GAIN Symptoms: Post-traumatic Headache

Study Overview
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Brief Summary
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The overall aim of the study is to advance the knowledge on the characterization and underlying pathophysiological mechanisms of persistent post-traumatic headache (PTH) with a direct impact on the ability to diagnose and manage PTH effectively. The investigators also aim to evaluate the efficacy of repetitive transcranial magnetic stimulation (rTMS), a novel intervention on PTH.

Detailed Description
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Post-traumatic headache (PTH) is one of the most common and persistent symptoms following mild traumatic brain injury (mTBI), with an estimation of 18-22% developing persistent (> 3 months) PTH. PTH is highly disabling. Unfortunately, its typical characteristics and pathophysiology are poorly understood leading to its complicated and diverse management. There is no agreement on the clinical presentation of PTH.This is largely due to the scarcity of longitudinal prospective data on large cohorts of PTH. Describing headache phenotypes longitudinally might improve disease characterization, facilitate better classification and provide evidence based-criteria of diagnosing PTH. Furthermore, exploring biomarkers associated with mTBI may provide new knowledge on the poorly understood pathophysiology of post commotional symptoms (PCS) and PTH. Additionally, there are indications of somatosensory disturbances and impaired endogenous analgesic systems in PTH patients. Assessment of somatosensory signs and symptoms in relation to pain complaints and functioning of endogenous analgesic system may also aid in better understanding of pain mechanisms in these patients. Functioning of endogenous analgesic system can be assessed using conditioned pain modulation (CPM) paradigms. Further, a curious observation in concussion patients with face and/or head pain is that they perceive painful/affected area (head and/or face region) as swollen or different without any clinical signs or obvious physical differences. Hence, such illusions represent body image distortions or perceptual distortion (PD) of the head or face region, and may contribute to the chronification of pain. PD can significantly affect psychosocial well-being of patients as the face/head region is a key feature of one´s identity. Unfortunately, such a distressing phenomenon has not been investigated before in these patients. Currently, no strong evidence-based treatment guidelines for PTH exist. Neuromodulation using repetitive transcranial magnetic stimulation (rTMS) targeting involved brain regions and functional networks has recently been employed to treat several chronic pain conditions including migraine. Thus, rTMS could offer an optimal new treatment strategy for PTH, as there is an evidence of brain network dysfunction in these patients. The overall aim is to advance the knowledge on the characterization and underlying pathophysiological mechanisms of persistent PTH. The aim is also to measure the prevalence of perceived size changes (PD) of head and/or face region in patients with mild traumatic brain injury and its association with pain/PTH and other post commotional symptoms (PCS). The investigators will also evaluate the efficacy of rTMS on PTH. Deep phenotyping of PTH will be performed. Blood samples from mTBI patients will be examined for the biomarkers of PCS and PTH and the association between the biomarkers and the symptom levels of PCS, in particular PTH frequency and intensity will be evaluated. Additionally, the association between somatosensory function including CPM and the PTH frequency and intensity will be examined. Further, the effect of rTMS on headache severity and frequency (primary outcome) and somatosensory function, PD and other PCS (secondary outcome) after 1 and 3 months of stimulation will be evaluated.

Official Title
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Post-traumatic Headache: Phenotyping and Exploring Pathophysiological Insights and Novel Treatment Strategies

Conditions
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Post-Traumatic Headache, Concussion, Mild, MTBI - Mild Traumatic Brain Injury

Intervention / Treatment
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* Device: Active repetitive transcranial magnetic stimulation (rTMS)
* Device: Sham repetitive transcranial magnetic stimulation (rTMS)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: mTBI within the last 2 to 4 months according to the diagnostic criteria recommended by the WHO task force age ≥ 18 years at the time of mTBI Rivermead Post-Concussion Symptoms Questionnaire (RPQ) score ≥ 3 (moderate or severe problem) for subitem headache and a diagnosis of persistent PTH attributed to mTBI according to ICHD-3. Additionally, for study 2 and 3, subjects have to be stable on preventative headache medication. However, subjects are permitted to take ''as needed'' (PRN) medications throughout the study with documentation in a daily headache diary. Exclusion Criteria: objective neurological findings and/or acute trauma CT scan indicating neurological disease or brain damage previous mTBI within the last 2 years years leading to PCS lasting ≥ 3 months. Additionally, for study 2 and 3, Pre-trauma headache frequency ≥ 10 days in average per month the last 3 months prior to mTBI. past history of TMS therapy or TMS-related contraindications (pacemaker, epilepsy etc.).

