Clinical trial NCT04568369: Treatment of Post-concussion Syndrome With TMS: Using FNIRS as a Biomarker of Response
Official title: Functional Near Infrared Spectroscopy as a Biomarker of Response in Patients With Post-concussion Syndrome Treated With Transcranial Magnetic Stimulation
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: NA
Conditions: Transcranial Magnetic Stimulation
Functional Near-Infrared Spectroscopy
Post-Concussion Syndrome
Concussion
Mild Traumatic Brain Injury
Post-traumatic Stress Disorder
Lead sponsor: University of Calgary
Sponsor class: OTHER
First posted: 2020-09-29
Enrollment: 91
Sex: ALL
Minimum age (years): 18
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Intervention model description: This study will be a double-blind, sham-controlled, concealed allocation, randomized, cross over clinical trial.
Primary purpose: TREATMENT

Brief summary: Every year, approximately 2 million people in the United States and 280,000 in Canada experience a mild traumatic brain injury/concussion. In patients with concussion, symptoms experienced following injury usually get better within 3 months. However, approximately 5-25% of people will experience symptoms beyond the 3 month period, characterized by persistent headaches, fatigue, insomnia, anxiety, depression, and thinking or concentration problems, which contribute to significant functional impairment. Chronic headache is the most common symptom following concussions. They can last beyond 5 years following injury, significantly impacting daily activities. To date, post-concussion symptoms have no known "cure".

One potential approach to treating post-concussion symptoms may involve using drug-free interventions, such as neuromodulation therapy. This has the goal of restoring normal brain activity. Repetitive transcranial magnetic stimulation (rTMS) is one method currently being explored as a treatment option. TMS is a procedure where brain electrical activity is influenced by a magnetic field. Numerous studies using rTMS to treat other disorders, such as dementia, stroke, cerebral palsy, addictions, depression and anxiety, have shown much promise. The primary objective of this study is to determine whether rTMS treatment can significantly improve persistent post-concussion symptoms. A secondary objective is to explore the relationship between potential changes in brain function and clinical markers associated with rTMS treatment and how functional near-infrared spectroscopy (fNIRS), a neuroimaging technology, may be used to assess rTMS-treatment response.

Detailed description: Annually, up to 280,000 people in Canada and 42 million worldwide experience a mild traumatic brain injury (mTBI). In patients with mTBI, symptoms experienced following injury usually resolve within 3 months. However, up to 25% of patients will experience persistent post-concussion symptoms (PPCS), which can continue up to 1 year following injury. Common symptoms include headaches, dizziness, fatigue, irritability, depression, anxiety, emotional lability, concentration or memory difficulties, insomnia, and reduced alcohol tolerance (ICD-10 post-concussion syndrome diagnostic criteria). To date, there is no "cure" for PPCS and current treatment entails trial and error with behavior management, environmental modifications and medications. Consequently, there is a significant need for new approaches to symptom management in order to help improve functional impairment and disease burden, associated with PPCS. Transcranial magnetic stimulation (TMS) has been studied as an intervention for many mental health and neurological conditions, including major depression and migraines, and has shown initial promise for PPCS. We intend to study the efficacy of TMS for PPCS further in a randomized sham-controlled trial.

Mild traumatic injury is considered a risk factor in the development of post-traumatic stress disorder. As such, post-traumatic stress disorder and mild traumatic brain injury often co-occur and share similar symptoms, such as irritability, post-traumatic amnesia, sleep disturbances, concentration difficulties and cognitive processing deficits. Several studies have suggested the efficacy and safety of rTMS for the treatment of PTSD; however, a gap in the literature exists regarding treating comorbid post-traumatic stress disorder and PPCS following mild traumatic brain injury. To study potential differences in response to treatment between individuals experiencing PPCS with or without co-morbid post-traumatic stress disorder, we intend to measure PTSD symptoms for those with a clinical diagnosis of post-traumatic stress disorder. Tracking PTSD symptoms will allow insight into whether the presence of PTSD symptoms affects rTMS treatment outcomes in individuals experiencing PPCS.

RESEARCH QUESTIONS AND OBJECTIVES

The overall goal is to study the application of rTMS treatment to the left dorsal lateral prefrontal cortex (DLPFC) in patients with PPCS to improve overall symptom burden and to explore biomarkers of response, specifically functional near infrared spectroscopy (fNIRS).

Specifically the objectives are:

1. Primary Objective: to determine changes in brain physiology associated with rTMS treatment as recorded by fNIRS.
2. Secondary Objective: to determine whether patients with PPCS have significant improvement to a 20-day high frequency rTMS treatment protocol of the left DLPFC compared to patients with PPCS receiving a sham rTMS protocol as measured by the Rivermead post-concussion symptom questionnaire at 1 and 3 months post-treatment.
3. Third Objective: To determine what exploratory outcomes such as quality of life, headaches, anxiety, depression, sleep, and somatic symptoms also improve with TMS treatment in individuals suffering with PPCS. Quality of life will be measured via the Quality of Life after Brain Injury questionnaire (QOLIBRI), headache intensity will be measured via the Headache intensity Test - 6 (HIT-6), feelings of depression will be measured via the Patient Health Questionnaire -9 (PHQ-9), anxiety via the Generalized Anxiety Disorder -7 (GAD-7), sleep via the Sleep and Concussion Questionnaire and somatic symptoms which are commonly present in functional neurological disorders via the SOMS-CD and Patient Health Questionnaire-15 (PHQ-15). Since Functional Neurological Disorder is often associated with past trauma, trauma history will be assessed via the Brief Trauma Questionnaire (BTQ) and the Life Stress Questionnaire (LSQ).
4. To determine whether those with PPCS and PTSD respond differently to rTMS and what effect this has on their PTSD symptoms measured via the Clinician-Administered PTSD Scale for DSM-5 (CAPS-5) and the Montgomery-Asberg Depression Rating Scale. Participants with PTSD will be identified as those with scores higher than 33 in the PCL-5 and a clinical diagnosis of PTSD by a medical professional.
5. To examine potential blood biomarkers of post-concussion syndrome and post-traumatic stress disorder.

METHODS

This study will be a double-blind, sham-controlled, concealed allocation, randomized clinical trial.

Clinical Assessments: Demographic information will be collected prior to starting the study including age, sex, education, headache history, concussion history, past medical history, medication use, and family medical history. Baseline questionnaires will be completed including Headache Impact Test - 6 (HIT-6), Rivermead PPCS questionnaire, British Columbia post-concussion symptom inventory (BC-PSI), quality of life after brain injury questionnaire (QOLIBRI), patient health questionnaire-9 (PHQ-9), generalized anxiety disorder scale-7 (GADS-7),the St. Louis University Mental examination Tool (SLUMS), the screening for somatoform symptoms questionnaire (SOMS-CD), the post traumatic stress disorder checklist for DSM-5 (PCL-5), the Brief Trauma Questionniare (BTQ), the Life Stress Questionnaire (LSQ), the Patient Health Questionnaire-15 (PHQ-15), and the Sleep and Concussion Questionnaire (SCQ). Those who are identified as having a PCL-5 score of greater than 33, in addition to a clinical diagnosis of post-traumatic stress disorder, will also complete the LEC-5, CAPS-5, MADRS and Columbia Suicide Severity Rating Scale. Patients will be reassessed at the completion of their rTMS treatment, and at 1 and 3 months post-treatment. The questionnaires that will be completed at all follow-up visits include the Rivermead PPCS questionnaire, the HIT-6, the BC-PSI, the QOLIBRI, the PHQ-9, the GAD-7, the PCL-5, the SLUMS, the SOMS-CD, the PHQ-15, and the Sleep and Concussion Questionnaire. For the Sleep and Concussion Questionnaire, the initial screening section will not be completed at follow-ups. Participants in the PTSD sub-group will also complete the MADRS, CAPS-5 and Columbia Suicide Severity Rating Scale at the 1 month and 3-month follow-up visits.

TMS Protocol: Patients will engage in a four-week treatment protocol (20 treatments). This was chosen as it is the midpoint between typical depression and migraine protocol durations. A standardized atlas brain with Montreal Neurologic Institute (MNI) coordinates will be used for navigation. The DLPFC will be located through MNI coordinates (-50, 30, 36). The intensity of the rTMS will be 100-120% of resting motor threshold amplitude, with a frequency of 10 Hz, 10 trains of 60 pulses/train (total of 600 pulses) and inter-train interval of 45s. In the sham condition, a sham coil will be applied to the scalp after the resting motor threshold is determined. Patients will be able to hear the sound and feel the vibration of sham coil, but will not experience any effective stimulation. Previous sham studies have demonstrated efficacy of the blinding method.

