Deep Brain Stimulation of Treatment-Resistant Bipolar Depression

This study is only enrolling at Baylor College of Medicine. The other research locations listed serve to support data analysis only.

Enrollment: A subject is considered enrolled upon signing informed consent and deemed eligible to be screened by the investigator. The informed consent process may include discussions with the patients family and referring clinician.

Screening: Potential subjects meeting inclusion/exclusion criteria and willing to participate in the study as demonstrated by signing the informed consent will be enrolled in the study and undergo a screening and baseline visit (Visit 1 and Visit 2) spaced over an approximate 1 month period. Diagnostic and screening ratings are completed, followed by complete medical, neurological and neurosurgical evaluations. Final selection of candidates will be made by consensus of the multi-disciplinary investigator team.

Surgical Procedures: All patients will be implanted with bilateral leads targeting the VC/VS using the investigators previously described robotic DBS workflow. In brief, preoperative high-resolution MRI (3D, T1-weighted with and without contrast) and 3D CT will be obtained and uploaded to the ROSA (Zimmer Biomet) planning station. Images will be merged, and the AC, posterior commissure, and interhemispheric plane will be marked as is routinely done for stereotactic procedures. The investigatorswill plan two trajectories for each hemisphere and use intraoperative awake testing to validate the optimal target. One trajectory will be planned just anterior to AC (VC/VS), the other just posterior (bed nucleus stria terminalis (BNST)). The investigatorshave successfully implemented intraoperative behavioral testing to adjudicate between VC/VS and BNST in patients with treatment resistant OCD. Both trajectories will be planned such that the deepest contact is at the white/gray matter junction (i.e., VC/VS for the anterior trajectory, BNST for the posterior trajectory). The trajectory will follow the coronal contour of the anterior limb of the internal capsule (ALIC).

The investigators will use the postcontrast scan to ensure lack of vessel collision. A stereotactic frame (Leksell model G, Elekta) will be placed under local anesthesia. Under light sedation (to minimize movement), a fluoroscopic CT scan (O-arm 2, Medtronic) will be obtained and merged with the other image sets on the robotic navigation system. Using the frame skull pins as bone fiducials, the robot will be registered to the fixed head, and entry points marked according to preoperative planning. The head will be prepped and draped to allow for awake evaluation of the patient later in the procedure. The fluoroscopic CT will be draped into the field so that an intraoperative scan can be easily acquired. A single burr hole on each side will be drilled. The burr hole will be large enough to accommodate both trajectories.

Intraoperative Behavioral Testing. Lead securing devices will be installed bilaterally, and sedation stopped for intraoperative testing. A cannula (0 mm above target, 192 mm length, Alpha Omega) will be introduced to the first target as usual in DBS surgery. In general, the left VC/VS will be chosen as the first target. In cases in which the BNST is the safer trajectory, this target will be tested first. A DBS lead will be placed, and the cannula withdrawn to expose the contacts. Intraoperative evaluation will be conducted by a psychiatrist (W.K.G.), including a quick monopolar survey of all 4 contacts up to 5 mA. The investigators will ask whether the patient experiences any change in mood, energy, or anxiety while evaluating for positive valence (PV) affect (improved mood, increased energy, and reduced anxiety) on all contacts, and for adverse effects (increased anxiety, worsened mood, or other negative valence (NV) response). If a strong, consistent PV is produced during the monopolar survey, and no side effects are evident, the lead will be secured in that position. If no PV is evident, or if NV is produced, or other side effects are present, the lead will be removed, and the cannula repositioned to the second target. The investigators will then conduct another monopolar review at the second target in the same manner. Following stimulation of the second target, the neurosurgery and psychiatry teams will discuss the results to choose the final location of the lead. The patient will be blinded to stimulation target, amplitude, and side. The DBS system will be activated approximately 2 weeks following surgery during the first programming visit.

NeuroBehavioral Monitoring Unit (NBU). To capture high-density neural data coupled with multimodal measures (including sleep), subjects will spend 24 hours in the NBU - located at The Menninger Clinic's main campus in Houston - at multiple time points in the study:

