(Session held at the 2014 SharpBrains Virtual Summit; October 28-30th, 2014) 3-4pm. What’s next: The future of non-invasive neurotechnology - Dr. Bruce Cuth­bert, Direc­tor of Adult Trans­la­tional Research and Treat­ment Devel­op­ment at the NIMH - Charles Fisher, Pres­i­dent of Fisher Wal­lace Laboratories - Chair: James Cavuoto, Edi­tor and Pub­lisher at Neu­rotech Reports Learn more here: http://sharpbrains.com/summit-2014/agenda/

1. What’s next: The future of non-invasive
neurotechnology

2. Sponsors
Welcome!

3. What’s next: The future of non-invasive
neurotechnology
Chaired by: James Cavuoto,
Editor and Publisher at
Neurotech Reports
Dr. Bruce Cuthbert
Director of Adult Translational
Research and Treatment
Development at the NIMH
Charles Fisher,
President of Fisher
Wallace Laboratories

4. What’s Next: The future of targets
for non-invasive neurotechnology
SharpBrains Virtual Summit
October 29, 2014
Bruce N. Cuthbert, Ph. D.
Director, NIMH RDoC Unit
National Institute of Mental Health

5. Why RDoC? ~~ Problems with
the DSM system for research ….
• Current diagnostic systems (DSM/ICD) based on
clinical symptoms and signs: cannot identify
biological/psychological mechanisms of disorders.
• Waiting until symptoms appear: makes prevention
more difficult
• Problems such as heterogeneity, co-morbidity,
over-specification, NOS diagnoses
• BUT: DSM/ICD is the de facto standard for research
grants – as well as journal publications, clinical trials,
and regulatory approval.
5

6. …. and problems for clinical use (& new treatments)
6
“On average, a marketed psychiatric drug is efficacious in approximately
half of the patients who take it. One reason for this low response rate is
the artificial grouping of heterogeneous syndromes with different
pathophysiological mechanisms into one disorder.”

7. 7
What may come next:
Research Domain Criteria (RDoC)
• “Develop, for research purposes, new ways of classifying
mental disorders based on dimensions of observable
behavior and neurobiological measures.” research purposs.”
• Identify fundamental components that may span multiple
disorders (e.g., executive function, affect regulation)
• Determine the full range of variation, from normal to
abnormal
• Integrate genetic, neurobiological, behavioral,
environmental, and experiential components
• Develop reliable and valid measures of these
fundamental components for use in basic and clinical
studies

8. 8
Exactly what does RDoC involve?
• A focused research grant funding initiative (~ 40 funded to
date; 14 child, 11 adult of the RFAs)
• Research “toward a new classification system”: study and
validate dimensional constructs that cut across current
disorders
• A *framework* for research – NOT a finished system
• Goal: more homogeneous groupings for interventions –
developing new treatments, or matching current treatments
to precision assessment

9. The RDoC Framework: Four dimensions

10. • Elevated Stress Reactivity
• Problems with emotion regulation
[Symptoms]
• Lack of pleasure in usual activities
• Lack of energy for productive tasks
• Memory problems
• Problems with executive function
• Social withdrawal
• Poor relationships
• Problems with arousal-modulating systems
• Sleep problems

11. Example: BSNIP (Sz-bipolar spectrum)
0=“textbook” bipolar, 9=“txtbook Sz”
Sweeney et al., SOBP Symposium, 2012
Composite Cognitive Functioning

12. BSNIP: Sz-bipolar spectrum (DSM analysis)
Sweeney et al.,
2012
NB: A significant DSM effect does not indicate
meaningful differences at the individual level!
Composite Cognitive Functioning

13. BSNIP: Sz-bipolar spectrum (RDoC approach, look at
factors in better or worse cognitive function)
Sweeney et al., SOBP Symposium, 2012
Composite Cognitive Functioning

