Evaluating denoising strategies in resting-state functional magnetic resonance in traumatic brain injury (EpiBioS4Rx).

Resting-state functional MRI is increasingly used in the clinical setting and is now included in some diagnostic guidelines for severe brain injury patients. However, to ensure high-quality data, one should mitigate fMRI-related noise typical of this population. Therefore, we aimed to evaluate the ability of different preprocessing strategies to mitigate noise-related signal (i.e., in-scanner movement and physiological noise) in functional connectivity (FC) of traumatic brain injury (TBI) patients. We applied nine commonly used denoising strategies, combined into 17 pipelines, to 88 TBI patients from the Epilepsy Bioinformatics Study for Anti-epileptogenic Therapy clinical trial. Pipelines were evaluated by three quality control (QC) metrics across three exclusion regimes based on the participant's head movement profile. While no pipeline eliminated noise effects on FC, some pipelines exhibited relatively high effectiveness depending on the exclusion regime. Once high-motion participants were excluded, the choice of denoising pipeline becomes secondary - although this strategy leads to substantial data loss. Pipelines combining spike regression with physiological regressors were the best performers, whereas pipelines that used automated data-driven methods performed comparatively worse. In this study, we report the first large-scale evaluation of denoising pipelines aimed at reducing noise-related FC in a clinical population known to be highly susceptible to in-scanner motion and significant anatomical abnormalities. If resting-state functional magnetic resonance is to be a successful clinical technique, it is crucial that procedures mitigating the effect of noise be systematically evaluated in the most challenging populations, such as TBI datasets.

Neural oscillations track recovery of consciousness in acute traumatic brain injury patients.

Electroencephalography (EEG), easily deployed at the bedside, is an attractive modality for deriving quantitative biomarkers of prognosis and differential diagnosis in severe brain injury and disorders of consciousness (DOC). Prior work by Schiff has identified four dynamic regimes of progressive recovery of consciousness defined by the presence or absence of thalamically-driven EEG oscillations. These four predefined categories (ABCD model) relate, on a theoretical level, to thalamocortical integrity and, on an empirical level, to behavioral outcome in patients with cardiac arrest coma etiologies. However, whether this theory-based stratification of patients might be useful as a diagnostic biomarker in DOC and measurably linked to thalamocortical dysfunction remains unknown. In this work, we relate the reemergence of thalamically-driven EEG oscillations to behavioral recovery from traumatic brain injury (TBI) in a cohort of N = 38 acute patients with moderate-to-severe TBI and an average of 1 week of EEG recorded per patient. We analyzed an average of 3.4 hr of EEG per patient, sampled to coincide with 30-min periods of maximal behavioral arousal. Our work tests and supports the ABCD model, showing that it outperforms a data-driven clustering approach and may perform equally well compared to a more parsimonious categorization. Additionally, in a subset of patients (N = 11), we correlated EEG findings with functional magnetic resonance imaging (fMRI) connectivity between nodes in the mesocircuit-which has been theoretically implicated by Schiff in DOC-and report a trend-level relationship that warrants further investigation in larger studies.

EEG Power spectra and subcortical pathology in chronic disorders of consciousness.

