Treatment of Post-concussion Syndrome With TMS: Using FNIRS as a Biomarker of Response

• ClinicalTrials.gov Identifier: NCT04568369
• Recruitment Status: Recruiting
• First Posted: September 29, 2020
• Last Update Posted: September 30, 2021
• Sponsor: University of Calgary
• Information provided by (Responsible Party): University of Calgary

Study Description

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. 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.

Condition or disease	Intervention/treatment	Phase
Transcranial Magnetic Stimulation; Functional Near-Infrared Spectroscopy; Post-Concussion Syndrome; Concussion; Mild Traumatic Brain Injury	Device: rTMS	Not Applicable

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 treating PPCS. Transcranial magnetic stimulation (TMS) has a high degree of safety and has been studied as an intervention for many mental health and neurological conditions, including major depression and migraines, and even showing initial promise for PPCS. The investigators propose to study this further in a randomized sham controlled trial of TMS for PPCS.

RESEARCH QUESTIONS AND OBJECTIVES

The overall aim 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 whether patients with PPCS have significant improvement to a 20-day high frequency rTMS treatment protocol of the left DMPFC compared to patients with PPCS receiving a sham rTMS protocol as measured by the Rivermead post-concussion symptom questionnaire at 1, 3 and 6 months post-treatment.
2. Secondary Objective: To determine what secondary outcomes such as quality of life, headaches, anxiety, and depression also improve with the 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 PHQ-9 and anxiety via the GADS-7 at 1, 3 and 6 months post treatment.
3. Third objective: To explore whether fNIRS would be a useful biomarker of TMS-response in patients with PPCS.

METHODS

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

Clinical Assessments: Demographic information will be collected two weeks 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), Montreal cognitive assessment (MoCA), quality of life after brain injury questionnaire (QOLIBRI), patient health questionnaire-9 (PHQ-9), generalized anxiety disorder scale-7 (GADS-7), Repeatable battery for the assessment of neurological status (RBANS), and the post traumatic stress disorder checklist for DSM-5 (PCL-5). Patients will keep a two-week baseline symptom diary before treatment, 2 weeks during treatment, 2 weeks following rTMS, and for 2 weeks at the 1, 3, and 6 month follow up assessments (total of 12 weeks). Patients will be reassessed at the completion of their rTMS treatment, and at 1, 3, and 6 months post-treatment. The questionnaires including: Rivermead PPCS questionnaire, HIT-6, BC-PSI, QOLIBRI, PHQ-9, GAD-7 and RBANS will be completed at all 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. If available, patient MR brain scans will be loaded and processed using the Brainsight TMS neuronavigation software and stereotaxic data for localization of the TMS stimulation site will be determined through a co-registration method between the TMS coil position and the projected site on the MR brain scan. If not available, a standardized atlas brain with Montreal neurologic institute (MNI) coordinates will be used for navigation. The DLPFC will be located through MNI coordinates (-48, 26, 36) vs. (-41, 21, 38). 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) scans will be recorded at baseline, immediately following rTMS, and at one month 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 NIRScout fNIRS system (NIRx Medical Technologies, Berlin, Germany). Each recording will consist of a 5 min rest period, followed by a finger tapping exercise, and a graded working memory task. 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.

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

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 40 participants
• Allocation: Randomized
• Intervention Model: Crossover Assignment
• Intervention Model Description: This study will be a double-blind, sham-controlled, concealed allocation, randomized, cross over clinical trial.
• Masking: Triple (Participant, Care Provider, Investigator)
• Masking Description: Patients will be randomized with a random number generator to receive either sham or rTMS. All individuals involved in the study except the research assistant administering the rTMS will be blinded to the treatment protocol and allocation will be concealed. Following the three months, patients and study personnel will be unblinded. Subjects in the sham group will be given the opportunity to cross over to the treatment group.
• Primary Purpose: Treatment
• Official Title: Functional Near Infrared Spectroscopy as a Biomarker of Response in Patients With Post-concussion Syndrome Treated With Transcranial Magnetic Stimulation
• Actual Study Start Date: May 2, 2020
• Estimated Primary Completion Date: August 2022
• Estimated Study Completion Date: November 2022

Arms and Interventions

Arm	Intervention/treatment
Experimental: Treatment group; 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. If available, patient MR brain scans will be loaded and processed using the Brainsight TMS neuronavigation software and stereotaxic data for localization of the TMS stimulation site will be determined through a co-registration method between the TMS coil position and the projected site on the MR brain scan. If not available, a standardized atlas brain with Montreal neurologic institute (MNI) coordinates will be used for navigation. The DLPFC will be located through MNI coordinates (-48, 26, 36) vs. (-41, 21, 38). 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.	Device: rTMS; See treatment arm description.
Sham Comparator: Sham group; 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.	Device: rTMS; See treatment arm description.

