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NCT Number: NCT04152993

Responsive Neurostimulation for Post-Traumatic Stress Disorder

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.

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Key information

Conditions

Post-traumatic Stress Disorder Mental Disorders Stress Disorders, Post-Traumatic Stress Disorders, Traumatic Trauma and Stressor Related Disorders

Age range

25 year–60 year

Sex eligibility

Male

Study type

Interventional

Phase

Early Phase 1

Primary location

VA Greater Los Angeles

Los Angeles, California, 90073, United States

Location status: Recruiting

Location contact

Virginia Janovsky

CONTACT

[email protected]

Who can participate

Healthy volunteers accepted: No

Only the study team can determine whether someone qualifies for participation.

Inclusion criteria

  • Male aged 25-60 years.
  • Able to give informed consent in accordance with institutional policies and participate in the 4-year follow-up, involving assessments and stimulator adjustments.
  • 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.
  • Chart diagnosis of chronic and treatment-refractory PTSD as the principal psychiatric diagnosis and cause of distress and social/occupational impairment.
  • Confirmation of PTSD as the primary psychiatric diagnosis by the study psychiatrist via clinical interview and CAPS.
  • Minimum 5-year total illness duration, with no 6-month period of clinical remission during the 2 years prior to entry in the study.
  • 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
  • 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.
  • All evidence-based psychotherapy for PTSD has been completed a minimum of 3 months prior to enrolment.
  • 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.
  • 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.
  • 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.
  • Willingness to have unexpected neurological or psychiatric symptom shared with the study psychiatrists and other study clinicians.
  • Other medical conditions must be stable for at least 1 year, (conditions that require intermittent use of steroids or chemotherapy are excluded).

Exclusion criteria

  • 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);
  • Unstable psychosis or bipolar disorder; significant acute or ongoing risk for violence;
  • Patients primarily diagnosed with DSM-IV-TR Axis I disorder other than PTSD as determined by the MINI;
  • Within the 3 months prior to enrolment, subject has started a new psychotherapy program;
  • 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;
  • 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.
  • Uncontrolled medical condition including cardiovascular problems and diabetes;
  • Uncontrolled chronic pain;
  • Baseline Montgomery Asberg Depression Rating Scale (MADRS) of ≥ 28;
  • Use of warfarin;
  • Significant abnormality on preoperative structural brain MRI;
  • ECT in the past 6 months;
  • Contraindications to MRIs or the need for recurrent body MRIs;
  • Immunosuppression;
  • High risk for surgery;
  • Current pursuit of new or increased disability compensation for PTSD;
  • Intracranial implants (aneurysm clip, shunt, cochlear implant, electrodes);
  • Patient has had past cranial neurosurgery;
  • Use of other investigational drugs within 30 days of baseline.
  • Patients suffering from a neurovascular condition or other intracranial process.
  • Patients suffering from a condition associated with a significant cognitive impairment.

Treatment and study plan

NeuroPace® RNS® System

Device

In this intervention, patients suffering from PTSD undergo a surgical procedure to implant the responsive neurostimulation device (RNS, NeuroPace). This procedure involves the placement of a depth lead bilaterally in the amygdala and hippocampus following a trans-occipital trajectory. The two leads are then connected to a pulse generator fixated to the skull. RNS is able to detect specific signals from the target and to respond with a programmed electrical stimulation. One month after the implantation of the system, the patients will undergo 3 tasks: a fear conditioning task, the international affective picture system and the subsequent memory recall paradigm. These tasks will yield electrophysiological biomarkers of arousal and re-experiencing. We will then program RNS to detect and respond to those biomarkers. The patients will be followed longitudinally for improvement and evidence of target engagement as seen on cerebral metabolism and global electroencephalography.

Primary outcomes

  1. Spectral power analysis and oscillatory properties

    Time frame: Baseline

    This is associated with Specific Aim 1: To determine electrophysiological biomarkers of fear, extinction and PTSD symptoms. The metric for measurement will be Better Oscillation Detection (BOSC)

  2. Spectral power analysis and oscillatory properties

    Time frame: through study completion, an average of 1 year

    This is associated with Specific Aim 1: To determine electrophysiological biomarkers of fear, extinction and PTSD symptoms. The metric for measurement will be Better Oscillation Detection (BOSC)

  3. Cross-frequency coupling and power coherence comodulograms

    Time frame: Baseline

    This is associated with Specific Aim 1: To determine electrophysiological biomarkers of fear, extinction and PTSD symptoms. The metric for measurement will be modulation index.

  4. Cross-frequency coupling and power coherence comodulograms

    Time frame: through study completion, an average of 1 year

    This is associated with Specific Aim 1: To determine electrophysiological biomarkers of fear, extinction and PTSD symptoms. The metric for measurement will be modulation index.

