Clinical trial NCT04152993: Responsive Neurostimulation for Post-Traumatic Stress Disorder
Official title: Responsive Neurostimulation for Post-Traumatic Stress Disorder
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: EARLY_PHASE1
Conditions: Post-Traumatic Stress Disorder
Lead sponsor: VA Greater Los Angeles Healthcare System
Sponsor class: FED
Collaborators: name: University of California, Los Angeles
First posted: 2019-11-06
Enrollment: 6
Sex: MALE
Minimum age (years): 25
Maximum age (years): 60
Standard ages: ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: Post-traumatic stress disorder (PTSD) refractory to treatment is marked by failure of fear extinction and its biological substrate, amygdala reactivity to trauma reminders. Decades of research have clarified the neuronal mechanisms coordinating fear extinction and consolidation. Fear cells and extinction cells in the basolateral amygdala (BLA) alter their firing rate based on the nature of the stimulus and the influence from the medial prefrontal cortex (mPFC) and the ventral hippocampus (vHPC). Together, the BLA, mPFC, and the vHPC form an anxiety-processing network where the BLA links stimulus to emotion, the vHPC provides memory context, and the mPFC coordinates extinction or consolidation. Local field potential (LFP) recordings from the BLA have revealed specific signals that correspond to an enhanced fear state. Previous studies have shown that neuromodulation of the BLA can promote extinction in a rodent model and in a treatment-refractory PTSD patient. This action is likely carried by disrupting fear signals within the BLA; however, continuous neurostimulation may also disrupt normal function of the amygdala. The present application proposes to investigate the use of Responsive Neurostimulation (RNS, Neuropace) in six (6) veterans suffering from severe treatment-resistant PTSD. This dual-activity device will allow us to chronically record LFPs from the BLA under specific conditions such as fear conditioning, exposure to trauma reminders, and emotional memory encoding and retrieval. In addition, the neural activity will be captured during real-life symptoms of flashback and nightmares. These recordings will provide the specific electrophysiological biomarkers of hypervigilance and re-experiencing. The device will then be programmed to detect and treat these biomarkers with a pre-determined electrical pulse. The patients will be followed prospectively using psychological scales but also with functional neuroimaging and electroencephalograms. These modalities will be used to determine the extent of circuit engagement as a result of the therapy. By approaching PTSD from a fear processing mechanism perspective, our project will serve as a proof of concept for other circuit-based therapies in psychiatry. This proposal is a multi-departmental effort involving 11 investigators across 7 departments and requires a close collaboration between clinical and basic scientists. As a result, the findings underlying chronic recordings will bridge the basic science results from fear conditioning research to clinical neural processes in PTSD patients.


Eligibility criteria: Inclusion Criteria:

1. Male aged 25-60 years.
2. Able to give informed consent in accordance with institutional policies and participate in the 4-year follow-up, involving assessments and stimulator adjustments.
3. Patients must be stable on their current psychotropic medication for a period of 2 months before implantation and agree to not increase dosages or add any new medications for the first 6 months of the study, unless medically necessary.
4. Chart diagnosis of chronic and treatment-refractory PTSD as the principal psychiatric diagnosis and cause of distress and social/occupational impairment.
5. Confirmation of PTSD as the primary psychiatric diagnosis by the study psychiatrist via clinical interview and CAPS.
6. Minimum 5-year total illness duration, with no 6-month period of clinical remission during the 2 years prior to entry in the study.
7. Stage 2 level of treatment resistance as per Sippel et al.136: Clinical record documented failure to respond to adequate (minimum 3 month, with adherence) trials of at least 3 of the following evidence-based treatments including at least one pharmacologic agent below, and at least one trauma-focused individual cognitive-behavior psychotherapy among the following: Pharmacologic: sertraline, paroxetine, fluoxetine or venlafaxine, at maximally tolerated FDA recommended doses. Psychotherapy: Prolonged Exposure Therapy (PE); Cognitive Processing Therapy (CPT); Eye movement Desensitization and Reprocessing (EMDR); or other form of evidence-based cognitive behavior therapy for PTSD
8. Patients who are unable to complete trauma-focused psychotherapy may be included if they began treatment, and the cause of treatment cessation was that the risks of further treatment, including intense psychological suffering, outweighed the potential benefits of continuing the treatment.
9. All evidence-based psychotherapy for PTSD has been completed a minimum of 3 months prior to enrolment.
10. Minimum baseline past month CAPS-5 Score of 47, with full PTSD diagnostic criteria met, and scores of ≥ 3 on at least one item from the intrusive (CAPS-5 items 1-5) and hyperarousal (CAPS-5 Items 15-20) clusters; and this severity maintained for at least one month during the baseline period based on two separate measures.
11. Clinically significant impairment in occupational functioning due to PTSD, manifested by one or more of the following: a) Total federal (service connected ≥ 70%), or State (SSI) disability compensation for at least the past 2 years for PTSD; b) global assessment of functioning score ≤ 45; c) no period of full time gainful employment ≥ 3 months in the past 5 years. Or clinically significant impairment in social functioning due to PTSD, manifested by one or more of the following: (i) little or no social activity outside the household other than as necessary for medical appointments, practical matters such as grocery shopping, or to interact with other veterans; (ii) reliable description by a spouse or significant other, living with the patient, of repeated avoidance/refusal to participate in customary social engagements with friends, family or for recreational activities due to PTSD; (iii) two or more verbal or physical interpersonal altercations within the past year requiring another person's intervention to prevent further escalation, or involving law enforcement.
12. Presence in the veteran's life of a spouse, family member or friend who can confirm the symptoms and impairment from PTSD and lack of symptomatic remission in the past 2 years; participate with the study psychiatrist in answering questions about symptoms and functioning at scheduled follow-up visits; and report unexpected adverse neurological or psychiatric events to study investigators and, if advised by study investigators, assist the patient in accessing necessary services to address obtain care.
13. Willingness to have unexpected neurological or psychiatric symptom shared with the study psychiatrists and other study clinicians.
14. Other medical conditions must be stable for at least 1 year, (conditions that require intermittent use of steroids or chemotherapy are excluded).