Imaging: Functional near infrared spectroscopy (fNIRS) measurements will be recorded at baseline, immediately following rTMS, and at one month and 3-month follow-ups post-rTMS to investigate changes in brain physiology associated with rTMS treatment. fNIRS data will be recorded over the frontoparietal cortex at a sampling rate of 3.91 Hz, using the TechEn fNIRS system (TechEn Inc., Milford, MA USA). Each recording will consist of a 5 min rest period, followed by a finger tapping exercise, and a graded working memory task, previously described by Hocke et al (2018). The fNIRS data will be processed and analyzed for task-evoked activation using an ordinary least squares method of general linear modeling, as implemented in the NIRS Brain AnalyzIR Toolbox.

Blood Samples: Blood samples will be collected from a certified phlebotomist at the Heritage Medical Research Clinic located in the Cal Wenzel Precision Health building at the Foothills Medical Centre Campus. Analysis will focus on blood biomarkers of inflammation and CNS injury.

Statistical Analysis: Outcome parameters within each specific group (rTMS, sham, sex, PTSD diagnosis) will be analyzed by a one-way repeated measures analysis of variance (RM-ANOVA).

Eligibility criteria: Inclusion Criteria:

* Diagnosis of persistent post-concussion syndrome based on the ICD-10 criteria. This diagnosis should be given to the patient from a clinical practitioner.
* Concussion in the past 5 years attributed to current symptoms.
* Age 18-75 yrs.
* Current pharmacologic management can remain stable throughout the protocol such as use of abortive headache medications (i.e. triptans, opioids, tricyclic antidepressants, anti-seizure medications).

Exclusion Criteria:

* Prior history of TMS therapy
* TMS-related contraindications (pacemaker, metallic implant)
* Other medical conditions such as structural brain disease, previous seizures, psychiatric disorders excluding depression, PTSD and anxiety (schizophrenia, bipolar disorder), liver or kidney disease, malignancy, uncontrolled hypertension or diabetes, and pregnancy.

