DBS for TRD Medtronic Activa PC+S

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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-o...

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 fMRI/MRI/DTI preop Activa PC+S continuous from day1 post-op until battery depleted EEG Pre-op, post-surg, acute testing, 1, 3, 6, dc, 12 mo Audiovisual recording Pre-op, post-surg, acute testing, 1, 3, 6, dc, 12 mo Affectiva SCR, actigraph Pre-op, post-surg, acute testing, 1, 3, 6, dc, 12 mo 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.

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