Exclusion Criteria:

1. Suicide attempt in the last 2 years and/or presence of a suicide plan (an answer of "Yes" to Question C4 in Section C-Suicidality of MINI International Neuropsychiatric Interview);
2. Unstable psychosis or bipolar disorder; significant acute or ongoing risk for violence;
3. Patients primarily diagnosed with DSM-IV-TR Axis I disorder other than PTSD as determined by the MINI;
4. Within the 3 months prior to enrolment, subject has started a new psychotherapy program;
5. Alcohol or illicit substance use disorder within the last 6 months, unstable remission of substance abuse, or chart evidence that co-morbid substance use disorder could account for lack of treatment response;
6. Current significant neurological conditions, including epilepsy, stroke, movement disorder; history of serious head injury with loss of consciousness if associated with neurological or neuropsychological deficit that could interfere with study participation or outcome assessment; or if associated with structural MRI abnormality.
7. Uncontrolled medical condition including cardiovascular problems and diabetes;
8. Uncontrolled chronic pain;
9. Baseline Montgomery Asberg Depression Rating Scale (MADRS) of ≥ 28;
10. Use of warfarin;
11. Significant abnormality on preoperative structural brain MRI;
12. ECT in the past 6 months;
13. Contraindications to MRIs or the need for recurrent body MRIs;
14. Immunosuppression;
15. High risk for surgery;
16. Current pursuit of new or increased disability compensation for PTSD;
17. Intracranial implants (aneurysm clip, shunt, cochlear implant, electrodes);
18. Patient has had past cranial neurosurgery;
19. Use of other investigational drugs within 30 days of baseline.
20. Patients suffering from a neurovascular condition or other intracranial process.
21. Patients suffering from a condition associated with a significant cognitive impairment.