1. week prior to surgery and week preceding activation, and
2. week following activation, then after 2 weeks, 4 weeks, 6 months, 9 months, and 12 months. The total days in NBU per subject is 8. Each of those visits will correspond to a period "in-situ", which will generally be 5 days long (Monday through Friday), including one day in the NBU. These are times when subjects will reside locally due to frequency of assessments or need for high-density recordings in NBU. In general, subjects will be asked to stay locally (in the greater Houston area) for the first 4 weeks following activation. To support recording neural time-domain local field potentials streaming while in the NBU, a Percept clinician programmer will be placed inside the room and configured to stream from the subject's implanted device for the duration of the participant's stay. A research coordinator will be responsible for restarting streaming sessions every eight hours, ensuring the patient's device stays charged, and ensuring the tablet stays connected as the patient moves through common spaces in on the Menninger campus. The clinician programmer tablet will be physically secured such that the subject cannot mistakenly tamper with it. Within the NBU, the subject will be asked to wear the mobile sensing systems (Apple watch, Oura ring, and audioband) to be deployed in the participant's home for sensor performance characterization. Multimodal Biobehavioral Measurement. Unlike movement disorders where the effect of stimulation can be acquired near instantaneously during programming, psychological state fluctuations require monitoring over days or weeks which can be best accomplished using wearable systems in naturalistic settings. The Rune patient app collects patient reported events, diary info and wearable data and pushes it up to the cloud (StrivePD portal). The neural data need to be uploaded to the Rune StrivePD web portal for integrating and synching the neural data with the behavioral data. The Percept-RC sensing capabilities will allow the investigators to collect high density neural data in the clinic and NBU, and less dense but chronic neural data collected in parallel with ecological data obtained outside the clinic. Passive and active (e.g., EMA survey pushes) behavioral data will be collected throughout the clinical trial, including baseline before surgery and baseline pre-activation following surgery. Weeks -8-0 (Screening and Baseline) The following Clinician-administered assessments will take place: Vital Signs, Structured Interview (SCID-5), SCID-5-PD (Personality Disorders); Montgomery Asberg Rating Scale (MADRS), Global Severity/Change (CGI-S/I), Young Mania Rating Scale (YMRS)56, Suicidality (C-SSRS), Anxiety (HAM-A), Medication Recommendation Tracking Form (MRTF) , Side-Effects (PRISE),; The following Subject Reported assessments will take place: Depression (QIDS-SR), Quality of Life Scale (QOLS), Sheehan Disability (SDS), Barratt Impulsiveness Scale (BIS), Altman Self-Rating Mania Scale (ASRM), Insomnia Severity Index (ISI) , Positive and Negative Affect Schedule (PANAS), Morning-Eveningness Questionnaire (MEQ), Internal State Scale (ISS),; The following Medical and Laboratory Testing will take place: Physical Exam, Vital Signs, ECG, UA, CMP, CBC, PT/PTT/INR, Hepatitis serology, pregnancy, tox screen; Brain Imaging: 3T: sMRI, DTI; MEG, rsfMRI. All blood draws are for clinical purposes ONLY and not research. The following Neuropsychological Testing (Neuropsych) will occur: MMSE, HVLT-R*, BVMT-R*, MoCA, TOPF, Weschler Adult Intelligence Scale IV Edition: Digit Span, Coding, Similarities, Information, Visual Puzzles; Trails A \& B; WCST-64Rey-Osterrieth Complex Figure, DKEFS lexical and semantic fluency*, STROOP, BDI-II, PSWQ, OCI-R, Millon Behavioral Medicine diagnostic (MBMD) (baseline only) [Alternate forms for follow-up testing]; The following Behavioral Tasks will occur: Probabilistic Reward Task (PRT) and Immediate Memory Task (IMT) will be given at baseline Mobile biobehavioral measures: (e.g., Rune app ingested data from wearables, peripherals, self-reports). Administer 5-10-minute Ecological Momentary Assessment (EMA) sessions will be triggered starting at baseline and throughout the course of the study. Peripherals and wearables for activity and sleep monitoring will be provided for continuous use. Neurobehavioral Unit: Will be "in-situ" (staying locally) during much of this time and spend one 24-hour period in in a clinical monitoring environment) for highdensity streaming coupled with multi-modal behavioral measures including computer vision for affect and activity analysis, speech analysis, peripherals and wearables for activity and sleep. Polysomnography at baseline overnight stay at NBU to conduct baseline sleep study for validation of concurrent and subsequent Oura Ring sleep monitoring. (This will be NBU visit 1 of 8) DBS SURGERY VISIT: CT scans will be performed prior to, during and after surgery. The DBS System Implantation of bilateral VC/VS current steering electrodes. Week 1-2: Following one week recovery, seen for repeat baseline assessments pre-DBS activation. These include: Clinician-administered: Vital Signs, MADRS, CGIS, YMRS, C-SSRS,HAM-A, MRTF, PRISE, Subject Reported: QIDS-SR, QOLS, SDS, BIS, ASRM, PANAS, MEQ, ISS. Medical and Laboratory Testing: Repeat MEG, rsfMRI. Neuropsychological Testing (Neuropsych): Repeat the neuropsych battery defined in the screening/baseline period. Behavioral Tasks: PRT, and IMT. Mobile Biobehavioral measures: ongoing data collection through continuous use of wearable sensors, peripherals, and EMA. NeuroBehavioral Unit: two 24-hour periods in NBU. (This will include NBU visit 2 of 8) Week 2 following surgery: Following two week recovery, subject will be seen for baseline assessments and system activation of theDBS device. Repeat Assessments: Clinician-administered: Vital Signs, MADRS, CGIS, YMRS, C-SSRS, HAM-A, MRTF, PRISE, Subject Reported: QIDS-SR, QOLS, SDS, BIS, ASRM, PANAS, MEQ, ISS. Neuropsychological Testing (Neuropsych): Repeat the neuropsych battery defined in the screening/baseline period. Behavioral Tasks: PRT, and IMT. Mobile Biobehavioral measures: ongoing data collection through continuous use of wearable sensors, peripherals, and EMA. NeuroBehavioral Unit: Will be "in-situ" (staying locally) during much of this time and spend one 24-hour period in the NBU (This will include NBU visit 3 of 8) Week 3-8: Following two weeks recovery, seen for initial DBS programming session for monopolar survey. The subject will be seen every 1-2 weeks for programming optimization. Repeat assessments: Clinician-administered: Vital Signs, MADRS, CGIS, YMRS, C-SSRS, HAM-A, MRTF, PRISE, Subject Reported: QIDS-SR, QOLS, SDS, BIS, ASRM, PANAS, MEQ, ISS. Neuropsychological Testing (Neuropsych): Likert-like scales assessing mood, anxiety and energy will be given before and after programming. Behavioral Tasks: PRT and IMT at month 1. Mobile Biobehavioral measures: ongoing data collection through continuous use of wearable sensors, peripherals, and EMA. Begin collection of LFPs to be synchronized other measures for offline analysis. Neurobehavioral Unit: One 24-hour stay in NBU. (NBU visits 4 and 5 out of 8 will occur during this time) Months 2-9: These will include once a month visits in order to optimize chronic DBS programming for efficacy and safety. Repeat assessments: Clinician-administered: Vital Signs, MADRS, CGIS, YMRS, C-SSRS, HAM-A, MRTF, PRISE, Subject Reported: QIDS-SR, QOLS, SDS, BIS, ASRM, PANAS, MEQ, ISS. Medical and Laboratory Testing: Repeat MEG, rsfMRI, at end-of-month 6. Neuropsychological Testing (Neuropsych): Repeat the neuropsych battery defined in the screening/baseline period. Behavioral Tasks: PRT, and IMT. Mobile Biobehavioral measures: ongoing data collection through continuous use of wearable sensors, peripherals, and EMA. NeuroBehavioral Unit: Will be "in-situ" (staying locally) during much of this time and spend one 24-hour period in the NBU. (This will be NBU visit 6 of 8) Month 9 visit: At this visit the team will determine if subject meets responder criteria Repeat Assessments: Clinician-administered: Vital Signs, MADRS, CGIS, YMRS, C-SSRS, HAM-A, MRTF, PRISE, Subject Reported: QIDS-SR, QOLS, SDS, BIS, ASRM, PANAS, MEQ, ISS. Medical and Laboratory Testing: Repeat MEG, rsfMRI. Neuropsychological Testing (Neuropsych): Repeat post-op baseline Neuropsych battery. Behavioral Tasks: PRT, and IMT at end-of-month 9. Mobile Biobehavioral measures: ongoing data collection through continuous use of wearable sensors, peripherals, EMA, and neural LFPs. NeuroBehavioral Unit: Will be "in-situ" (staying locally) during much of this time and spend one 24-hour period in the NBU. (This will be NBU visit 7 of 8) Months 9-12: Continuation of monthly visits for key clinical evaluations Repeat Assessments: Clinician-administered: Vital Signs, MADRS, CGIS, YMRS, C-SSRS, HAM-A, MRTF, PRISE, Subject Reported: QIDS-SR, QOLS, SDS, BIS, ASRM, PANAS, MEQ, ISS. Mobile Biobehavioral measures: ongoing data collection through continuous use of wearable sensors, peripherals, EMA, and neural LFPs. End Month 12: Begin 1 month withdrawal period. The DBS system will be turned off completely at some point during this gradual taper period. The study doctor will make the clinical decision whether to restart stimulation. Repeat Assessments: Clinician-administered: Vital Signs, MADRS, CGIS, YMRS, C-SSRS, HAM-A, MRTF, PRISE, Subject Reported: QIDS-SR, QOLS, SDS, BIS, ASRM, PANAS, MEQ, ISS. Medical and Laboratory Testing: Repeat MEG, rsfMRI, Behavioral Tasks: PRT, and IMT at end-of-month 12. NeuroBehavioral Unit: Will be "in-situ" (staying locally) during much of this time and spend one 24-hour period in the NBU. (This will be NBU visit 8 of 8) Months 13-20: The team and subject will make the clinical decision whether to reinstate or deactive DBS following discontinuation phase. Repeat Assessments: Clinician-administered: Vital Signs, MADRS, CGIS, YMRS, C-SSRS, HAM-A, MRTF, PRISE, Subject Reported: QIDS-SR, QOLS, SDS, BIS, ASRM, PANAS, MEQ, ISS. Month 20: Last set of formal study visits. All evaluations and labs will be repeated. Clinician-administered: Vital Signs, MADRS, CGIS, YMRS, C-SSRS, HAM-A, MRTF, PRISE, Subject Reported: QIDS-SR, QOLS, SDS, BIS, ASRM, PANAS, MEQ, ISS.