Clinical trial NCT05857761: GAIN Symptoms: Post-traumatic Headache
Official title: Post-traumatic Headache: Phenotyping and Exploring Pathophysiological Insights and Novel Treatment Strategies
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: NA
Conditions: Post-Traumatic Headache
Concussion, Mild
MTBI - Mild Traumatic Brain Injury
Keywords: Post-traumatic headache
Concussion
Mild Traumatic Brain Injury
Lead sponsor: University of Aarhus
Sponsor class: OTHER
Collaborators: name: Hammel Neurorehabilitation Centre and University Research Clinic
name: Central Denmark Region
First posted: 2023-05-15
Enrollment: 62
Sex: ALL
Minimum age (years): 18
Maximum age (years): 60
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: The intervention study will be conducted as a randomized, sham-controlled, parallel group clinical trial consisting of an active (n=31) and a sham group (n=31).
Primary purpose: HEALTH_SERVICES_RESEARCH

Brief summary: 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: 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. Baseline biomarker levels in the blood samples from patients with mTBI will be compared to biomarker levels in blood samples from anonymous healthy age- and sex matched controls (blood donors) or published reference intervals from the litterature. 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.

Eligibility criteria: Inclusion Criteria:

1. mTBI within the last 2 to 4 months according to the diagnostic criteria recommended by the WHO task force
2. age ≥ 18 years at the time of mTBI
3. 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:

1. objective neurological findings and/or acute trauma CT scan indicating neurological disease or brain damage
2. previous mTBI within the last 2 years years leading to PCS lasting ≥ 3 months. Additionally, for study 2 and 3,
3. Pre-trauma headache frequency ≥ 10 days in average per month the last 3 months prior to mTBI.
4. past history of TMS therapy or TMS-related contraindications (pacemaker, epilepsy etc.).

Primary outcomes:
measure: Change in the number of headache days of moderate to severe intensity
timeFrame: Prior to intervention compared to 1 month after end of treatment.
measure: Changes in the concentration of biomarkers
timeFrame: Prior to rTMS intervention, immediately after rTMS intervention and 1 month after end of treatment
measure: A comparison at baseline of the blood biomarker concentrations in the mTBI patients compared to healthy controls
timeFrame: Prior to rTMS intervention
measure: Characterization of PTH headache phenotypes using a self-constructed headache questionaire.
timeFrame: 3 months after mTBI
Secondary outcomes:
measure: Change in the number of headache days of moderate to severe intensity
timeFrame: Prior to intervention compared to 3 months after end of treatment.
measure: Change in severity of post-concussion symptoms covering physical, cognitive, and emotional symptoms.
timeFrame: Prior to intervention compared to 1 and 3 months after end of treatment
measure: Change in the use of medication, non-pharmacological treatment and management strategies.
timeFrame: Prior to intervention compared to 1 and 3 months after end of treatment
measure: Change in health-related quality of life
timeFrame: Prior to intervention compared to 1 and 3 months after end of treatment
measure: Change in self-reported impact on participation and autonomy
timeFrame: Prior to intervention compared to 1 and 3 months after end of treatment.
measure: Change in Psychological Distress
timeFrame: Prior to intervention compared to 1 and 3 months after end of treatment.
measure: Change in illness perception
timeFrame: Prior to intervention compared to 1 and 3 months after end of treatment
measure: Change in Pain Catastrophizing
timeFrame: Prior to intervention compared to 1 and 3 months after end of treatment
measure: Change in facial perception
timeFrame: Prior to intervention compared to 1 and 3 months after end of treatment
measure: Change in self-reported efficacy of treatment
timeFrame: Prior to intervention compared to 1 and 3 months after end of treatment
measure: Change in how neck pain affects daily life
timeFrame: Prior to intervention compared to 1 and 3 months after end of treatment
measure: Changes in sleep quality
timeFrame: Prior to intervention compared to 1 and 3 months after end of treatment
measure: Changes in the somatosensory function.
timeFrame: prior to rTMS intervention, immediately after rTMS intervention and 1 month after end of treatment
measure: Characterization of PTH headache phenotypes using the Headache Impact Scale.
timeFrame: 3 months after mTBI
measure: Changes in headache phenotype using a self-constructed headache questionaire.
timeFrame: 3, 9 and 12 months after mTBI
measure: Changes in headache phenotype using the Headache Impact Scale .
timeFrame: 3, 9 and 12 months after mTBI
Other outcomes:
Locations:
city: Hammel
country: Denmark
facility: Reseach Unit Hammel Neurocenter
Study officials:
affiliation: Research Unit Hammel Neurocenter
name: Jørgen Feldbæk Nielsen, Proffessor
role: STUDY_DIRECTOR
References:
citation: Ebener M, Hasselhorn HM. Validation of Short Measures of Work Ability for Research and Employee Surveys. Int J Environ Res Public Health. 2019 Sep 12;16(18):3386. doi: 10.3390/ijerph16183386.
citation: Mollica A, Safavifar F, Fralick M, Giacobbe P, Lipsman N, Burke MJ. Transcranial Magnetic Stimulation for the Treatment of Concussion: A Systematic Review. Neuromodulation. 2021 Jul;24(5):803-812. doi: 10.1111/ner.13319. Epub 2020 Nov 12.