Solvason Neural targ..

stanfordhospital.org

Solvason Neural targ..

Neural Targets for Neuromodulation

in the Treatment of Depression

Hugh Brent Solvason PhD MD

Associate Professor of Psychiatry

Stanford University


Neuromodulation and treatment resistant

depression

Current approaches that target neural targets

FDA Approved

Electroconvulsive Therapy (ECT)

Vagal Nerve Stimulation (VNS)

Transcranial Magnetic Stimulation (TMS)

Deep Brain Stimulation for OCD (special circumstance)

Research

Magnetic Seizure Therapy (MST)

Deep Brain Stimulation (DBS)

Other


Overview: what’s to come

Introduction: what’s the story with serotonin?

Phenomenology and illness course

Plasticity and dysregulation of circuitry in depression

Functional neuroanatomy

Targeting deep brain structures for treatment resistant depression

Transcranial ilMagnetic i Stimulation S i l i

Vagal Nerve Stimulation

Electroconvulsive Therapy py


An introduction


Serotonin and pathophysiology of depression

serotonin

The world of psychiatry

was consumed by the

IDEA of serotonin

Why?

Abbrev: dorsal raphe nucleus DRN; locus ceruleus LC; ventral tegmental area VTA; dopamine DA, norepinepherine NE, serotonin 5HT, glutamate glu,


Serotonin and pathophysiology of depression

serotonin

Prozac (fluoxetine)

Abbrev: dorsal raphe nucleus DRN; locus ceruleus LC; ventral tegmental area VTA; dopamine DA, norepinepherine NE, serotonin 5HT, glutamate glu,


Serotonin (5HT) and pathophysiology of depression

The ‘serotonin hypothesis’ lacked robustness

‘i ‘increases 5HTergic 5HT i t tone’ ’

serotonin

didn’t explain an incredibly complex system:

14+ types of 5HT receptors

( (genes, transcription t i ti splice li variants, i t post t translational)

t l ti l)

‘depression is low serotonin’

Sometimes included low NE

Didn’t address locality –where is it low?

different structures do dramatically different things

‘medication increases serotonin’

Easy to be mislead by what appears an obvious mechanism

Abbrev: dorsal raphe nucleus DRN; locus ceruleus LC; ventral tegmental area VTA; dopamine DA, norepinepherine NE, serotonin 5HT, glutamate glu,


Serotonin and pathophysiology of depression

serotonin

And it was at its heart

( (very) ) misleading i l di

Abbrev: dorsal raphe nucleus DRN; locus ceruleus LC; ventral tegmental area VTA; dopamine DA, norepinepherine NE, serotonin 5HT, glutamate glu,


Serotonin and pathophysiology of depression

Glutamate

NMDAR

AMPAR

Glumate and GABA are

the major neurotransmitters

for communication in

cortical,

subcortical

and limbic circuits

Abbrev: dorsal raphe nucleus DRN; locus ceruleus LC; ventral tegmental area VTA; dopamine DA, norepinepherine NE, serotonin 5HT, glutamate glu,


*

Cortical and limbic connections: role of

monoamines i ( (serotonin, t i norepinepherine, i h i ddopamine) i )

5HT AT A GLUTAMATE SYNAPSE:

WHAT IT REALLY IS --

varicosities

A CIRCUIT MODULATOR

5HT

5HT

5HT

glu

gl glu

5HT 5HT2aR

Glutamate Receptors

NMDAR

AMPAR

Abbrev: dorsal raphe nucleus DRN; locus ceruleus LC; ventral tegmental area VTA; dopamine DA, norepinepherine NE, serotonin 5HT, glutamate glu,


*

Cortical and limbic connections: role of the

monoamines i (5HT (5HT, NE, NE DA)

DA, NE and 5HT

projections j i arise i from f

brainstem nuclei glu

VTA

5HT at a glutamate g synapse y p

5HT

varicosities

5HT

5HT

5HT

glu

5HT

5HT

5HT2aR

midbrain

pons

NMDAR

AMPAR

Abbrev: dorsal raphe nucleus DRN; locus ceruleus LC; ventral tegmental area VTA; dopamine DA, norepinepherine NE, serotonin 5HT, glutamate glu,

LC

DRN


*

Cortical and limbic connections: role of the

monoamines i (5HT (5HT, NE, NE DA)

