Neurostimulation Treatments in Psychiatry

1
Neurostimulation Treatments in Psychiatry

• Charles R. Conway, MDAssociate Professor of
  Psychiatry
• Washington University Department of Psychiatry

2
Current Uses of Neurostimulation (VNS, DBS, TMS)

• -- Primarily for conditions that have not
  responded to pharmacotherapy
• -- treatment resistant major depressive
  disorder (TRD)
• -- obsessive compulsive disorder
• (one form DBS Medtronics FDA-approved
  compassionate use in OCD)

3
Overview of Talk

• Background on Treatment-resistant major
  depression (TRMD)
• Vagus Nerve Stimulation
• Deep Brain Stimulation
• Transcranial Magnetic Stimulation

4
Goal of Lecture

• To motivate you to understand the big picture
  of neurostimulation treatments, not to get lost
  in the minutia.

his students
Matt Foley, motivational speaker, who lives in a
van, down by the river.
5
Treatment-Resistant Depression
6
Major Depressive Disorder

• Affects 18 million US residents and 340 million
  worldwide1 (16.2 lifetime risk)2 2/3 are female
• Depression is chronic or recurrent
• Twenty-five percent to 40 experience a
  recurrence within 2 years of the index episode3
• Sixty percent experience recurrence after 5
  years3
• Twenty percent to 35 of patients who experience
  one episode of depression have chronic
  depression4-6
• 1. Greden JF. J Clin Psychiatry. 200162(suppl
  22)5-9. 2. Kessler RC, et al. JAMA.
  20032893095-3105. 3. Keller MB, et al. Biol
  Psychiatry. 199844348-360. 4. Keller MB, et al.
  Am J Psychiatry. 1982139438-442. 5. Mueller TI,
  et al. Psychiatr Clin North Am. 19961985-102.
  6. Fava M, et al, for the STARD Investigators
  Group. Psychiatr Clin North Am. 200326457-494.

7
The Need for Long-Term Treatment Options in
Depression

• Fourth most disabling condition worldwide1 most
  disabling condition for females (US)
• Increased morbidity of comorbid general medical
  conditions2 and increased rate of suicide as
  percent of total mortality3
• Loss of productivity in workplace2
• Patients with depression use substantially more
  healthcare services than do patients without
  depression4-6
• Depression is life shortening
• Increased risk of CV, stroke, etc.
• 1. World Health Organization Web Site. Accessed
  July 7, 2005. 2. Greden JF. J Clin Psychiatry.
  200162(suppl 22)5-9. 3. Fawcett J. Int Clin
  Psychopharmacol. 19938217-220. 4. Rowan PJ, et
  al. Psychol Med. 200232903-908. 5. Druss BG, et
  al. Am J Psychiatry. 20001571274-1278. 6. Simon
  GE. Biol Psychiatry. 200354208-215.

8
TRD Overview Levels of Resistance
Thase ME, Rush AJ. Treatment-resistant
depression. In Bloom FE, Kupfer DJ, eds.
Psychopharmacology The Fourth Generation of
Progress. New York, NY Raven Press, Ltd.
19951082-1097.
9
STARD Results Demonstrate Diminishing
Effectiveness of TRD Treatments
1Trivedi MH, et al. Am J Psychiatry 200616328.
2Trivedi MH, et al. N Engl J Med 20063541243.
3Rush AJ, et al N Engl J Med 20063541231.
4Nierenberg AA, et al. Am J Psychiatry
20061631519. 5Fava M, et al. Am J Psychiatry
20061631161. 6McGrath PJ, et al. Am J
Psychiatry 20061631531.
10
Treatment Intolerance Increases With Each
Treatment Level
Percentage of Patients Intolerant to Treatment
Participants were considered to have intolerable
side effects if they left the treatment level
prior to 4 weeks for any reason or left
thereafter citing treatment intolerance as the
reason.
Rush AJ, et al. Am J Psychiatry.
20061631905-1917.
11
Healthcare Utilization Increases With Greater
Degrees of Treatment Resistance
1,400
Inpatient
Outpatient
1,200
Pharmaceutical
Total
1,000
800
Healthcare Costs per Month ()
600
400
200
0
2
4
6
8
Number of Depression Medication Regimen Changes
Russell JM, et al. J Clin Psychiatry.
200465341-347.
12
For ECT Medication Resistance Predicts Relapse

