1. Brain Stimulation & Neuromodulation
Jay A. Yeomans, MD, DFAPA
Medical Director of Psychiatry Consult
Liaison and Brain Stimulation Service
Carolinas HealthCare System
September 27th, 2016
First Annual CHS BH Summit

2. • No disclosures
• Acknowledgements
Dr. Mark George, et al. at MUSC
• Objectives:
• The participant will:
• Be aware of the underlying premise of neuromodulation.
• Be aware of the Neuropsychiatric indications for Brain Stimulation.
• Be aware of the FDA approved classifications and non-FDA approved
brain stimulation devices.

3. The Burden of Depression
• Approximately 18.8 million adults aged 18 and older
are stricken with depression in an given year (NIMH)
• Suicides eclipse homicides in the US annually by one
third (DHHS). The elderly are particularly at risk
• Medications and psychotherapy may fail to alleviate
severe depressions, particularly those complicated by
psychosis or catatonia
• Antidepressants may increase suicidality in some
patients and may not be safely used during
pregnancy.

4. Why Brain Stimulation for Depression?
• limits of current treatment strategies
NIMH STAR*D study:
Sequenced treatment alternatives to relieve depression (screened > 4K pts)
Focus on treatment of depressed patients when the 1st prescribed
antidepressant proved inadequate & included remission as an outcome
measure
 4 levels (SSRI / antidepressant & CBT / Li or T3 & antidepressant /
MAOI or combo antidepressant)
• Level one: 1/3 remitted, then 1/3 with 2nd, 13% with 3rd and 13% with 4th
 Data suggest that a patient with persistent depression can get well after
trying several treatment strategies, but his or her odds of beating
depression diminish as additional treatment strategies are needed
12 months later: 25% sustained remission w/level 1; 13% (L2),
4 % (L3) and 3% (L4)

5. Why Brain Stimulation for Depression?
• Medication under treatment, e.g.
‘pseudoresistance’ – have not received
sufficient guideline-concordant treatment
• Side Effects from medication (non
discriminate): e.g. weight gain, fatigue, etc.
• Psychotherapy (patient resistance / limited INS
coverage)

7. Important Points
• Underlying premise of neuromodulation is that the
brain is an electrochemical organ that can be
modulated by pharmacotherapy or devise-based
(ECT / TMS) approaches or their combination
• There is an explosion of new techniques for
electrically stimulating the brain, primarily focally
• These new tools are changing neuroscience research
and neuropsychiatric therapies
• They validate and inform us about functional
neuroanatomy

8. Figure 3.12. This is an example of the electro-chemical signaling from a dopamine neuron.
If this were an inhibitory neuron, GABAor g lycine for example, the postsynaptic potential
would be an IPSP and not an EPSP.The Brain is an Electrochemical Organ
Electricity is the Currency of the Brain
All of synaptic pharmacology simply serves to transmit electrical
signals to the next neuron

9. Brain Stimulation Techniques (partial listing)
• ECT - Electroconvulsive Therapy
- Alternating current, directionless
• Ultra brief pulse
• (FEAST (Focal Electrically Administered Seizure Therapy)
- Cycle it, turning it on and off rapidly and make sure all pulses are rectified,
causing a direct current-like direction - Extremely fast tDCS.
• TMS - Transcranial Magnetic Stimulation
• VNS - Vagus Nerve Stimulation
• DBS - Deep Brain Stimulation
FDA
Approved

10. Brain Stimulation Techniques (partial listing)
• tACS – transcranial Alternating Current Stimulation
Cranial Electrotherapy Stimulators (CES)
• tDCS - transcranial Direct Current Stimulation
• MST - Magnetic Seizure Therapy - Super TMS
– limited to cortex for site of seizure
• LFMS- Low field magnetic stimulation
• TENS - transcutaneous Electrical Nerve Stimulation
• Transcranial pulsed ultrasound
• eTNS (external trigeminal nerve stimulation)
FDA
Classi-
fication