5HT modulates activity at

glutamate

and GABA synapses

VTA

5HT at a glutamate g synapse y p

5HT

varicosities

5HT

5HT

5HT

glu

5HT

glu

5HT

5HT2aR

midbrain

pons

NMDAR

AMPAR

Abbrev: dorsal raphe nucleus DRN; locus ceruleus LC; ventral tegmental area VTA; dopamine DA, norepinepherine NE, serotonin 5HT, glutamate glu,

LC

DRN


*

Cortical and limbic connections: role of the

monoamines i (5HT (5HT, NE, NE DA)

5HT fibers bypass these

synapses and release 5HT

from varicosities along the

5HT axon coming from

nuclei uc e in brainstem b a ste

VTA

LC

DRN

5HT at a glutamate g synapse y p

5HT

varicosities

5HT

5HT

5HT

glu

5HT

glu

5HT

5HT2aR

midbrain

pons

NMDAR

AMPAR

Abbrev: dorsal raphe nucleus DRN; locus ceruleus LC; ventral tegmental area VTA; dopamine DA, norepinepherine NE, serotonin 5HT, glutamate glu,


Depression is a systems-level disorder


Dysregulated ciruits appear as symptoms

The symptoms of depression are the result of

ddysregulated l dneurocircuits. i i


Dysregulated ciruits appear as symptoms

This concept is primary to understanding how neuronal

and glial viability, neurotransmitters, synaptic plasticity,

second messenger systems and gene expression influence

neurocircuit i itbh behavior, i and dsymptoms t


Dysregulated ciruits appear as symptoms

Brain stimulation makes use of interconnected structures

and related neurocircuits to directly influence circuit

behavior, and ameliorate or cease the symptoms of

depression


Mood disorders

Nosology and illness course


Illness progression in bipolar disorder

Bipolar I: progressive change in illness over 20 years

• dysphoric/mixed episodes more than euphoric mania

• rapid cycling

• well interval decreased

• chronicity of depression

stressor stressor stressor stressor stressor

age

20 25 30 35 40 years old

Adapted from R.Post http://www.medscape.com

Intermittent episodes Rapid cycling


Illness progression in MDD

Unipolar: progression with recurrence and chronicity

• first episode usually preceded by stressor

• after 5 episodes less likely to have precipitant

• well interval decreased

• more residual symptoms between episodes

• clinically more difficult to treat

stressor stressor

MDE recovered MDE residual symptoms MDE

minor

depression chronic MDE

age 20 25 30 35 40

45


Poor outcomes with advanced illness course

Unipolar Bipolar

hi higher h relapse l risk i k

greater g number of prior p episodes p

more residual symptoms-insomnia, fatigue, anxiety

severity? y

medical and psychiatric comorbidity

stressful events

disability


Key points

Mood disorders are characterized by symptoms:

the consequence q of dysregulated y g neurocircuitryy

regulating mood, anxiety, interest …


Key points

Mood disorders are characterized by symptoms

that are the result of dysregulated neurocircuitry

regulating mood, mood anxiety, anxiety interest …

Mood disorders have a progressive illness course


Key points

Mood disorders are characterized by symptoms

that are the result of dysregulated neurocircuitry

regulating mood, mood anxiety, anxiety interest …

Mood disorders have a progressive illness course

Prefrontal-subcortical/prefrontal-limbic

circuits c cu ts implicated p cated


Implicated neurocircuits

Identification through pathology


Plasticity and circuit dysregulation

Volumetric studies


Volumetric studies in mood disorders

Unipolar (+studies) Bipolar (+studies)

ventricles (2/2) ventricles (10/16)

Cortical volume

ttemporal l llobe b (0/1)

prefrontal lobe (6/9)

dorsollateral pfc (0/0)

orbitofrontal pfc (9/13)

subgenual pfc (1/2)

anterior cingulate (3/3)

Konarski et al. Bipolar Disorder 10:1-37 (2008)

Cortical volume

ttemporal l lobe l b (10/20)

prefrontal lobe (4/8)

dorsolateral pfc (4/6)

orbitofrontal pfc (7/10)

subgenual pfc (2/4)

anterior cingulate (7/9)


*

Volumetric studies in bipolar disorder

Postmortem: amygdala volume decreased

lateral nucleus total volume

total neuron number

neuron density

accessory basal nucleus total neuron number

MRI: progressive decrease in gray matter prospectively over 4 years

hi hippocampus

temporal lobe

cerebellum

Cognitive decline:

gray matter loss: correlates with verbal and performance IQ

illness course: also correlates with number of mood episodes in 4 yr follow up period

lithium: increases hippocampal and amygdalar volume compared to untreated

Frazier, J. A. et al. Schizophr Bull 2008 34:37-46; doi:10.1093/schbul/sbm120.; William T Biol Psych 62: 894-090 2007;