• Relapse was more than twice as likely among
  medication-resistant patients (68.6) compared to
  patients who had not received an adequate
  medication trial prior to ECT (33.3), likelihood
  ratio 5.96, P0.01.

Sackeim et al. Arch Gen Psychiatry, 2000
13
Treatment Resistant Depression some conclusions

• -- TRD is relatively common (15-20 depressives)
• estimates at 3.5 million in US (exceeds
  epilepsy1
• multiple sclerosis x62 cerebral palsy x33).
  
• -- TRD is very costly (lost productivity,
  co-morbid medical illnesses)
• -- our existing treatments dont work very well
  at keeping patients well (e.g., ECT)
• -- we need better understanding of this complex
  illness better treatments to sustain wellness.

1http//www.epilepsyfoundation.org/about/statistic
s.cfm 2http//www3.niaid.nih.gov/ 3http//www.cdc.
gov/ncbddd/dd/cp3.htm
14
Cortico-limbic Model of Depression
mF medial prefrontal aCg rostral anterior
cingulate oF orbital frontal cd-vs
caudate-ventral striatum thal thalamus
mb-p midbrain-pons Cg25 subgenual
cingulate a-ins anterior insula am
amygdala, hth hypothamus bs brainstem PF
dorsolateral prefrontal p parietal pCg
posterior cingulate
-- Regions with anatomical interconnections are
grouped into 4 main behavioral compartments. The
cortical limbic (dorsalventral) segregation
within each compartment additionally identifies
those brain regions where an inverse relationship
is seen across the different PET paradigms. --
Sadness and depressive illness are both
associated with decreases in dorsal neocortical
regions (sensory-cognitive compartment) and
relative increases in ventral limbic and
paralimbic areas (autonomic compartment).
15
Vagus Nerve Stimulation for Treatment Resistant
Depression

• What happens in vagus does not stay in vagus

16
Neuroanatomy of the Vagus Nerve (CN X)
17
Gross Anatomical Distribution of the Vagus (vag
Latin for Wandering) Nerve
Berthoud H-R, Neuhuner WL. Auton Neurosci.
2000851-17.
18
Cranial Nerve X Vagus Nerve

• Cranial nerve X
• Afferent pathway to the brain efferent pathways
  to viscera of thorax and abdomen
• Affarent projections to to areas believed to be
  responsible for seizures, mood, appetite, memory,
  and anxiety.

Henry TR. Neurology. 200259(suppl 4)S3-S14.
19
Vagus Nerve Projects Bilaterally to Key
Brainstem Regions
STNspinal trigeminal nucleus DMNdorsal motor
nucleus of the vagus AParea postrema
NAnucleus ambiguus CN-Xcranial nerve X
RFreticular formation. Henry TR. Neurology.
200259(suppl 4)S3-S14.
20
Vagus Nerve and NTS Project to Key Brainstem
Regions

• Parabrachial nucleus (PBN) of pons has widespread
  cerebral projections
• Locus coeruleus (LC) supplies norepinephrine
• Raphe magnus nuclei supply serotonin

.
KFNKölliker-Fuse nucleus ICHinferior
cerebellar hemisphere RMNraphe magnus nucleus.
Henry TR. Neurology. 200259(suppl 4)S3-S14.
21
Vagus Nerve, NTS, and PBNProject to Key Cerebral
Regions

• Limbic structures
• Amygdala
• Insula
• Autonomic structures
• Hypothalamus
• Periaqueductal gray
• Reticular structures
• Thalamus