14. BSNIP “Biotypes”: Better ways to diagnose (& treat)?
Clementz, Keshavan, Pearlson, Sweeney, & Tamminga, ICOSR, 2013, shared by permisson

15. 15
What you should know: current
approaches to validating new treatments
• NIMH new Clinical Trials Program
• Consistent with new trials across all of medicine
• Therapeutics: major form of validation
• Measurement issues, very important (for multiple
units of analysis) – in a dimensional approach

16. Test the hypothesis about the drug’s mechanism of
action:
1. Show that the treatment reaches the target, establish
optimal dose (receptor occupancy or covert measures =
“target engagement”)
1. Show that the treatment causes a change in relevant
brain activity or mental process in the hypothesized
direction (mechanism of action)
2. Correlate change in mechanism with change in clinical
signal (proof of concept)
16
High Priority: Experimental Medicine, Fast-Fail Trials

17. What could you start doing?
RDoC considerations for early phase clinical trials:
1. Focus on a novel mechanism relevant to a clinical problem
17
regardless of DSM diagnosis (e.g., anhedonia, working
memory)
2. Enroll patients based on deficits in the mechanism, not DSM
diagnosis
3. Both the experimental medicine paradigm and RDoC require
trial outcomes that reflect the target mechanism

18. 18
The Latest RDoC developments
• RDoC Unit in NIMH Office of the Director
• RDoC as an informatics platform
• Based on National Database for Autism Research (NDAR)
• http://rdocdb.nimh.nih.gov
• Work in progress:
• (1) focused number of common data elements
• (2) online discussion forum
• (3) online availability of tasks and paradigms

19. 19
Conclusions: RDoC approach for
innovation in applied neurotechnology
• Standard functions (constructs) for developing new
treatments
• Framework for developing new constructs (or revising
current ones)
• Criteria for new constructs: (1) data for functional dimension
of behavior/cognition; (2) data for neural circuit/system that
implements the behavior
• Prevents making up new targets, “gaming” the trials with
measures of convenience
• Can bring standardization and credibility to field
• http://www.nimh.nih.gov/research-priorities/rdoc/index.shtml

20. What’s next: The future of non-invasive
neurotechnology
Charles Fisher,
President of Fisher
Wallace Laboratories

21. THE AGE OF DIGITAL PHARMA:
CRANIAL
ELECTROTHERAPY
STIMULATION
(“CES”)

22. Today’s Presentation
• Brief History of CES
• The Current Technology
• Peer Reviewed Research
• Clinical Applications
• Q & A

23. Humble Beginnings of CES
• 46 AD – Scribonius Largus
- Black Torpedo
• 1700’s – Charles Kite
- electric defibrillator
- reviving dead “work of the
Devil”
• 1850’s – Strange Contraption

24. Early Devices
* Electro-medical apparatus, A. Gaiffe, Paris 1868

25. Modern CES = Digital Pharma
Example: The Fisher Wallace Stimulator®
• FDA Cleared to treat depression,
anxiety and insomnia
• Portable & Easy-to-Use
• No Serious Side Effects
• Use at home for 20 - 40 minutes
per day
• Gentle Alternating Current 1-4 mA
• Frequencies: 15 hZ
500 hZ
15,000 hZ
• Refined by Bernard and Saul Liss –
M.I.T. / NASA

26. Mechanism of Action
• Increases Serotonin*
• Increases Beta-Endorphins*
• Increases GABA*
• Decreases Cortisol*
• Decreases in Neuronal Activity
Unlike tDCS and repetitive TMS, the effects of cranial AC
stimulation seems to decrease neuronal activity, helping
explain reduction in anxiety.
* Proven in blood, cerebral spinal fluid & saliva tests published in
peer reviewed journals

27. Ease of Use
• Clinical Recommendations (Brown)
• 20 Minutes per Treatment Session
– Automatic Timer
– 2X per day for Severe Symptoms (1-2 mA)
• 30-45 Day Treatment Regimen
• Outpatient & Inpatient
• Low Maintenance
– Sponges & Batteries