Foland LC et al. Neuroreport 22:19(2) 2008 et al


*

Volumetric studies in bipolar disorder

Postmortem: amygdala volume decreased

lateral nucleus total volume

total neuron number

neuron density

accessory basal nucleus total neuron number

MRI: progressive decrease in gray matter prospectively over 4 years

hi hippocampus

temporal lobe

cerebellum

Cognitive decline:

gray matter loss: correlates with verbal and performance IQ

illness course: also correlates with number of mood episodes in 4 yr follow up period

lithium: increases hippocampal and amygdalar volume compared to untreated

Frazier, J. A. et al. Schizophr Bull 2008 34:37-46; doi:10.1093/schbul/sbm120.; William T Biol Psych 62: 894-090 2007;

Foland LC et al. Neuroreport 22:19(2) 2008 et al


*

Volumetric studies in bipolar disorder

Postmortem: amygdala volume decreased

lateral nucleus total volume

total neuron number

neuron density

accessory basal nucleus total neuron number

MRI: progressive decrease in gray matter prospectively over 4 years

hi hippocampus

temporal lobe

cerebellum

Cognitive decline:

gray matter loss: correlates with verbal and performance IQ

illness course: also correlates with number of mood episodes in 4 yr follow up period

lithium: increases hippocampal and amygdalar volume compared to untreated

Frazier, J. A. et al. Schizophr Bull 2008 34:37-46; doi:10.1093/schbul/sbm120.; William T Biol Psych 62: 894-090 2007;

Foland LC et al. Neuroreport 22:19(2) 2008 et al


*

Cortical gray matter atrophy

Results: red highlighted areas have significant gray

matter tt thi thinning i iin ddepressed d subjects bj t

Severity circled areas where

gray matter reduction correlated

with severity y (MADRS) ( )

Vasic N, et al.. J Affective Disorders epub 10 Jan 2008

Temporal ctx

Ventrolateral pfc

Cognition: circled areas where

gray matter reduction correlated

with ihperformance f on WCST


*

Hippocampal atrophy: a highly replicated finding

Degree of atrophy in depression correlated with:

duration of current episode

duration of depressive illness

duration untreated depression

First episode of depression, atrophy correlates with:

number of stressful experiences prior to 1st episode

Cognition Negatively affected

Impaired performance on Wisconsin Card Sorting Test

coorelated with reduced hippocampal volume

Vasic N, et al. Affective Disorders epub 10 Jan 2008. Sheline Y, et al. Proc Natl Acad Sci 83(9):3908-13 1996

Sheline Y, Mokhtar H, Gado M. et al. Am J Psychiatry 160:1516-18 2003. Kronmuller KT, et al. J Affective Disorders epub Mar 5 2008;

hippocampus


*

Metanalysis: volumetric studies of subgenual PFC

Bipolar and unipolar MRI volumetric studies: 10 studies

Results: Mood disorders all together

sgPFC

Suggested differences in effect

among g depressive p illnesses

Hajek T et al. J Psychiatry Neurosci 33(2):91-99 2008;

Bremner J, et al. Biol Psychiatry 51(4): 273-79 2002


Plasticity and circuit dysregulation

Connectivity


*

Functional imaging studies in Bipolar disorder

Frontal subcortical neural network dissconnected in euthymic subjects

• euthymic th i bi bipolar l and d hhealthy lth control t l subjects bj t id identifying tif i sad d affect ff t dduring i fMRI

• controls: processing negative affect activate cortical-subcortical network

• BP: activate hippocampal/amygdalar (subcortical) without cortical activation

• BP: lamotrigine increases cortical activation, decreases overactivity in temporal lobe

Cortical structures showed abnormal activation pattern in two tasks

• euthymic bipolar I vs healthy controls with fMRI

• N-back test shows abnormal DLPFC activation; increased parietal cortex activation

• gambling task (assess ventral pfc function) showed decreased pfc activation

• Bipolar subjects had increased activation of the temporal cortex and temporal pole

Lagopoulos J, Malhi GS.. Neuroreport 18(15): 1583-7 200; Frangou S Kington J et al. Eur Psychiatry epub Jul;24 2007

Jogia J, et al. Br J Psychiatry 192:197-201 2008


*

Circuit dysregulaton in Bipolar Disorder

Frontal subcortical neural network dissconnected in euthymic subjects

• euthymic th i bi bipolar l and d hhealthy lth control t l subjects bj t id identifying tif i sad d affect ff t dduring i fMRI