PAGperiaqueductal gray CNAcentral nucleus
amygdala PVNperiventricular nucleus of
hypothalamus VPMventral posteromedial nucleus
of thalamus. Henry TR. Neurology. 200259(suppl
4)S3-S14.
22
Basics of the Vagus Nerve Stimulation Device
23
VNS Therapy

• Mild pulses applied to the left vagus nerve in
  the neck send signals to the brain
• Automatic intermittent stimulation
• In-office dose adjustment
• Assured treatment adherence

24
VNS Therapy System Components

• Pulse Generator
• Weighs less than 1 ounce and measures 2?2?0.27
  inches
• Location
• Subcutaneously in left chest
• Function
• Delivers mild pulses at programmed time intervals
• Stores selected information
• Battery life
• Dependent upon dose settings 3 years at a
  higher setting, compared to 8 years at a lower
  setting

25
Components Programming Software and Wand

• Computer and Software
• Users
• Treating psychiatrist or implanting surgeon
• Function
• Dose adjustment or adjusting device parameters
  (therapy)
• Performing and reporting device diagnostics
• Storing historical records of adjustments and
  diagnostics
• Central electronic location of all your patients
  data
• Programming Wand
• Location
• Accessory to handheld computer
• Function
• Communication tool between computer and pulse
  generator

26
VNS Therapy Procedure

• Typically performed under general anesthesia as
  an outpatient procedure
• Two incisions
• Left upper chest or axillary border (pulse
  generator)
• Left neck area in skin crease (lead connection to
  left vagus nerve)
• Standard wound care first week after procedure

27
VNS Therapy Implant Post-Procedure Scars
3 months post-procedure
28
Overview of Vagus Nerve Stimulation Studies in
Depression
29
Pivotal Study Design

Treatment Group
Stimulation adjustment
Fixed Dose VNS
Long-Term Phase
2 weeks
8 weeks
Implant
Recovery and randomization
Baseline
Up to 45 days before implant
2 weeks
Sham-Control
Rush AJ, et al. Biol Psychiatry. 200558347-354.
30
Acute Pivotal VNS Study Results 12-Week
Response Rates (N221)
p0.032
p0.238
20
17
15
15
10
Responders
10
8
5
0
HAMD24
IDS-SR30
VNS Therapy
Sham-control
Rush AJ, et al. Biol Psychiatry. 200558347-354.
31
Long-Term Pivotal Study Response
(n203-205)
(n192-197)
(n185-186)
(n180-181)
(n157)
35
30
25
20
of Patients
15
10
5
0
24
This graph reports the available population for
each assessment at each visit. Montgomery-Åsberg
Depression Rating Scale (MADRS) data not
available for 24-month group. 1. Rush AJ, et
al. Biol Psychiatry. 200558355-363.
32
Long-Term Pivotal Study Remission1
(n203-205)
(n192-197)
(n185-186)
(n180-181)
(n157)
35
30
25
of Patients
20
15
10
5
0
24
This graph reports the available population for
each assessment at each visit. MADRS data not
available for 24-month group. 1. Rush AJ, et al.
Biol Psychiatry. 200558355-363.
33
Long-Term Pivotal Study Maintaining Response
With Adjunctive VNS Therapy
of patients who maintained HAMD response
Response at 3 Monthsand at 1 Year (18/30)
Response at 3 Monthsand at 2 Years(21/30)
Response at 12 Monthsand at 2 Years(37/54)
Response ?50 improvement from
baseline.Maintained response ?40 improvement
from baseline. Observed data. .
34
Pivotal Study vs. Comparative Study Secondary
Analysis
HAMD24 and IDS-SR30 Categorical Outcomes at 12
Months (Observed Cases)
IDS-SR30
HAMD24
40
p0.003
30
p0.029
30
p0.031
p0.006
22
of Patients
20
17
15
13
12
10
7
4
0
Response
Remission
Response
Remission
Pivotal study (n180)
Pivotal study (n181)
Comparative study (n112)
Comparative study (n104)
Evaluable observed analysis. George MS, et al.
Biol Psychiatry. 200558364-373.
35
DRN Firing Rate Acute

