause symptoms and diseases 2

3 Background: Not just a side to side brain balance issue Distribution of electrical amplitudes across frequencies (proportionation, harmony, overall arousal) also important Maldistribution of amplitudes across frequencies, or overactivation (hyperarousal) in specific frequency bands, may interfere with performance, lead to dysfunction Like if the entire brass section is playing too loudly, the orchestra will not sound good (disharmony) Excess amplitudes in high frequencies appear to correlate with reported insomnia, anxiety, etc. (e.g. the hyperarousal theory of insomnia) Allostasis/Allostatic Model (Stability through change) Healthy set points can adapt flexibly to changing demands Medication set point is clamped (loses flexibility and range) Diseased set points are stuck to respond at a particular level Recalibration Sterling,

4 High-resolution, relational, resonance-based, electroencephalic mirroring (HIRREM) High-resolution, relational, resonance-based, electroencephalic mirroring (HIRREM, Brain State Technologies, Scottsdale, AZ) Noninvasive, non-drug, closed-loop, allostatic, acoustic stimulation neurotechnology using software-guided algorithmic analysis to identify and translate selected brain frequencies into audible tones of varying pitch Rapid updating on electrical pattern (brain listens to song it is playing), and resonance, supports recipient-unique, whole brain auto-calibration, self-optimization, and relaxation, or re-set of oscillating neural-networks (as with a musical instrument tuning itself; like new sensory system) Brain electrical activity is observed to shift, on its own, towards improved balance/proportionation, often with reduced hyperarousal Premise is that with this precision-guided, inside-out process, if balance, optimal proportionation, and increased flexibility are restored (allostatic load relieved), symptoms may be reduced, and function improved HIRREM Inside-out Process Facilitates Relaxation and Increased Flexibility of Brain Rhythms Relaxation and Flexibility of Brain Rhythms HIRREM Potential Impacts on Health, Performance = HIRREM path to relaxation and flexibility in brain rhythms = Recipient path from relaxation to achieving health and other objectives 4

Data reviewed after each session for future

5 HIRREM In-Office Process Initial brain assessment at standard locations Series of sessions ( minutes each): 3-10 protocols 6-40 minutes for each protocol Data reviewed after each session for future protocols Some protocols done with eyes closed, others eyes open 5

6 HIRREM Research Program at WFSM Launched in 2011; > 450 now enrolled Completed studies: Randomized, wait list control study for insomnia (n = 20) Randomized, placebo pilot trial for migraine (n = 33) Randomized, placebo trial for insomnia (n = 122) Ongoing studies: Open label developmental study (currently n = 253) Pilot trial for military-related traumatic stress (n = 25) Supported to date by grants from foundations (SMCF), philanthropy, and DoD/US SOCOM 9 peer-reviewed publications, > 30 posters/platforms Randomized Pilot Trial HIRREM for Insomnia (n = 20): Primary Outcome Measure (HIRREM vs Continued Current Care) Tegeler,

7 HIRREM for Insomnia: ISI Before and After HIRREM, and One Month After HIRREM (n = 19) Tegeler, 2012 HIRREM for Mod/Severe Insomnia Placebo trial (10 sessions of HIRREM vs. sham placebo) Primary outcome of change of Insomnia Severity Index (ISI) score from baseline to 2 months post-intervention Mean age 53.5, 69 women No difference in expectations after 4 th session: 65% vs 68% Primary outcome (n = 101): Significant added benefit to HIRREM ( point reduction in ISI, p = 0.04) Autonomic changes (n = 97): Significant increases at V3 for multiple measures of HRV/ BRS, with durability through V4 for HIRREM; No significant increase with Placebo at V3 or V4 (Autonomics were not fooled by expectations) 7

Case Series with Self-reported PTSD (n = 19, 11 women, mean age 47) Measure n Baseline Score Mean (SD) Post-HIRREM Score Mean (SD) Change Estimate (SD) p value PCL-C (PTSD) 18 59 (11.6) 36.4 (15.

