Noninvasive magnetic resonance imaging techniques in mild traumatic brain injury research and diagnosis.

Mild traumatic brain injury (mTBI), frequently referred to as concussion, is one of the most common neurological disorders. The underlying neural mechanisms of functional disturbances in the brains of concussed individuals remain elusive. Novel forms of brain imaging have been developed to assess patients postconcussion, including functional magnetic resonance imaging (fMRI), susceptibility-weighted imaging (SWI), diffusion MRI (dMRI), and perfusion MRI [arterial spin labeling (ASL)], but results have been mixed with a more common utilization in the research environment and a slower integration into the clinical setting. In this review, the benefits and drawbacks of the methods are described: fMRI is an effective method in the diagnosis of concussion but it is expensive and time-consuming making it difficult for regular use in everyday practice; SWI allows detection of microhemorrhages in acute and chronic phases of concussion; dMRI is primarily used for the detection of white matter abnormalities, especially axonal injury, specific for mTBI; and ASL is an alternative to the BOLD method with its ability to track cerebral blood flow alterations. Thus, the absence of a universal diagnostic neuroimaging method suggests a need for the adoption of a multimodal approach to the neuroimaging of mTBI. Taken together, these methods, with their underlying functional and structural features, can contribute from different angles to a deeper understanding of mTBI mechanisms such that a comprehensive diagnosis of mTBI becomes feasible for the clinician.

A Prospective, Multicenter Study to Assess the Safety and Efficacy of Translingual Neurostimulation Plus Physical Therapy for the Treatment of a Chronic Balance Deficit Due to Mild-to-Moderate Traumatic Brain Injury.

OBJECTIVES: Translingual neurostimulation (TLNS) studies indicate improved outcomes in neurodegenerative disease or spinal cord injury patients. This study was designed to assess the safety and efficacy of TLNS plus targeted physical therapy (PT) in people with a chronic balance deficit after mild-to-moderate traumatic brain injury (mmTBI). MATERIALS AND METHODS: This international, multicenter, randomized study enrolled 122 participants with a chronic balance deficit who had undergone PT following an mmTBI and had plateaued in recovery. Randomized participants received PT plus either high-frequency pulse (HFP; n = 59) or low-frequency pulse (LFP; n = 63) TLNS. The primary efficacy and safety endpoints were the proportion of sensory organization test (SOT) responders (SOT composite score improvement of ≥15 points) and fall frequency after five weeks of treatment, respectively. RESULTS: The proportion of SOT responders was significant in the HFP + PT (71.2%) and LFP + PT (63.5%) groups compared with baseline (p < 0.0005). For the pooled population, the SOT responder rate was 67.2% (p < 0.00005), and there were clinically and statistically significant improvements in SOT composite scores after two and five weeks (p < 0.0005). Both groups had reductions in falls and headache disability index scores. Mean dynamic gait index scores in both groups also significantly increased from baseline at weeks 2 and 5. CONCLUSIONS: Significant improvements in balance and gait, in addition to headaches, sleep quality, and fall frequency, were observed with TLNS plus targeted PT; in participants who had a chronic balance deficit following an mmTBI and had plateaued on prior conventional physiotherapy.

A Prospective Study of Childhood Predictors of Traumatic Brain Injuries Sustained in Adolescence and Adulthood.

OBJECTIVE: Traumatic brain injuries (TBIs) are sustained by approximately 17% of males in the general population, many of whom subsequently present mental disorders, cognitive, and physical problems. Little is known about predictors of TBIs and how to prevent them. The present study aimed to determine whether inattention-hyperactivity and/or all externalizing problems presented by boys at age 10 predict subsequent TBIs to age 34 after taking account of previous TBIs and family social status (FSS). METHOD: 742 Canadian males were followed, prospectively, from age 6 to 34. Diagnoses of TBIs were extracted from health files, parents-reported sociodemographic and family characteristics at participants' age 6, and teachers-rated participants' behaviors at age 10. Separate logistic regression models predicted TBIs sustained from age 11 to 17 and from age 18 to 34. For each age period, two models were computed, one included previous TBIs, inattention-hyperactivity, FSS, and interaction terms, the second included previous TBIs, externalizing problems, FSS, and interaction terms. RESULTS: In models that included inattention-hyperactivity, TBIs sustained from age 11 to 17 were predicted by age 10 inattention-hyperactivity (odds ratio [OR] = 1.46, 1.05 to 2.05) and by TBIs prior to age 11 (OR = 3.50, 1.48 to 8.24); TBIs sustained from age 18 to 34 were predicted by age 10 inattention-hyperactivity (OR = 1.31, 1.01 to 170). In models that included all externalizing problems, TBIs from age 11 to 17 were predicted by prior TBIs (OR = 3.66, 1.51 to 8.39); TBIs sustained from age 18 to 34 were predicted by age 10 externalizing problems (OR = 1.45, 1.12 to 1.86). Neither FSS nor interaction terms predicted TBIs in any of the models. CONCLUSIONS: Among males, using evidence-based treatments to reduce inattention-hyperactivity and externalizing problems among boys could, potentially, decrease the risk of TBIs to age 34. Further, boys who sustain TBIs in childhood require monitoring to prevent recurrence in adolescence.

