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The Management of Anxiety, Insomnia and Depression with

Cranial Electrotherapy Stimulation (CES): Theory and Practice

Jeff Marksberry, MD, FAIS Science and Education Director

© Copyright 2013 EPI, Mineral Wells, Texas, USA ALL RIGHTS RESERVED

Cranial Electrotherapy Stimulation (CES)

The application of low level current of <1 milliampere applied across the head for treatment of

anxiety (including PTSD), depression and insomnia with additional applications such as ADHD being studied.

4-Step Procedure: 1. Wet Electrodes

2. Place on Ear Lobes 3. Turn on CES Device

4. Set to Comfortable Current for 20 Minutes to One Hour

83%

78%

67%

70%

84%

81%

68%

56%

85%

90%

80%

84%

0% 10% 20% 30% 40% 50% 60% 70% 80% 90% 100%

Alpha-‐S4m (N=311)

Alpha-‐S4m (N=89)

Wellbutrin (N=1168)

ZoloD (N=2028)


Alpha-‐S4m (N=98)

Sonata (N=62)

Lunesta (N=462)



A4van (N=838)

Xanax (N=2238)

2011 Military Service Member and Civilian Postmarke4ng Surveys: Alpha-‐S4m® CES Compared to WebMD Drug Surveys

Alpha-‐S(m Data from October 2011 Military Service Member Survey Analysis (N=152) and Alpha-‐S(m Pa(ent Survey (N=1,745) October 2011 Conducted by Larry Price PhD, Associate Dean of Research and Professor of Psychometrics and Sta(s(cs, Texas State University.

Pharmaceu(cal Survey Data from: www.WebMD.com/drugs. Accessed on October 28th, 2011.

Service Member Civilian

Anxiety

Depression

Insomnia

Percent of Pa4ents Repor4ng Improvement

2

Traditional View of Synaptic Activity

But only 2% of neuronal communication occurs at the chemical synapse.

Pert, Candace. Molecules of Emotion: Why You Feel The Way You Feel. Scribner, New York, 1997.

Models of Receptor Activation 21st

Century

The New Proposed

Theory: Physical/ Atomic

Electromagnetic Communication

19th & 20th Century

The Current Theory:

Structural Matching; Chemical/ Molecular Physical

Communication The 3D nature of the ligand matches the receptor. Physical proximity induces receptor conformational changes which triggers the cascade of events prompting cell function

Proximity favors co-resonance specific bioelectrical signals with frequencies that perfectly match the resonance of the receptor to amplify molecular conformational changes at all steps of the cascade including cell function, even from long distances (like tuning in a radio).

Benveniste, J. A fundamental basis for the effects of EMFs in biology and medicine: The interface between matter and function. Chapter 13 in Bioelectromagnetic Medicine. Rosch, P and Markov, M, eds. Marcel Dekker, New York, 2004.

Alpha-Stim® Waveform On Oscilloscope It is the waveform that differentiates

devices.

Through periodic, but slow, reversal of the polarization of the DC current,

the Alpha-Stim waveform is able

to inject a spectrum of low frequencies into

the neuronal tissue to match

frequencies with different receptors,

thus activating them in a way

similar to chemical ligands.

3

Saul H. Rosenthal, MD, Psychiatrist and CES Researcher

Studied Medical Students at UT Austin Who Reported:

Relaxed

Alert

Tranquil

Not Worrying

Bright and Happy

Increased Energy

Improved Sleep

No Confusion, Memory Loss or Disorientation

Feelings Experienced During CES Treatment Stages

Dosage equals time inversely proportional to current level (i.e., less current requires longer treatment time per session)

SLEEPY

AWAKE

TIME

ALERT

20 minutes to 1 or more hours

HEAVY, GROGGY, EUPHORIC (never stop here)