8 Case Series with Self-reported PTSD (n = 19, 11 women, mean age 47) Measure n Baseline Score Mean (SD) Post-HIRREM Score Mean (SD) Change Estimate (SD) p value PCL-C (PTSD) (11.6) 36.4 (15.9) (11.9) p < ISI (Insomnia) (4.5) 9.2 (6.9) (5.9) p < CES-D (Depression) (10.0) 12.7 (10.4) (12.1) p < Clinically relevant reductions in all 3 symptom clusters (PTSD, insomnia, depressive mood) Tegeler et. al., y/o male s/p IED blast in 2006 with TBI/PTSD Pre-HIRREM TT EC with increased HF amplitude bilaterally, and a left dominant pattern (parasympathetic) Left Temporal T3 Right Temporal T4 8

flight attendant in plane crash, with severe PTSD for 4 years Pre-HIRREM TT

9 TT EC pattern with penultimate HIRREM session Greatly decreased amplitudes in HF s, balanced pattern Left Temporal T3 Right Temporal T4 53 y/o woman, flight attendant in plane crash, with severe PTSD for 4 years Pre-HIRREM TT EC, % right dominant (sympathetic) Left Temporal T3 Right Temporal T4 9

Penultimate HIRREM session TT EC, with overall quieting, 7-24% right dominant, reported marked clinical improvement Left Temporal T3 Right Temporal T4 HIRREM for Military-related PTS Open-label pilot

10 Penultimate HIRREM session TT EC, with overall quieting, 7-24% right dominant, reported marked clinical improvement Left Temporal T3 Right Temporal T4 HIRREM for Military-related PTS Open-label pilot study, 20 HIRREM sessions, over 12 days DoD funding, via contract with US SOCOM Symptom inventories (PTSD, depression, insomnia, and anxiety); autonomic cardiovascular regulation; functional testing (reaction testing, grip strength); brain fmri (network connectivity) All outcomes collected at baseline (V1), and immediately upon completion of HIRREM (V2) Symptom outcomes repeated at 1, 3, and 6 months after completion (V3, V4, and V5, respectively) Primary outcome was PTSD symptoms (PCL-M) at V2 10

HIRREM for Military-related PTS 18 participants (15 active duty, most with NSW Group Ten, 3 veterans, 1 female), all referred for, diagnosed with, or treated for PTS Age 39.

5 years in service (8-33), and 8 deployments (2-19) No drop-outs, no serious adverse events Example of brain pattern changes (29 year old male): Baseline Assessment T3/T4 EC Penultimate minute T3/T4

11 HIRREM for Military-related PTS 18 participants (15 active duty, most with NSW Group Ten, 3 veterans, 1 female), all referred for, diagnosed with, or treated for PTS Age 39.5 (29-50), symptom duration of 2-12 years, 20.5 years in service (8-33), and 8 deployments (2-19) No drop-outs, no serious adverse events Example of brain pattern changes (29 year old male): Baseline Assessment T3/T4 EC Penultimate minute T3/T4 EC 19 th session Improved Symptom Outcomes after HIRREM for Military-related PTS Key Symptom Outcomes Measure Baseline Mean (n=18) V2 Post-HIRREM (n=18) V3 1 month (n=18) V4 3 months (n=18) V5 6 months (n=18) PCL-M 48.4 (12.9) (8.2)*** (12.8)*** -16 (12.5)*** (8.9)*** CES-D 24.7 (11.5) (9.5)*** (11.6)*** (11.2)*** (8.0)*** ISI 16.0 (5.5) -5.4 (4.6)*** -9.2 (5.3)*** -5.9 (7.4)** -5.8 (5.5)*** GAD (5.7) -5.3 (4.4)*** -6.2 (5.5)*** -5.3 (7.5)** -4.5 (6.5)** Wilcoxon p values: ** = p 0.01 *** = p For PCL-M, 72% reported a Minimal Clinically Important Difference ( 10 point reduction) at one month, with 61% still reporting reductions reaching the MCID after 6 months Tegeler et.al., 2016 (AAN and MHSRS) 11

12 HIRREM for Symptoms of Military-related Traumatic Stress (updated for n = 24; significant reductions at all points) V1 = Baseline, V2 = Day of departure, V3, V4, V5 = 1, 3, 6 months post-hirrem HIRREM for Symptoms of Military-related Traumatic Stress (n = 6 initial results for Army SOF) V1 = Baseline, V2 = Day of departure, V3, V4, V5 = 1, 3, 6 months post-hirrem 12