• No significant difference between groups

1.5
1
Mean Firing Rate (Mean SEM)
0.5
0
n 97
77
84
64
Control
24 Hours
1 Hour
3 Days
Dorr, AE and Debonnel G. J Pharmacol. Exp. Ther.
2006 318, 890-898.
36
DRN Firing Rate Long Term
3

• Time-dependent increase in firing rate
• Significant group effect for long-term VNS as
  compared with controls (plt0.001)
• All groups significant from control (plt0.05)

2
1.5
Mean Firing Rate (Mean SEM)
1
0.5
0
n 97
93
100
64
Control
21 Days
14 Days
90 Days
One way ANOVA on ranks. Dunnetts post-hoc
test. Dorr, AE and Debonnel G. J Pharmacol. Exp.
Ther. 2006 318, 890-898.
37
LC Firing Rates Long Term
6
4.5
Mean Firing Rate (Mean SEM)
3
1.5
0
105
n 64
70
64
90 Days
21 Days
14 Days
Control
Dorr, AE and Debonnel G. J Pharmacol. Exp. Ther.
2006 318, 890-898.
38
Neuroimaging of VNS in MDD
39
fMRI Shows Increased Limbic Activity in Brains of
Patients With TRD During VNS Therapy
Right Insula
Mid-Cingulate Gyrus
Orbitofrontal Cortex
R
L
fMRIfunctional magnetic resonance imaging. Data
from the Medical University of South Carolina
Center for Advanced Imaging Research.
40
Ongoing Projects-preliminary data analysis

• Acute effects of VNS larger study using 20
  subjects with O15 H20
• goals
• -- better delineate regional activation
  patterns in severe TRD
• -- can you predict a priori, who
  will respond to VNS using a ROI model?
• -- potentially study modulatory
  effects of brain on VNS (follow-up O15 H20
  study at 12-14 months).

41
preliminary analysis acute stimulation (on vs
- off) N 12 (increased blood flow)
42
preliminary analysis acute stimulation (on vs
- off) N 12 (inc. blood flow) t 3.5 (plt.005)

• bilateral lateral orbital cortex (BA 47, 11) left
  gt right

43
preliminary analysis acute stimulation (on vs
- off) N 12 (decreased blood flow)
44
preliminary analysis acute stimulation (on vs
- off) N 12 (dec. blood flow) t 3.5 (plt.005)

• superior region dorsal anterior cingulate (BA
  24/32)
• t 3.89
• inferior region subgenual cingulate (BA 25)
  ventral caudate nucleus accumbens t 4.10

45
preliminary analysis acute stimulation (on vs
- off) N 12 (dec. blood flow) t 3.5 (plt.005)

• left periaqueductal gray t 3.95

46
Ongoing Projects-preliminary data analysis (cont.)

• Chronic Effects of VNS in TRD
• Fluorodeoxyglucose (FDG) PET
• goals
• -- can you determine, a priori, which subjects
  will respond to VNS based on baseline FDG scan?
• -- is there a differential response pattern (12
  or 18 months) when comparing antidepressant
  responders vs- non-responders?
• -- can we make sense of the evolving chronology
  of events of VNS on the brain in TRD? Is there a
  different chronology in responders vs-
  nonresponders

47
preliminary analysis chronic stimulation 3
months stimulation N 7 (increased glucose
uptake) t 2.4 (plt.05)

• region 1(red) gtgt left precuneus t 2.80
• region 2 (green) gtgt posterior cingulate t 2.70

48
preliminary analysis chronic stimulation 3
months stimulation N 7 (increased glucose
uptake) t 2.4 (plt.05)

• right posterior orbital gyrus (t 2.99) left
  lateral orbital gyrus (t 2.69)

49
preliminary analysis chronic stimulation 3
months stimulation N 7 (decreased glucose
uptake) t 2.4 (plt.05)