No “brainfog”, vision is clear, and energetic as if the patient slept all night

LIGHT FEELING Some patients feel light rig

ht away

Putative Mechanism of CES CES engages the serotonergic (5-HT) raphe nuclei of the brainstem. 5-HT inhibits brainstem cholinergic (ACh) and noradrenergic (NE) systems that project supratentorially. This suppresses thalamo-cortical activity, arousal, agitation, alters sensory processing and induces EEG alpha rhythm. 5-HT can also act directly to modulate pain sensation in the dorsal horn of the spinal cord, alter pain perception, cognition and emotionality within the limbic forebrain. Legend: Blue arrows: inhibitory interactions Purple arrows: excitatory interactions X: suppressed pathways/interactions Ach actetylcholine LDT laterodorsal tegmental nucleus of the brainstem PPN pediculo-ponitne nucleus of the brainstem NE norepinephrine; LC locus ceruleus, 5-HT serotonin

Giordano, James. Illustrating how CES works. Insert in Kirsch, Daniel L. Cranial electro-therapy

stimulation for the treatment of anxiety, depression, insomnia and other conditions. Natural Medicine,

23:118-120, 2006.

4

QEEG Changes in 30 Subjects Treated with 20 Minutes of CES There is an increase in alpha activity with a simultaneous decrease in delta.

Blue = decrease Red = increase

Kennerly, Richard. QEEG analysis of cranial electrotherapy: a pilot study. Journal of Neurotherapy, (8)2, 2004.

Presented at the International Society for Neuronal Regulation conference, September 18-21, 2003, Houston, Texas

MNI x= 48 MNI x= 4

Regional deactivation associated with 0.5 Hz (blue) and 100 Hz (yellow)

Regions positively associated with current intensity for 0.5 Hz

Effects of Cranial Electrotherapy Stimulation on fMRI Brain Activity in the Resting State

Feusner , Jamie D., Madsen , Sarah, Moody, Teena D., Bohon , Cara, Hembacher, Emily, Bookheimer , Susan Y. and Bystritsky, Alexander. Effects of cranial electrotherapy stimulation on resting state brain activity. Brain and Behavior. Pp 1-10, 2012.

Beta-endorphins

98% in plasma

219% in CSF

Serotonin

15 - 40% in plasma

50 - 200% in CSF Shealy, C. Norman, Cady, Roger K., Culver-Veehoff, Diane, Cox, Richard & Liss, Saul.

Cerebralspinal fluid and plasma neurochemicals: response to cranial electrical stimulation. Journal of Neurological and Orthopaedic Medicine and Surgery. 18(2):94-97, 1998

Effects of CES on Cerebralspinal Fluid and Plasma Neurochemicals

5

Safety Considerations

Primary Contraindications

Interference with pre-1998 implants (e.g., pacemakers and defibrillators)

– No longer applicable?

Pregnancy – possible miscarriage and potential

unsubstantiated legal arguments in case of developmental defects

Adverse Effects from CES

From 144 human studies encompassing 10,556 people where 8,792 received active CES:

9 headaches (0.10%, 1:977) 6 cases of skin irritation (0.07%, 1:1,465)

These are both mild and self-limiting.

If the current is set too high headaches, vertigo or nausea could develop and might endure for hours to

days in people with a history of vertigo. If the treatment is stopped too soon

a heavy feeling accompanied by disorientation may persist for hours or even days.

6

Topics of Scientific Research on CES

Number of Pivotal Scientific Studies on Indicated Uses:

42 Anxiety

27 Insomnia

26 Depression

Research is done independently

Double blinding capabilities

Follow up studies show a durable effect

State (Situa4onal) Anxiety

State anxiety can be effectively treated in a single CES treatment session.

Results will vary based on initial anxiety level, length of treatment, comorbidities and overall patient health.

This is demonstrated in medical and dental studies and in mechanistic studies of EEG and fMRI changes from a single CES treatment.

Trait (Chronic) Anxiety

May require up to 6 weeks of CES treatments to see significant reduc(on in trait anxiety levels.

Treatment outcome may also depend on comorbidi(es such as depression and insomnia.

7

Generalized Anxiety Disorder

•  RCT with an N of 115 at Liberty University

•  83.7% of the ac(ve group reported at least 50% improvement

•  P=0.001, Cohen’s d=0.93

•  The mean decrease on the HAM-‐A in the ac(ve group (32.8%) was more than 3 (mes the mean decrease of the sham group.