  5. Region of Interest analysis (FDG PET)

    Time frame: Baseline

    This is associated with Specific Aim 2: To determine engagement of fear processing neural networks by neurostimulation. The metric for measurement will be Cerebral metabolic rate of glucose (CMRglc)

  6. Region of Interest analysis (FDG PET)

    Time frame: After initial exposure session

    This is associated with Specific Aim 2: To determine engagement of fear processing neural networks by neurostimulation. The metric for measurement will be Cerebral metabolic rate of glucose (CMRglc)

  7. Region of Interest analysis (FDG PET)

    Time frame: 12 months post-operatively

    This is associated with Specific Aim 2: To determine engagement of fear processing neural networks by neurostimulation. The metric for measurement will be Cerebral metabolic rate of glucose (CMRglc)

  8. Alpha rhythm frequency (EEG)

    Time frame: Baseline

    This is associated with Specific Aim 2: To determine engagement of fear processing neural networks by neurostimulation. The metric for measurement will be frequency (Hertz)

  9. Alpha rhythm frequency (EEG)

    Time frame: monthly after implantation for the first year

    This is associated with Specific Aim 2: To determine engagement of fear processing neural networks by neurostimulation. The metric for measurement will be frequency (Hertz)

  10. Alpha rhythm frequency (EEG)

    Time frame: quarterly during year 2-4

    This is associated with Specific Aim 2: To determine engagement of fear processing neural networks by neurostimulation. The metric for measurement will be frequency (Hertz)

  11. Source localization (EEG)

    Time frame: Baseline

    This is associated with Specific Aim 2: To determine engagement of fear processing neural networks by neurostimulation. The metric for measurement will be discrete dipole fitting.

  12. Source localization (EEG)

    Time frame: through study completion, an average of 1 year

    This is associated with Specific Aim 2: To determine engagement of fear processing neural networks by neurostimulation. The metric for measurement will be discrete dipole fitting.

Secondary outcomes

  1. Clinician Administered PTSD Scale

    Time frame: Baseline

    This is associated with Specific Aim 3: To assess the efficacy and safety of BLA stimulation for treatment-resistant PTSD. This test will be measured by the score.

  2. Clinician Administered PTSD Scale

    Time frame: monthly after implantation for the first year

    This is associated with Specific Aim 3: To assess the efficacy and safety of BLA stimulation for treatment-resistant PTSD. This test will be measured by the score.

  3. Occurrence of adverse events

    Time frame: through study completion, an average of 1 year

    This is associated with Specific Aim 3: To assess the efficacy and safety of BLA stimulation for treatment-resistant PTSD. This test will be measured by frequency/severity.

  4. Psychological scales (HAMA)

    Time frame: Baseline

    This is associated with Specific Aim 3: To assess the efficacy and safety of BLA stimulation for treatment-resistant PTSD. This test will be measured by the score

  5. Psychological scales (HAMA)

    Time frame: monthly after implantation for the first year

    This is associated with Specific Aim 3: To assess the efficacy and safety of BLA stimulation for treatment-resistant PTSD. This test will be measured by the score

  6. Psychological scales (HAMA)

    Time frame: every three months up to 48 months after baseline

    This is associated with Specific Aim 3: To assess the efficacy and safety of BLA stimulation for treatment-resistant PTSD. This test will be measured by the score

  7. Psychological scales (MADRS)

    Time frame: Baseline

    This is associated with Specific Aim 3: To assess the efficacy and safety of BLA stimulation for treatment-resistant PTSD. This test will be measured by the score

  8. Psychological scales (MADRS)

    Time frame: monthly after implantation for the first year

    This is associated with Specific Aim 3: To assess the efficacy and safety of BLA stimulation for treatment-resistant PTSD. This test will be measured by the score

  9. Psychological scales (MADRS)

    Time frame: every three months up to 48 months after baseline

    This is associated with Specific Aim 3: To assess the efficacy and safety of BLA stimulation for treatment-resistant PTSD. This test will be measured by the score

  10. Psychological scales (YBOC)

    Time frame: Baseline

    This is associated with Specific Aim 3: To assess the efficacy and safety of BLA stimulation for treatment-resistant PTSD. This test will be measured by the score

  11. Psychological scales (YBOC)

    Time frame: monthly after implantation for the first year

    This is associated with Specific Aim 3: To assess the efficacy and safety of BLA stimulation for treatment-resistant PTSD. This test will be measured by the score

  12. Psychological scales (YBOC)

    Time frame: every three months up to 48 months after baseline

    This is associated with Specific Aim 3: To assess the efficacy and safety of BLA stimulation for treatment-resistant PTSD. This test will be measured by the score