Are Traumatic Brain Injuries Associated With Criminality After Taking Account of Childhood Family Social Status and Disruptive Behaviors?

OBJECTIVE: The authors aimed to elucidate the links between traumatic brain injuries (TBIs) and criminal convictions in a sample of 724 Canadian males with and without criminal records followed up to age 24. METHODS: Prospectively collected data were analyzed to determine whether prior TBIs predicted subsequent criminal convictions after taking account of family social status (FSS) and childhood disruptive behaviors. At age 24, diagnoses of TBIs were extracted from health records and convictions from official criminal records. In childhood, teachers rated disruptive behaviors and parents reported FSS. RESULTS: Proportionately more individuals with offender status than nonoffender status sustained a TBI from age 18 to age 24 but not before age 18. Individuals with offender status who had sustained a TBI before and after their first conviction were similar in numbers, were raised in families of low social status, and presented high levels of disruptive behaviors from age 6 to age 12. When FSS and childhood disruptive behaviors were included in multivariable regression models, sustaining a prior TBI was not associated with an increased risk of juvenile convictions for any type of crime, for violent crimes, for convictions for any crime or violent crime from age 18 to age 24, or for a first crime or a first violent crime from age 18 to age 24. CONCLUSIONS: Among males, there was no evidence that prior TBIs were associated with an increased risk of subsequent criminal convictions from age 12 to age 24 when taking account of FSS and childhood disruptive behaviors, although these latter factors may be associated with an increased prevalence of TBIs among adult offenders.

Impact of non-invasive brain stimulation on transcallosal modulation in mild traumatic brain injury: a multimodal pilot investigation.

Background: We combined performance on working memory (WM) tasks with diffusion (dMRI) and functional (fMRI) magnetic resonance imaging in young adults who had suffered a concussion to better understand the inter-hemispheric effects of unilateral repetitive transcranial magnetic stimulation (rTMS). Methods: The article is presenting pilot data on 8 symptomatic patients with persistent post-concussion symptoms for over 6 months. They received 20 sessions of rTMS over the left dorsolateral prefrontal cortex. Fractional anisotropy and mean diffusivity of the corpus callosum (CC) and fMRI measurement of blood-oxygen-level dependent signal changes during WM tasks were carried out before and after rTMS stimulation. Results: After participants had completed the rTMS sessions, we observed three main results: (1) bilateralization of activation within the WM network; (2) shift from transcallosal inhibition to transcallosal activation of the right-sided WM network via the anterior callosal fibres; and (3) shift from transcallosal activation to transcallosal inhibition of the right-sided WM network via the posterior parts of the CC. More nuanced patterns of transcallosal mediation in the region of the right-sided WM network were observed via the medial part of the CC. Conclusion: Our preliminary results encourage trends of further research supporting the use of rTMS to restore inter-hemispheric balance within the bilateral WM network in young adults with a history of concussion.

Evaluating task-based brain network activity in pediatric subjects with an mTBI: mechanisms of functional compensation are symptom-level dependent.

The diagnosis of a mild traumatic brain injury (mTBI) places large emphasis on patient-reported symptoms which has restricted our ability to evaluate patients. Task-based functional magnetic resonance imaging has the potential to act as an objective measurement of abnormal brain activity and inform clinical decision-making; however, there is little research evaluating pediatric subjects as a function of mTBI-related symptoms. The objective of this study was to evaluate the extent to which brain activity during a spatial navigation task is different between children with mTBI and a group of healthy controls (HCs) based on symptom reporting. A group of patients with mTBI (n = 27) were divided into low- and high-symptom cohorts and compared with HCs (n = 27) on a task that required participants to locate specific landmarks. No difference was found in the level of symptoms reported between patients with low-symptom participants and HCs despite the low-symptom group showing increased activity within the frontal and occipital cortices. In participants with high-symptoms, an increase in the number of reported symptoms was found relative to HCs alongside an increase in the number of active brain regions. Findings suggest that persons with an mTBI may display unique symptom-dependent patterns of altered task-related brain activity.