• controls: processing negative affect activate cortical-subcortical network

• BP: activate hippocampal/amygdalar (limbic) without cortical activation

• BP: lamotrigine increases cortical activation, decreases overactivity in temporal lobe

Cortical structures showed abnormal activation pattern in two tasks

• euthymic bipolar I vs healthy controls with fMRI

• N-back test shows abnormal DLPFC activation; increased parietal cortex activation

• gambling task (assess ventral pfc function) showed decreased pfc activation

• Bipolar subjects had increased activation of the temporal cortex and temporal pole

Lagopoulos J, Malhi GS.. Neuroreport 18(15): 1583-7 200; Frangou S Kington J et al. Eur Psychiatry epub Jul;24 2007

Jogia J, et al. Br J Psychiatry 192:197-201 2008


Cognitive impairment in well patients with BPD

Euthymic bipolar patients have persisting cognitive impairment?

2 year follow up study of lithium treated patients

BP I or II, 44/106 subjects met criteria for study

33/44 seen at 2 year follow up

lithium levels 0.43 to 0.95 (only mood stabilizer during study)

Outcomes

executive dysfunction y

Trails B

verbal fluency (FAS) of Controlled Oral Word Association Test-Categories

Stoop word-color interference test

processing speed

Trails A

Connors Continuous Performance Test II

no o effect e ec oon memory e o y tasks as s

Mur et al. J Clin Psych 69 (5) 712-719 2008


Cognitive impairment in well patients with BPD

Euthymic bipolar patients have persisting cognitive impairment?

2 year follow up study of lithium treated patients

BP I or II, 44/106 subjects met criteria for study

33/44 seen at 2 year follow up

lithium levels 0.43 to 0.95 (only mood stabilizer during study)

Outcomes

executive dysfunction y

Trails B

verbal fluency (FAS) of Controlled Oral Word Association Test-Categories

Stoop word-color interference test

processing speed

Trails A

Connors Continuous Performance Test II

no o effect e ec oon memory e o y tasks as s

Mur et al. J Clin Psych 69 (5) 712-719 2008


*

KEY POINTS Plastic change in mood disorders

PPost-mortem: t t loss l of f gray matter tt in i limbic li bi structures t t

Progressive pfc/limbic gray matter loss may explain illness progression

increased chronicity

more residual symptom burden

incomplete interepisode recovery

decreased well-interval

lloss of f euphoric h i mania i

mixed episodes

cognitive impairment

response p to treatment?

Change prefrontal-limbic connectivity when ‘asymptomatic’

Plastic changes appear to be assoicated with cognitive impairment


*

KEY POINTS Plastic change in mood disorders

PPost-mortem: t t loss l of f gray matter tt in i limbic li bi structures t t

Progressive pfc/limbic gray matter loss - illness progression?

increased chronicity

more residual symptom burden

incomplete interepisode recovery

decreased well-interval

loss of euphoric mania

mixed episodes

cognitive impairment

response to treatment?

Change prefrontal-limbic connectivity when ‘asymptomatic’

Plastic changes appear to be assoicated with cognitive impairment


*

KEY POINTS Plastic change in mood disorders

PPost-mortem t t findings fi di support t lloss of f gray matter tt in i li limbic bi structures t t

Progressive pfc/limbic gray matter loss may explain illness progression

increased chronicity

more residual symptom burden

incomplete interepisode recovery

decreased well-interval

loss of euphoric mania

mixed episodes

cognitive impairment

response to treatment?

Change prefrontal-limbic connectivity when ‘asymptomatic’

Plastic changes appear to be assoicated with cognitive impairment


*

KEY POINTS Plastic change in mood disorders

PPost-mortem t t findings fi di support t lloss of f gray matter tt in i li limbic bi structures t t

Progressive pfc/limbic gray matter loss may explain illness progression

increased chronicity

more residual symptom burden

incomplete interepisode recovery

decreased well-interval

loss of euphoric mania

mixed episodes

cognitive impairment

response to treatment?