BACKGROUND: Despite a growing understanding of disorders of consciousness following severe brain injury, the association between long-term impairment of consciousness, spontaneous brain oscillations, and underlying subcortical damage, and the ability of such information to aid patient diagnosis, remains incomplete. METHODS: Cross-sectional observational sample of 116 patients with a disorder of consciousness secondary to brain injury, collected prospectively at a tertiary center between 2011 and 2013. Multimodal analyses relating clinical measures of impairment, electroencephalographic measures of spontaneous brain activity, and magnetic resonance imaging data of subcortical atrophy were conducted in 2018. RESULTS: In the final analyzed sample of 61 patients, systematic associations were found between electroencephalographic power spectra and subcortical damage. Specifically, the ratio of beta-to-delta relative power was negatively associated with greater atrophy in regions of the bilateral thalamus and globus pallidus (both left > right) previously shown to be preferentially atrophied in chronic disorders of consciousness. Power spectrum total density was also negatively associated with widespread atrophy in regions of the left globus pallidus, right caudate, and in the brainstem. Furthermore, we showed that the combination of demographics, encephalographic, and imaging data in an analytic framework can be employed to aid behavioral diagnosis. CONCLUSIONS: These results ground, for the first time, electroencephalographic presentation detected with routine clinical techniques in the underlying brain pathology of disorders of consciousness and demonstrate how multimodal combination of clinical, electroencephalographic, and imaging data can be employed in potentially mitigating the high rates of misdiagnosis typical of this patient cohort.

Longitudinal changes in blood-based biomarkers in chronic moderate to severe traumatic brain injury: preliminary findings.

Objectives: This longitudinal study aims at 1) providing preliminary evidence of changes in blood-based biomarkers across time in chronic TBI and 2) relating these changes to outcome measures and cerebral structure and activity.Methods: Eight patients with moderate-to-severe TBI (7 males, 35 ± 7.6 years old, 5 severe TBI, 17.52 ± 3.84 months post-injury) were evaluated at monthly intervals across 6 time-points using: a) Blood-based biomarkers (GFAP, NSE, S100A12, SDBP145, UCH-L1, T-tau, P-tau, P-tau/T-tau ratio); b) Magnetic Resonance Imaging to evaluate changes in brain structure; c) Resting-state electroencephalograms to evaluate changes in brain function; and d) Outcome measures to assess cognition, emotion, and functional recovery (MOCA, RBANS, BDI-II, and DRS).Results: Changes in P-tau levels were found across time [p = .007]. P-tau was positively related to functional [p < .001] and cognitive [p = .006] outcomes, and negatively related to the severity of depression, 6 months later [R = -0.901; p =.006]. P-tau and P-tau/T-tau ratio were also positively correlated to shape change in subcortical areas such as brainstem [T(7) = 4.71, p = .008] and putamen [T(7) = 3.25, p = .012].Conclusions: Our study provides preliminary findings that suggest a positive relationship between P-tau and the recovery of patients with chronic TBI.

Early brain biomarkers of post-traumatic seizures: initial report of the multicentre epilepsy bioinformatics study for antiepileptogenic therapy (EpiBioS4Rx) prospective study.

BACKGROUND: Traumatic brain injury (TBI) causes early seizures and is the leading cause of post-traumatic epilepsy. We prospectively assessed structural imaging biomarkers differentiating patients who develop seizures secondary to TBI from patients who do not. DESIGN: Multicentre prospective cohort study starting in 2018. Imaging data are acquired around day 14 post-injury, detection of seizure events occurred early (within 1 week) and late (up to 90 days post-TBI). RESULTS: From a sample of 96 patients surviving moderate-to-severe TBI, we performed shape analysis of local volume deficits in subcortical areas (analysable sample: 57 patients; 35 no seizure, 14 early, 8 late) and cortical ribbon thinning (analysable sample: 46 patients; 29 no seizure, 10 early, 7 late). Right hippocampal volume deficit and inferior temporal cortex thinning demonstrated a significant effect across groups. Additionally, the degree of left frontal and temporal pole thinning, and clinical score at the time of the MRI, could differentiate patients experiencing early seizures from patients not experiencing them with 89% accuracy. CONCLUSIONS AND RELEVANCE: Although this is an initial report, these data show that specific areas of localised volume deficit, as visible on routine imaging data, are associated with the emergence of seizures after TBI.

Memory in repeat sports-related concussive injury and single-impact traumatic brain injury.

