INTERVENTIONAL NEUROPSYCHIATRY: MOVING BEYOND NEURAL CUBISM

Interventional Neuropsychiatry: Moving Beyond Neural Cubism Nolan Williams, MD Instructor Department of Psychiatry Stanford University

Classic Neuropsychiatrist: Trained as Both a Neurologist and a Psychiatrist

Theodor Meynert

Joseph Babinski

Jean-Martin Charcot

Pioneers of Interventional Neuropsychiatry

Helen Mayberg MD

Mark George MD

Benjamin Greenberg MD

Neurologist, developer of SCC DBS for depression, started career studying PD & HD depression.

NeurologistPsychiatrist, developer of rTMS and VNS for TRD, started career studying TS and OCD.

Neurologist-Psychiatrist, developer of VCVS DBS for OCD, started career studying motor physiology in OCD.

Not a coincidence that all are neurologists, channeling the classic neuropsychiatrist.

2014

2014

"Make everything as simple as possible, but not simpler." - Albert Einstein

The Merger of Neurology and Psychiatry Has Already Started at the Level of the Circuit

Proficiency in: • Electroencephalography: with focus on learning principles of quantitative EEG • Structural Brain Imaging: MRI, CT • Functional Brain Imaging: fMRI, PET, SPECT • Transcranial Magnetic Stimulation: repetitive and paired pulse • Transcranial Direct Current Stimulation • Electroconvulsive Therapy and Focal Electrically Administered Seizure Therapy • Vagus Nerve Stimulation • Deep Brain Stimulation, psychiatric clearance, intraoperative testing, and programming

It All Started in an Elevator in London 20 Years Ago

Neuropsychiatric Disorders are Disorders of Distributed Neural Networks

Neurology: • Parkinson’s Disease • Tourette’s syndrome

Psychiatry: • ObsessiveCompulsive Disorder • Depression • BPAD

All Neuropsychiatric Disorders Have an Emerging Circuit Diagram Like This One

Neurologic and Psychiatric Disorders Utilize Overlapping Circuits

Interventional Tools

Invasive Interventional Neuropsychiatry

Deep Brain Stimulation (DBS)

The Motor System is a Model System

The Motor System is a Model System

DBS Implantation

Intraoperative Testing

Programming DBS

2013

“Neurology”

“Psychiatry”

Rule: All Interventional Psychiatry Tools Were Developed in Neurological Disorders First (with the exception of ECT)

Rule: The Motor System is the Model System for New Interventions in Psychiatry

Lancet, 1985

Rule: No Node in a Given Network is Pure

Rule: Target Node Dictates Intervention EpCS

DBS

-Cortical Target Node

-Subcortical Target Node

-Has been performed for depression, BPAD, stroke rehab, and apahsia.

-Has been performed for depression, BPAD, tremor, Parkinson’s disease, and dystonia among others.

Both interventions are intended to change activity in the targeted node and thereby changing the activity in the distributed neural network.

Rule: Stimulating a Single Node has Distributed Effects Through The Network

OCD

Depression

Parkinson’s

Tourette

2014

Rule: While Multiple Nodes Can “Work”, Each Node May Work Better on Specific Domains

2014

Building a Circuit Bridge from/to Neurology from/to Psychiatry: Cross-Disorder/Disease Circuit Localization

Stimulating one node with DBS for treatment may act as a probe for a second disorder/disease. = Interaction was observed. target.

= Observed Interaction resulted in new trial (indication) for

BLUE= Neurology and RED=Psychiatry

Coagulation Target

1999

Lesion Target

Tourette Circuit Conceptual Diagram

1999

“Neurology Target”=1 “Psychiatry Target”=0

Tourette DBS

OCD Circuit

Conceptual Diagram

1999


OCD Circuit

Milad & Rauch 2012

Based on Delong Map 2002

Based on Animal Studies 2003


1999

2002


OCD Circuit

Conceptual Diagram

2003

1999


Intraoperative Assessment

Haq, 2011

Nucleus Accumbens OR Testing

2005

Novel target selected from past experience + animal models.


2005

2005


1999

2002

Anteromedial GPi as OCD Target along with TS target

Nair 2014

CM nucleus as OCD Target along with TS target Porta 2009

OCD Circuit

Conceptual Diagram

2003

2014 “Neurology Target”=2 “Psychiatry Target”=2

1999

2009

2005

2008

2007


2007

2005

2005

2005


1999

2002

2005

2008

2009

Novel Psychiatric DBS Target Based on Functional Imaging 2005

Modified Mayberg Target

Riva-Posse 2014

Mood Disorders Conceptual Diagram

2005


2008

2009

2013

OCDvCircuit

Conceptual Diagram 2013

2003

2014


1999

2009

2002

2004

200 8

OCD Circuit

Conceptual Diagram

2013

2003

2002

2014


1999

2009

VCVS Stimulation

Parkinson’s Circuit Conceptual Diagram


STN DBS Stimulation

Mood can be turned down…

…by incidentally inhibiting a node in the mood regulation network.

Contact 0 of the left electrode was located in the central substantia nigra, including part of the pars compacta and pars reticulata.

Mood can be turned up…

…by activating adjacent reward circuitry…

2009

Medial Lemniscus=Internal Capsule=Medial Forebrain Bundle: All white matter fibers which course close to the STN.

2013

Mood Disorders

2009

2005 “Neurology Target”=1 “Psychiatry Target”=3

2008

2009

Treatment-Resistant Depression • Depression is a state of extreme sadness or melancholia that affects a person’s activities of daily life as well as social functioning (Williams 2009). • Treatment-resistant depression (TRD) is a severely disabling disorder with no proven treatment options once standard/approved therapies (medication, psychotherapy, TMS, VNS, ECT) have failed (Williams 2013).