Primary outcomes:
measure: Spectral power analysis and oscillatory properties
timeFrame: Baseline
measure: Spectral power analysis and oscillatory properties
timeFrame: through study completion, an average of 1 year
measure: Cross-frequency coupling and power coherence comodulograms
timeFrame: Baseline
measure: Cross-frequency coupling and power coherence comodulograms
timeFrame: through study completion, an average of 1 year
measure: Region of Interest analysis (FDG PET)
timeFrame: Baseline
measure: Region of Interest analysis (FDG PET)
timeFrame: After initial exposure session
measure: Region of Interest analysis (FDG PET)
timeFrame: 12 months post-operatively
measure: Alpha rhythm frequency (EEG)
timeFrame: Baseline
measure: Alpha rhythm frequency (EEG)
timeFrame: monthly after implantation for the first year
measure: Alpha rhythm frequency (EEG)
timeFrame: quarterly during year 2-4
measure: Source localization (EEG)
timeFrame: Baseline
measure: Source localization (EEG)
timeFrame: through study completion, an average of 1 year
Secondary outcomes:
measure: Clinician Administered PTSD Scale
timeFrame: Baseline
measure: Clinician Administered PTSD Scale
timeFrame: monthly after implantation for the first year
measure: Occurrence of adverse events
timeFrame: through study completion, an average of 1 year
measure: Psychological scales (HAMA)
timeFrame: Baseline
measure: Psychological scales (HAMA)
timeFrame: monthly after implantation for the first year
measure: Psychological scales (HAMA)
timeFrame: every three months up to 48 months after baseline
measure: Psychological scales (MADRS)
timeFrame: Baseline
measure: Psychological scales (MADRS)
timeFrame: monthly after implantation for the first year
measure: Psychological scales (MADRS)
timeFrame: every three months up to 48 months after baseline
measure: Psychological scales (YBOC)
timeFrame: Baseline
measure: Psychological scales (YBOC)
timeFrame: monthly after implantation for the first year
measure: Psychological scales (YBOC)
timeFrame: every three months up to 48 months after baseline
measure: Digit Span subtest
timeFrame: Baseline
measure: Digit Span subtest
timeFrame: Months 6, 12, 24 and 48
measure: Trail Making Test A and B
timeFrame: Baseline
measure: Trail Making Test A and B
timeFrame: Months 6, 12, 24 and 48
measure: Ruff Figural Fluency Test (RFFT)
timeFrame: Baseline
measure: Ruff Figural Fluency Test (RFFT)
timeFrame: Months 6, 12, 24 and 48
measure: Brief Visual Memory Test
timeFrame: Baseline
measure: Brief Visual Memory Test
timeFrame: Months 6, 12, 24 and 48
measure: Revised (BVMT-R)
timeFrame: Baseline
measure: Revised (BVMT-R)
timeFrame: Months 6, 12, 24 and 48
measure: California Verbal Learning Test
timeFrame: Baseline
measure: California Verbal Learning Test
timeFrame: Months 6, 12, 24 and 48
measure: Attention, Processing Speed and Memory: Wechsler Adult Intelligence Scale IV (WAIS-IV)143 - Digit Span subtest, Trail Making Test A and B, Ruff Figural Fluency Test (RFFT), Brief Visual Memory Test - Revised (BVMT-R), California Verbal Learning Test
timeFrame: Baseline
measure: Attention, Processing Speed and Memory: Wechsler Adult Intelligence Scale IV (WAIS-IV)143 - Digit Span subtest, Trail Making Test A and B, Ruff Figural Fluency Test (RFFT), Brief Visual Memory Test - Revised (BVMT-R), California Verbal Learning Test
timeFrame: Months 6, 12, 24 and 48
measure: Wechsler Adult Intelligence Scale IV (WAIS-IV)
timeFrame: Months 6, 12, 24 and 48
measure: Wechsler Adult Intelligence Scale IV (WAIS-IV)
timeFrame: Baseline
measure: Wechsler Test of Adult Reading
timeFrame: Baseline
measure: Wechsler Test of Adult Reading
timeFrame: Months 6, 12, 24 and 48
measure: Controlled Oral Word Association (COWAT)
timeFrame: Baseline
measure: Controlled Oral Word Association (COWAT)
timeFrame: Months 6, 12, 24 and 48
measure: Hooper Visual Organization Test (VOT)
timeFrame: Baseline
measure: Hooper Visual Organization Test (VOT)
timeFrame: Months 6, 12, 24 and 48
measure: Rey-Osterrieth Complex Figure Test (CFT)
timeFrame: Baseline
measure: Rey-Osterrieth Complex Figure Test (CFT)
timeFrame: Months 6, 12, 24 and 48
measure: Wisconsin Card Sorting Test (WCST)
timeFrame: Baseline
measure: Wisconsin Card Sorting Test (WCST)
timeFrame: Months 6, 12, 24 and 48
measure: Stroop Color and Word Test
timeFrame: Baseline
measure: Stroop Color and Word Test
timeFrame: Months 6, 12, 24 and 48
measure: Iowa Gambling Task (IGT)
timeFrame: Baseline
measure: Iowa Gambling Task (IGT)
timeFrame: Months 6, 12, 24 and 48
measure: Montreal Cognitive Assessment (MOCA)
timeFrame: Baseline
measure: Montreal Cognitive Assessment (MOCA)
timeFrame: Months 6, 12, 24 and 48
measure: Frontal Systems/ Executive Functions: Wisconsin Card Sorting Test (WCST), Stroop Color and Word Test, Iowa Gambling Task (IGT)
timeFrame: Months 6, 12, 24 and 48
measure: Rey-15 Recognition test of Mental Effort
timeFrame: Months 6, 12, 24 and 48
measure: Rey-15 Recognition test of Mental Effort
timeFrame: Baseline
measure: SF-36V (quality of life)
timeFrame: Baseline
measure: SF-36V (quality of life)
timeFrame: through study completion, an average of 1 year
Other outcomes:
Locations:
city: Los Angeles
country: United States
facility: VA Greater Los Angeles
state: California
Study officials:
References: