Combined Neuromodulation and Cognitive Training for Post-mTBI Depression

Study Overview
=================
Brief Summary
-----------------
The primary goal of this clinical trial is to evaluate whether Personalized Augmented Cognitive Training (PACT) plus intermittent theta burst stimulation (iTBS) is effective for treating depression in Service Members, Veterans, and civilians who have sustained a mild TBI. Participants will receive PACT plus 20 sessions of iTBS or sham iTBS over 4 weeks. Assessments will occur at baseline, 2 weeks, 4 weeks, and 8 weeks. Researchers will compare the PACT+iTBS group to the PACT+sham iTBS group to see if PACT+iTBS is associated with more depression improvement.

Official Title
-----------------
Combined Neuromodulation and Cognitive Training for Post-mTBI Depression

Conditions
-----------------
Depression, Mild Traumatic Brain Injury, Concussion, Brain

Intervention / Treatment
-----------------
* Device: iTBS
* Device: sham iTBS
* Behavioral: Personalized, Augmented Cognitive Training (PACT)


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Male or female All racial and ethnic groups Ages 18 to 65 Military service members receiving treatment at NMCSD or civilians receiving treatment at UCSD Health History of mild TBI (as defined by the DoD/VA criteria used in conjunction with the OSU TBI-ID method) over 3 months prior to study entry Meets criteria for current Major Depressive Episode within the context of Major Depressive Disorder, per MINI Score of 18 or higher on the HAMD-17, indicating moderate to severe depressive symptoms Stable on psychiatric medications for 6 weeks, with no changes to psychiatric medications expected during the study period No contraindications to TMS (passes the TMS Adult Safety Screening questionnaire) No contraindications to MRI (passes MRI safety screening questionnaire) Able to commit to the treatment schedule Able to complete assessment procedures in English Intact decision-making capacity and ability to provide voluntary informed consent Exclusion Criteria: History of moderate, severe, or penetrating TBI History of other neurological condition unrelated to TBI, including but not limited to: conditions associated with increased intracranial pressure; space occupying brain lesions; cerebral aneurysm; stroke; transient ischemic attack within past two years; Parkinson's disease; Huntington's disease; dementia; multiple sclerosis; history of brain surgery; epilepsy; seizure except those therapeutically induced by electroconvulsive therapy (ECT) or a febrile seizure of infancy Implanted medical devices including cardiac pacemaker, medication pump, aneurysm clip, shunt, stimulator, cochlear implant, electrodes, or any other metal object within or near the head (excluding the mouth) that cannot be safely removed Active manic or psychotic illness per MINI Current substance use disorder per MINI Current active suicidal or homicidal ideation Pregnant or intending to become pregnant within the study period; breastfeeding Other sensory conditions or illnesses precluding participation in assessments or treatment Current dose of lorazepam 2 mg or greater daily (or benzodiazepine equivalent) or any anticonvulsant due to the potential to limit iTBS efficacy Taking medication that lowers seizure threshold Previous failed treatment with rTMS, iTBS, or ECT Completed >4 sessions of cognitive rehabilitation within the last 3 years

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: PACT+iTBS<br>Personalized, Augmented Cognitive Training (PACT; 6 sessions over 4 weeks) + intermittent theta burst stimulation (iTBS; 20 sessions over 4 weeks) | Device: iTBS<br>* iTBS over the left dorsolateral prefrontal cortex<br>Behavioral: Personalized, Augmented Cognitive Training (PACT)<br>* 6 sessions of PACT<br>|
| Sham Comparator: PACT+sham iTBS<br>Personalized, Augmented Cognitive Training (PACT; 6 sessions over 4 weeks) + sham intermittent theta burst stimulation (sham iTBS; 20 sessions over 4 weeks) | Device: sham iTBS<br>* sham iTBS over the left dorsolateral prefrontal cortex<br>Behavioral: Personalized, Augmented Cognitive Training (PACT)<br>* 6 sessions of PACT<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Hamilton Rating Scale for Depression |  | change over 8 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Patient Health Questionnaire-9 |  | change over 8 weeks | 
| Neurobehavioral Symptom Inventory |  | change over 8 weeks | 
| PTSD Checklist for DSM-5 |  | change over 8 weeks | 
| Headache Impact Test |  | change over 8 weeks | 
| Pittsburgh Sleep Quality Index |  | change over 8 weeks | 
| WHO Disability Assessment Schedule |  | change over 8 weeks | 
| Glasgow Outcome Scale - Extended |  | change over 8 weeks | 
| PROMIS Cognitive Function Abilities Short Form |  | change over 8 weeks | 
| Patient Global Impression of Change | This measure asks the participant to rate their status since the start of the study from 1 (very much improved) to 7 (very much worse) | rating at 8 weeks | 
| Traumatic Brain Injury Quality of Life | The Traumatic Brain Injury Quality of Life The Traumatic Brain Injury Quality of Life measurement system (TBI-QOL) is a TBI-specific extension of the NIH PROMIS and Neuro-QoL measures that includes 20 items measuring physical, emotional, social, and cognitive domains | change over 8 weeks | 
| D-KEFS Trail Making Test |  | change over 8 weeks | 
| D-KEFS Color Word Interference Test |  | change over 8 weeks | 
| WMS-IV Digit Span |  | change over 8 weeks | 
| WAIS-IV Processing Speed |  | change over 8 weeks | 
| Hopkins Verbal Learning Test - Revised |  | change over 8 weeks | 
| UCSD Performance-Based Skills Assessment-Brief | The UCSD Performance-Based Skills Assessment-Brief is a performance-based measure that uses role play scenarios to assess capacity for financial and communication tasks. | change over 8 weeks | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
brain stimulation, neuromodulation, transcranial magnetic stimulation, theta burst stimulation, TMS, TBS, rTMS, iTBS, cognitive training, cognitive rehabilitation