28. Patient Populations
• Patients / Doctors seeking alternatives to medication
• Patients with Generalized Anxiety Disorder, Major Depressive Disorder and
Bipolar Disorder
• Military veterans suffering from PTSD and TBI related depression, anxiety and
insomnia
• Women who are pregnant or nursing and therefore cannot use antidepressants or
other medications
• Patients who cannot tolerate the side effects of medication or are resistant to
medication
• Patients and doctors seeking to enhance the effect of medication (many
psychiatrists prescribe our device in conjunction with antidepressant medication in
order to enhance the effect of medication or to reduce medication dosage)
• Patients seeking alternatives to TMS or ECT therapy
• Patients suffering from mild depression, seasonal depression, jet lag, temporary
anxiety, or other conditions that are not appropriately treated with long term
medication
• Drug and alcohol rehabilitation clinics (Phoenix House, Day Top Village, Samaritan
Village)

29. Advantages of CES
• Use With or Without Medication
• Extremely Low Risk
• Portable
• Affordable
• Easy to Use
• 100% Refund Policy

30. PTS Symptoms are Drug Resistant
A recent study published in The Journal of the American Medical
Association and reported by The New Times:
Antidepressants such as Risperdal, Seroquel, Geodon and Abilify
that are widely prescribed to treat severe post-traumatic stress
symptoms for veterans are no more effective than placebos and
come with serious side effects, including weight gain and
fatigue.
A LOW COST, NON-DRUG THERAPY TO TREAT PTS SYMPTOMS,
ESPECIALLY DEPRESSION, IS ESSENTIAL

31. Addiction Recovery Pilot Program
• Largest Non-Profit Drug Rehab
Center in USA
• 392 Subjects – Cocaine and
Heroine Addicts
- 293 Non-CES (control)
- 99 CES (for first 10 days of detox)
• PTSD & Detox Symptoms:
Depression, Anxiety, Insomnia

32. Phoenix House – Outcome
• 50% increase in retention after 90 days
(versus control group)
• Reported profound reduction of PTSD &
Detox symptoms (Anxiety & Insomnia)