Barclay, Timothy H and Barclay, Raymond D., A Clinical Trial of cranial electrotherapy s(mula(on for anxiety disorders. In Process. Conducted at Liberty and Stetson Universi(es and presented at the American

Psychological Associa(on 121st annual conven(on, Honolulu, July 31 – Aug. 4, 2013.

19.89

13.37

21.98

19.98

12

14

16

18

20

22

24

Baseline Week 5

Mean Anxiety Scores

Ac4ve Sham



P=0.001

PTSD in a 54 Year Old Male Veteran Overall Decrease in Severity by 39% in One Month

PTSD Symptom Scale – Interview (PSS-I)

PRE

POST

PSS-I (Range: 0-51)

34

13

Re-experiencing (0-15)

7

2

Avoidance (0-21)

15

7

Increased Arousal (0-15)

12

4

Bracciano, Alfred G., Chang, Wen-Pin, Kokesh, Stephanie, Martinez, Abe, Meier , Melissa & Moore, Kathleen. Cranial Electrotherapy Stimulation in the Treatment of Posttraumatic Stress Disorder: A Pilot Study of Two Military

Veterans. Journal of Neurotherapy, 16(1): 60-69, 2012.

8

PTSD Symptom Scale – Interview (PSS-I)

PRE

POST

PSS-I (Range: 0-51)

29

10

Re-experiencing (0-15)

9

2

Avoidance (0-21)

9

5

Increased Arousal (0-15)

11

3

PTSD in a 38 Year Old Male Veteran Overall Decrease in Severity by 43% in One Month

Bracciano, Alfred G., Chang, Wen-Pin, Kokesh, Stephanie, Martinez, Abe, Meier , Melissa & Moore, Kathleen. Cranial Electrotherapy Stimulation in the Treatment of Posttraumatic Stress Disorder: A Pilot Study of Two Military

Veterans. Journal of Neurotherapy, 16(1): 60-69, 2012.

Mean HARS Score

21.17

15.36

10.44

0

5

10

15

20

25

1 3 6

Time (weeks)

Bystritsky et al, Journal of Clinical Psychiatry, 2008

CES Significantly Reduced the Symptom Burden of GAD with a Decrease in HARS Score (P=.01) Similar to that

Found in Clinical Psychopharmacology Trials – APA 2009

Bystritsky, Alexander, Kerwin, Lauren and Feusner, Jamie. A pilot study of cranial electrotherapy stimulation for generalized anxiety disorder. Journal of Clinical Psychiatry, 69:412-417, 2008

Situational Anxiety in Dentistry Following Real or Sham CES Treatment

Winick, Reid L. Cranial electrotherapy stimulation (CES): a safe and effective low cost means of anxiety control in a dental practice. General Dentistry. 47(1):50-55, 1999.

Treatment Phase

Visu

al A

nalo

gue

Scal

e A

nxie

ty S

core

P<.02 P<.02 P<.04 NS

9

Childs, Allen and Price, Larry. Cranial electrotherapy stimulation reduces aggression in violent neuropsychiatric patients. Primary Psychiatry, 14(3):50-56, 2007; Presented at American Psychiatric Association annual meeting, 2007.

0

200

400

600

800

1000

1200

1400

Aggressiveepisodes

Seclusions Restraints PRN Meds

Incidents

Pre CES

Post CES

3 Month Trial with 48 Severe Aggressive Patients

41% reduction in episodes of violence (P<.001); 40% reduction in episodes requiring restraint (P<.001) and seclusion (P<.05), and 42% fewer as-needed emergency medications (P<.01).

The decrease of 271 PRN med doses in 3 months saved >$12,000 for these med expenses alone.

Insomnia Insomnia pa(ents usually see results aber one treatment.

Or it may take up to 4 weeks of treatment, especially if insomnia is associated with depression.

Recent study completed at Walter Reed showed an average increase of +46 minutes of sleep aber only 5 treatments.

3 Week RCT of CES for Insomnia in Fibromyalgia Patients

Lichtbroun, A.S., Raicer, M.M.C. and Smith, R.B. The treatment of fibromyalgia with cranial electrotherapy stimulation. Journal of Clinical Rheumatology. 7(2):72-78, 2001.