11. When it First Started, Things Were Rough

12. History of ECT
• 16th century, camphor by mouth to induce convulsions to ‘cure lunacy’
• 1934: Meduna, Hungarian Neuropsychiatrist, believed Schizophrenia
and Epilepsy were antagonistic disorders
- epileptics have many glial cells, Schizophrenia have too few
- ergot, causing seizures might stop or cure schizophrenia (sic)
• Injected patients w/Schizophrenia with camphor oil to cause a seizure,
Patient had a 60 sec grand mal seizure, ‘woke up’.. Full recovery, left hospital …
• Later replaced camphor with metrazol … spread throughout Europe.
• 1937: AmJPsych: ‘therapeutic seizure’ (worldwide)
(Drawing by Renato Sabattini, PhD)

13. What about ‘Electrical’ CT?
• 1938 -Italian psychiatrists, working in Rome, Cerletti
and Bini, worked on electrical parameters that could
induce seizures. Dog model
• treated Italian man, ? Psychotic depression - recovered after 11 treatments
Nominated for the Nobel Prize
ECT was born…
• Kalinowsky started ECT at NY State Psychiatric Hospital/
Columbia Presbyterian Hospital in NY
1940’s – Widespread use throughout the world … RUL
1950’s – Modifications in ECT technique initially curare then (‘52 –
Holmberg) used succinylcholine as a muscle relaxant with ECT
Standard treatment for hospitalized depression

14. History of ECT
• 1960’s – 1980s … Decline in use of ECT
• Psychoanalyst marginalized ECT
• Pharmaceutical industry marginalized ECT
• 1960s counterculture hostility toward ECT
• 1961: Erving Goffman’s Asylums
• 1962: Ken Kesey’s anti-psychiatry novel / play
(‘70) / movie (‘75):
One Flew Over the Cuckoo’s Nest

16. 1980’s: Resurgence in the use of ECT
1985: JAMA “not a single controlled study has shown another form of
treatment to be superior to ECT in the short-term management
of severe depression”
How does ECT (therapeutic seizures) modify mood?
• A) Brain Structure …
o hippocampal neurogenesis
• B) Neurotransmitter Enhancement …
o after Seizure - flood of Catecholamines: 5HT, NE DA, GABA & BDNF
• C) Normalization of Neuro-Endocrine Abnormalities …
o Surge of Hypothalamic & Pituitary peptide (prolactin & TRH)
o Hypercortisolemia frequently found in Melancholia -
Cortisol function normalizes; TSH & GH responses are abnormal
during illness and normalize with remission

17. How does ECT (therapeutic seizures) modify mood?
D) Electrophysiology … Anticonvulsant effects (kindling)
Analogous to Cardioversion: heart in a dysrhythmic state is restored to normal rhythm by an electrical stimulus
Cerebroversion: hyperactive hypothalamic-pituitary system (leads to a
breakdown of the feedback mechanism in the stress response) is normalized after a
therapeutic seizure.
•

18. How does ECT (therapeutic seizures)
modify mood?
Ctrl-Alt-Delete
-----------------------------
Downsides
Headache
Nausea
Myalgia
Retrograde / anterograde amnesia
Mini Mental State Exam / Montgomery Depression Rating Scale

20. BITEMPORAL (BT), RIGHT UNILATERAL (RU),
and BIFRONTAL (BF) POSITIONS
Letemendia et al., 1993

21. Electroconvulsive Therapy
ECT
• Guideline recommendations
– Acute Treatment of Depression, especially psychotic or suicidal
– Acute Mania
– Catatonia
– Helpful in treatment refractory conditions (e.g. treatment for intractable seizures)
– Need for rapid definitive intervention
– Medically ill, risk of inanition
– Elderly
– Pregnancy (teratogenicity a function of exposure duration / succinylcholine: low ratio of
placental transfer)
• New findings / where the field is going?
– Right unilateral, ultra brief pulse
– Perhaps FEAST, MST