34. New Bipolar II Study at
Beth Israel Medical Center
A double-blind randomized placebo controlled study of cranial electrotherapy
stimulation for the treatment of depression in bipolar II disorder
S Greenman BA, D McClure BA, G Kazariants PhD, M Varvara MD, S Koppolu MBBS, Z Yaseen MD, I Galynker MD PhD
Beth Israel Mount Sinai Medical Center, New York, NY, USA
Abstract
Introduction: Cranial Electrical Stimulation (CES) technology has been used widely for treatment of depression, anxiety and
insomnia, but to date, there have been no studies examining the efficacy of this technology to treat bipolar II depression. Our
goal in this study was to evaluate the use of CES for treatment of the symptoms of depression in bipolar II disorder. We
examined changes in levels of depression and quality of life during the four week treatment period.
Methods: Patients diagnosed with bipolar II disorder and currently depressed by SCID-P were recruited from the Family Center
for Bipolar in NYC. Participants were randomly assigned to either a placebo group or an active group for the first two weeks of
daily 20 minute CES treatment sessions. Both groups received open-label active treatment for an additional two weeks following
the randomization period. Participants were assessed at baseline, and weekly during the treatment period, using the Hamilton
Depression Rating Scale (HAM-D), the Beck Depression Inventory (BDI), Clinical Global Impressions Scale (CGI-S), and the
Quality of Life Satisfaction and Enjoyment Questionnaire (Q-LES-Q). ANOVAs were run to compare the groups at baseline, 1st
assessment and 2nd assessment; independent t-tests to analyze differences at each time period between groups, and paired t-tests
to analyze the quantitative changes between each time point.
Results: The sixteen participants were 50% female, with a mean age of 47.69 (15.88), and an average level of education of
16.81 (2.401) years. Results showed a significant interaction between BDI scores and the treatment group (p =.006). There is a
significant main effect of treatment group on HAM-D scores (p=.00). Groups did not differ significantly on any of the assessment
measures at baseline. At week two, the active group compared to placebo had significantly higher scores on Q-LES-Q scale
(p=.010) There was a significant decrease in participants’ HAM-D and BDI scores in the active group from baseline to the
second week (p=.004, p=.004) and baseline to the fourth week (p=.002, p=.015).The placebo group showed a significant
decrease on BDI scale scores from baseline to week four (p=.012), but no significant change from baseline to week two. In the
placebo group, there was a significant change from baseline to 2 weeks on HAM-D scores, (p=.015), and during the open label
treatment phase from 2 weeks to 4 weeks, (p=.022). In the active group, there was a significant decrease in severity scores
using CGI-S from baseline to second week, and baseline to 4th week, (p=.017), while there is no significant difference in means
for the placebo group.
Discussion: Our preliminary results indicate that the active group had significantly higher reduction in depression levels
compared to the placebo group. During the double-blind randomized and controlled trial of the first 2 weeks, there was a
significant decrease in BDI scores for only the active group. However, the data displays improvement effects for both groups on
the Hamilton Depression Rating Scale, which may be due to the difference in brain regions associated with HAM-D and BDI.
Also, patients who received active treatment had decreased severity of the illness on CGI-S measures, while the placebo group
had no change on the CGI-S scale. Clinical implications of this study include validating the safety and efficacy for CES in
treatment of depression in bipolar II disorder.
Keywords: bipolar II depression, cranial electrical stimulation This research was funded by the Fisher Wallace Laboratories.
Introduction
