DBS for TRD Medtronic Activa PC+S
DBS for TRD Medtronic Activa PC+S
Major depressive disorder is a common disease. For many people, conventional treatments such
 as antidepressants are very helpful in relieving the symptoms of this condition. But as many
 as 30% of patients with depression have less than a full response or become resistant to
 conventional treatments. When treatment resistance develops, the depression becomes a chronic
 disease with a very significant burden of morbidity and mortality. The reasons that some
 patients develop Treatment Resistant Depression (TRD) are not known. One current theory for
 depression is that it results from the dysfunction of a network of regions in the brain and
 that in treatment resistant patients the network is permanently stuck in the dysfunctional
 state. We have been investigating an experimental treatment for treatment resistant
 depression (TRD), based on this network theory known as subcallosal deep brain stimulation
 (SCC DBS). This treatment involves placement of electrodes in a specific region of the brain
 (subcallosal cingulate cortex, area 25) and then stimulating that area with electricity,
 which resets the regulation of the network resulting in a significant antidepressant
 response. While still experimental our results suggest this may eventually be a useful
 treatment for some patients with TRD. The experiment described in this application is to use
 a new DBS device that can record the electrical activity in the brain around the site of
 stimulation. The electrical activity is known as Latent Field Potential (LFP) and is a
 reflection of the activity if the neural network. The new DBS device is an experimental
 device that has not been approved by the Food and Drug Administration (FDA), but allows for
 simultaneous recording of LFP while stimulation is being delivered. The device is
 manufactured by Medtronics and is known as Activa Primary Cell + Sensing(PC+S), but because
 it can be used to record the brain electrical activity it is also known as "the Brain Radio".
 The Brain Radio is based on an approved device commonly used for DBS for other conditions
 that has the added sensor capacity. The stimulation system is identical to that in the
 approved device. The goal of this investigation is to use the Brain Radio to study LFP in the
 brains of people with TRD before and during active stimulation. The ultimate goal is to
 understand the neural network that causes TRD and the changes that DBS cause in that network
 that results in the antidepressant effects. We will recruit 10 patients with advanced TRD and
 implant them with the Brain Radio system. The recording system will be to record LFP over 3
 years, while patients receive stimulation. A brief discontinuation study will be conducted
 after 6 months of stimulation when the device will be turned off and patterns of LFP changes
 will be recorded. All LFP measures will be correlated with the primary clinical response
 outcome metric, the Hamilton Depression Rating Scale. The knowledge gained with this
 experiment will be invaluable to understanding the basic pathology of depression and the
 antidepressant response. This is a unique, first in humans test of this device and as such
 the results are expected to impact our understanding of depression at a fundamental basis.
TITLE: Deep Brain Stimulation for Treatment Resistant Depression: Exploration of Local Field
 Potentials (LFP) with the Medtronic Activa PC+S "Brain Radio" System

 PRINCIPAL INVESTIGATOR: Helen Mayberg, MD

 SCHEMA

 Recruitment: Telephone screening Screening: Eligibility assessment Informed Consent
 Pre-operative Evaluation: Confirmatory psychiatric interview (4-6 weeks pre-op) Neurosurgical
 evaluation Behavioral Activation therapy evaluations (1-4 sessions) Neuropsychological
 testing #1 Activity Monitoring and GPS Route Logging EEG recording High-resolution anatomical
 MRI Diffusion tensor imaging Resting BOLD fMRI Weekly mood ratings including the Primary
 Outcome Measures the Hamilton Depression Rating Scale (HDRS)

 Audiovisual recordings all weekly sessions Surgical procedure: Pre-operative anatomical MRI
 Implantation of bilateral deep brain stimulation electrodes Intraoperative testing of DBS
 electrode contacts

 ActivaPC+S Recording: Implantation of ActivaPC+S system/ Stimulation OFF Post-operative
 anatomical MRI Experiment #1A: Immediate Post-Op Recovery and Carryover Activa PC+S LFP and
 scalp EEG recording of carryover in hospital (48 hours)

 Recovery Period: Stimulation OFF (4 weeks post-op) Weekly mood ratings and clinical
 evaluation Activity Monitoring, GPS Route Logging High-resolution computed tomography (CT)
 Experiment #1B: 1 month carryover ActivaPC+S LFP/EEG recordings weekly

 Active stimulation: Experiment #2: Acute stimulation parameter testing (24 weeks) Test
 different Frequency and Current settings Activa PC+S LFP/EEG recording (4 hours)

 Experiment #3: Chronic stimulation; Stimulation ON Activa PC+S LFP recordings EEG (1, 3, 6
 months) Activity Monitoring, GPS Route Logging (1, 3, 6 months)

 Mood ratings and clinical evaluation and HDRS:

 Weekly for four weeks Weekly to Bi-weekly for next 20 weeks Audiovisual recording of all
 sessions Neuropsychological testing #2 (6 months) Behavioral Activation therapy (up to 30
 sessions)