Development, implementation and assessment of a concussion education programme for high school student-athletes.

Although experts have noted that adolescent athletes should be educated about concussions to improve their safety, there is no agreement on the most effective strategy to disseminate concussion education. The purpose of this study was to develop, implement and assess a concussion education programme. More precisely, four interactive oral presentations were delivered to high school student-athletes (N = 35, Mage = 15.94, SD = 0.34) in a large urban centre. Participants completed a questionnaire at three time-points during the season to measure changes in their knowledge (CK) and attitudes (CA) of concussions, and focus group interviews were conducted following the concussion education programme. Questionnaire data revealed participants' post-intervention CK scores were higher than their pre-intervention scores. During the focus groups, the student-athletes said they acquired CK about the role of protective equipment and symptom variability, and in terms of CA, they intended to avoid dangerous in-game collisions in the future. Our study was the first to create and deliver a concussion education intervention across multiple time-points, and to use mixed-methods in its assessment. These findings may be of interest to researchers, practitioners and stakeholders in sport who are invested in making the sport environment safer through concussion education and awareness.

Role of advanced neuroimaging, fluid biomarkers and genetic testing in the assessment of sport-related concussion: a systematic review.

OBJECTIVE: To conduct a systematic review of published literature on advanced neuroimaging, fluid biomarkers and genetic testing in the assessment of sport-related concussion (SRC). DATA SOURCES: Computerised searches of Medline, PubMed, Cumulative Index to Nursing and Allied Health Literature (CINAHL), PsycINFO, Scopus and Cochrane Library from 1 January 2000 to 31 December 2016 were done. There were 3222 articles identified. STUDY SELECTION: In addition to medical subject heading terms, a study was included if (1) published in English, (2) represented original research, (3) involved human research, (4) pertained to SRC and (5) involved data from neuroimaging, fluid biomarkers or genetic testing collected within 6 months of injury. Ninety-eight studies qualified for review (76 neuroimaging, 16 biomarkers and 6 genetic testing). DATA EXTRACTION: Separate reviews were conducted for neuroimaging, biomarkers and genetic testing. A standardised data extraction tool was used to document study design, population, tests employed and key findings. Reviewers used a modified quality assessment of studies of diagnostic accuracy studies (QUADAS-2) tool to rate the risk of bias, and a modified Grading of Recommendations Assessment, Development, and Evaluation (GRADE) system to rate the overall level of evidence for each search. DATA SYNTHESIS: Results from the three respective reviews are compiled in separate tables and an interpretive summary of the findings is provided. CONCLUSIONS: Advanced neuroimaging, fluid biomarkers and genetic testing are important research tools, but require further validation to determine their ultimate clinical utility in the evaluation of SRC. Future research efforts should address current gaps that limit clinical translation. Ultimately, research on neurobiological and genetic aspects of SRC is predicted to have major translational significance to evidence-based approaches to clinical management of SRC, much like applied clinical research has had over the past 20 years.

The impact of symptomatic mild traumatic brain injury on complex everyday activities and the link with alterations in cerebral functioning: Exploratory case studies.

The objective of the study was to explore the neurophysiological correlates of altered functional independence using functional magnetic resonance imaging (fMRI) and event-related potentials (ERP) after a mild traumatic brain injury (mTBI). The participants consisted of three individuals with symptomatic mTBI (3.9 ± 3.6 months post-mTBI) and 12 healthy controls. The main measures used were the Instrumental Activities of Daily Living (IADL) Profile observation-based assessment; a visual externally ordered working memory task combined to event-related potentials (ERP) and fMRI recordings; neuropsychological tests; post-concussion symptoms questionnaires; and the Activities of Daily Living (ADL) Profile interview. Compared to normal controls, all three patients had difficulty with a real-world complex budgeting activity due to deficits in planning, ineffective strategy use and/or a prolonged time to detect and correct errors. Reduced activations in the right mid-dorsolateral prefrontal cortex on fMRI as well as abnormal frontal or parietal components of the ERP occurred alongside these deficits. Results of this exploratory study suggest that reduced independence in complex everyday activities in symptomatic mTBI may be at least partly explained by a decrease in brain activation in the prefrontal cortex, abnormal ERP, or slower reaction times on working memory tasks. The study presents an initial attempt at combining research in neuroscience with ecological real-world evaluation research to further our understanding of the difficulties in complex everyday activities experienced by individuals with mTBI.

Persistent Postconcussive Symptoms Are Accompanied by Decreased Functional Brain Oxygenation.

Diagnostic methods are considered a major concern in the determination of mild traumatic brain injury. The authors examined brain oxygenation patterns in subjects with severe and minor persistent postconcussive difficulties and a healthy control group during working memory tasks in prefrontal brain regions using functional near-infrared spectroscopy. The results demonstrated decreased working memory performances among concussed subjects with severe postconcussive symptoms that were accompanied by decreased brain oxygenation patterns. An association appears to exist between decreased brain oxygenation, poor performance of working memory tasks, and increased symptom severity scores in subjects suffering from persistent postconcussive symptoms.

Assessment of Oculomotor Functions as a Biomarker in Mild Traumatic Brain Injury.

Mild traumatic brain injury (mTBI), or concussion, is a major public health problem, and ambiguity still exists regarding its diagnosis. While functional magnetic resonance imaging (fMRI) has been identified as a helpful screening tool for concussion, its limited accessibility in clinical or field settings necessitates a more efficient alternative. Oculomotor function deficit is an often-reported pathology in mTBI. Due to the neuroanatomical overlap between eye-movement circuitry and mTBI pathophysiology, visual deficits are expected. In this study, we investigate the possibility of using an oculomotor assessment tool for finding biomarkers in concussion. We used fMRI with tasks evaluating oculomotor functions: smooth pursuit (SP), saccades, anti-saccades, and optokinetic nystagmus (OKN). Before the scanning, the testing with a system of virtual reality goggles with integrated eye- and head-tracking was used where subjects performed the same tasks as those used in fMRI. Twenty-nine concussed symptomatic adults (CSA) within 1-month postconcussion and 29 age- and sex-matched healthy controls (HCS) were tested to examine blood oxygen level-dependent (BOLD) fMRI alterations associated with performances in oculomotor function after mTBI and evaluate the efficacy of the oculomotor assessment in detecting oculomotor and gaze deficits following mTBI. Comparing CSA with HCS, significant differences were observed in anti-saccades and OKN performance. CSA group exhibited elevated %BOLD signal change on each task compared with HCS: in the superior frontal gyrus during the smooth pursuit, inferior frontal gyrus during the saccades, putamen and dorsolateral prefrontal cortex (DLPFC) during the anti-saccades, and lingual gyrus and IFG during the OKN. Key findings include the following: (1) oculomotor deficits in concussed subjects compared with controls, (2) abnormal activation patterns in areas related to the regulation and control of oculomotor movements, suggesting concussion-induced disruptions, and (3) the potential of oculomotor assessment as a promising approach for mTBI biomarkers, with anti-saccades and OKN identified as the most sensitive tasks.

Exploring oculomotor functions in a pilot study with healthy controls: Insights from eye-tracking and fMRI.

Eye-tracking techniques have gained widespread application in various fields including research on the visual system, neurosciences, psychology, and human-computer interaction, with emerging clinical implications. In this preliminary phase of our study, we introduce a pilot test of innovative virtual reality technology designed for tracking head and eye movements among healthy individuals. This tool was developed to assess the presence of mild traumatic brain injury (mTBI), given the frequent association of oculomotor function deficits with such injuries. Alongside eye-tracking, we also integrated fMRI due to the complementary nature of these techniques, offering insights into both neural activation patterns and behavioural responses, thereby providing a comprehensive understanding of oculomotor function. We used fMRI with tasks evaluating oculomotor functions: Smooth Pursuit (SP), Saccades, Anti-Saccades, and Optokinetic Nystagmus (OKN). Prior to the scanning, the testing with a system of VR goggles with integrated eye and head tracking was used where subjects performed the same tasks as those used in fMRI. 31 healthy adult controls (HCs) were tested with the purpose of identifying brain regions associated with these tasks and collecting preliminary norms for later comparison with concussed subjects. HCs' fMRI results showed following peak activation regions: SP-cuneus, superior parietal lobule, paracentral lobule, inferior parietal lobule (IPL), cerebellartonsil (CT); Saccades-middle frontal gyrus (MFG), postcentral gyrus, medial frontal gyrus; Anti-saccades-precuneus, IPL, MFG; OKN-middle temporal gyrus, ACC, postcentral gyrus, MFG, CT. These results demonstrated brain regions associated with the performance on oculomotor tasks in healthy controls and most of the highlighted areas are corresponding with those affected in concussion. This suggests that the involvement of brain areas susceptible to mTBI in implementing oculomotor evaluation, taken together with commonly reported oculomotor difficulties post-concussion, may lead to finding objective biomarkers using eye-tracking tasks.