• region 1 (red) gtgt right insular cortex (t 3.12)

50
preliminary analysis chronic stimulation 3
months stimulation N 7 (decreased glucose
uptake) t 2.4 (plt.05)

• significant deactivation of temporal regions
  bilaterally, non-significant suggestion
  deactivation of hippocampal/parahippocampal
  region (t 1.99)

51
Deep Brain Stimulation
52
Deep Brain Stimulation (DBS)

• Premise very specific targeting of distinct
  regions/loci or networks in an effort to
  modulate specific mood networks.
• ? refers to the stereotactic placement of
  unilateral or bilateral electrodes in target
  brain regions connected to a permanently
  implanted neurostimulator, which electrically
  stimulates that brain region.

53
Deep Brain Stimulation (DBS) history

• DBS currently widely used for Parkisons,
  Dystonias, Severe Tremor
• Typically these patients have electrodes placed
  in the subthalamic nucleus or the globus pallidus
  internus
• Currently, DBS (targeting nucleus accumbens)
  has compassionate use approval for
  treatment-refractory OCD (Greenberg et al, 2003).
  
• Greenberg et al, CNS Spectrums, 2003

54
Two Current Targets for DBS in MDD Brodmanns
area 25 and Nucleus Accumbens

• Mayberg et al (Emory University) Targeting white
  matter close to subgenual cingulate cortex (area
  25 Mayberg 2005).
• chose this region b/c (1) functional imaging
  studies have demonstrated that Cg25 is implicated
  in acute-induced sadness (2) Cg 25 is
  metabolically overactive in treatment-resistant
  depression (3) Cg25 has been noted to decrease
  in activity following successful antidepressant
  treatment with pharmacotherapy and psychotherapy.
  
• Actually targeting the white matter just outside
  of this region.

BA 25
Mayberg et al, 2005, Neuron
55
Two Current Targets for DBS in MDD Brodmanns
area 25 and Nucleus Accumbens

• Schlaepfer et al. Univ. of Bonn, Johns Hopkins
  Targeting ventral striatum/nucleus accumbens
  region (Schlaepfer et al., 2008).
• The Ventral Striatum/nucleus accumbens was chosen
  because
• (1) the ventral striatum is heavily implicated in
  both normal and
• abnormal reward processes, (2) the nucleus
  accumbens acts
• as a motivation gateway between limbic systems
  involved
• in emotion and systems involved in motor control,
  and (3)
• the ventral striatum is uniquely located to
  modulate activity
• in other regions of the brain.

Schlaepfer et al., 2008, Neuropsychopharm
56
Schlaepfer et al. Univ. of Bonn, Johns Hopkins
Targeting ventral striatum/nucleus accumbens
region

• Nucleus accumbens critical center for experience
  of reward and pleasure and is dysfunctional in
  patients with depression.
• imaging studies demonstrate that increases in nuc
  accumbens activity with reward expectation and
  experience of reward.
• the nucleus accumbens acts as a gateway to
  transmit, and therefore enhance or degrade,
  information from emotion centers of the brain to
  motor control regions of the brain.
• the nucleus accumbens mediates motivational
  behavior related to obtaining rewards. This is
  particularly relevant to the treatment of
  depression because anhedonia, which can be
  conceptualized as lack of reward motivated
  behavior, is one of the key defining symptoms of
  MDD.
• Human neuroimaging studies have shown that the
  ventral striatum is very active during reward
  seeking behaviors. (Juckel et al, 2006 Knutson
  et al, 2001b, 2003).
• Schlaepfer et al., 2008, Neuropsychopharm

57
Schlaepfer et al. Univ. of Bonn, Johns Hopkins
Targeting ventral striatum/nucleus accumbens
region

• Ventral Striatum/Nuc Accumbens is a crossroads
  between the emotive, cognitive, and motor
  systems it is in a particularly unique position
  to modulate activity in many other regions of the
  brain.
• The nucleus accumbens receives projections from
  