Treatment-Resistant Depression Targets There are multiple cortical and subcortical targets for treating TRD: – Cortical: • Dorsolateral Prefrontal Cortex • Frontopolar Cortex

– Subcortical: • Subcallosal Cingulate [FAILED] • Medial Forebrain Bundle • Ventral Capsule/ Ventral Striatum [FAILED]

Ideal Depression Implanted Device • So straightforward that any major medical center can do it (like rTMS). – Easy surgical approach that requires nonfunctional neurosurgeon and trained psychiatrist. – Easy programming approach.

• Low risk. – Low to no ICH risk. – Low risk of hardware failure.

EpCS for TRD

“Most likely deep brain stimulation for depression will be a transitional technology, which will lead to even more refined, but less invasive treatments of the brain.” Thomas E. Schlaepfer, MD—Scientific American Interview, 2013

Ziad Nahas MD, MSCR

Istvan Takacs MD

EpCS: Two Cortical Stimulation Sites •

The frontopolar (FP-BA 10) and dorsolateral (DL-BA 9/46) prefrontal cortices (PFC) play distinct, yet complementary roles in the integration of emotional and cognitive experiences (Nahas 2010).

•

One or both of these two cortical areas appear to be central to the efficacy of deep targets (Williams 2014).

•

Our study utilized bilateral dorsolateral prefrontal and the frontopolar cortex as stimulation sites (Nahas 2010).

EpCS: Dorsolateral Prefrontal Cortex •

Established cortical stimulation site for non-invasive brain stimulation (transcranial magnetic stimulation) (George 2010).

•

In TRD, L DLPFC hypoactivity is associated with negative emotional judgment and right DLPFC hyperactivity is linked to attentional modulation (Grimm 2008).

•

DLPFC has been demonstrated to be anticorrelated with subcallosal cingulate (SCC) (Fox 2012).

EpCS: Frontopolar Cortex • The medial prefrontal cortex has been implicated in animal (Covington 2010) and human studies (Downar 2013) as playing a central role in the pathogenesis of depression as well as in its recovery. • There is a consistent finding of increased restingstate activity in the frontopolar cortex (FPC) in patients with depression (Fitzgerald 2008). • Effective SCC DBS requires functional connection to the FPC (Riva Posse 2014).

Modified Mayberg Target

Riva-Posse 2014

Epidural Prefrontal Cortical Stimulation • We implanted five adults with four stimulation paddles over dura (between dura and skull) covering FP and DLPFC. • These five individuals had failed an average of 5.8 antidepressants prior to implant with three who had failed VNS and four who had failed or were unable to tolerate ECT. • All subjects received ongoing clinical assessments at baseline, seven-month (7mo), one-year (1yr), two-year (2yr), and five-year (5yr) time points.

Epidural Prefrontal Cortical Stimulation • All patients have continued to tolerate the therapy. • There were five serious adverse events: one paddle infection and four device malfunctions, all resulting in suicidal ideation and/or hospitalization with three involving the battery (2-drain, 1-turned off) and one involving connectors. • Three of five (60%) subjects continued to be in remission at 5yr. • One of the non-responders converted to a responder (80%) once a technical error was discovered.

Average HAMD Scores

Results • There was a statistically significant reduction of the MADRS (p=.05) and CGI (p=0.043) for baseline to 5 years. • No significant change in cognitive measures (choice reaction test, continuous performance task, MMSE, cognitive failures test).

Sam’s Experience

One of five epidural patients that gave permission to tape/show interview.

Mood Disorders

2010

2010 “Neurology Target”=1

2009

2005

2008

2009

“Psychiatry Target”=5

Score Card

Mood Disorders

OCD

Tourette

Parkinson’s

“Neurology Target”=1








EpCS is Qualitatively Different from DBS • Except for NAc TRD target, DBS has no potential for long-term recording. • DBS has at least 1% intracranial hemorrhage risk. • DBS has complex targeting which can result in unintended neural elements to be stimulated (3D).

EpCS is Qualitatively Different from DBS • EpCS has the potential for long-term recording. • EpCS inherently has the ability to develop closed loop system. • EpCS has no intracranial hemorrhage risk. • EpCS has the potential to test spike timing in multiple ways/sites (L DLPFC—R DLPFC & DLPFC --- FPC). • The EpCS sites that were chosen are rTMS sites for numerous disorders which are comorbid with depression. • EpCS has a simple targeting method (2D).

Psychiatrist Targeting of EpCS with rTMS Targeting Technology

Cautionary Tale: • Team could not get voltage over 0.5V (very low) with significant side effects. • CAPS scores barely changed from 10595 in 6 months. • Patient with very limited benefit and significant side effects along with risk of ICH.

The Third Age of Psychiatry:

Stigma Cannot Survive at the Level of the Circuit

Meetings of Psychiatrists, Neurologists, and Neurosurgeons are Already Happening

Unexpected Changes Can Occur

Emily’s Rule • I asked my wife Emily what her estimation of my hours dedicated to a patient with an implanted device was relative to the surgeon. • I said 1:10 and she said 1:30. We averaged this estimation and will say 1:20. • For every one hour that the neurosurgeon spends with an implanted device patient, I must spend 20 hours. • We agreed that the only implanted device patients that I should accept are those that I 100% believe in the science.

Acknowledgements: Brain Stimulation Lab: Mark George Baron Short DBS Program: Gonzalo Revuelta Functional Neurosurgery Program: Istvan Takacs Ziad Nahas

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INTERVENTIONAL NEUROPSYCHIATRY: MOVING BEYOND NEURAL CUBISM

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