Deciphering Principles of Network Dynamics Underlying Depression Symptom Severity From Multi-day Intracranial Recordings in Patients With Major Depression

NCT06953362 | Completed DMC

• 1 other identifier: 5R21MH124759
• Study Type: observational
• Target: 6
• Locations: 1 country
• Sites: 1

Brief Summary

Major depressive disorder (MDD) is common and causes significant disability world-wide. While typically responsive to medications and therapy, there remain a subset of patients who are treatment resistant. Novel approaches are critical to treat these patients. MDD is likely caused by dysfunction in distributed neural networks, a perspective consistent with the etiological and diagnostic heterogeneity of this disorder. While imaging and electroencephalography (EEG) have helped identify MDD circuitry, no consensus has been reached on the identification of diagnostic biomarkers. Furthermore, the dynamics of MDD circuitry in relation to symptom severity is unknown. Characterization of circuit signatures that define MDD symptom severity states and the extent to which these circuits are modifiable using electrical stimulation are critical for therapeutic advancement. Intracranial EEG (iEEG) offers a high spatial and temporal resolution method to study depression networks. For the first time, we have an unparalleled opportunity to study such circuits in MDD patients participating in a clinical trial of personalized responsive neurostimulation for treatment resistant depression (PRESIDIO). In stage 1 of this trial, participants are implanted with 160 electrodes from 10 sub-chronic intracranial leads across 10 brain sites for 10 days. The goal of this parent study stage is to optimize brain-site targeting for deep brain stimulation. In the current project, we will leverage the opportunity to study MDD circuit principles from cortical and deep brain structures over a multi-day time period. In this ancillary study to the parent clinical trial, we carry out a set of experiments that establish basic principles of network dynamics underlying MDD from direct neural recordings. This study is organized around the principal concept that brain circuit dysfunction is reflected in abnormal signatures of functional connectivity and rhythmic local-field activity. This concept is supported by our pilot work where we found evidence of distinct MDD networks characterized by functional connectivity and spectral activity. This project builds on our preliminary findings in two aims. In Aim 1, we characterize state-dependent functional connectivity and spectral activity in relation to symptom severity. In Aim 2, we will examine the manner and time course in which targeted electrical stimulation acutely modifies circuits. Together, this research will yield the first characterization of connectivity and activity dynamics in MDD over a multi-day period from direct neural recordings. This rare insight into MDD circuity provided by this novel dataset establishes proof-of-concept principles for biomarker development and therapeutic target selection that could critically advance personalized MDD treatments.

Conditions

Treatment Resistant Depression

Keywords

Major Depression; Treatment Resistant Depression; Neural Network Dynamics

Outcome Measures

Primary Outcomes (1)

• Network Connectivity and Activity Pattern: Relationship to Symptom Severity and Impact of Neurostimulation

  The pattern of network connectivity and activity that is associated with symptom severity and the effect of intracranial electrical stimulation on the connectivity and activity pattern.

  Up to 10 days

Study Arms (1)

All Subjects

No treatment is being administered in this study. Direct neural electrical stimulation is being administered across a large number of sites in the corticolimbic network in order to determine its effects on neural network electrical activity and connectivity.

Device: Direct Neural Electrical Stimulation

Interventions

Direct Neural Electrical Stimulation DEVICE

We are not delivering treatment in this study. Direct neural electrical stimulation is being administered to determine its effect on neural circuit activity and connectivity.

All Subjects

Eligibility Criteria

• Age: 22 Months - 70 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)
• Sampling Method: Non-Probability Sample

Study Population

6 Individuals meeting the inclusion/exclusion criteria who are participating in the PRESIDIO trial of personalized intracranial closed-loop stimulation for treatment of treatment-resistant major depression.

You may qualify if:

• Meet Diagnostic and Statistical Manual-V (DSM-V) diagnostic criteria for Major Depressive Disorder (MDD) without psychosis based on a Structured Clinical Interview for DSM-V (SCID)
• Current episode ≥ 2 years
• Treatment-resistant (4 adequate trials including electroconvulsive therapy (ECT)), 3 classes of medications, one augmentation strategy, psychotherapy) as measured by the antidepressant treatment history form (ATHF)
• Failed ECT due to inability to achieve sustained response (2 failed attempts to discontinue ECT treatment) or discontinued due to intolerable side effects
• Montgomery Asberg Depression Rating Scale (MADRS) score of \> 26 at both baseline and screening visit
• Presence of variability on repeated administrations of depression rating scales (minimum of 2-point variation on the HAMD-6 administered 3 times a day for 3 days), which is required for the identification of a neural biomarker
• No changes to psychotropic medication regimen during the 4 weeks prior to entry into and the duration of the study
• Willing and able to undergo invasive brain recording/stimulation study
• Willing and able to attend multiple research visits and perform at-home research protocol
• Willing and able to provide informed consent
• Ability to speak and read English

You may not qualify if:

• Meets DSM-V criteria for a psychotic disorder, eating disorder, panic disorder, posttraumatic stress disorder, bipolar disorder, obsessive compulsive disorder, tic disorder, or another comorbid psychiatric disorder other than MDD or generalized anxiety disorder based on a SCID
• Generalized anxiety disorder is the primary DSM-V disorder during the current MDD episode
• Active suicidal ideation with intent and plan as defined by a score of 5 on the Columbia suicide severity rating scale (C-SSRS)
• History of suicide attempt requiring hospitalization in previous 2 years
• Meets criteria for alcohol or substance abuse or dependence (other than caffeine) in previous 6 months, determined by the SCID
• Has a personality disorder based on the investigator's assessment that the investigator believes will adversely impact subject compliance or safety
• Fibromyalgia or chronic fatigue syndrome
• Current condition requiring chronic narcotic use
• History of traumatic brain injury, another neurological disorder, or developmental delay
• History of seizures
• MRI (done within one year of the first visit) with significant abnormalities
• Previous ablative intracranial surgery or previously implanted deep brain stimulation system or any previously implanted device treatment involving brain stimulation
• Implantable hardware not compatible with MRI or with the study
• Major medical co-morbidities increasing the risk of surgery including severe diabetes, major organ system failure, history of hemorrhagic stroke, need for chronic anticoagulation other than aspirin, active infection, intracranial space occupying lesion, increased intracranial pressure, cardiovascular accident within the last month, aneurysm abnormality, retinal detachment, unstable cardiovascular disease (recent MI, severe ischemia, severe or uncontrolled hypertension), immunocompromised state, or malignancy with \< 5 years life expectancy
• Inability to stop Coumadin or platelet anti-aggregation therapy for surgery and after surgery

Sponsors & Collaborators

• University of California, San Francisco: lead
• National Institute of Mental Health (NIMH): collaborator

Study Sites (1)

UCSF

San Francisco, California, 94143, United States

Location

MeSH Terms

Conditions

Depressive Disorder, Treatment-Resistant; Depressive Disorder, Major

Condition Hierarchy (Ancestors)

Depressive Disorder; Mood Disorders; Mental Disorders

Study Officials

• Andrew Krystal, MD, MS

  University of California, San Francisco

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: observational
• Observational Model: CASE ONLY
• Time Perspective: PROSPECTIVE
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: November 16, 2023
• First Posted: May 1, 2025
• Study Start: January 1, 2021
• Primary Completion: December 31, 2024
• Study Completion: December 31, 2024
• Last Updated: May 1, 2025

Record last verified: 2025-04

Data Sharing

• IPD Sharing: Will share
• Time Frame: We will release and share data in a timely manner, with the date of release to be no later than acceptance for publication of our main findings from our final data set.

Locations

US (1)