• midbrain dopamine regions (e.g., ventral
  tegmental area)
• Regions involved in emotion (amygdala,
  orbitofrontal cortex, medial frontal cortex)
• Regions involved motor activity (dorsal caudate,
  globus pallidus)
• Regions involved in memory (hippocampus)
• The nucleus accumebens indirectly projects to
• Cg25 and medial prefrontal cortex
• The vental pallidum
• Thalamus, amygdala, hypothalamus
• Many of these regions are also implicated in
  normal and abnormal emotion processing,especially
  the medial prefrontal cortex and Cg25, suggesting
  a network of tightly anatomically and
  functionally connected regions (Mayberg, 1997).
• Schlaepfer et al., 2008, Neuropsychopharm

58
Schlaepfer et al. Univ. of Bonn, Johns Hopkins
Targeting ventral striatum/nucleus accumbens
region
59
Schlaepfer et al. Univ. of Bonn, Johns Hopkins
Targeting ventral striatum/nucleus accumbens
region

• Design single-blind 6 weeks on, 4 weeks off,
  turned back on. If score dropped precipitously,
  you could restart device early (rescue option).
• PET imaging FDG PET at start (1 week before) and
  after 1 week stimulation.
• patients received stimulation at increasing
  voltages up to 4V, 145Hz during 7 days.
• Subjects did NOT score high on a standardized
  euphoria scale to rule out euphoria vs-
  antidepressive effect. (Addiction resource
  center inventory).
• Schlaepfer et al., 2008, Neuropsychopharm

60
Schlaepfer et al. Univ. of Bonn, Johns Hopkins
Targeting ventral striatum/nucleus accumbens
region

• Immediate Effects
• Almost immediately (60 s) after switching
  the stimulation on, one patient was unable to
  identify any changes, but spontaneously reported
  that he realized that he was in Cologne, that he
  never visited the famous Cologne Cathedral, and
  he planned on doing this in the immediate future,
  which he indeed did the day following the
  operation. Asked about depressive symptomatology,
  he did not report any acute subjective changes.
• A second patients immediate (60 s) reaction
  to stimulation was quite similar she did not
  report any acute changes in depressive
  symptomatology but spontaneously mentioned that
  she wished to take up bowling again (a favorite
  pastime of hers 12 years ago, before onset of her
  depression). She noted, This would be quite
  pleasurable.
• These immediate and unprompted behavioral
  responses demonstrate a sharp increase in
  exploratory motivation, consistent with the
  accumbens
• role in reward-seeking behaviors. This is
  especially noteworthy given these patients
  severe lack of motivation during their long
  depressive episode.
• Schlaepfer et al., 2008, Neuropsychopharm

61
Schlaepfer et al. Univ. of Bonn, Johns Hopkins
Targeting ventral striatum/nucleus accumbens
region

• Results
• The scores dropped significantly to 19.7 (HRDS)
  and 24.7 (MADRS from 34 and 36 respectively)
  after 1 week of deep brain stimulation (titration
  period plt0.02 and plt0.02). After the first week
  of double-blind constant stimulation, the scores
  dropped to 24.7 (plt0.07 and plt.04), respectively.
  
• After the first week without stimulation
  (double-blind), the scores increased again to
  29.3 and 33.3. These ratings in the
  off-stimulation phase did not differ from
  baseline (plt0.25 and plt0.39).
• Subanalysis of anhedonia measures of HRDS-24 and
  MADRS did NOT reveal any specific targeting of
  these symptoms.