  13. Digit Span subtest

    Time frame: Baseline

    This is associated with Specific Aim 3: To assess the efficacy and safety of BLA stimulation for treatment-resistant PTSD. This test will be measured by the score

  14. Digit Span subtest

    Time frame: Months 6, 12, 24 and 48

    This is associated with Specific Aim 3: To assess the efficacy and safety of BLA stimulation for treatment-resistant PTSD. This test will be measured by the score

  15. Trail Making Test A and B

    Time frame: Baseline

    This is associated with Specific Aim 3: To assess the efficacy and safety of BLA stimulation for treatment-resistant PTSD. This test will be measured by the score

  16. Trail Making Test A and B

    Time frame: Months 6, 12, 24 and 48

    This is associated with Specific Aim 3: To assess the efficacy and safety of BLA stimulation for treatment-resistant PTSD. This test will be measured by the score

  17. Ruff Figural Fluency Test (RFFT)

    Time frame: Baseline

    This is associated with Specific Aim 3: To assess the efficacy and safety of BLA stimulation for treatment-resistant PTSD. This test will be measured by the score

  18. Ruff Figural Fluency Test (RFFT)

    Time frame: Months 6, 12, 24 and 48

    This is associated with Specific Aim 3: To assess the efficacy and safety of BLA stimulation for treatment-resistant PTSD. This test will be measured by the score

  19. Brief Visual Memory Test

    Time frame: Baseline

    This is associated with Specific Aim 3: To assess the efficacy and safety of BLA stimulation for treatment-resistant PTSD. This test will be measured by the score

  20. Brief Visual Memory Test

    Time frame: Months 6, 12, 24 and 48

    This is associated with Specific Aim 3: To assess the efficacy and safety of BLA stimulation for treatment-resistant PTSD. This test will be measured by the score

  21. Revised (BVMT-R)

    Time frame: Baseline

    This is associated with Specific Aim 3: To assess the efficacy and safety of BLA stimulation for treatment-resistant PTSD. This test will be measured by the score

  22. Revised (BVMT-R)

    Time frame: Months 6, 12, 24 and 48

    This is associated with Specific Aim 3: To assess the efficacy and safety of BLA stimulation for treatment-resistant PTSD. This test will be measured by the score

  23. California Verbal Learning Test

    Time frame: Baseline

    This is associated with Specific Aim 3: To assess the efficacy and safety of BLA stimulation for treatment-resistant PTSD. This test will be measured by the score

  24. California Verbal Learning Test

    Time frame: Months 6, 12, 24 and 48

    This is associated with Specific Aim 3: To assess the efficacy and safety of BLA stimulation for treatment-resistant PTSD. This test will be measured by the score

  25. 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

    Time frame: Baseline

    This is associated with Specific Aim 3: To assess the efficacy and safety of BLA stimulation for treatment-resistant PTSD. This test will be measured by the score

  26. 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

    Time frame: Months 6, 12, 24 and 48

    This is associated with Specific Aim 3: To assess the efficacy and safety of BLA stimulation for treatment-resistant PTSD. This test will be measured by the score

  27. Wechsler Adult Intelligence Scale IV (WAIS-IV)

    Time frame: Months 6, 12, 24 and 48

    This is associated with Specific Aim 3: To assess the efficacy and safety of BLA stimulation for treatment-resistant PTSD. This test will be measured by the score

  28. Wechsler Adult Intelligence Scale IV (WAIS-IV)

    Time frame: Baseline

    This is associated with Specific Aim 3: To assess the efficacy and safety of BLA stimulation for treatment-resistant PTSD. This test will be measured by the score

  29. Wechsler Test of Adult Reading

    Time frame: Baseline

    This is associated with Specific Aim 3: To assess the efficacy and safety of BLA stimulation for treatment-resistant PTSD. This test will be measured by the score

  30. Wechsler Test of Adult Reading

    Time frame: Months 6, 12, 24 and 48

    This is associated with Specific Aim 3: To assess the efficacy and safety of BLA stimulation for treatment-resistant PTSD. This test will be measured by the score

  31. Controlled Oral Word Association (COWAT)

    Time frame: Baseline

    This is associated with Specific Aim 3: To assess the efficacy and safety of BLA stimulation for treatment-resistant PTSD. This test will be measured by the score

  32. Controlled Oral Word Association (COWAT)

    Time frame: Months 6, 12, 24 and 48

    This is associated with Specific Aim 3: To assess the efficacy and safety of BLA stimulation for treatment-resistant PTSD. This test will be measured by the score