Bipolar II disorder is challenging to treat, with only marginally effective treatments.
CES has been used for pain, anxiety, insomnia and depression (Kirsch & Nichols, 2013).
Lack of research with controlled, randomized and double-blind trials, specifically with bipolar II
patients currently depressed.
Another study examining CES on bipolar disorder looked at chart reviews, N=7, and yielded no
significant results. (Mostafa et al, 2013)
Clinical implications include validating the safety and efficacy of Cranial Electrotherapy Stimulation
for the treatment of depression.
Hypothesis
In this study, we hypothesize that CES will reduce depression symptom severity in the active group
more than in placebo group. We also hypothesize that CES administered for 20 minutes daily for
four weeks is safe and well tolerated when treating bipolar II patients.
Methods
Table 1. Demographic and Clinical Characteristics
Safety of CES:
A repeated analysis of variance was conducted on AMI, MMS, and CFQ, and
no significant trends or effects were displayed. There were no changes
within groups or between groups throughout the treatment.
Blood Pressure:
Text
Mean aggregates for each week, from weeks 1-4 for active and placebo
were conducted.
No significant changes in systolic or diastolic pressure were found.
Table 2. Side effects associated with the use of CES
16 patients diagnosed with Bipolar II Disorder and currently depressed by SCID-P & HAMD were
recruited by the Family Center for Bipolar in New York City and randomly assigned to active or
placebo group for the first 2 weeks of tx.
Assessments of depression: HAM-D, BDI, CGI-S, Q-LESQ
Cognition: AMI, MMS, CFQ
Safety: pre and post treatment blood pressure, EEGS, EKGS, side effects
Side effects were calculated by counting the incidences during active treatment (total=210) versus
during non-active treatment (n=90). The number of participants who reported event were counted.
A symptom was noted as having a change greater than or equal to one difference from pre treatment
to post treatment. Side effects were rated from 1=none to 4=severe.
ANOVAs were run to compare trends during phase I, and independent t- tests were used to
analyze the quant itat ive differences at each t ime point . Paired t- tests were used to analyze
the within group changes f rom baseline to week 1, and baseline to end of Phase I. Discussion
Efficacy:
Results
22.00
20.67
18.75
18.14
15.50
12.25
35.00
31.17
28.25
21.50
14.75
Results of the paired sample t test revealed that the active group experienced greater
reduction in depressive symptoms, such as BDI, CGI-S, and Q-LES-Q.
Both groups improved on HAM-D, possible explanation is the placebo effect or
different brain regions being associated with HAM-D and BDI.
Safety & Tolerability:
Results support our hypothesis that CES is a safe and non-invasive course of
treatment.
The results indicate that there was no significant difference between groups on AMI
(autobiographical memory), MMS, or CFQ during phase I.
Blood pressure showed no significant changes after analysis of mean aggregates per
week for four weeks.
This supports our hypothesis that physical functioning and limitations due to physical
functioning are not negatively impacted from use of cranial electrotherapy stimulation.
Implications of this study include improving treatment for depression in bipolar II
disorder.
Limitations of this study include the small sample size, and the specificity of the
population in regards to low external validity.
Future studies replicating the safety and efficacy of CES on a larger sample size would
help validate our results.
Results (continued)
HAM-D
BDI
18.67
*
14.67
12.00
Table 3.ANOVA & T- test results
*
Study Design
Randomization
2 weeks
Sham Active
Non-Responders
(Open label treatment)
2 weeks
Follow up
Phase I
Phase II
Phase III
Responders Responders
9.00
placebo, n=9
active, n=7
15.11
10.86
baseline First Week Second Week
Figure 1.A: HAM-D scores during double-blind