Background: Repeat sports-related concussive/subconcussive injury (RC/SCI) is related to memory impairment. Objective & Methods: We sought to determine memory differences between persons with RC/SCI, moderate-to-severe single-impact traumatic brain injury (SI-TBI), and healthy controls. MRI scans from a subsample of participants with SI-TBI were used to identify the neuroanatomical correlates of observed memory process differences between the brain injury groups. Results: Both brain injury groups evidenced worse learning and recall in contrast to controls, although SI-TBI group had poorer memory than the RC/SCI group. Regarding memory process differences, in contrast to controls, the SI-TBI group evidenced difficulties with encoding, consolidation, and retrieval, while the RC/SCI group showed deficits in consolidation and retrieval. Delayed recall was predicted by encoding, with consolidation as a secondary predictor in the SI-TBI group. In the RC/SCI group, delayed recall was only predicted by consolidation. MRI data showed that the consolidation index we used mapped onto hippocampal atrophy. Conclusions: RC/SCI is primarily associated with consolidation deficits, which differs from SI-TBI. Given the role of the hippocampus in memory consolidation and the fact that hyperphosphorylated tau tends to accumulate in the medial temporal lobe in RC/SCI, consolidation deficits may be a cognitive marker of chronic traumatic encephalopathy in athletes.

Early seizures and temporal lobe trauma predict post-traumatic epilepsy: A longitudinal study.

OBJECTIVE: Injury severity after traumatic brain injury (TBI) is a well-established risk factor for the development of post-traumatic epilepsy (PTE). However, whether lesion location influences the susceptibility of seizures and development of PTE longitudinally has yet to be defined. We hypothesized that lesion location, specifically in the temporal lobe, would be associated with an increased incidence of both early seizures and PTE. As secondary analysis measures, we assessed the degree of brain atrophy and functional recovery, and performed a between-group analysis, comparing patients who developed PTE with those who did not develop PTE. METHODS: We assessed early seizure incidence (n = 90) and longitudinal development of PTE (n = 46) in a prospective convenience sample of patients with moderate-severe TBI. Acutely, patients were monitored with prospective cEEG and a high-resolution Magnetic Resonance Imaging (MRI) scan for lesion location classification. Chronically, patients underwent a high-resolution MRI, clinical assessment, and were longitudinally monitored for development of epilepsy for a minimum of 2 years post-injury. RESULTS: Early seizures, occurring within the first week post-injury, occurred in 26.7% of the patients (n = 90). Within the cohort of subjects who had evidence of early seizures (n = 24), 75% had a hemorrhagic temporal lobe injury on admission. For longitudinal analyses (n = 46), 45.7% of patients developed PTE within a minimum of 2 years post-injury. Within the cohort of subjects who developed PTE (n = 21), 85.7% had a hemorrhagic temporal lobe injury on admission and 38.1% had early (convulsive or non-convulsive) seizures on cEEG monitoring during their acute ICU stay. In a between-group analysis, patients with PTE (n = 21) were more likely than patients who did not develop PTE (n = 25) to have a hemorrhagic temporal lobe injury (p < 0.001), worse functional recovery (p = 0.003), and greater temporal lobe atrophy (p = 0.029). CONCLUSION: Our results indicate that in a cohort of patients with a moderate-severe TBI, 1) lesion location specificity (e.g. the temporal lobe) is related to both a high incidence of early seizures and longitudinal development of PTE, 2) early seizures, whether convulsive or non-convulsive in nature, are associated with an increased risk for PTE development, and 3) patients who develop PTE have greater chronic temporal lobe atrophy and worse functional outcomes, compared to those who do not develop PTE, despite matched injury severity characteristics. This study provides the foundation for a future prospective study focused on elucidating the mechanisms and risk factors for epileptogenesis.

Restoration of thalamo-cortical connectivity after brain injury: recovery of consciousness, complex behavior, or passage of time?

In 2000, a landmark case report described the concurrent restoration of consciousness and thalamo-frontal connectivity after severe brain injury (Laureys et al., ). Being a single case however, this study could not disambiguate whether the result was specific to the restoration of consciousness per se as opposed to the return of complex cognitive function in general or simply the temporal evolution of post-injury pathophysiological events. To test whether the restoration of thalamo-cortical connectivity is specific to consciousness, 20 moderate-to-severe brain injury patients (from a recruited sample of 42) underwent resting-state functional magnetic resonance imaging within a week after injury and again six months later. As described in the single case report, we find thalamo-frontal connectivity to be increased at the chronic, compared with the acute, time-point. The increased connectivity was independent of whether patients had already recovered consciousness prior to the first assessment or whether they recovered consciousness in-between the two. Conversely, we did find an association between restoration of thalamo-frontal connectivity and the return of complex cognitive function. While we did replicate the findings of Laureys et al. (), our data suggests that the restoration of thalamo-frontal connectivity is not as tightly linked to the reemergence of consciousness per se. However, the degree to which the return of connectivity is linked to the return of complex cognitive function, or to the evolution of other time-dependent post-injury mechanisms, remains to be understood.

Testing Proposed Neuronal Models of Effective Connectivity Within the Cortico-basal Ganglia-thalamo-cortical Loop During Loss of Consciousness.

In recent years, a number of brain regions and connectivity patterns have been proposed to be crucial for loss and recovery of consciousness but have not been compared in detail. In a 3 T resting-state functional magnetic resonance imaging paradigm, we test the plausibility of these different neuronal models derived from theoretical and empirical knowledge. Specifically, we assess the fit of each model to the dynamic change in effective connectivity between specific cortical and subcortical regions at different consecutive levels of propofol-induced sedation by employing spectral dynamic causal modeling. Surprisingly, our findings indicate that proposed models of impaired consciousness do not fit the observed patterns of effective connectivity. Rather, the data show that loss of consciousness, at least in the context of propofol-induced sedation, is marked by a breakdown of corticopetal projections from the globus pallidus. Effective connectivity between the globus pallidus and the ventral posterior cingulate cortex, present during wakefulness, fades in the transition from lightly sedated to full loss of consciousness and returns gradually as consciousness recovers, thereby, demonstrating the dynamic shift in brain architecture of the posterior cingulate "hub" during changing states of consciousness. These findings highlight the functional role of a previously underappreciated direct pallido-cortical connectivity in supporting consciousness.

Disentangling disorders of consciousness: Insights from diffusion tensor imaging and machine learning.

Previous studies have suggested that disorders of consciousness (DOC) after severe brain injury may result from disconnections of the thalamo-cortical system. However, thalamo-cortical connectivity differences between vegetative state (VS), minimally conscious state minus (MCS-, i.e., low-level behavior such as visual pursuit), and minimally conscious state plus (MCS+, i.e., high-level behavior such as language processing) remain unclear. Probabilistic tractography in a sample of 25 DOC patients was employed to assess whether structural connectivity in various thalamo-cortical circuits could differentiate between VS, MCS-, and MCS+ patients. First, the thalamus was individually segmented into seven clusters based on patterns of cortical connectivity and tested for univariate differences across groups. Second, reconstructed whole-brain thalamic tracks were used as features in a multivariate searchlight analysis to identify regions along the tracks that were most informative in distinguishing among groups. At the univariate level, it was found that VS patients displayed reduced connectivity in most thalamo-cortical circuits of interest, including frontal, temporal, and sensorimotor connections, as compared with MCS+, but showed more pulvinar-occipital connections when compared with MCS-. Moreover, MCS- exhibited significantly less thalamo-premotor and thalamo-temporal connectivity than MCS+. At the multivariate level, it was found that thalamic tracks reaching frontal, parietal, and sensorimotor regions, could discriminate, up to 100% accuracy, across each pairwise group comparison. Together, these findings highlight the role of thalamo-cortical connections in patients' behavioral profile and level of consciousness. Diffusion tensor imaging combined with machine learning algorithms could thus potentially facilitate diagnostic distinctions in DOC and shed light on the neural correlates of consciousness. Hum Brain Mapp 38:431-443, 2017. © 2016 Wiley Periodicals, Inc.