 Stimulation discontinuation: Experiment #4: Brief Stimulation Discontinuation

 (1 week) 7-day discontinuation during 6th month Daily clinical assessments ActivaPC+S LFP/
 EEG recordings

 Long Term Stimulation: Experiment #5: Naturalistic follow-up; Stimulation ON (10 years)
 ActivaPC+S LFP/ EEG recording until battery depletion (every 6 month) IPG Battery replacement
 with commercially available Medtronic Activa system (estimate at year 3) Activity Monitoring,
 GPS Route Logging (12, 24 months)

 Mood Ratings and clinical evaluation including HDRS:

 every month for 3 months every 3 months for 9 months every 3-6 months 10 years Audiovisual
 recordings during clinical visits

 Equipment

 1. fMRI/MRI/DTI preop

 2. Activa PC+S continuous from day1 post-op until battery depleted

 3. EEG Pre-op, post-surg, acute testing, 1, 3, 6, dc, 12 mo

 4. Audiovisual recording Pre-op, post-surg, acute testing, 1, 3, 6, dc, 12 mo

 5. Affectiva SCR, actigraph Pre-op, post-surg, acute testing, 1, 3, 6, dc, 12 mo

 6. GPS/Pedometer Pre-op, post-surg, acute testing, 1, 3, 6, dc, 12 mo

 Primary Clinical Outcome Meausure: Hamilton Depression Rating Scale (HDRS measured at time
 points outlined.

 INTRODUCTION Deep brain stimulation of the subcallosal cingulate white matter (SCC25 DBS) has
 been investigated as a new interventional strategy for treatment resistant depression (TRD).
 In addition to growing evidence of long-term antidepressant efficacy with chronic
 stimulation, immediate changes in mood, attention, and psychomotor speed during
 intra-operative testing have been repeatedly observed. These acute, electrode
 contact-specific behavioral effects have successfully guided selection of the optimal contact
 for chronic DBS. The presence of intraoperative behavioral effects is often predictive of
 long-term outcome. It is clear that sustained high frequency stimulation appears to be
 required to maintain the antidepressant response long-term, as discontinuation even after
 several years of remission is associated with deterioration and return of depression symptoms
 over several weeks. Imaging studies examining effects of chronic SCC25 DBS using positron
 emission tomography (PET) demonstrate changes in blood flow and metabolism both in the
 vicinity of the DBS target, and remotely in frontal cortex, ventral striatum, hypothalamus
 and amygdala/hippocampus. These findings, combined with more recent diffusion tensor imaging
 (DTI) studies, provide evidence of the anatomical and functional extent of regional changes
 mediating antidepressant effects of DBS over time [5-6].

 Brain changes mediating the observed intra-operative behavioral changes or
 discontinuation-precipitated relapse are unknown. To date, none of the studies have been able
 to address explicit mechanisms of DBS for TRD at the neuronal level, during chronic
 stimulation. It is possible to make measurements of neuronal activity with available
 recording systems only during intraoperative testing. Given that TRD requires chronic
 stimulation to achieve full remission, characterization of changes in neural activity
 throughout the duration of stimulation and development of therapeutic response will be
 invaluable in further developing and refining this treatment modality. Furthermore, tracking
 of neural changes and their behavioral correlates with chronic stimulation and controlled
 discontinuation would allow characterization of physiologic markers for potential use as
 feedback signals for further treatment development and optimization.

 This set of new experiments will build on past experience of utilizing SCC25 DBS in patients
 with TRD to explore potential neural correlates of antidepressant response. This will be done
 using the ActivaPC+S, which is a prototype DBS system developed by Medtronic that combines
 conventional DBS brain electrodes and pulse generator with a sensing device that can
 chronically read, record and download the electrical brain activity known as Local Field
 Potential (LFP) at the brain area surrounding the DBS electrode. These recordings can be
 downloaded from the implanted device with an external antenna device similar to the device
 used to control the pulse generator. Given the ability to record LFP locally in the brain and
 to transmit this information to a receiving station the ActivaPC+S device is referred to as
 the "Brain Radio".

 The ActivaPC+S, "Brain Radio" device is an experimental system currently not approved by the
 FDA. This device is based on the ActivaPC system, which has FDA approval for use in
 Parkinson's disease, Essential Tremor and has Humanitarian Device Exemption (HDE) for
 Dystonia. The ActivaPC also has an HDE for use in intractable Obsessive Compulsive Disorder
 (OCD). The Brain Radio has sensing technology in addition to the standard stimulation
 capacity of the approved device that allows for real time recording of LFP in the anatomical
 location of the electrode both during active stimulation and when stimulation is off. As such
 this is a very powerful research tool that will facilitate investigation of the neuronal
 changes associated with antidepressant response to chronic DBS. This will be the first ever
 use of this unique, cutting edge system in human patients with treatment resistant depression
 and has the potential to provide unprecedented insight into the fundamental neuronal
 processes that underlie depressive illness and antidepressant response.