Changes in prefrontal-limbic connectivity even when ‘asymptomatic’

Plastic changes correlate with cognitive impairment


Prefrontal dysregulation in depression

Medial prefrontal p

structures


Functional neuroanatomy of the mPFC structures

dmPFC

rACC

sgACC

DS

VS

dACC

thalamus

STN

Function of mPFC structures

sgACC: sadness, autonomic/endocrine response to stress; appraisal +/- stimuli

rACC: emotional stroop (distinguishing emotional affect with distractor)

dACC dACC: cognitive iti appraisal i l of f aversive/rewarding i / di stimuli ti li

dmPFC: self referential processing of emotion


Functional neuroanatomy of the mPFC structures

dmPFC

rACC

sgACC

DS

VS

dACC

thalamus

STN

Function of mPFC structures

sgACC: sadness, autonomic/endocrine response to stress; appraisal +/- stimuli

rACC: emotional stroop (distinguishing emotional affect with distractor)

dACC: cognitive appraisal of aversive/rewarding stimuli

dmPFC: self referential processing of emotion


Functional neuroanatomy of the mPFC structures

dmPFC

rACC

sgACC

DS

VS

dACC

thalamus

STN

Function of mPFC structures

sgACC: sadness, autonomic/endocrine response to stress; appraisal +/- stimuli

rACC: emotional stroop (distinguishing emotional affect with distractor)

dACC: cognitive appraisal of aversive/rewarding stimuli

dmPFC: self referential processing of emotion


Functional neuroanatomy of the mPFC structures

dmPFC

rACC

sgACC

DS

VS

dACC

thalamus

STN

Function of mPFC structures

sgACC: sadness, autonomic/endocrine response to stress; appraisal +/- stimuli

rACC: emotional stroop (distinguishing emotional affect with distractor)

dACC: cognitive appraisal of aversive/rewarding stimuli

dmPFC: self referential processing of emotion


Based on patterns of connectivity

ddysregulation l i of fthe h mPFC may affect ff -

Hypothalamus

HPA axis is dysregulated dysregulated, as well as cortisol response to stress

Hippocampus

Impaired processing of information/memory processing

IImpaired i d contextual t t l memory

Impaired inhibition of the HPA axis

NAc

mPFC can dysregulate the DA reward system causing anhedonia

Ventral striatum

Dysregulated y g mPFC output p will not be pprocessed normally y by y Nac

Amygdala

mPFC regulates activation dysregulated of the central nucleus, which is

reponsible for the neuroendocrine and autonomic response to stress


Based on patterns of connectivity

ddysregulation l i of fthe h mPFC may affect ff -

Hypothalamus

HPA axis is dysregulated, y g , as well as cortisol response p to stress

Hippocampus

Impaired processing of information/memory processing

IImpaired i d contextual t t l memory

Impaired inhibition of the HPA axis

NAc

mPFC can dysregulate the DA reward system causing anhedonia

Ventral striatum

Dysregulated mPFC output will not be processed normally by Nac

Amygdala

mPFC regulates activation dysregulated of the central nucleus, which is

reponsible ibl ffor the th neuroendocrine d i and d autonomic t i response tto stress

t


Based on patterns of connectivity

ddysregulation l i of fthe h mPFC may affect ff -

Hypothalamus

HPA axis is dysregulated, y g , as well as cortisol response p to stress

Hippocampus

Impaired processing of information/memory processing

Impaired contextual memory

Impaired inhibition of the HPA axis

NAc

mPFCC can dysregulate the DA reward system causing anhedonia

Ventral striatum

Dysregulated y g mPFC output p will not be pprocessed normally y by y Nac

Amygdala

mPFC regulates activation dysregulated of the central nucleus, which is

reponsible for the neuroendocrine and autonomic response to stress


Based on patterns of connectivity

ddysregulation l i of fthe h mPFC may affect ff -

Hypothalamus

HPA axis is dysregulated, y g , as well as cortisol response p to stress

Hippocampus

Impaired processing of information/memory processing

Impaired contextual memory

Impaired inhibition of the HPA axis

NAc

mPFC can dysregulate the DA reward system causing anhedonia

Ventral striatum

Dysregulated y g mPFC output p will not be pprocessed normally y by y NAc

Amygdala

mPFC regulates activation dysregulated of the central nucleus, which is

reponsible for the neuroendocrine and autonomic response to stress


Based on patterns of connectivity

ddysregulation l i of fthe h mPFC may affect ff -

Hypothalamus

HPA axis is dysregulated, y g , as well as cortisol response p to stress

Hippocampus

Impaired processing of information/memory processing

Impaired contextual memory

Impaired inhibition of the HPA axis

NAc

mPFC can dysregulate the DA reward system causing anhedonia

Ventral striatum

Dysregulated mPFC output will not be processed normally by Nac

Amygdala

mPFC regulates activation dysregulated of the central nucleus, which is

reponsible for the neuroendocrine and autonomic response to stress


Based on patterns of connectivity

ddysregulation l i of fthe h mPFC may affect ff -

OFC

DDysregulated l t d bbehavioral h i l and d visceral i l response tto hhedonic d i

and punishing stimuli

Ventrolateral pfc

Integration of stimuli with emotions and changing behavior based on

changing g g reward contingencies g

Rostral Mid-dorsal ACC

Integration of self referential information and understanding the state of

mind and behavior of others (theory of mind)