Thalamic and extrathalamic mechanisms of consciousness after severe brain injury.

OBJECTIVE: What mechanisms underlie the loss and recovery of consciousness after severe brain injury? We sought to establish, in the largest cohort of patients with disorders of consciousness (DOC) to date, the link between gold standard clinical measures of awareness and wakefulness, and specific patterns of local brain pathology-thereby possibly providing a mechanistic framework for patient diagnosis, prognosis, and treatment development. METHODS: Structural T1-weighted magnetic resonance images were collected, in a continuous sample of 143 severely brain-injured patients with DOC (and 96 volunteers), across 2 tertiary expert centers. Brain atrophy in subcortical regions (bilateral thalamus, basal ganglia, hippocampus, basal forebrain, and brainstem) was assessed across (1) healthy volunteers and patients, (2) clinical entities (eg, vegetative state, minimally conscious state), (3) clinical measures of consciousness (Coma Recovery Scale-Revised), and (4) injury etiology. RESULTS: Compared to volunteers, patients exhibited significant atrophy across all structures (p < 0.05, corrected). Strikingly, we found almost no significant differences across clinical entities. Nonetheless, the clinical measures of awareness and wakefulness upon which differential diagnosis rely were systematically associated with tissue atrophy within thalamic and basal ganglia nuclei, respectively; the basal forebrain was atrophied in proportion to patients' response to sensory stimulation. In addition, nontraumatic injuries exhibited more extensive thalamic atrophy. INTERPRETATION: These findings provide, for the first time, a grounding in pathology for gold standard behavior-based clinical measures of consciousness, and reframe our current models of DOC by stressing the different links tying thalamic mechanisms to willful behavior and extrathalamic mechanisms to behavioral (and electrocortical) arousal.

Dynamic change of global and local information processing in propofol-induced loss and recovery of consciousness.

Whether unique to humans or not, consciousness is a central aspect of our experience of the world. The neural fingerprint of this experience, however, remains one of the least understood aspects of the human brain. In this paper we employ graph-theoretic measures and support vector machine classification to assess, in 12 healthy volunteers, the dynamic reconfiguration of functional connectivity during wakefulness, propofol-induced sedation and loss of consciousness, and the recovery of wakefulness. Our main findings, based on resting-state fMRI, are three-fold. First, we find that propofol-induced anesthesia does not bear differently on long-range versus short-range connections. Second, our multi-stage design dissociated an initial phase of thalamo-cortical and cortico-cortical hyperconnectivity, present during sedation, from a phase of cortico-cortical hypoconnectivity, apparent during loss of consciousness. Finally, we show that while clustering is increased during loss of consciousness, as recently suggested, it also remains significantly elevated during wakefulness recovery. Conversely, the characteristic path length of brain networks (i.e., the average functional distance between any two regions of the brain) appears significantly increased only during loss of consciousness, marking a decrease of global information-processing efficiency uniquely associated with unconsciousness. These findings suggest that propofol-induced loss of consciousness is mainly tied to cortico-cortical and not thalamo-cortical mechanisms, and that decreased efficiency of information flow is the main feature differentiating the conscious from the unconscious brain.

Structural and functional neuroimaging phenotypes in dysbindin mutant mice.