White matter microstructure, traumatic brain injury, and disruptive behavior disorders in girls and boys.

Introduction: Girls and boys presenting disruptive behavior disorders (DBDs) display differences in white matter microstructure (WMM) relative to typically developing (TD) sex-matched peers. Boys with DBDs are at increased risk for traumatic brain injuries (TBIs), which are also known to impact WMM. This study aimed to disentangle associations of WMM with DBDs and TBIs. Methods: The sample included 673 children with DBDs and 836 TD children, aged 9-10, from the Adolescent Brain Cognitive Development Study. Thirteen white matter bundles previously associated with DBDs were the focus of study. Analyses were undertaken separately by sex, adjusting for callous-unemotional traits (CU), attention-deficit hyperactivity disorder (ADHD), age, pubertal stage, IQ, ethnicity, and family income. Results: Among children without TBIs, those with DBDs showed sex-specific differences in WMM of several tracts relative to TD. Most differences were associated with ADHD, CU, or both. Greater proportions of girls and boys with DBDs than sex-matched TD children had sustained TBIs. Among girls and boys with DBDs, those who had sustained TBIs compared to those not injured, displayed WMM alterations that were robust to adjustment for all covariates. Across most DBD/TD comparisons, axonal density scores were higher among children presenting DBDs. Discussion: In conclusion, in this community sample of children, those with DBDs were more likely to have sustained TBIs that were associated with additional, sex-specific, alterations of WMM. These additional alterations further compromise the future development of children with DBDs.

What evidence exists for new strategies or technologies in the diagnosis of sports concussion and assessment of recovery?

OBJECTIVE: The purpose of this critical review is to summarise the evidence for the following technologies/strategies related to diagnosing or managing sports-related concussion: quantitative EEG, functional neuroimaging, head impact sensors, telemedicine and mobile devices. DATA SOURCES: MEDLINE, PubMed, Cochrane Controlled Trials Registers, SportDiscus, EMBASE, Web of Science and ProQuest databases. Primary search keywords were concussion, sports concussion and mild traumatic brain injury. The keywords used for secondary, topic specific searches were quantitative electroencephalography, qEEG, functionalMRI, magnetoencephalography, near-infrared spectroscopy, positron emission tomography, single photon emissionCT, accelerometer, impact sensor, telemetry, remote monitoring, robotic medicine, telemedicine, mobile device, mobile phone, smart phone and tablet computer. RESULTS: The primary search produced 8567 publications. The secondary searches produced nine publications that presented original data, included a comparison group in the study design and involved sports-related concussion. Four studies spoke to the potential of qEEG as a diagnostic or management tool, while five studies addressed the potential of fMRI to be used in the same capacity. CONCLUSIONS: Emerging technologies and novel approaches that aid in sports concussion diagnosis and management are being introduced at a rapid rate. While some technologies show promise, their clinical utility remains to be established.

Production of co-speech gestures in the right hemisphere: Evidence from individuals with complete or anterior callosotomy.

INTRODUCTION: A right-hand preference for co-speech gestures in right-handed neurotypical individuals as well as the co-occurrence of speech and gesture has induced neuropsychological research to primarily target the left hemisphere when investigating co-speech gesture production. However, the substantial number of spontaneous left-hand gestures in right-handed individuals has, thus far, been unexplained. Recent studies in individuals with complete callosotomy and exclusive left hemisphere speech production show a reliable left-hand preference for co-speech gestures, indicating a right hemispheric generation. However, the findings raise the issue if the separate right hemisphere is able to also generate representational gestures. The present study challenges the proposition of a specific right hemispheric contribution to gesture production by differentiating gesture types including representational ones in individuals with complete callosotomy and by including individuals with anterior callosotomy in whom neural reorganization is less extensive. METHODS: Three right-handed individuals with complete commissurotomy (A.A., N.G., G.C.) and three right-handed individuals with anterior callosotomy (C.E., S.R., L. D), all with left hemisphere language dominance, and a matched right-handed neurotypical control group (n = 10) were examined in an experimental setting, including re-narration of a nonverbal animated cartoon and responding to intelligence questions. The participants' video-taped hand movement behavior was analyzed by two independent certified raters with the NEUROGES-ELAN system for nonverbal behavior and gesture. Unimanual right-hand and left-hand gestures were classified into eight gesture types. RESULTS: The individuals with complete and anterior callosotomy performed unimanual co-speech gestures with the left as well as the right hand, with no significant preference of one hand for gestures overall. Concerning the specific gesture types, the group with complete callosotomy showed a significant right-hand preference for pantomime gestures, which also applied to the callosotomy total group. The group with anterior callosotomy displayed a significant left-hand preference for form presentation gestures. As a trend, the callosotomy total group differed from the neurotypical group as they performed more left-hand egocentric deictic and left-hand form presentation gestures. DISCUSSION: The present study replicates the finding of a substantial left-hand use for unimanual co-speech gestures in individuals with complete callosotomy. The proposition of a right hemispheric contribution to gesture production independent from left hemispheric language production is corroborated by the finding that individuals with anterior callosotomy show a similar pattern of hand use for gestures. Representational gestures were displayed with either hand, suggesting that in particular right hemispheric spatial cognition can be directly expressed in gesture. The significant right-hand preference for pantomime gesture was outstanding and compatible with the established left hemispheric specialization for tool use praxis. The findings shed a new light on the left-hand gestures in neurotypical individuals, suggesting that these can be generated in the right hemisphere.