P i d t l

Periaqueductal gray

Dysregulation of pain and affective behaviors


Based on patterns of connectivity

ddysregulation l i of fthe h mPFC may affect ff -

OFC

Dysregulated behavioral and visceral response to hedonic and

punishing stimuli

VVentrolateral t l t l pfc f

Integration of stimuli with emotions and changing behavior

based on changing g g reward contingencies g

Rostral Mid-dorsal ACC

Integration of self referential information and understanding the state of

mind and behavior of others (theory of mind)

P i d t l

Periaqueductal gray

Dysregulation of pain and affective behaviors


Based on patterns of connectivity

ddysregulation l i of fthe h sgPFC may affect ff -

OFC

Dysregulated behavioral and visceral response to hedonic and

punishing stimuli

Ventrolateral pfc

Integration of stimuli with emotions and changing behavior based on

changing reward contingencies

Rostral Mid-dorsal ACC

Integration of self referential information and understanding

the state of mind and behavior of others (theory of mind)

Periaqueductal gray

Periaqueductal gray

Dysregulation of pain and affective behaviors


Based on patterns of connectivity

ddysregulation l i of fthe h mPFC may affect ff -

OFC

Dysregulated behavioral and visceral response to hedonic and

punishing stimuli

Ventrolateral pfc

Integration of stimuli with emotions and changing behavior based on

changing reward contingencies

Rostral Mid-dorsal ACC

Integration of self referential information and understanding the state of

mind i d and d bbehavior h i of f others h ( (theory h of f mind) i d)

Periaqueductal gray

Periaqueductal gray

Dysregulation of pain and affective behaviors


Impact p of dysregulation y g of the sgPFC g

Impairment of function in depression

mPFC PFC ( (sgACC, ACC ddmPFC, PFC rACC) ACC)

dysregulation of connected structures:

rACC, sgPFC, thalamus, ventral striatum

Impact on insight

appraisal, comprehension, integration of thought, feeling and action related to self

and others and situations where dynamic change occurs in rewarding or

negatively reinforcing stimuli


Impact p of dysregulation y g of the sgPFC g

Impairment of function

mPFC (sgACC (sgACC, dmPFC dmPFC, rACC) indepression

in depression

dysregulation of connected structures:

rACC, sgPFC, thalamus, ventral striatum

Impact on insight

appraisal, comprehension, integration of thought, feeling and action

related to self and others and situations where dynamic change occurs in

rewarding or negatively reinforcing stimuli


KEY POINTS

The impact of ddysregulation sreg lationin in mPFC str structures ct res

Progressive plastic change (connectivity, parenchymal change)

More difficult to control dysregulation,

More difficult to control symptoms (treatment resistance)


Targeting deep brain targets

Functional neurosurgery

Deep p Brain Stimulation

Cyberknife safety and feasibility study


Functional neurosurgery

Poor patient selection

Poor assessments

Early efforts affected broad areas of

white matter tracts

Many severe neuropsychiatric and

cognitive side effects

Affected a diverse number of

prefrontal and subcortical circuits

IInternal t l capsulotomy

l t


Stereotaxic functional neurosurgery

History: Freeman/Watts 1940s

OCD

retrospective

n=800; 40 year period at MGH

safety – 2 infections

prospective studies

n=33; 30% responded

n=18; ; 30% responded p

n=8; 47% responded 24 mo

n=44; 32% responded 18 mo

AAnterior t i cingulotomy

i l t


Stereotaxic functional neurosurgery

Indications

MDD

Retrospective

n=198; 60% improved

Prospective

n=21; 60% responded

AAnterior t i cingulotomy

i l t


Stereotaxic functional neurosurgery

History: Talairach/Leksell 1940s

OCD

prospective studies

n=15; 53% responded

17% very much improved

n=35; 35% ‘free of symptoms’

86% responded

AAnterior t i capsulotomy

l t


Stereotaxic functional neurosurgery

History: Knight 1965

OCD

MDD

Retrospective p

n=1300 40-60% improved

SSubcaudate b d t ttractotomy t t

substantia inominata

‘ ‘extended t d d amygdala’

d l ’