22. Acute & Maintenance ECT

23. ECT Summary
• ECT is a safe & very effective treatment for
depressive disorders either first-line treatment
or after medications fail.*
• Between 80% and 90% of patients will respond
to ECT. It is the most efficient and fast-acting
treatment for urgent-care, severely depressed
patients for which medications take 4-6 weeks
to work.*
• Treatment of choice for Catatonia, Failure-to
thrive, Psychotic & Suicidal depression.
*APA Taskforce book, The Practice of Electroconvulsive Therapy, 2001

25. Functional neuroimaging studies suggest a role of
cortical governance over limbic activity
Transcranial Magnetic Stimulation for
Depression
Holy Grail
Focal
Noninvasive
Nonconvulsive
stimulate the prefrontal cortex to
lance depression

26. Brain Connectivity
This area is
involved in
depression
TMS
• Takes advantage of the natural brain circuitry
• Dorsolateral prefrontal cortex: DLPFC –
(lateral aspect of the middle frontal gyrus)
• Interconnected with limbic structures that play
a role in mood modulation & depression
• Effect neural activity at the site of stimulation
as well as distal regions that are interconnected
with the DLPFC – implicated in mood,
motivation and arousal

27. TMS HISTORY
• 1831 - *Michael Faraday - principle of electromagnetic
induction
• 1896 - D’Arsonval - first TMS
• 1903 - patent: Pollacsek and Beer
• 1910 - Sylvanius P. Thompson: 3 papers on TMS and
phosphenes
• 1959 - Kolin demonstrated magnetic fields stimulate
frog muscle
• 1985 - Barker, modern TMS
• 1993 - First therapeutic cases reported in depression

28. Early TMS
Sylvanius
P.Thompson
with one of the first
transcranial magnetic
stimulators (1910)
Thompson SP. A physiological effect of an
alternating magnetic field.
Proc R Soc Lond B Biol Sci. 1910;82:396-
398.

29. Applications of TMS
• Investigative Tool
– (sTMS) Mapping the cortex of the brain
– Probing neural networks by stimulation or inhibition at different places
and times
– Measuring cortical excitability in health and disease, and response to
drugs
– Modulating brain function to study the pathophysiology of a variety of
neuropsychiatric conditions
• Treatment Tool
– Neuropsychiatric conditions; depression, pain, substance craving, anxiety
(OCD), Tourette’s Disorder, etc.
– Alter physiologic states like reversing sleep deprivation

30. Faraday’s law
A time-varying current (di/dt) in a wire loop will induce a magnetic field
Electricity and magnetic energy are interchangeable
current flowing through a coil produces a
magnetic field proportional to the current (&
perpendicular to the current)

31. 35
How TMS works
• Electrical current flowing through a coil induces a
magnetic field
• Pass a current through a hand held coil, whose shape
determines the properties and the size of the field
• The coil is driven by a machine - switches the large
current necessary in a very precise / controlled way
• The coil is held on the scalp and the magnetic field (2
Tesla) passes through the skull (unimpeded) and into
the brain
• Alternating (pulsating) magnetic fields induce electrical
current in underlying brain tissue
• Small induced currents influence the brain areas below

32. How TMS Works
George MS. Sci Am. 2003;289:66-73.

33. Output:
Motor Evoked Potential
Single Pulse TMS is an Investigational Tool

34. homunculus

35. TMS Intensity
Motor Threshold (MT)
• Stimulate the motor cortex (gyrus) which is oriented 45
degrees backwards – axon lies on the gyrus
• Evoked muscle twitch threshold in response to motor
cortex stimulation.
• Defined as lowest intensity capable of inducing at least
5 out of 10 MEPs (of ≥ 50 v in thumb muscle).
• Or, approximately, lowest intensity capable of making
thumb muscle visibly twitch 5 0f 10 times
• Best available index of how sensitive an individual's
cortex is to having a seizure with rTMS.