Evaluating the cognitive consequences of mild traumatic brain injury and concussion by using electrophysiology.

OBJECT: Mild traumatic brain injury (MTBI), often referred to as concussion when it occurs in sports, produces persistent cognitive problems in at least 15% of patients. Unfortunately, conventional neuropsychological tests usually yield results within normal limits in this population. The main objective of this event-related potential (ERP) study was to understand brain functioning during the performance of a working memory (WM) task in patients who have sustained an MTBI, mostly due to motor vehicle accident or sports concussion. This study also aimed for a better understanding of the association between brain functioning as measured with ERP, behavioral performance on the WM task, postconcussion symptoms, type of injury (that is, sports concussion vs other types), and time since the injury. METHODS: Forty-four patients with MTBI (7.6 ± 8.4 months postinjury) were tested on a visual WM task with simultaneous recording of ERP, and were compared with 40 control volunteers who were their equivalent for age and sex. Amplitude and latency of frontal (N200 and N350) and parietal (P200 and P300) ERP waves were measured and were compared between groups. Correlation analyses were also performed between ERP characteristics, clinical variables, and behavioral performance. RESULTS: A significant group difference was found for behavioral performance on the WM task, in which the MTBI group had a lower percentage of correct answers than the control group (p < 0.05). The patients with MTBI also had smaller amplitudes of both frontal N350 and parietal P300 ERP components when compared with control volunteers (p < 0.05). No changes were found for latency of ERP components. Smaller ERP amplitudes were associated with slower reaction times and worse accuracy on the WM task among patients with MTBI (p < 0.05). Types of injury (that is, sports concussion vs other mechanisms) were not associated with different ERP characteristics. CONCLUSIONS: Abnormal ERP results are observed in patients after MTBI or sports concussion, even for those in the nonacute stage after their injury. Current standard clinical evaluations most often fail to detect cerebral dysfunction after MTBI, even when patients or athletes report symptoms. Clinicians should be aware that patients with MTBI, including sports concussion, probably have underlying mild but persistent cerebral dysfunctions that require further investigation.

Multi-tract multi-symptom relationships in pediatric concussion.

Background: The heterogeneity of white matter damage and symptoms in concussion has been identified as a major obstacle to therapeutic innovation. In contrast, most diffusion MRI (dMRI) studies on concussion have traditionally relied on group-comparison approaches that average out heterogeneity. To leverage, rather than average out, concussion heterogeneity, we combined dMRI and multivariate statistics to characterize multi-tract multi-symptom relationships. Methods: Using cross-sectional data from 306 previously concussed children aged 9-10 from the Adolescent Brain Cognitive Development Study, we built connectomes weighted by classical and emerging diffusion measures. These measures were combined into two informative indices, the first representing microstructural complexity, the second representing axonal density. We deployed pattern-learning algorithms to jointly decompose these connectivity features and 19 symptom measures. Results: Early multi-tract multi-symptom pairs explained the most covariance and represented broad symptom categories, such as a general problems pair, or a pair representing all cognitive symptoms, and implicated more distributed networks of white matter tracts. Further pairs represented more specific symptom combinations, such as a pair representing attention problems exclusively, and were associated with more localized white matter abnormalities. Symptom representation was not systematically related to tract representation across pairs. Sleep problems were implicated across most pairs, but were related to different connections across these pairs. Expression of multi-tract features was not driven by sociodemographic and injury-related variables, as well as by clinical subgroups defined by the presence of ADHD. Analyses performed on a replication dataset showed consistent results. Conclusions: Using a double-multivariate approach, we identified clinically-informative, cross-demographic multi-tract multi-symptom relationships. These results suggest that rather than clear one-to-one symptom-connectivity disturbances, concussions may be characterized by subtypes of symptom/connectivity relationships. The symptom/connectivity relationships identified in multi-tract multi-symptom pairs were not apparent in single-tract/single-symptom analyses. Future studies aiming to better understand connectivity/symptom relationships should take into account multi-tract multi-symptom heterogeneity. Funding: Financial support for this work came from a Vanier Canada Graduate Scholarship from the Canadian Institutes of Health Research (G.I.G.), an Ontario Graduate Scholarship (S.S.), a Restracomp Research Fellowship provided by the Hospital for Sick Children (S.S.), an Institutional Research Chair in Neuroinformatics (M.D.), as well as a Natural Sciences and Engineering Research Council CREATE grant (M.D.).