Stereotaxic functional neurosurgery

Anterior Cingulotomy

+

Subcaudate tractotomy

History: Kelly/Richardson 1970s

OCD

Prospective

n=21; ‘35-50%’ 35-50% response

n=16; HDRS at 7 years

LLeukotomy k t


Functional neurosurgery for OCD and MDD

OOverall ll outcomes t

17-?% remitted

30-86% responded

Variable follow up period

Rule of thumb:

30% markedly improved

30% improved

30% no response


DBS for Depression

Ventral capsule/ventral striatum

VC/VS

Nucleus

Accumbens

SSaggital SSaggital it l CCoronal CCoronal l HHorizontal HHorizontal i t l

Subgenual pfc


CyberKnife low dose (60Rad) treatment for

refractory bipolar depression subgenual PFC

Intent:

To develop a non-invasive

treatment for refractory

depression

Hypothesis:

bbased don work k in i animals i l and d

treatment of trigeminal neuralgia,

low dose radiation may modulate

neural networks without causing

necrosis

Targeting area Cg25 Cg25, can we reduce

symptoms of depression as seen

in DBS studies?

Results

Appears safe, no apparent lesion

Enrolled 2 subjects with refractory

bipolar depression

Preliminary data very encouraging


*

KEY POINTS Targeting deep brain structures

Proof of concept

It is possible to target single brain structures or larger but limited areas

that appears to re-regulate dysregulated circuits

This approach can result in resolution of depressive symptoms

Such approaches support a view of depression as a

systems level disorder

Future research will determine the clinical efficacy of such treatments,

and the appropriate pp p ppatient ggroup p that should be candidates for

such procedures


Transcranial Magnetic Stimulation

(TMS)


TMS: General principles

The bioelectric field arises from the rapid discharge

of capacitors. The more rapid the discharge, the more

intense the magnetic field.

Contours of the magnetic field are determined by the

shape of the coiled wires of the wand

(eg. circular or figure 8)


Targeting the prefrontal cortex

5cmrule 5 cm rule

Prefrontal area of stimulation

Padberg, George. Exp Neuro 210, 2-13 2009 Herwig, Padberg. Biol Psych 58–61 2001

Motor cortex: motor threshold


fMRI – high frequency vs low frequency

9 unmedicated depressed

subjects

immediate response p to rTMS

middle frontal

gyrus

Right 1Hz and left 20Hz TMS have very different

metabolic effects on linked neurocircuits

Left 20Hz activates many linked structures

Right 1Hz 1H is striking for its lack of

recruitment of connected structures

superior temporal Inhibition: Increased:

gyrus

insul

a

middle frontal pfc posterior lateral pfc

orbitofrontal

cortex

hippocampu

s

Li, X., Nahas, J. Psychiatr. Res. 40, 307–314 2004


Efficacy low vs high frequency rTMS

4 wks low frequency rTMS

4 wks high frequency rTMS

Efficacy: Mean MADRS

At 4 weeks

Limitation: small n


High frequency TMS: MADRS continuous variable

MADRS Total Score Baseline to Endpoint Change

Change

from Baseline B

-1

-2

-3

-4

-5

-6

Week 2 Week 4 Week 6

p = .057 p = .058

p = .038 p = .052

p-values shown with correction for baseline imbalance in

total MADRS Score [N=6 patients censored w/total MADRS < 20]


MADRS categorical outcomes: Remission

* P < .05 vs. sham LOCF analysis

Remission Rates

*


Efficacy outcomes

Active response rates were generally about two-fold

higher than those with sham TMS

Remission rates were ere also about abo t two-fold t o fold higher than

sham on the MADRS and HDRS-24 scales at week 6

Placebo response rates were very low

response 11% at 4 weeks and 13% at 6 weeks

remission rates


Vagal Nerve Stimulation

(VNS)


The NCP System: An Implantable Vagus Nerve Stimulator

Cyberonics, Inc., Houston, TX


fMRI acute activation by VNS

Henry et al. Epilepsia 1998;39:983-990.

Significant bilateral in blood flow:

Amygdala

Hippocampu

(not shown)

Significant bilateral in blood flow:

Brainstem

Hypothalamus

Thalamus


Pivotal Study vs Comparative Study: Primary Analysis

IDS-SR30 3 Score

45

40

35

1-Year Scores by Month (Evaluable population)

30

Baseline 3 Month 6 Month 9 Month 12 Month

Adapted from George MS, et al. Biol Psychiatry.2005;58:364-373.