Schizophrenia is a highly heritable psychiatric disorder that is associated with a number of structural and functional neurophenotypes. DTNBP1, the gene encoding dysbindin-1, is a promising candidate gene for schizophrenia. Use of a mouse model carrying a large genomic deletion exclusively within the dysbindin gene permits a direct investigation of the gene in isolation. Here, we use manganese-enhanced magnetic resonance imaging (MEMRI) to explore the regional alterations in brain structure and function caused by loss of the gene encoding dysbindin-1. We report novel findings that uniquely inform our understanding of the relationship of dysbindin-1 to known schizophrenia phenotypes. First, in mutant mice, analysis of the rate of manganese uptake into the brain over a 24-hour period, putatively indexing basal cellular activity, revealed differences in dopamine rich brain regions, as well as in CA1 and dentate subregions of the hippocampus formation. Finally, novel tensor-based morphometry techniques were applied to the mouse MRI data, providing evidence for structural volume deficits in cortical regions, subiculum and dentate gyrus, and the striatum of dysbindin mutant mice. The affected cortical regions were primarily localized to the sensory cortices in particular the auditory cortex. This work represents the first application of manganese-enhanced small animal imaging to a mouse model of schizophrenia endophenotypes, and a novel combination of functional and structural measures. It revealed both hypothesized and novel structural and functional neural alterations related to dysbindin-1.

Ultrasonic Deep Brain Neuromodulation in Acute Disorders of Consciousness: A Proof-of-Concept.

The promotion of recovery in patients who have entered a disorder of consciousness (DOC; e.g., coma or vegetative states) following severe brain injury remains an enduring medical challenge despite an ever-growing scientific understanding of these conditions. Indeed, recent work has consistently implicated altered cortical modulation by deep brain structures (e.g., the thalamus and the basal ganglia) following brain damage in the arising of, and recovery from, DOCs. The (re)emergence of low-intensity focused ultrasound (LIFU) neuromodulation may provide a means to selectively modulate the activity of deep brain structures noninvasively for the study and treatment of DOCs. This technique is unique in its combination of relatively high spatial precision and noninvasive implementation. Given the consistent implication of the thalamus in DOCs and prior results inducing behavioral recovery through invasive thalamic stimulation, here we applied ultrasound to the central thalamus in 11 acute DOC patients, measured behavioral responsiveness before and after sonication, and applied functional MRI during sonication. With respect to behavioral responsiveness, we observed significant recovery in the week following thalamic LIFU compared with baseline. With respect to functional imaging, we found decreased BOLD signals in the frontal cortex and basal ganglia during LIFU compared with baseline. In addition, we also found a relationship between altered connectivity of the sonicated thalamus and the degree of recovery observed post-LIFU.

Sedation-Induced Burst Suppression Predicts Positive Outcome Following Traumatic Brain Injury.

While electroencephalogram (EEG) burst-suppression is often induced therapeutically using sedatives in the intensive care unit (ICU), there is hitherto no evidence with respect to its association to outcome in moderate-to-severe neurological patients. We examined the relationship between sedation-induced burst-suppression (SIBS) and outcome at hospital discharge and at 6-month follow up in patients surviving moderate-to-severe traumatic brain injury (TBI). For each of 32 patients recovering from coma after moderate-to-severe TBI, we measured the EEG burst suppression ratio (BSR) during periods of low responsiveness as assessed with the Glasgow Coma Scale (GCS). The maximum BSR was then used to predict the Glasgow Outcome Scale extended (GOSe) at discharge and at 6 months post-injury. A multi-model inference approach was used to assess the combination of predictors that best fit the outcome data. We found that BSR was positively associated with outcomes at 6 months (P = 0.022) but did not predict outcomes at discharge. A mediation analysis found no evidence that BSR mediates the effects of barbiturates or propofol on outcomes. Our results provide initial observational evidence that burst suppression may be neuroprotective in acute patients with TBI etiologies. SIBS may thus be useful in the ICU as a prognostic biomarker.

Subcortical atrophy correlates with the perturbational complexity index in patients with disorders of consciousness.