Concussions can damage networks of connections in the brain. Scientists have spent decades and millions of dollars studying concussions and potential treatments. Yet, no new treatments are available or in the pipeline. A major reason for this stagnation is that no two concussions are exactly alike. People affected by concussions may have different genetic or socioeconomic backgrounds. The nature of the injury or how its effects change over time may also vary among people with concussions. One central question facing scientists is whether there are multiple types of concussions. If so, what distinguishes them and what characteristics do they share. Some studies have looked at differences among subgroups of patients with concussions. But questions remain about whether ­ beyond differences between the patients ­ the brain injury itself differs and what impact that has on symptoms or patient trajectory. To better characterize different types of concussion, Guberman et al. analyzed diffusion magnetic resonance imaging scans from 306 nine or ten-year-old children with a previous concussion. The children were participants in the Adolescent Brain Cognitive Development Study. Using specialized statistical techniques, the researchers outlined subgroups of concussions in terms of connections and symptoms and studied how many of these subgroups each patient had. Some types of injury were linked with a category of symptoms like cognitive, mood, or physical symptoms. Some types of damage were linked with specific symptoms. Guberman et al. also found that one symptom, sleep problems, was part of many different injury subtypes. Sleep problems may occur in different patients for different reasons. For example, one patient with sleep difficulties may have experienced damage in brain regions controlling sleep and wakefulness. Another person with sleep problems may have injured parts of the brain responsible for mood and may have depression, which causes excessive sleepiness and difficulties waking up. Guberman et al. suggest a new way of thinking about concussions. If more studies confirm these concussion subgroups, scientists might use them to explore which types of therapies might be beneficial for patients with specific subgroups. Developing subgroup-targeted treatments may help scientists overcome the challenges of trying to develop therapies that work across a range of injuries. Similar disease subgrouping strategies may also help researchers study other brain diseases that may vary from patient to patient.

Biomedical Research and Informatics Living Laboratory for Innovative Advances of New Technologies in Community Mobility Rehabilitation: Protocol for Evaluation and Rehabilitation of Mobility Across Continuums of Care.

BACKGROUND: Rapid advances in technologies over the past 10 years have enabled large-scale biomedical and psychosocial rehabilitation research to improve the function and social integration of persons with physical impairments across the lifespan. The Biomedical Research and Informatics Living Laboratory for Innovative Advances of New Technologies (BRILLIANT) in community mobility rehabilitation aims to generate evidence-based research to improve rehabilitation for individuals with acquired brain injury (ABI). OBJECTIVE: This study aims to (1) identify the factors limiting or enhancing mobility in real-world community environments (public spaces, including the mall, home, and outdoors) and understand their complex interplay in individuals of all ages with ABI and (2) customize community environment mobility training by identifying, on a continuous basis, the specific rehabilitation strategies and interventions that patient subgroups benefit from most. Here, we present the research and technology plan for the BRILLIANT initiative. METHODS: A cohort of individuals, adults and children, with ABI (N=1500) will be recruited. Patients will be recruited from the acute care and rehabilitation partner centers within 4 health regions (living labs) and followed throughout the continuum of rehabilitation. Participants will also be recruited from the community. Biomedical, clinician-reported, patient-reported, and brain imaging data will be collected. Theme 1 will implement and evaluate the feasibility of collecting data across BRILLIANT living labs and conduct predictive analyses and artificial intelligence (AI) to identify mobility subgroups. Theme 2 will implement, evaluate, and identify community mobility interventions that optimize outcomes for mobility subgroups of patients with ABI. RESULTS: The biomedical infrastructure and equipment have been established across the living labs, and development of the clinician- and patient-reported outcome digital solutions is underway. Recruitment is expected to begin in May 2022. CONCLUSIONS: The program will develop and deploy a comprehensive clinical and community-based mobility-monitoring system to evaluate the factors that result in poor mobility, and develop personalized mobility interventions that are optimized for specific patient subgroups. Technology solutions will be designed to support clinicians and patients to deliver cost-effective care and the right intervention to the right person at the right time to optimize long-term functional potential and meaningful participation in the community. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): PRR1-10.2196/12506.