Outcome Measures

Primary Outcome Measures :

1. Rivermead post-concussion symptom questionnaire [ Time Frame: Patients will complete this measure at baseline to 1 month post-TMS treatment ]
   Our primary outcome measure is the RIvermead post-concussion symptom questionnaires (RPQ), which assesses the severity of 16 commonly experienced PCS symptoms. Participants are instructed to rate the extent to which they have suffered from each of the listed symptoms in the past 24 hours, as compared to pre-injury levels, using a scale of 0 ("not experienced at all") to 4 ("a severe problem"). The RPQ has been demonstrated as a valid measure of PPCS with a minimal clinically important difference (MCID) of 4.5 points[LM1] . It is advised to use this assessment as two separate scales (RPQ-13 and RRQ-3). Using these sub-scales, the instrument has good test-retest reliability and external construct validity. This questionnaire probes the separate cognitive, emotional and somatic components of PPCS.

Secondary Outcome Measures :

1. QOLIBRI [ Time Frame: Patients will complete these measures at baseline, and will be reassessed for change at 1, 3 and 6 months post treatment. ]
   Secondary outcome measures will include a questionnaire which assesses quality of life measured via the Quality of Life after brain injury questionnaire (QOLIBRI).
2. HIT-6 [ Time Frame: Patients will complete this measure at baseline, and will be reassessed for change at 1, 3 and 6 months post treatment ]
   Secondary outcome measures will include a questionnaire which assesses headache intensity via the Headache Intensity Test -6 (HIT-6).
3. PHQ-9 [ Time Frame: Patients will complete this measure at baseline, and will be reassessed for change at 1, 3 and 6 months post treatment ]
   Secondary outcome measures will include a questionnaire which assesses feelings of depression via the Patient Health Questionnaire-9 (PHQ-9).
4. GADS-7 [ Time Frame: Patients will complete this measure at baseline, and will be reassessed for change at 1, 3 and 6 months post treatment ]
   Secondary outcome measures will include a questionnaire which assesses feelings of anxiety via the Generalized Anxiety Disorder-7 scale (GADS-7).
5. Rivermead Post-concussion Questionnaire [ Time Frame: Secondary outcomes baseline, 3 and 6 months post-TMS treatment ]
   Questionnaire assesses post-concussion symptoms

Other Outcome Measures:

1. Functional near infrared spectroscopy [ Time Frame: Functional near infrared spectroscopy (fNIRS) scans will be recorded at baseline, immediately following rTMS, and at one month post-rTMS. ]
   Functional near infrared spectroscopy (fNIRS) will used as a diagnostic tool to determine TMS response

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 65 Years (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes

Criteria

Inclusion Criteria:

• Diagnosis of persistent post-concussional syndrome based on the ICD-10 criteria. This diagnosis should be given to the patient from a clinical practitioner.
• Age 18-65 yrs.
• Current pharmacologic management can remain stable throughout the protocol. The medication will be maintained without intervention during the treatment study such as use of abortive headache medications (i.e. triptans, opioids, tricyclic antidepressants, anti-seizure medications). Patient's undergoing botox treatment will undergo rTMS treatment 6-8 weeks following their injection, which is around the time of peak botox efficacy.

Exclusion Criteria:

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

Contacts and Locations

Contacts

Contact: Chantel T Debert, MD MSc FRCPC CSCN; (403) 944-4500; cdebert@ucalgary.ca

Contact: Sane S DuPlessis, BSc; (403) 955-5793; sane.duplessis@ucalgary.ca

Locations

Canada, Alberta

Chantel T Debert; Recruiting

Calgary, Alberta, Canada, T2N2T9

Contact: Chantel T Debert, MD MSc 4039445235 chantel.debert@ahs.ca

Contact: Regan king, Msc 4039441580 regan.king@ahs.ca

Sponsors and Collaborators

University of Calgary

Investigators

• Principal Investigator: Chantel T Debert, MD MSc FRCPC CSCN; University of Calgary

More Information

Publications:

