GAIN Symptoms: Post-traumatic Headache

NCT ID: NCT05857761

Last Updated: 2025-03-11

Basic Information

• Recruitment Status: ACTIVE_NOT_RECRUITING
• Clinical Phase: NA
• Total Enrollment: 62 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2023-08-28
• Study Completion Date: 2027-12-31

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.

Conditions

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

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: HEALTH_SERVICES_RESEARCH
• Blinding Strategy: SINGLE

Study Groups

Sham group

participants (n=31) will receive sham rTMS.

Group Type: SHAM_COMPARATOR

Sham repetitive transcranial magnetic stimulation (rTMS)

Intervention Type: DEVICE

Five sessions of sham rTMS therapy will be distributed over 2 weeks

Active rTMS treatment

Participants (n=31) will receive active rTMS treatment.

Group Type: ACTIVE_COMPARATOR

Active repetitive transcranial magnetic stimulation (rTMS)

Intervention Type: DEVICE

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.

Interventions

Active repetitive transcranial magnetic stimulation (rTMS)

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.

Intervention Type: DEVICE

Sham repetitive transcranial magnetic stimulation (rTMS)

Five sessions of sham rTMS therapy will be distributed over 2 weeks

Intervention Type: DEVICE

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.).

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 60 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: Yes

Sponsors

Hammel Neurorehabilitation Centre and University Research Clinic

OTHER

Sponsor Role: collaborator

Central Denmark Region

OTHER

Sponsor Role: collaborator

University of Aarhus

OTHER

Sponsor Role: lead

Responsible Party

Charlotte Nygaard

Medical Doctor, PhD student

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Jørgen Feldbæk Nielsen, Proffessor

Role: STUDY_DIRECTOR

Research Unit Hammel Neurocenter

Locations

Reseach Unit Hammel Neurocenter

Hammel, , Denmark

Countries

Denmark

References

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.

Reference Type: BACKGROUND

PMID: 31547466 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 33184973 (View on PubMed)

Other Identifiers

GAIN: Post-traumatic Headache

Identifier Type: -

Identifier Source: org_study_id