62
Schlaepfer et al. Univ. of Bonn, Johns Hopkins
Targeting ventral striatum/nucleus accumbens
region
Gray regions device on White regions device
off MADRS red line HRDS-24 green line
63
Schlaepfer et al. Univ. of Bonn, Johns Hopkins
Targeting ventral striatum/nucleus accumbens
region
PET FINDINGS Increased metabolism (yellow)
after 1 week stimulation -- bilateral ventral
striatum (including the nucleus accumbens) --
bilateral dorsolateral and dorsomedial
prefrontal cortex and cingulate cortex,
and bilateral amygdala. Decreased metabolism
(blue) after 1 week stimulation --
ventromedial and ventrolateral prefrontal
cortex,dorsal caudate nucleus, and thalamus.
uncorrected p lt .05 (due to low subjects).
64
Helen Mayberg, Emory University
65
Mayberg et al., Univ of Toronto, Cg25WM

• This study reports the use of high-frequency
  subgenual cingulate DBS in white matter (Cg25WM)
  using high setting (up to 9.0 Volts) in six TRD
  patients.
• Subjects (N 6) severely depressed subjects
  (all failed 4 ADs and psychotherapy or ECT)
  minimum score of 20 on the 17 item Hamilton
  Depression Rating Scale.
• design DBS electrodes implanted in Cg25 White
  Matter under local anesthesia using MR imaging
  guidance. Intraoperative lead testing at set
  frequency (130Hz and set pulse width 60 µs
  pulsewidths, 130 Hz).
• Mayberg et al, 2005 Neuron

66
Mayberg et al., Univ of Toronto, Cg25WM

• Dose Titration
• Voltage progressively increased up to 9.0 V at
  each of the eight electrode contacts (four per
  side), as tolerated.
• Voltage was increased by approximately 1.0 V
  every 30 s, with a 1520 s pause between
  adjustments allowing time for patients to
  indentify an effect
• Eight electrode contacts (four per side), as
  tolerated.
• Patient then underwent five days of device
  programming (varying the pulse width, frequency,
  voltage in each side). Patients were instructed
  to inform the investigator if they noted positive
  feelings. Some of these good feelings persisted
  after DBS turned off.
• Mayberg et al, 2005 Neuron

67
Mayberg et al., Univ of Toronto, Cg25WM

• Dose Titration (cont.)
• One week later, chronic DBS was initiated using
  the lowest
• voltage and specific electrode contacts that had
  previously
• produced acute behavioral effects.
• Parameters of stimulation were reassessed at
  weekly intervals with minor adjustments in
  voltage made to optimize clinical
• effects.
• Following a 4 week period of parameter
  optimization, settings generally remained stable
  for the remainder of the 6 month follow-up
  period. The mean stimulation parameters used in
  this group at 6 months were 4.0 Volts, 60 µs
  pulsewidths, at a frequency of 130 Hz.
• Mayberg et al, 2005 Neuron

68
Mayberg et al., Univ of Toronto, Cg25WM

• Immediate Effects (in operating room)
• All patients spontaneously reported acute
  effects including sudden calmness or lightness,
  disappearance of the void, sense of heightened
  awareness,
• increased interest, connectedness, and sudden
  brightening of the room, including a description
  of the sharpening of visual details and
  intensification of colors in response to
  electrical stimulation.
• Reproducible and reversible changes in these
  phenomena, time locked with stimulation, were
  observed at specific contacts and parameters for
  individual patients and not with sham or
  subthreshold stimulation at those same sites.
• Increases in motor speed, volume, and rate of
  spontaneous speech and improved prosody were
  observed.
• There were no overt adverse affective or
  autonomic changes with stimulation at settings
  producing these improvements. However, all
  patients experienced stimulation dose-dependent
  adverse effects including lightheadedness and
  psychomotor slowing at high settings (over 7.0
  Volts), most often seen at the superior
  electrode.
• Mayberg et al, 2005 Neuron

69
Mayberg et al., Univ of Toronto, Cg25WM results
70
Mayberg et al., Univ of Toronto, Cg25WM PET
results
Top ROW increases in subgenual cingulate (Cg25)
and decrease in dorsolateral prefrontal (F9),
ventrolateral prefrontal (F47) and anterior
cingulate (Cg24) cortices (row 1, patients 15).
ROW 2 Three months of DBS relative to baseline
(row 2, patients 1, 3, and 5) decreases in Cg25,
hypothalamus (Hth), anterior insula (ins),
medial frontal (mF10) and orbital frontal (oF11)
increases in prefrontal (F9/46) and dorsal
cingulate (cg24). ROW 3 similar to changes at
3 months AND additional increases are seen in the
brainstem (bs)
71