Maas AIR, Menon DK, Adelson PD, Andelic N, Bell MJ, Belli A, Bragge P, Brazinova A, Büki A, Chesnut RM, Citerio G, Coburn M, Cooper DJ, Crowder AT, Czeiter E, Czosnyka M, Diaz-Arrastia R, Dreier JP, Duhaime AC, Ercole A, van Essen TA, Feigin VL, Gao G, Giacino J, Gonzalez-Lara LE, Gruen RL, Gupta D, Hartings JA, Hill S, Jiang JY, Ketharanathan N, Kompanje EJO, Lanyon L, Laureys S, Lecky F, Levin H, Lingsma HF, Maegele M, Majdan M, Manley G, Marsteller J, Mascia L, McFadyen C, Mondello S, Newcombe V, Palotie A, Parizel PM, Peul W, Piercy J, Polinder S, Puybasset L, Rasmussen TE, Rossaint R, Smielewski P, Söderberg J, Stanworth SJ, Stein MB, von Steinbüchel N, Stewart W, Steyerberg EW, Stocchetti N, Synnot A, Te Ao B, Tenovuo O, Theadom A, Tibboel D, Videtta W, Wang KKW, Williams WH, Wilson L, Yaffe K; InTBIR Participants and Investigators. Traumatic brain injury: integrated approaches to improve prevention, clinical care, and research. Lancet Neurol. 2017 Dec;16(12):987-1048. doi: 10.1016/S1474-4422(17)30371-X. Epub 2017 Nov 6. Review.

Hunt C, Zanetti K, Kirkham B, Michalak A, Masanic C, Vaidyanath C, Bhalerao S, Cusimano MD, Baker A, Ouchterlony D. Identification of hidden health utilization services and costs in adults awaiting tertiary care following mild traumatic brain injury in Toronto, Ontario, Canada. Concussion. 2016 Aug 8;1(4):CNC21. doi: 10.2217/cnc-2016-0009. eCollection 2016 Dec.

Hendrikse J, Kandola A, Coxon J, Rogasch N, Yücel M. Combining aerobic exercise and repetitive transcranial magnetic stimulation to improve brain function in health and disease. Neurosci Biobehav Rev. 2017 Dec;83:11-20. doi: 10.1016/j.neubiorev.2017.09.023. Epub 2017 Sep 23. Review.

Daoud H, Alharfi I, Alhelali I, Charyk Stewart T, Qasem H, Fraser DD. Brain injury biomarkers as outcome predictors in pediatric severe traumatic brain injury. Neurocrit Care. 2014 Jun;20(3):427-35. doi: 10.1007/s12028-013-9879-1. Review.

Mychasiuk R, Hehar H, Ma I, Kolb B, Esser MJ. The development of lasting impairments: a mild pediatric brain injury alters gene expression, dendritic morphology, and synaptic connectivity in the prefrontal cortex of rats. Neuroscience. 2015 Mar 12;288:145-55. doi: 10.1016/j.neuroscience.2014.12.034. Epub 2014 Dec 30.

Henry LC, Tremblay S, Boulanger Y, Ellemberg D, Lassonde M. Neurometabolic changes in the acute phase after sports concussions correlate with symptom severity. J Neurotrauma. 2010 Jan;27(1):65-76. doi: 10.1089/neu.2009.0962.

Liu G, Feng D, Wang J, Zhang H, Peng Z, Cai M, Yang J, Zhang R, Wang H, Wu S, Tan Q. rTMS Ameliorates PTSD Symptoms in Rats by Enhancing Glutamate Transmission and Synaptic Plasticity in the ACC via the PTEN/Akt Signalling Pathway. Mol Neurobiol. 2018 May;55(5):3946-3958. doi: 10.1007/s12035-017-0602-7. Epub 2017 May 26.

Lewis CP, Port JD, Frye MA, Vande Voort JL, Ameis SH, Husain MM, Daskalakis ZJ, Croarkin PE. An Exploratory Study of Spectroscopic Glutamatergic Correlates of Cortical Excitability in Depressed Adolescents. Front Neural Circuits. 2016 Nov 29;10:98. eCollection 2016.

Yang XR, Kirton A, Wilkes TC, Pradhan S, Liu I, Jaworska N, Damji O, Keess J, Langevin LM, Rajapakse T, Lebel RM, Sembo M, Fife M, MacMaster FP. Glutamate alterations associated with transcranial magnetic stimulation in youth depression: a case series. J ECT. 2014 Sep;30(3):242-7. doi: 10.1097/YCT.0000000000000094.

Covassin T, Elbin RJ 3rd, Larson E, Kontos AP. Sex and age differences in depression and baseline sport-related concussion neurocognitive performance and symptoms. Clin J Sport Med. 2012 Mar;22(2):98-104. doi: 10.1097/JSM.0b013e31823403d2.