CARE frailty e-health scale: Association with incident adverse health outcomes and comparison with the Cardiovascular Health Study frailty scale in the NuAge cohort.

BACKGROUND: This study examines and compares CARE and Cardiovascular Health Study (CHS) frailty states (i.e., robust, prefrail and frail) for their association with incident adverse health outcomes, including falls, depression, cognitive and functional decline, major neurocognitive disorders, hospitalization and mortality in community-dwelling older adults living in the province of Quebec (Canada). METHODS: A subset of individuals (n = 1098) who participated in "Nutrition as a determinant of successful aging: The Quebec longitudinal study" (NuAge), which is an elderly population-based observational cohort study with 3 years of follow-up, were selected. CARE and CHS frailty states were determined using the NuAge baseline assessment. Incident falls (i.e., ≥1, ≥2 and severe falls), depression (i.e., 30-item Geriatric Depression Scale score > 10/30), decline in cognition (i.e., Modified Mini Mental State (3MS) score < 79/100) and functionality (i.e., Activity Daily Living (ADL) score ≤ 3/4 and an Instrumental Activity Daily Living (IADL) score ≤ 6/8), major neurocognitive disorders (i.e., 3MS score < 79/100 and IADL score < 6/8), hospitalization and mortality were annually recorded over a 3-year follow-up period. RESULTS: 66.8% and 23.6% of participants were classified as pre-frail and frail with CARE respectively, whereas this distribution of frailty states differed with CHS (47.9% and 8.4%). There were significant associations of CARE pre-frail and frail states with all incident adverse health outcomes, the lowest odds ratio (OR) being reported with falls and the highest with cognitive decline (OR ranging from 1.63 to 12.85 with P ≤ 0.032). All ORs of the CARE frailty states were greater than those of the CHS, except for frail participants with IADL decline (OR = 4.92 for CARE versus OR = 9.62 for CHS). CONCLUSIONS: CARE frail states were associated with incident adverse health outcomes and these associations were greater than with CHS, suggesting that the CARE scale is of clinical interest when screening for frailty and related adverse health outcomes in the elderly population.

Patterns of cortical thickness and surface area in early Parkinson's disease.

Idiopathic Parkinson's disease (PD) is a neurodegenerative disorder diagnosed on the basis of motor symptoms, but that also includes cognitive and visuo-spatial deficits. Though PD is known to initially affect subcortical regions, the cortex also exhibits neuronal loss in the course of the disease as post mortem studies have shown. So far, PD-related pattern of cortical damage remains unclear, because of disease-caused heterogeneity, and also in part because of methodological issues such as the limitations of Voxel Based Morphometry. Here corticometry was used, a technique that decouples local surface from thickness, to obtain a better picture of PD corticomorphometric patterns. We acquired MRI volumes for 33 healthy controls (HC) and 49 PD patients, extracted local cortical thickness and surface area and modeled both of them as a function of group and age for each participant. Cortical thickness averaged on the whole cortex did not differ between the two groups while mean surface area was significantly larger in the PD group. The bilateral parietal lobule, the right superior frontal gyrus, the left cingulate cortex and the left insular cortex exhibited larger local surface area in the PD group. The right precuneus exhibited cortical thinning associated with age in the PD group and not in the HC group. Furthermore, cortical thinning was observed in the PD group compared with the control group in the left medial supplementary motor area (SMA) and in the right dorsal pre-SMA. Finally, we found the left temporal pole thickness to correlate with disease duration, as well as the bilateral occipital cortex and Broca's area. These results suggest that PD etiology is associated with specific cortical alterations, which could account for cognitive deficits that arise as the disease evolves. Finally, our results observed in the occipital cortex as a function of disease duration may indicate the increase in PD-related visuo-spatial deficits, which can sometimes result in hallucinations later on in the disease. In the future, MRI-generated corticometry, combined with additional behavioral markers, may prove to be a useful diagnosis tool to characterize the evolution of motor and cognitive deficits in PD.