13 Improved Autonomic Cardiovascular Regulation (n = 18) Tegeler et.al., 2016 (AAN and MHSRS) Biomarkers for Stress/Inflammation (n = 14) 13

Functional Brain Networks Whole Brain Rest MRI Network Community

permutation statistic analysis Sensorimotor Network (SMN) Baseline

005) Default Mode Network (DMN) Baseline frontal

009) Salience Network (SN) Trends for increased connectivity for

14 Functional Brain Networks Whole Brain Rest MRI Network Community Consistency Maps Pre- to post-hirrem changes evaluated using a permutation statistic analysis Sensorimotor Network (SMN) Baseline network hyper-connectivity significantly reduced (p = 0.005) Default Mode Network (DMN) Baseline frontal hyper-connectivity significantly reduced (p = 0.009) Salience Network (SN) Trends for increased connectivity for the insula bilaterally Central Executive Network (CEN) No meaningful changes Tegeler et.al., 2016 (AAN and MHSRS) 14

Narrative Feedback Quotes Military Pilot Study MP01: I must say though that the two weeks down there did me a world of good. Thank you again and please tell everyone hi for me.

15 Narrative Feedback Quotes Military Pilot Study MP01: I must say though that the two weeks down there did me a world of good. Thank you again and please tell everyone hi for me. (V5 scores; PCL-M -24, ISI -9, CES-D 23) MP20: I feel that you have restored my hope in life and given me another shot at this world. (PCL-M -27 points at V2) MP21: Thanks for everything. You have given me a second chance at being happy in life!! (CES-D -30 points at V2) 15

16 HIRREM for Military-Related PTS In a cohort with symptoms of military-related PTS, we observed reduced symptoms of PTS, depression, insomnia, and anxiety associated with the use of HIRREM No dropouts, serious adverse events, and benefits appear durable to 6 months post-hirrem Noninvasive, non-drug, precision-guided, patient-centric, relatively brief intervention Improved autonomic cardiovascular regulation (HRV/BRS) Improved network connectivity on brain fmri No control group was possible, but taken together these results suggest that HIRREM merits further consideration as an alternative approach to reduce symptoms of militaryrelated PTS, particularly in the Special Ops community Overall Future Directions Support FDA application for indication of insomnia Additional controlled trials (civilian PTSD, persisting symptoms after TBI, pre-hypertension, others) Extend/expand military work, and explore opportunities in law enforcement/firefighters, others Explore wellness/prevention, stress reduction, improved sleep, resilience, and relaxation Potential to avoid/mitigate adverse effects of acute or chronic stress (turn off the stress spigot before it turns into a raging torrent downstream; prevention/wellness, improved performance) 16

improvement Seek additional collaborators and collaborations Study medical students, nurses, athletes, law enforcement, other

17 Other Directions and Opportunities Explore dose-response, potential of fewer in-office sessions Explore use of a new wearable, limited scope device to minimize in-office sessions, extend benefit, or use alone, for prevention, wellness, performance improvement Seek additional collaborators and collaborations Study medical students, nurses, athletes, law enforcement, other populations Audacious goal to eliminate PTSD as a formal diagnosis Thank You The HIRREM Research Team ctegeler@wakehealth.edu 17

HIRREM: Closed Loop, Noninvasive, Acoustic Stimulation Feedback Brain data assessed in highly granular frequency bins; brain selfoptimizes its activity patterns, on its own terms EEG Operant

18 HIRREM: Closed Loop, Noninvasive, Acoustic Stimulation Feedback Brain data assessed in highly granular frequency bins; brain selfoptimizes its activity patterns, on its own terms EEG Operant Conditioning: Learner-in-the-loop Noninvasive Feedback Neurotechnologies: Brain data assessed in broad-band frequency bins; individual is trained in conscious self-control of brain rhythms 18

19 Open-loop stimulatory technologies No assessment of brain data; individual himself or herself, or care provider, evaluates outcomes 19

Rewiring the Brain: Neurofeedback Insights from The Body Keeps the Score

Rewiring the Brain: Neurofeedback Insights from The Body Keeps the Score Lois A. Ehrmann PhD, LPC, NCC Certified EMDR Consultant; Certified IFS Clinician Certified Attachment Focused Family Therapist Certified