36. Prefrontal Positioning
F3 and other rules for positioning
Borckardt, in blue
Anderson, in red
MUSC
Locate F3?
EEG
Beam F3
Brain net

37. Factors that influence
the effects of TMS:
Length/Distance
Frequency
Shape of the coil
Intensity (Cognitive)
Engagement
• Depth of penetration ~2 cm, at
junction between grey and white
matter
• Cannot stimulate medial or sub-
cortical areas

38. THE BIGGEST
FACTOR THAT
EFFECTS
MOTOR
THRESHOLD IS
DISTANCE FROM
THE SCALP TO
THE CORTEX LowmotorthresholdHighmotorthreshold

39. Frequency
High vs. Low Frequency rTMS
• Low frequency rTMS = stimulation rates  1 Hz
• High frequency rTMS = stimulation rates  1 Hz
•In the motor cortex high frequency rTMS (5-20 Hz) may temporarily increase
excitability while low frequency rTMS may temporarily decrease excitability.
*(TBS) Theta burst suppression
3 burst of pulses given at 50Hz & repeated every 200ms
Depression Treatment in 6 minutes

40. Stimulate 1.5 cm Stimulate 3 cm
Non focal

41. Transcranial Magnetic Stimulation
Neuronetics (2008): 10 Hz for 37.5 min
Brainsway (2013): 18 Hz for 20 min
(deep / helmet / H coil)
MagVenture (2015): 35-37 min
(theta burst: 5 Hz for 6 min)
Magstim (2015)
4 devices
FDA
Approved

42. Transcranial Magnetic
Stimulation (TMS)

43. Overview of TMS
1) Electrical energy in
insulated coil on the
scalp induces
2) Pulsed magnetic
field of about 1.5 Tesla
in strength
3) Passes unimpeded
through the
cranium for 2-3 cm
4) In turn induces a
focal electrical current
in the brain
5) Get desired local
and distal effects on
the target neural
circuitry
6) Delivered as single
pulses or repeated
trains (rTMS)

44. Migraine w/aura sTMS – occipital
Other TMS Applications?
(April 2016)
Pain
acute/chronic: standard LPFC daily several weeks or motor cortex
Fibromyalgia
very positive results (Short, et al 2014)
Stroke recovery
usually subacute (after 2-3 mo): either high frequency ipsilateral or low
frequency contralateral, combined w/rehab
Addictions
ability to decrease cue-induced craving in the lab / open label potential
clinical reduction in 1-2/52
(Brainsway)
OCD
RDLPFC / R orbitofrontal low frequency *acute ?sustained
(Brainsway)
P

45. Other TMS Applications
(April 2016)
Schizophrenia
inhibitory stimulus over auditory cortex : decreased auditory hallucinations /
negative sxs
Development Disorders / Autism
Epilepsy
patient w/cortical focus / inhibitory TMS can reduce szs
Tinnitus
TMS over auditory cortex or prefrontal cortex
(VNS)
Depression (LDLPFC)
pregnancy / BPD with mood component
Dementia
Aging/Cognitive
Enhancement
Epilepsy
(Treatment
Assessment
Vulnerability?)

46. tACS
Transcranial Alternating Current Stimulation
Cranial Electrotherapy Stimulation (CES)
‘Electroceuticals’
• April 2016- FDA reclassified tACS (CES)
into a split classification
• Tx of insomnia / anxiety: Class II
• Tx of depression: Class III
• Fisher Wallace Stimulator: alternate
current of 2mA of neurostimulation for 20’ per
day
• AlphaStim Device

48. tDCS
Transcranial Direct Current Stimulation
• ¼ potency of TMS
• 1-2 milliampere current (ECT: 200 milliamperes)
• floats ‘up & down excitability’ vs TMS
which causes depolarization (change resting
membrane potential - activated circuit is a better target)
• Build up a tolerance (vs. TMS)?
• tDCS will lower the seizure threshold
• Shows promise during rehab for aphasia / Hopkins U.
study on cognition in patients with Schizophrenia.
• DOD & Video gamers

49. tDCS
Transcranial Direct Current Stimulation
• Consumer tDCS devices
Thync – neurosignaling product – ‘vibing’
energy vibe or calm vibe
foc.us - 5-35 min (intensity/duration)
: edream (lucid dreams at 40Hz stim)
• Anode (-) (front of head) –cathode (+) (back of
head)
like neutroceuticals; St. John’s Wort, Prevagen
Caveat emptor

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51. questions???
Stay tuned