Presented at the 15th Annual International Symposium on Acupuncture and Electro Therapeutics, Columbia University, New York, October 1999.

0

10

20

30

40

50

60

70

P r e S t ud y S ham R x S ub s ens a t io n C E S S ens a t e C E S

G ro up R ep o r t ing

S leep P attern o f S tudy G ro ups

Little or No Sleep

Moderate Sleep

Good, Very Restful Sleep

P< .02

10

8 Week CES Fibromyalgia RCT Study

Taylor, Ann G., Anderson, Joel G., Riedel, Shannon L., Lewis, Janet E., Kinser, Patricia A., and Bourguignon, Cheryl. In Press, Pain Management Nursing, 2013.

(P<.001) (P<.071)

Depression

Expect a minimum of 3 weeks of daily CES treatment before results are seen.

A pa(ent who suffers from anxiety with a depression component will take up to 3 weeks to improve as well.

FDA Public Health Advisory March 22, 2004

WORSENING DEPRESSION AND SUICIDALITY IN PATIENTS BEING TREATED WITH

ANTIDEPRESSANT MEDICATIONS

Today the Food and Drug Administration (FDA) asked manufacturers of the following antidepressant drugs to

include in their labeling a Warning statement that recommends close observation of adult and pediatric

patients treated with these agents for worsening depression or the emergence of suicidality. The drugs

that are the focus of this new Warning are: Prozac (fluoxetine); Zoloft (sertraline); Paxil (paroxetine);

Luvox (fluvoxamine); Celexa (citalopram); Lexapro (escitalopram); Wellbutrin (bupropion);

Effexor (venlafaxine); Serzone (nefazodone); and Remeron (mirtazapine)

11

Example of Side Effect Profile for the Popular Antidepressant Zoloft (sertaline)

Results from a placebo controlled clinical trial (n=2799) As cited by www.drugs.com/sfx/sertraline-side-effects.htm

6% Appe4te

>2% Abdominal Pain

>2% Paresthesia

21% Insomnia

8% Respiratory

13% Drowsiness

12% Fa4gue

14% Dry Mouth 12%

Dizziness

20% Diarrhea

21% Sexual

Dysfunc4on

7% Swea4ng

6% Libido

8% Tremor

6% Cons4pa4on

>2% Back Pain

25% Headache

>2% Malaise

>2% Flatulence

5% Nervousness

3% Rash

4% Vomi4ng

5% Agita4on

4% Anxiety

>2% Pain

25% Nausea

Depression Study

•  RCT with an N of 115 at Liberty University

•  82.2% of the ac(ve group reported at least 50% improvement

•  P=0.001, Cohen’s d=0.75

•  The mean decrease on the HAM-‐A in the ac(ve group (32.9%) was more than 12 (mes the mean decrease of the sham group.



9.64

6.47

10.22 9.96

6

7

8

9

10

11

Baseline Week 5

Mean Depression Scores

Ac4ve Sham



P=0.001

12

Effects of 2 and 3 Weeks of CES on Depression 4 Studies that used the POMS Depression/Dejection Scale

Matteson M et al. An exploratory investigation of CES as an employee stress management technique. Journal of Health and Human Resource Administration. 9:93‑109, 1986

Smith R et al. Electrosleep in the management of alcoholism. Biological Psychiatry. 10(6):675‑680, 1975

Smith R et al. The use of cranial electrotherapy stimulation in the treatment of closed-head-injured patients. Brain Injury, 8(4):357-361, 1994

Smith R et al. The use of transcranial electrical stimulation in the treatment of cocaine and/or polysubstance abuse, 2002

Post CES Pre CES 0

2 4 6 8

10 12 14 16 18

Group Means

P< .05

P< .001 P< .03

P< .05

CES Induced Changes in Beck Depression Inventory Over 7 Months in Alcoholic Patients

1

Pre-test Mid-test Post-test

0

2

4

6

8

10

12

14

16

May, Brad & May, Carole. Pilot project using the Alpha-Stim 100 for drug and alcohol abuse. August, 1993

Pain Management •  Acute •  Chronic •  Post-operative

Pain relief is cumula(ve with con(nued use.