 Hypothesis 1: Aberrant oscillations in the SCC-prefrontal circuitry are present in TRD
 patients. SCC25 DBS exerts its therapeutic effects by altering these network dynamics.
 Behavioral improvements in TRD patients treated with SCC25 DBS will correlate with
 discernible LFP changes at specific DBS electrode contacts, both acutely and chronically.

 Hypothesis 2: Stable maintenance of stimulation-induced LFP changes is required for sustained
 antidepressant response, with loss of these changes heralding impending depression relapse.

 This study will test these hypotheses in 10 TRD patients via recording LFPs with the
 ActivaPC+S system throughout the course of chronic SCC25 DBS. Measures of SCC LFP oscillatory
 activity will be correlated with clinical measures of antidepressant response and with scalp
 EEG signals.

 OBJECTIVES Experiment #1: To quantify electrophysiological changes, behavioral correlates and
 EEG changes in the month following implantation when the stimulator is turned OFF.

 Experiment #1A: To characterize the LFP changes for 48 hours post op in response to the
 brief, acute stimulation the patient receives during the implantation procedure Experiment
 #1B: To characterize the changes in LFP patterns in the month after implantation and to
 establish a baseline before chronic stimulation is initiated. The Activa PC+S system will be
 utilized to record LFP during this phase of the protocol.

 Experiment #2: The stimulator will be turned on 1 month after implantation. This experiment
 will occur on the day of stimulation initiation. Clinical data will be recorded and LFP
 changes will be captured by the Activa PC+S system and scalp EEG. The stimulator will be
 cycled through a series of different frequency and current settings while LFPs are recorded.

 Experiments #3: To quantify LFP changes in response to chronic high frequency SCC25
 stimulation and to correlate change patterns with long-term antidepressant response and EEG
 patterns. Stimulation will be initiated one month after implantation and maintained
 chronically for the subsequent 6 months. Clinical assessments, LFP and scalp EEG will be
 routinely recorded during this 6-month period.

 Experiment #4: To quantify LFP changes when the stimulation is briefly stopped (1 week) after
 6 months of chronic stimulation. Correlation will be made between LFP, clinical/ symptomatic
 changes and EEG patterns.

 Experiment #5: To quantify LFP changes over the extended period of exposure to chronic high
 frequency SCC25 stimulation. Clinical response and EEG patterns will be recorded every 6
 months and compared to LFP over the battery life of the ActivaPC+S system; currently
 estimated at 3 to 5 years after initiation of stimulation.

 The primary clinical outcome metric is the Hamilton Depression Rating Scale.
Inclusion Criteria:

 -  Age 25-70 years old.

 -  Ability to provide written informed consent.

 -  Agrees to relocate to the Atlanta Metro region for the duration of the acute phase of
 the investigation (approximately 8-10 months) and to return regularly for clinical and
 research assessments

 -  Current depressive episode of at least two years duration OR a history of more than 4
 lifetime depressive episodes.

 -  Failure to respond to a minimum of four different antidepressant treatments, including
 at least three medications from at least three different drug classes, evidence-based
 psychotherapy or electroconvulsive therapy (ECT) administered at adequate doses and
 duration during the current episode.

 -  Failure or intolerance of an adequate course of electroconvulsive therapy (ECT) during
 any episode

 -  All patients must have an established outpatient psychiatrist and be willing to sign a
 written release to allow study investigators to give and receive information from this
 psychiatrist.

 Exclusion Criteria:

 -  Refusal or inability to relocate to Atlanta Metro region for acute phase of protocol
 or to return for regular assessments in long term follow up

 -  Inability to tolerate general anesthesia.

 -  Significant cerebrovascular risk factors or a previous stroke, documented major head
 trauma or neurological disorder.

 -  Other currently active clinically significant Axis I psychiatric diagnosis including
 bipolar disorder, schizophrenia, panic disorder, obsessive-compulsive disorder,
 generalized anxiety disorder or post-traumatic stress disorder.

 -  Current psychotic symptoms.

 -  Evidence of global cognitive impairment.

 -  Substance abuse or dependence not in full, sustained remission.

 -  Active suicidal ideation with intent; suicide attempt within the last six months; more
 than three suicide attempts within the last two years.

 -  Pregnancy or plan to become pregnant during the study period.

 -  General contraindications for DBS surgery (cardiac pacemaker/defibrillator or other
 implanted devices).

 -  Inability or unwillingness to comply with long-term follow-up.

 -  History of intolerance to neural stimulation of any area of the body.

 -  Participation in another drug, device or biologics trial within the preceding 30 days
 prior to initial screening.

 -  Conditions requiring repeated MRI scans.

 -  Conditions requiring diathermy.

 -  Conditions requiring anticoagulant medication.

 -  Terminal illness associated with expected survival of <12 months.