• Transcranial Magnetic Stimulation (rTMS)

72
Transcranial Magnetic Stimulation

• Introduced as a neurophysiological tool in 1985
  when Anthony Barker and his team developed a
  compact machine that permits non-invasive
  stimulation of the cortex.
• In the early 1990s researchers began to look at
  studying rTMS in depression.
• Uses other than depression
• --to study function of cerebral cortex.
• -- studies looking at TMS for stroke recovery
• -- irritable bowel syndrome traumatic head
  injury

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rTMS methods of application
Nature Neuroscience Reviews
74
Transcranial Magnetic Stimulation

• Premise stimulate focal areas of cortex
  noninvasively using magnetic field
• Advantages no general anesthesia or seizure
• Repetitive Transcranial Magnetic Stimulation
  (rTMS) involves the rhythmic and repetitive
  application of magnetic field.

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rTMS Methodology

• Right Dorsolateral Application (typically low
  frequency)
• Left Dorsolateral Application (typically high
  frequency)
• Can vary
• stimulus frequency(pulses/second)
• -- intensity of the stimulus
• -- total number of pulses (duration)

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rTMS Studies in Depression design issues

• -- is study truly blinded? (person applying
  treatment has to know stim vs- nonstim) also
  patients experience stimulus on their scalp when
  delivered some researchers use minimal stimulus
  delivery as placebo, but is this low magnetic
  field affecting response?
• -- most studies have exceptionally low N
• --too many variables (device placement, stim
  frequency, stim, sessions, stims/session)
• -- continued debate as to best site of delivery
  and best mode (high vs- low Hz), right vs-
  left duration, etc.

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rTMS Metanalysis Conclusions

• Burt et al. (2002) reported on two separate
  meta-analyses, for nine open depression trials of
  rTMS and 16 controlled
• trials.
• -- yielded weighted mean effect sizes of 1.37
  for the open studies and 0.67 for the controlled
  studies(moderate to large effect sizes however,
  difference b/t open and blinded studies suggests
  placebo effects contribute substantially to
  positive outcome in open studies.
• Burt et al. noted that the effect sizes for rTMS
  treatment were far smaller than those calculated
  for ECT
• 2.26 for bilateral ECT
• 2.12 for high dose right unilateral
  ECT (Sackeim et al., 2000).

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rTMS Metanalysis Conclusions

• A Cochrane Review by Martin et al. (2003)
  compared the results of 14 randomized controlled
  studies
• Conclusions
• ?high frequency left prefrontal rTMS and low
  frequency right prefrontal rTMS were
  statistically superior to a sham comparison, but
  only at
• one time point (immediately after the two weeks
  of treatment, with the difference not sustained
  two weeks later).
• ?b/c the the overall difference between active
  and sham treatment was not large, though
  significant (standardised mean difference
• of 0.35 for high frequency left prefrontal rTMS),
  they concluded that there was not strong evidence
  at this stage to support the benefit of rTMS as
  an antidepressant treatment.

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rTMS Metanalysis Conclusions summary

• Metanalysis studies of rTMS conclude that rTMS
  demonstrates a modest improvement over sham,
  though the clinical meaningfulness of this
  improvement is questionable.
• Which patient groups should receive rTMS
• ? rTMS may be less effective in psychotic
  depression (Grunhaus et al., 2000, 2003), elderly
  subjects (Figiel et al., 1998 Padberg et al.,
  1999) and those with depressive episodes of
  longer duration (Holtzheimer et al., 2004).
• ?It is also likely that subjects who are more
  treatment resistant would be less likely to
  respond to rTMS, as is the case with other
  antidepressant treatments (Mitchell et al.,
  2000).