Usually results are seen from the first treatment.

There is no risk of accommoda(on or addic(on.

13

What is the first thing you think of when your computer breaks?

What is the first thing you think of treating when you have pain?

Tan, Gabriel, Dao, Tam K., Smith, Donna L., Robinson, Andrew and Jensen, Mark P. Incorporating Complementary and Alternative Medicine (CAM) Therapies to Expand Psychological Services to Veterans Suffering From Chronic Pain. Psychological Services, 7(3):148–161, 2010.

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Percent Improvement in 32 Veterans Across 158 Treatment Sessions

Tan, Gabriel, Dao, Tam K., Smith, Donna L., Robinson, Andrew and Jensen, Mark P. Incorporating Complementary and Alternative Medicine (CAM) Therapies to Expand Psychological Services to Veterans

Suffering From Chronic Pain. Psychological Services, 7(3):148–161, 2010.

0% 10%

20%

30%

40%

50%

60%

70%

80%

Pain Anxiety Depression Sleep Well-‐being

Holubec, Jerry T. Cumulative Response from Cranial Electrotherapy Stimulation (CES) for Chronic Pain. Practical Pain Management, 9(9):80-83, 2009.

42%

50%

54%

64%

71%

40%

45%

50%

55%

60%

65%

70%

75%

1 2 3 4 5 CES Treatment Sessions

Percen

t Red

uc4o

n in Pain Levels

Cumula4ve Improvement in Pain ADer 1-‐5 CES Treatments

Example of the CES Response Over Time in a Patient with Severe Migraine

Courtesy of COL Michael Singer, Walter Reed Army Medical Center

Stay with it!

0

2

4

6

8

10

0 60 120 180

Pain Level

minutes

15

Migraine Headaches -- Frequency and Intensity CES Doubles Effects of Biofeedback

Following 8 Treatments 2/week for 1 month After 1 Month

After 2 Months After 3 Months

0

200

400

600

800

1000

1200

Acc

umul

ated

Per

cent

Impr

ovem

ent

Time After Treatment Began

Biofeedback PLUS CES Biofeedback Alone

Brotman, Philip. Low-intensity transcranial electrostimulation improves the efficacy of thermal biofeedback and quieting reflex training in the treatment of classical migraine headache. American Journal of Electromedicine, 6(5):120-123, 1989.

Doctoral dissertation, City University Los Angeles, 117 pages, 1986.

8 Week CES Fibromyalgia RCT Study

Taylor, Ann G., Anderson, Joel G., Riedel, Shannon L., Lewis, Janet E., Kinser, Patricia A., and Bourguignon, Cheryl. In Press Pain Management Nursing, 2013

(P<.023) (P<.028)

fMRI RCT on CES Activity in Brain Pain Processing Regions in Fibromyalgia Patients

Subjects using an ac(ve CES device had a decrease in ac(va(on in the pain processing regions of the brain compared to those using a sham device.

Taylor, Ann G., Anderson, Joel G., Riedel, Shannon L., Lewis, Janet E. and Bourguignon, Cheryl. Explore, 9(1):32-49, 2013

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VA Houston CES Spinal Cord Injury Study

4

5

6

7

8

1 3 5 7 9 11 13 15 17 19 21 23 25 27 29 31 33 35 37 39 41

Day

Before Session After Session

Sham Open Label

Before and After Session Pain Ratings Sham Group and Their Open Label Treatment (n = 17)

Before and After Session Pain RatingsSham Group (n = 20)

4

5

6

7

8

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21

Day


Before and After Session Pain RatingsTreatment Group (n = 18)

4

5

6

7

8

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21

Day


Figures 1, 2, and 3: Daily Pain Rating for Active CES and Sham CES Groups Tan, Gabriel, Rintala, Diana H., Thornby, John, Yang, June, Wade, Walter, and Vasilev, Christine.

Using cranial electrotherapy stimulation to treat pain associated with spinal cord injury. Journal of Rehabilitation Research and Development, 43(4):461-474, 2006.