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 60 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Health Services Research
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: The intervention study will be conducted as a randomized, sham-controlled, parallel group clinical trial consisting of an active (n=50) and a sham group (n=50).
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Sham Comparator: Sham group<br>participants (n=50) will receive sham rTMS. | Device: Sham repetitive transcranial magnetic stimulation (rTMS)<br>* Five sessions of sham rTMS therapy will be distributed over 2 weeks<br>|
| Active Comparator: Active rTMS treatment<br>Participants (n=50) will receive active rTMS treatment. | Device: Active repetitive transcranial magnetic stimulation (rTMS)<br>* Five sessions of active rTMS therapy will be distributed over 2 weeks (20 Hz, 2000 pulses, 90% resting motor threshold) will be delivered to left dorsolateral pre-frontal cortex (DLPFC) around 6 months post-trauma.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Changes in the concentration of biomarkers | Changes in the blood biomarkers (such as neurofilament light chain, calcitonin gene related peptide, pituitary adenylate cyclase-activating polypeptide, cytokines, mRNA, microRNA and circular RNA) and somatosensory function from baseline to immediately after the completion of intervention (rTMS) and 1 month post-rTMS. | prior to rTMS intervention, immediately after rTMS intervention and 1 month after end of treatment | 
| Change in the number of headache days of moderate to severe intensity | Change in the number of headache days of moderate to severe intensity from baseline to 1-month post intervention based on a self-reported daily headache diary, a self-reported headache questionaire and Headache Impact test (HIT-6). | Prior to intervention compared to 1 month after end of treatment. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in the number of headache days of moderate to severe intensity | Change in the number of headache days of moderate to severe intensity from baseline to 1-month post intervention based on a self-reported daily headache diary, a self-reported headache questionaire and Headache Impact test (HIT-6). | Prior to intervention compared to 3 months after end of treatment. | 
| Change in severity of post-concussion symptoms covering physical, cognitive, and emotional symptoms. | Will be measured using the Rivermead Post-Concussion Symptoms Questionnaire (RPQ) [range 0-64 (worst)]. | Prior to intervention compared to 1 and 3 months after end of treatment | 
| Change in the use of medication, non-pharmacological treatment and management strategies. | Will be measured using a self-constructed, self-reported questionaire | Prior to intervention compared to 1 and 3 months after end of treatment | 
| Change in health-related quality of life | Will be measured using the EuroQol-5 Domain (EQ-5D-5L) [5 items, range 0-100. 100 means the best health you can imagine] | Prior to intervention compared to 1 and 3 months after end of treatment | 
| Change in self-reported impact on participation and autonomy | Will be measured using the Impact on Participation and Autonomy questionaire (IPAQ-DK). IPAQ DK consists of 32 items which can be answered from 0-4. Higher score corresponds to less participation and autonomy. | Prior to intervention compared to 1 and 3 months after end of treatment. | 
| Change in Psychological Distress | Will be measured using the Screening for Anxiety and depression (SCL-13). SCL-13 consists of 13 items from the Symptom Check List-90. Each item can be ranged from 0-4 (not at all- very much). A high score corresponds to a high level of depressive and/or anxiety symptoms. | Prior to intervention compared to 1 and 3 months after end of treatment. | 
| Change in illness perception | Will be measured using the The Brief Illness Perception Questionnaire (B-IPQ). B-IPQ consists of 9 items. Each item is rated on a 0-10 scale, with higher scores indicating a more threatening perception of the illness. The total score is calculated by summing the scores of all eight items, with a possible range of 0-80. Higher scores indicate worse illness perception. | Prior to intervention compared to 1 and 3 months after end of treatment | 
| Change in Pain Catastrophizing | Will be measured using the Pain Catastrophizing Scale (PCS-DK). Consists of 13 items. Each item is ranged from 0-4. A high score corresponds to a high degree of pain catastrophizing. | Prior to intervention compared to 1 and 3 months after end of treatment | 
| Change in facial perception | Will be measured using a self-constructed, self-reported questionaire | Prior to intervention compared to 1 and 3 months after end of treatment | 
| Change in self-reported efficacy of treatment | Will be measured using Patients Global Impression of Change (PGIC-DK). 1 item ranged 0-6. A high score corresponds to a subjective improvement. | Prior to intervention compared to 1 and 3 months after end of treatment | 
| Change in how neck pain affects daily life | Will be measured using the Neck Pain Disability Index (NDI-DK). 8 items ranged 0-6. A high score corresponds to a high impact on daily life. | Prior to intervention compared to 1 and 3 months after end of treatment | 
| Changes in sleep quality | Will be measured using the Pittsburgh Sleep Quality Index (PSQI-DK). seven component scores are derived, each scored 0 (no difficulty) to 3 (severe difficulty). The component scores are summed to produce a global score (range 0 to 21). Higher scores indicate worse sleep quality. | Prior to intervention compared to 1 and 3 months after end of treatment | 
| Changes in the somatosensory function. | Change in the somatosensory function from baseline to immediately after the completion of intervention (rTMS) and 1 month post-rTMS. | prior to rTMS intervention, immediately after rTMS intervention and 1 month after end of treatment | 
| Characterization of PTH headache phenotypes using a self-constructed headache questionaire. | Characterization of PTH headache phenotypes into e.g. migraine-like or tension-type like using a self-constructed headache questionnaire. | 3 months after mTBI | 
| Characterization of PTH headache phenotypes using the Headache Impact Scale. | Characterization of PTH headache phenotypes into e.g. migraine-like or tension-type like using the Headache Impact Scale (HIT-6). HIT-6 is a 6 item scale. Each item is ranged from 0-5 (never-always). A high total score corresponds to a high impact of the headache on daily functioning. | 3 months after mTBI | 
| Changes in headache phenotype using a self-constructed headache questionaire. | Describing changes in the headache phenotype (e.g. migraine-like or tension-type like) longitudinally using a self-constructed headache questionnaire. | 3, 9 and 12 months after mTBI | 
| Changes in headache phenotype using the Headache Impact Scale . | Describing changes in the headache phenotype (e.g. migraine-like or tension-type like) longitudinally using the Headache Impact Scale (HIT-6). HIT-6 is a 6 item scale. Each item is ranged from 0-5 (never-always). A high total score corresponds to a high impact of the headache on daily functioning. | 3, 9 and 12 months after mTBI | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Post-traumatic headache, Concussion, Mild Traumatic Brain Injury