  33. Hooper Visual Organization Test (VOT)

    Time frame: Baseline

    This is associated with Specific Aim 3: To assess the efficacy and safety of BLA stimulation for treatment-resistant PTSD. This test will be measured by the score

  34. Hooper Visual Organization Test (VOT)

    Time frame: Months 6, 12, 24 and 48

    This is associated with Specific Aim 3: To assess the efficacy and safety of BLA stimulation for treatment-resistant PTSD. This test will be measured by the score

  35. Rey-Osterrieth Complex Figure Test (CFT)

    Time frame: Baseline

    This is associated with Specific Aim 3: To assess the efficacy and safety of BLA stimulation for treatment-resistant PTSD. This test will be measured by the score

  36. Rey-Osterrieth Complex Figure Test (CFT)

    Time frame: Months 6, 12, 24 and 48

    This is associated with Specific Aim 3: To assess the efficacy and safety of BLA stimulation for treatment-resistant PTSD. This test will be measured by the score

  37. Wisconsin Card Sorting Test (WCST)

    Time frame: Baseline

    This is associated with Specific Aim 3: To assess the efficacy and safety of BLA stimulation for treatment-resistant PTSD. This test will be measured by the score

  38. Wisconsin Card Sorting Test (WCST)

    Time frame: Months 6, 12, 24 and 48

    This is associated with Specific Aim 3: To assess the efficacy and safety of BLA stimulation for treatment-resistant PTSD. This test will be measured by the score

  39. Stroop Color and Word Test

    Time frame: Baseline

    This is associated with Specific Aim 3: To assess the efficacy and safety of BLA stimulation for treatment-resistant PTSD. This test will be measured by the score

  40. Stroop Color and Word Test

    Time frame: Months 6, 12, 24 and 48

    This is associated with Specific Aim 3: To assess the efficacy and safety of BLA stimulation for treatment-resistant PTSD. This test will be measured by the score

  41. Iowa Gambling Task (IGT)

    Time frame: Baseline

    This is associated with Specific Aim 3: To assess the efficacy and safety of BLA stimulation for treatment-resistant PTSD. This test will be measured by the score

  42. Iowa Gambling Task (IGT)

    Time frame: Months 6, 12, 24 and 48

    This is associated with Specific Aim 3: To assess the efficacy and safety of BLA stimulation for treatment-resistant PTSD. This test will be measured by the score

  43. Montreal Cognitive Assessment (MOCA)

    Time frame: Baseline

    This is associated with Specific Aim 3: To assess the efficacy and safety of BLA stimulation for treatment-resistant PTSD. This test will be measured by the score

  44. Montreal Cognitive Assessment (MOCA)

    Time frame: Months 6, 12, 24 and 48

    This is associated with Specific Aim 3: To assess the efficacy and safety of BLA stimulation for treatment-resistant PTSD. This test will be measured by the score

  45. Frontal Systems/ Executive Functions: Wisconsin Card Sorting Test (WCST), Stroop Color and Word Test, Iowa Gambling Task (IGT)

    Time frame: Months 6, 12, 24 and 48

    This is associated with Specific Aim 3: To assess the efficacy and safety of BLA stimulation for treatment-resistant PTSD. This test will be measured by the score

  46. Rey-15 Recognition test of Mental Effort

    Time frame: Months 6, 12, 24 and 48

    This is associated with Specific Aim 3: To assess the efficacy and safety of BLA stimulation for treatment-resistant PTSD. This test will be measured by the score

  47. Rey-15 Recognition test of Mental Effort

    Time frame: Baseline

    This is associated with Specific Aim 3: To assess the efficacy and safety of BLA stimulation for treatment-resistant PTSD. This test will be measured by the score

  48. SF-36V (quality of life)

    Time frame: Baseline

    This is associated with Specific Aim 3: To assess the efficacy and safety of BLA stimulation for treatment-resistant PTSD. This test will be measured by the score

  49. SF-36V (quality of life)

    Time frame: through study completion, an average of 1 year

    This is associated with Specific Aim 3: To assess the efficacy and safety of BLA stimulation for treatment-resistant PTSD. This test will be measured by the score

Study contacts

Contact information is provided by the study sponsor or research team.

Sonja Hiller

CONTACT

[email protected]

3107947517

Virginia Janovsky

CONTACT

[email protected]

3107947517

Sponsors and collaborators

Lead sponsor

VA Greater Los Angeles Healthcare System

Fed

Collaborators

  • University of California, Los Angeles

Registry information

Important dates

Study start
2021
Primary completion
2026
Study completion
2026
First posted
Nov 6, 2019
Registry last updated
May 28, 2024

OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.

View the official ClinicalTrials.gov record (opens in a new tab)

This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.

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