Tan, Gabriel, Rintala, Diana, Jensen, Mark P., Richards, J. Scott, Holmes, Sally Ann, Parachuri, Rama, Lashgari-Saegh, Shamsi and Price, Larry R. Efficacy of cranial electrotherapy stimulation for neuropathic pain following spinal cord injury: a

multi-site randomized controlled trial with a secondary 6-month open-label phase. The Journal of Spinal Cord Medicine, 34(3):285-296, 2011

5.514.87 4.77

5.134.25 4.04 3.58

0

2

4

6

8

10

Baseline After Active 3 weeks

At 3-‐Month Follow-‐up

At 6-‐Month Follow-‐up

BPI Average Pa

in In

tensity

Participants in 3-‐Month Follow-‐up (n = 39)Participants in 6-‐Month Follow-‐up (n = 24)

3 Year, 5-Site Spinal Cord Injury Study

P<.01

P<.001

The Use of CES to Potentiate Anesthesia in Surgery

Fentanyl P<.05 N2O 50%

P<.05 N2O 62.5% P<.05 N2O 75%

P<.05

0 10 20 30 40 50 60 70 80 90

100

Am

ount

of A

nest

hetic

Req

uire

d

Anesthetic Used

Anesthesia Plus CES Anesthesia Alone

2 Studies

CES May Improve Efficacy of Meds, and May Warrant Reduced Dose

Stanley, TH, Cazalaa, JA, et al. Transcutaneous cranial electrical stimulation decreases narcotic requirements during neurolept anesthesia and operation in man. Anesthesia and Analgesia. 61(10):863-866, 1982

Stanley, TH, Cazalaa, JA, et al. Transcutaneous cranial electrical stimulation increases the potency of nitrous oxide in humans. Anesthesiology. 57:293-297, 1982

17

♦ Tail Flick Latency (TFL) studies

TFL as % of baseline

Drug Alone

Drug Plus CES

Revealed a significant increase in analgesic effect of opiates. (Stinus, 1990).

morphine fentanyl alfentanil dextromoramide

174% 176% 160% 267%

306% 336% 215% 392%

Results were also obtained after intracerebroventricular injection of morphine (10 micrograms; analgesic effect increase from 152% to 207% with CES) suggesting that CES potentiation of opiate- induced analgesia is centrally mediated.

♦ There was as much as a threefold increase in β-endorphin

concentration after just one CES treatment (Krupisky, 1991).

Experimental Rat Studies of CES CES May Improve Efficacy of Meds, May Warrant Reduced Dose

Krupisky, EM, Katznelson, YaS, Lebedev, VP, et al. Transcranial electrostimulation (TES) of brain opioid structures (BOS): experimental treatment of alcohol withdrawal syndrome (AWS) and clinical application.

Presented at the Society for Neuroscience Annual Meeting, New Orleans, November 10-15, 1991

Stinus, L, Auriacombe, M, et al. Transcranial electrical stimulation with high frequency intermittent current (Limoge's) potentiates opiate-induced analgesia: blind studies. Pain. 42(3):351-363, 1990

64% 60% 60% 53% 42% 45%

+ 9% + 12%

+ 26%

+ 9% + 20%

+ 55%

0%

20%

40%

60%

80%

100%

Anxiety PTSD Insomnia Depression Pain Headache

Percen

t Improvem

ent

Comparison of Service Members That Used Alpha-Stim With Or Without Medications

Alpha-‐S4m with Medica4ons Alpha-‐S4m Only

Alpha-‐S(m Data from October 2011 Military Service Member Survey Analysis (N=152) and Alpha-‐S(m Pa(ent Survey (N=1,745) October 2011 Conducted by Larry Price PhD, Associate Dean of Research and Professor of Psychometrics and Sta(s(cs, Texas State University.

Summary

•  CES is safe •  CES is easy to use •  CES is proven effective •  CES works quickly and lasts •  CES is FDA, CE and ISO certified •  DoD/VA is using and researching CES •  CES is available to help you NOW!

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Are Your Patients in Pain? Anxious? Depressed? Not Sleeping well?

Why Not Try Alpha-Stim?

Questions? Call 1-800-FOR-PAIN Email Dr. Jeff Marksberry: [email protected]

www.alpha-stim.com

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