Comparative study (n=124)

Pivotal study (n=205)

p


VNS categorical outcomes

Nahas et al. J Clin Psych 66:1097 (2005)

Remission

15.3% 3 months

27.1% 12 months

22.0% 24 months


VNS outcomes

8 week sham control trial non-significant findings on

primary outcome measure

Outcomes of comparison parallel group (D04) suggested

VNS had significant clinical benefit from 3 - 12 months

24 mo. follow up showed stable response and remission

rates

Approx. 3 of 10 showed response at 12 mos, 70% of those

continued well to 2 years


Electroconvulsive Therapy

(ECT)


ECT procedure p

Brief anesthesthetic agent: short acting barbiturate, or etomidate

Methohexital, thiopental 2.0 mg/kg, etomidate .25mg/kg

Use of depolarization blockade of muscarinic motor endplate terminal

Succinyl choline 1.0-1.5mg/kg

TTourniquet i t of f arm

Active management of blood pressure and heart rate

beta blockers (esmolol)

alpha blockers (phentolamine)

mixed agents (labetolol)

nitroglycerine

Hydralazine

Seizure induced by constant current, pulse width 0.25, 0.5ms, or 1.0ms, 30-70

hz adjusted for total charge delivered. Charge range 5 to 500mC

Stimulus delivered over 6-8 6 8 seconds seconds. Voltage maximum of 500V


Right Unilateral vs Bilateral Lead Placement

RUL BL Right unilateral lead placement

requires dose titration to determine

lowest charge rneeded to induced

seizure - the seizure threshold (ST)

charge 55-6x 6x above ST to be

clinically effective

Bitemporal lead placement

no threshold for clinical efficacy if

motor duration adequate

(by consensus, somewhere 15-25s)

charge delivery: increased charge more

cognitive side effects, but faster response

RUL causes less memory disturbance

(Lisanby, Archives General Psychiatry 2000)


Acute Response and Relapse Rates in a

community sample

Acute outcomes HDRS Parameters used with ECT

( (pulse l width, idth waveform, f charge) h )

have an important impact

non-remitters

remitters i

on acute and long term outcomes, outcomes

including relapse risk.

Treatment to remission by

standardized assessments

(HDRS, MADRS,QIDS, or PHQ-9)

crucial to reduce relapse rates

ECT is highly effective, with

75-90% of patients with TRD

Th These patients ti t have h severe and d relapsing l i illness ill

Maintaining the well state is the greatest challenge

Prudic et al. Biol Psych 55:301(2004)


Acute and Persistent Cognitive Disturbance Rates in a

CCommunity it Sample S l Post-ECT P t ECT

Cognition and memor memory are impaired shortl shortly after ECT

At six months there is improvement in nearly all tasks

Within subjects

measures may

not reflect a

comparison to

normal controls

Post acute ECT

6 months post ECT


Acute and Persistent Cognitive Disturbance Rates in a

CCommunity it Sample S l Post-ECT P t ECT

Acute Post-ECT

Note persistent effects of bilateral ECT on

Autobiographical Memory Index

6 months assessment

Lead placement

Right unilateral

Bilateral

Sinewave bilateral


Relapse after acute ECT: continuation pharmacotherapy

Sackheim JAMA 285:2001

highest relapse risk is in first 3 months overall

Large multi-site trial 290 enrolled

159 remitted 84 enrolled in 24 week continuation

Conclusion

NNor + lithi lithium hhad d

reduced relapse

greater than Nor + pbo

Relapse rates

Placebo 84%

Nor 60%

Nor/Li 39%


Key yppoints:

ECT

ECT is the most effective treatment for depression

Treatment parameters used in ECT

affect acute response

relapse rates

degree of cognitive impairment

Highest risk of relapse occurs in the first 6 months

Continuation ECT and aggressive pharmacotherapy

reduces relapse risk post-acute ECT treatment


Key yppoints:

Mood disorders

Mood disorders are the result of a systems level dysregulation

The h symptoms of fddepression i are the h expression i of fddysregulation l i

of this circuitry

Th The ill illness course appears to t mirror i plastic l ti changes h in i both b th

connectivity and apparent atrophy of some prefrontal

and limbic structures

These plastic changes with the progression of the illness course

appear to increase the likelihood of relapse, incomplete recovery

bbetween episodes, i d and d chronicity h i i

Targeting specific regions of the brain show potential for treating

those who have treatment refractory depression

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