Every year, 69 million people worldwide are estimated to suffer from a Traumatic Brain Injury (TBI) with approximately 80% of these cases diagnosed as a mild TBI (mTBI), defined as scoring 13–15 on Glasgow Coma Scale (GCS).1,2 The actual prevalence is difficult to determine as many individuals with mTBI or concussion, do not seek medical attention.3,4 Some authors use mTBI and concussion interchangeably while others refer to concussion as reversible pathological changes with most victims scoring 15 out of 15 on the GCS.5–7 These terms are used synonymously here to capture a broader range of articles in the literature.
Although most people who have experienced a concussion recover within weeks to months, in 10–15% of patients, symptoms including physical (e.g., headache, dizziness, fatigue), cognitive (e.g., memory issues, difficulty concentrating) and emotional (e.g., anxiety, depression) may persist longer than 3 months, which is referred to as Post-Concussion Syndrome (PCS).8–10 The 2016 Berlin Consensus Statement on Concussion in Sport defines persistent post-concussive symptoms as having complaints longer than normal recovery time, which is estimated to be 10–14 days in adults and 4 weeks in children.5 This is mostly accepted in literature related to contact sports. On the other hand, clinical criteria for diagnosing PCS were first proposed in 1992 in the International Classification of Diseases, Tenth Revision (ICD–10)11, and these criteria were later adapted and modified in the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV).12 ICD–10 clinical criteria require a history of TBI and the presence of three or more of the following eight symptoms: 1) headache, 2) dizziness, 3) fatigue, 4) irritability, 5) insomnia, 6) concentration or 7) memory difficulty, and 8) intolerance of stress, emotion, or alcohol.11 Alternatively, DSM-IV describes PCS as experiencing objective impairment in memory or attention with three of the following symptoms: headache, fatigue, sleep disturbance, dizziness, irritability, affective disturbance, personality change, apathy, anxiety or depression, for more than 3 months.12 Since many articles do not use DSM-IV or ICD–10 for assessing post-concussive symptoms, we extend our literature search to the studies with patients experiencing persistent symptoms 1 month post-injury based on other assessments such as Rivermead Post-Concussion Symptom Questionnaire.13
The symptoms listed above are, unfortunately, not specific to PCS, further complicating its diagnosis. Moreover, brains of patients with PCS often appear normal on conventional Computed Tomography (CT) and Magnetic Resonance Imaging (MRI) scans. The challenge is to develop and utilize more sensitive imaging tools to detect subtle changes in the structure or the functional connectivity within the brain to better understand the neuropsychiatric and behavioural outcomes. One promising biomarker could be the alterations of white matter tracts that transport information in the brain, detected with Diffusion Tensor or Weighted Imaging (DTI, DWI).14,15 The literature suggests a link between disruption of white matter integrity in patients experiencing post-concussive symptoms and neuropsychological deficits such as greater aggression16 and cognitive impairment17. Another potential biomarker for PCS involves the disruption of functional connectivity (i.e. interaction and activation) of various brain regions. Functional MRI (fMRI) allows us to investigate the alterations in the intrinsic connectivity of brain regions while the person is actively involved in a task or at rest18. Alterations in resting state functional connectivity in patients with mTBI related persistent symptoms have been correlated with symptom severity.19,20
Although these studies increase our understanding of the brain-behaviour relationship in PCS, they often report very distinct or even conflicting findings on DTI/DWI or fMRI parameters or the brain regions that are part of disrupted structural or functional brain networks. Such differences in findings may arise from many factors including the variability in recruitment sites (i.e. military, contact sports), patient population (i.e. age, sex, education levels), tests administered for assessing symptom severity or neuropsychiatric/cognitive deficits, and techniques used for processing neuroimages. It is necessary to contextualize, evaluate and summarize the existing findings to address the gap in the field of PCS, and provide guidance for researchers and clinicians.
There have been numerous systematic and scoping reviews on brain network disruptions in concussion/mTBI measured with DWI/DTI and fMRI techniques. A very detailed review by Shenton et al.21 reported a great deal of variability in DTI findings in mTBI research including the location of structural and functional connectivity alterations and the degree of these alterations measured with different metrics (i.e. Fractional Anisotropy, Medial Diffusivity). This review suggests that diffusion imaging techniques are promising for revealing subtle changes in the brain after mTBI; however, behavioural correlates of these brain changes were not investigated.21 A review by McDonald et al22 suggested that fMRI evaluating the brain function, either at rest or during a specific task, can provide an objective way to link the functional connectivity changes in particular brain regions to cognitive/behavioural outcomes or mTBI-related symptomatology. A recent scoping review estimated that 58% of these patients develop some sort of cognitive impairment, a much larger number than usually reported.23 According to the commentary by Iverson et al24, not every patient experiences the same persistent symptoms to the same degree. There have been few reviews summarizing existing literature on structural and functional changes along with behavioural outcomes, including cognitive impairments, neuropsychiatric deficits or symptomology, in patients with persisting post-concussive symptoms. Khong et al.25, reported that loss of integrity in long white matter tracts such as corpus callosum was the most cited abnormality in PCS literature, which was consistent with a previous review.17 The current literature in PCS is limited because of a lack of converging knowledge due to few studies published on the topic.25
As described, most of the knowledge synthesis in the field has focused on only one domain: loss of white matter integrity, disruption of functional connectivity or symptoms/behavioural deficits observed in patients with PCS. To our knowledge, there is no systematic summary of literature focused on understanding the structural or functional changes along with cognitive, neuropsychiatric measures or symptom severity in the adult population with PCS. In this paper, we provide a protocol for a scoping review that will summarize and synthesize the literature on both structural and functional connectivity changes and cognitive, neuropsychiatric measures or symptom severity in patients with PCS. We specifically target the studies that utilized DTI/DWI and resting state or task-based fMRI for detecting alterations in white matter integrity and functional connectivity in PCS patients, respectively. The objective of our scoping review is to provide an overview of the literature on the brain-behaviour relationship in patients with PCS, specifically using the neuroimaging tools mentioned above. The usage of highly variable terminology has led to confusion, not only in the diagnosis or detection of PCS, but also difficulty in finding relevant literature in this field. Thus, this scoping review will inform future studies that aim to find neuroimaging biomarkers for PCS while providing an approach for an effective search of the relevant literature.