Primary outcomes:
measure: Rivermead Post-Concussion Symptom Questionnaire (RPQ)
timeFrame: Baseline
measure: Rivermead Post-Concussion Symptom Questionnaire (RPQ)
timeFrame: Within 1 week post-intervention
measure: Rivermead Post-Concussion Symptom Questionnaire (RPQ)
timeFrame: 1-month post-intervention
measure: Rivermead Post-Concussion Symptom Questionnaire (RPQ)
timeFrame: 3-months post-intervention
Secondary outcomes:
measure: Quality of Life After Brain Injury (QOLIBRI)
timeFrame: Baseline
measure: Quality of Life After Brain Injury (QOLIBRI)
timeFrame: Within 1 week post-intervention
measure: Quality of Life After Brain Injury (QOLIBRI)
timeFrame: 1-month post-intervention
measure: Quality of Life After Brain Injury (QOLIBRI)
timeFrame: 3-months post-intervention
measure: Headache Impact Test (HIT-6)
timeFrame: Baseline
measure: Headache Impact Test (HIT-6)
timeFrame: Within 1 week post-intervention
measure: Headache Impact Test (HIT-6)
timeFrame: 1-month post-intervention
measure: Headache Impact Test (HIT-6)
timeFrame: 3-months post-intervention
measure: Patient Health Questionnaire (PHQ-9)
timeFrame: Baseline
measure: Patient Health Questionnaire (PHQ-9)
timeFrame: Within 1 week post-intervention
measure: Patient Health Questionnaire (PHQ-9)
timeFrame: 1-month post-intervention
measure: Patient Health Questionnaire (PHQ-9)
timeFrame: 3-months post-intervention
measure: Generalized Anxiety Disorder-7 (GAD-7)
timeFrame: Baseline
measure: Generalized Anxiety Disorder-7 (GAD-7)
timeFrame: Within 1 week post-intervention
measure: Generalized Anxiety Disorder-7 (GAD-7)
timeFrame: 1-month post-intervention
measure: Generalized Anxiety Disorder-7 (GAD-7)
timeFrame: 3-months post-intervention
measure: Screening for Somatoform Symptoms-7 (SOMS-7 CD Sub-scale)
timeFrame: Baseline
measure: Screening for Somatoform Symptoms-7 (SOMS-7 CD Sub-scale)
timeFrame: Within 1 week post-intervention
measure: Screening for Somatoform Symptoms-7 (SOMS-7 CD Sub-scale)
timeFrame: 1-month post-intervention
measure: Screening for Somatoform Symptoms-7 (SOMS-7 CD Sub-scale)
timeFrame: 3-months post-intervention
measure: Saint Louis University Mental Status Examination (SLUMS)
timeFrame: Baseline
measure: Saint Louis University Mental Status Examination (SLUMS)
timeFrame: Within 1 week post-intervention
measure: Saint Louis University Mental Status Examination (SLUMS)
timeFrame: 1-month post-intervention
measure: Saint Louis University Mental Status Examination (SLUMS)
timeFrame: 3-months post-intervention
measure: British Columbia Post-concussion Symptom Inventory
timeFrame: Baseline
measure: British Columbia Post-concussion Symptom Inventory
timeFrame: Within 1 week post-intervention
measure: British Columbia Post-concussion Symptom Inventory
timeFrame: 1-month post-intervention
measure: British Columbia Post-concussion Symptom Inventory
timeFrame: 3-months post-intervention
measure: Post-traumatic Stress Disorder Checklist for DSM-5 (PCL-5)
timeFrame: Baseline
measure: Post-traumatic Stress Disorder Checklist for DSM-5 (PCL-5)
timeFrame: Within 1 week post-intervention
measure: Post-traumatic Stress Disorder Checklist for DSM-5 (PCL-5)
timeFrame: 1-month post-intervention
measure: Post-traumatic Stress Disorder Checklist for DSM-5 (PCL-5)
timeFrame: 3-months post-intervention
measure: Patient Health Questionnaire-15 (PHQ-15)
timeFrame: Baseline
measure: Patient Health Questionnaire-15 (PHQ-15)
timeFrame: Within 1 week post-intervention
measure: Patient Health Questionnaire-15 (PHQ-15)
timeFrame: 1-month post-intervention
measure: Patient Health Questionnaire-15 (PHQ-15)
timeFrame: 3-months post-intervention
measure: Sleep and Concussion Questionnaire
timeFrame: Baseline
measure: Sleep and Concussion Questionnaire
timeFrame: Within 1 week post-intervention
measure: Sleep and Concussion Questionnaire
timeFrame: 1-month post-intervention
measure: Sleep and Concussion Questionnaire
timeFrame: 3-months post-intervention
measure: Brief Trauma Questionnaire
timeFrame: Baseline
measure: Brief Trauma Questionnaire
timeFrame: Within 1 week post-intervention
measure: Brief Trauma Questionnaire
timeFrame: 1-month post-intervention
measure: Brief Trauma Questionnaire
timeFrame: 3-months post-intervention
measure: Life Stress Questionnaire
timeFrame: Baseline
measure: Life Stress Questionnaire
timeFrame: Within 1 week post-intervention
measure: Life Stress Questionnaire
timeFrame: 1-month post-intervention
measure: Life Stress Questionnaire
timeFrame: 3-months post-intervention
measure: Clinician-Administered PTSD Scale for DSM-5 (CAPS-5)
timeFrame: Baseline
measure: Clinician-Administered PTSD Scale for DSM-5 (CAPS-5)
timeFrame: Within 1 week post-intervention
measure: Clinician-Administered PTSD Scale for DSM-5 (CAPS-5)
timeFrame: 1-month post-intervention
measure: Clinician-Administered PTSD Scale for DSM-5 (CAPS-5)
timeFrame: 3-months post-intervention
measure: Montgomery-Asberg Depression Rating Scale
timeFrame: Baseline
measure: Montgomery-Asberg Depression Rating Scale
timeFrame: Within 1 week post-intervention
measure: Montgomery-Asberg Depression Rating Scale
timeFrame: 1-month post-intervention
measure: Montgomery-Asberg Depression Rating Scale
timeFrame: 3-months post-intervention
measure: Columbia Suicide Severity Rating Scale
timeFrame: Baseline
measure: Columbia Suicide Severity Rating Scale
timeFrame: Within 1 week post-intervention
measure: Columbia Suicide Severity Rating Scale
timeFrame: 1-month post-intervention
measure: Columbia Suicide Severity Rating Scale
timeFrame: 3-months post-intervention
Other outcomes:
measure: Functional near infrared spectroscopy
timeFrame: Baseline
measure: Functional near infrared spectroscopy
timeFrame: Within 1 week post-intervention
measure: Functional near infrared spectroscopy
timeFrame: 1-month post-intervention
measure: Functional near infrared spectroscopy
timeFrame: 3-months post-intervention
Locations:
city: Calgary
country: Canada
facility: Foothills Medical Centre
state: Alberta
Study officials:
affiliation: University of Calgary
name: Chantel T Debert, MD MSc FRCPC CSCN
role: PRINCIPAL_INVESTIGATOR
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