Harmon KG, Drezner JA, Gammons M, Guskiewicz KM, Halstead M, Herring SA, Kutcher JS, Pana A, Putukian M, Roberts WO. American Medical Society for Sports Medicine position statement: concussion in sport. Br J Sports Med. 2013 Jan;47(1):15-26. doi: 10.1136/bjsports-2012-091941. Review. Erratum in: Br J Sports Med. 2013 Feb;47(3):184.

McCrory P, Meeuwisse WH, Aubry M, Cantu RC, Dvořák J, Echemendia RJ, Engebretsen L, Johnston KM, Kutcher JS, Raftery M, Sills A, Benson BW, Davis GA, Ellenbogen R, Guskiewicz KM, Herring SA, Iverson GL, Jordan BD, Kissick J, McCrea M, McIntosh AS, Maddocks DL, Makdissi M, Purcell L, Putukian M, Schneider K, Tator CH, Turner M. Consensus statement on concussion in sport--the 4th International Conference on Concussion in Sport held in Zurich, November 2012. PM R. 2013 Apr;5(4):255-79. doi: 10.1016/j.pmrj.2013.02.012. Epub 2013 Feb 27.

Covassin T, Elbin RJ, Harris W, Parker T, Kontos A. The role of age and sex in symptoms, neurocognitive performance, and postural stability in athletes after concussion. Am J Sports Med. 2012 Jun;40(6):1303-12. doi: 10.1177/0363546512444554. Epub 2012 Apr 26.

Scholkmann F, Kleiser S, Metz AJ, Zimmermann R, Mata Pavia J, Wolf U, Wolf M. A review on continuous wave functional near-infrared spectroscopy and imaging instrumentation and methodology. Neuroimage. 2014 Jan 15;85 Pt 1:6-27. doi: 10.1016/j.neuroimage.2013.05.004. Epub 2013 May 16. Review.

Kleinschmidt A, Obrig H, Requardt M, Merboldt KD, Dirnagl U, Villringer A, Frahm J. Simultaneous recording of cerebral blood oxygenation changes during human brain activation by magnetic resonance imaging and near-infrared spectroscopy. J Cereb Blood Flow Metab. 1996 Sep;16(5):817-26.

Hocke LM, Duszynski CC, Debert CT, Dleikan D, Dunn JF. Reduced Functional Connectivity in Adults with Persistent Post-Concussion Symptoms: A Functional Near-Infrared Spectroscopy Study. J Neurotrauma. 2018 Jun 1;35(11):1224-1232. doi: 10.1089/neu.2017.5365. Epub 2018 Mar 23.

Santosa H, Fishburn F, Zhai X, Huppert TJ. Investigation of the sensitivity-specificity of canonical- and deconvolution-based linear models in evoked functional near-infrared spectroscopy. Neurophotonics. 2019 Apr;6(2):025009. doi: 10.1117/1.NPh.6.2.025009. Epub 2019 May 30.

Huppert TJ, Diamond SG, Franceschini MA, Boas DA. HomER: a review of time-series analysis methods for near-infrared spectroscopy of the brain. Appl Opt. 2009 Apr 1;48(10):D280-98. Review.

Kontos AP, Huppert TJ, Beluk NH, Elbin RJ, Henry LC, French J, Dakan SM, Collins MW. Brain activation during neurocognitive testing using functional near-infrared spectroscopy in patients following concussion compared to healthy controls. Brain Imaging Behav. 2014 Dec;8(4):621-34. doi: 10.1007/s11682-014-9289-9.

Wu Z, Mazzola CA, Catania L, Owoeye O, Yaramothu C, Alvarez T, Gao Y, Li X. Altered cortical activation and connectivity patterns for visual attention processing in young adults post-traumatic brain injury: A functional near infrared spectroscopy study. CNS Neurosci Ther. 2018 Jun;24(6):539-548. doi: 10.1111/cns.12811. Epub 2018 Jan 22.

• Responsible Party: University of Calgary
• ClinicalTrials.gov Identifier: NCT04568369
• Other Study ID Numbers: 19-1552
• First Posted: September 29, 2020
• Last Update Posted: September 30, 2021
• Last Verified: September 2021

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:

Brain Injuries; Brain Injuries, Traumatic; Brain Concussion; Post-Concussion Syndrome; Syndrome; Disease; Pathologic Processes; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Craniocerebral Trauma; Trauma, Nervous System; Wounds and Injuries; Head Injuries, Closed; Wounds, Nonpenetrating