randomized control phase.
8.00
25.00
17.00
27.75
19.38
placebo, n=7
active, n=7
baseline First Week Second Week
5.0
4.5
4.57
4.0
3.5
55
45
35
34.33
29.22
25
15
CGI-S
4.00
4.22
Q-LESQ
48.50
placebo, n=9
active, n=7
3.71
4.33
53.50
39.33
29.44
placebo, n=9
active, n=7
4.33
baseline First Week Second Week
Figure 1.B: BDI scores during double-blind
randomized control phase.
Figure 1.C: Q-LESQ scores during double-blind
randomized control phase. P<.05 At week 2
3.0
baseline First Week Second Week
Figure 1.D CGI-S scores during double-blind
randomized control phase. p approaches
significance, p=.067 at week 2.
Characteristic
Active Tx,
N=7
Mean (SD)
Placebo,
N=9
Mean (SD)
p
Age 51.33(11.99) 43.78(18.26)
.279
Years of Education 15.83(1.84) 17.11(2.57)
.590
N(%) N(%)
Employed or student 2(28.6) 2(22.22)
Single/Separated/Divorced 3(42.9) 7(77.8)
.329
Sex: Male 5(71.4) 3(33.3)
.315
Comorbid personality
disorders
6(85.7) 7(77.8)
1.00
Borderline 1(14.3) 4(44.4)
.308
Narcissistic 3(42.9) 0
.063
OCPD 2(28.6) 3(33.3)
1.00
Side Effect
Percent of Pat ients Report ing
Event
Percent of Incidences per
Total Number of
Treatments
CES (n= 18) Placebo (n= 9) CES (n= 210) Placebo
(n= 90)
Drowsiness 61 66.7 8.1 10
Blurred Vision 22 22.2 4.8 7.8
Dizziness 16.7 16.7 1.9 1.1
Headache 44.4 77.8 9.5 10
References
Kirsch D., Nichols F., (2013).
Cranial Electrotherapy Stimulation for Treatment of Anxiety, Depresion, and Insomnia. The Psychiatry Clinics of North America.
Time
and
treatm
ent
interac
tion
Active
treatment
vs. placebo
Mostafa A., El-Wasify M., Elmaadawi A., Jeannie R., Mallakh R., Cranial Electrotherapy Stimulation for the Treatment of Chronically Symptomatic Bipolar Patients. (2013) Journal of ECT.
Treatment
effect over
time
Baseline Week 1 Week 2
Baseline -
Week 1
Baseline -
Week 2
Scales
Tota
l N F p Mean (SD)
Mean
diff. t p Mean (SD)
Mean
diff. t p Mean (SD)
Mean
diff. t p 95% CI p 95% CI p
Primary
Outcomes:
BDI
Placebo 9 27.75 (12.86) 3.42 0.52 0.62
19.38
(8.82) -1.02 -0.26 0.802
25.00
(12.07) -8.32 -2.44 0.172 [-1.01 - 17.76] 7.30E-02[-2.34 - 7.84] 0.242
Active 7 31.17 (11.43)
18.67
(6.68)
17.00
(12.28) [1.07 - 23.93] 3.80E-02
[7.01 -
21.33] 4.00E-03
time x tx group
interaction 10.89 6.00E-03
HAM-D
Placebo 9 18.14 (4.74) -2.52 -1 0.34
14.67
(4.47) -2.67 -1.29 0.218 15.11 (3.86) -4.25 1.7 0.112 [0.89 - 11.11] 2.70E-02[1.41 - 9.70] 1.50E-02
Active 7 20.67 (5.22) 12 (3.56) 10.86 (6.18) [3.61 - 8.67] 1.00E-03
[3.41 -
11.16] 4.00E-03
time x tx group
interaction 0.489 0.496
Secondary
Outcomes:
CGI-S
Placebo 9 4.33 (0.5) 0.24 0.92 0.38
4.22
(0.441) -0.22 -0.88 0.396 4.33 (0.5) -0.62 -1.97 6.90E-02 [-0.49 - 0.71] 0.681 [-0.54-0.54] 1
Active 7 4.57 (0.54)
4.00
(0.577) 3.71 (0.756) [0.08 - 1.07] 0.03 [0.22 - 1.5] 1.70E-02
time*tx group 5.906 2.90E-02
Q-LES Q
Placebo 9 29.22 (14.84) 5.11 0.6 0.56
39.33
(18.41) 8.67 1.08 0.299
29.44
(16.13) 23.56 2.984 0.01 [-21.94 - 1.72] 8.40E-02
[-12.2 -
11.75] 0.967
Active 6 34.33 (18.21)
48.5
(12.97) 53.5 (16.40)
[-24.54 -
(-3.79)] 1.70E-02
[-37.8 - (-.
53)] 4.60E-02
time*tx group 4.774 4.80E-02
GAF
Placebo 9 50.11 (5.93) 5.03 1.54 0.15
55.56
(7.49) -0.13 0.897 52.33 (7.68) 6.24 1.703 0.111 [-13.2 - 2.31] 0.144 [-9.55 - 5.11] 0.504
Active 7 55.14 (7.20)
55.14
(3.89) 58.57 (6.68) [-7.06 - 7.06] 1 [-7.63 - 0.77] 9.30E-02
time*tx group 9.40E-02 0.763
YMRS
Placebo 9 0.78 (1.20) -0.06 -0.11 0.911 1.11 (2.03) 0.46 0.43 0.672 1.11 (1.05) 0.75 0.902 0.383 [-2.29 - 1.63] 0.705 [-1.1 - 0.44] 0.347
Active 7 0.71 (0.951) 1.57 (2.23) 1.86 (2.19) [-2.31 - 0.6] 0.2 [-2.69 - 0.41] 0.121
Friday, May 9, 14

35. Hamilton Depression Rating Scale

37. Challenges ahead for field at large
• FDA regulation
• Reimbursement
• Distribution channels: B2B vs
B2C
• Integration of mature and new
technologies
• Proper adoption to maximize
value yet ensure safety

38. Additional Information
• www.FisherWallace.com
• Chip Fisher – President
• chip@fisherwallace.com
• Cell: 917-912-0629

39.  To learn more, visit SharpBrains.com