BACKGROUND: The complexity of neurophysiological brain responses to direct cortical stimulation, referred to as the perturbational complexity index (PCI), has been shown able to discriminate between consciousness and unconsciousness in patients surviving severe brain injury as well as several other conditions (e.g., wake, dreamless sleep, sleep and ketamine dreaming, anesthesia). OBJECTIVE: This study asks whether, in patients with a disorder of consciousness (DOC), the complexity of the neurophysiological response to cortical stimulation is preferentially associated with atrophy within specific brain structures. METHODS: We perform a retrospective analysis of 40 DOC patients and correlate their maximal PCI to MR-based measurements of cortical thinning and subcortical atrophy. RESULTS: PCI was systematically and inversely associated with the degree of local atrophy within the globus pallidus, a region previously linked to electrocortical and behavioral arousal. Conversely, we fail to detect any association between variance in cortical ribbon thickness and PCI. CONCLUSION: These findings corroborate the previously reported association between pallidal atrophy and low behavioral arousal and suggest that this region's role in maintaining the overall balance of excitation and inhibition may critically affect the emergence of complex cortical interactions in chronic disorders of consciousness. This finding thus also suggests a target for potential neuromodulatory intervention in DOC patients.

A systematic investigation of the association between network dynamics in the human brain and the state of consciousness.

An increasing amount of studies suggest that brain dynamics measured with resting-state functional magnetic resonance imaging (fMRI) are related to the state of consciousness. However, the challenge of investigating neuronal correlates of consciousness is the confounding interference between (recovery of) consciousness and behavioral responsiveness. To address this issue, and validate the interpretation of prior work linking brain dynamics and consciousness, we performed a longitudinal fMRI study in patients recovering from coma. Patients were assessed twice, 6 months apart, and assigned to one of two groups. One group included patients who were unconscious at the first assessment but regained consciousness and improved behavioral responsiveness by the second assessment. The other group included patients who were already conscious and improved only behavioral responsiveness. While the two groups were matched in terms of the average increase in behavioral responsiveness, only one group experienced a categorical change in their state of consciousness allowing us to partially dissociate consciousness and behavioral responsiveness. We find the variance in network metrics to be systematically different across states of consciousness, both within and across groups. Specifically, at the first assessment, conscious patients exhibited significantly greater variance in network metrics than unconscious patients, a difference that disappeared once all patients had recovered consciousness. Furthermore, we find a significant increase in dynamics for patients who regained consciousness over time, but not for patients who only improved responsiveness. These findings suggest that changes in brain dynamics are indeed linked to the state of consciousness and not just to a general level of behavioral responsiveness.

Multiplex Networks to Characterize Seizure Development in Traumatic Brain Injury Patients.

Traumatic brain injury (TBI) may cause secondary debilitating problems, such as post-traumatic epilepsy (PTE), which occurs with unprovoked recurrent seizures, months or even years after TBI. Currently, the Epilepsy Bioinformatics Study for Antiepileptogenic Therapy (EpiBioS4Rx) has been enrolling moderate-severe TBI patients with the goal to identify biomarkers of epileptogenesis that may help to prevent seizure occurrence and better understand the mechanism underlying PTE. In this work, we used a novel complex network approach based on segmenting T1-weighted Magnetic Resonance Imaging (MRI) scans in patches of the same dimension (network nodes) and measured pairwise patch similarities using Pearson's correlation (network connections). This network model allowed us to obtain a series of single and multiplex network metrics to comprehensively analyze the different interactions between brain components and capture structural MRI alterations related to seizure development. We used these complex network features to train a Random Forest (RF) classifier and predict, with an accuracy of 70 and a 95% confidence interval of [67, 73%], which subjects from EpiBioS4Rx have had at least one seizure after a TBI. This complex network approach also allowed the identification of the most informative scales and brain areas for the discrimination between the two clinical groups: seizure-free and seizure-affected subjects, demonstrating to be a promising pilot study which, in the future, may serve to identify and validate biomarkers of PTE.

The subcortical basis of outcome and cognitive impairment in TBI: A longitudinal cohort study.

OBJECTIVE: To understand how, biologically, the acute event of traumatic brain injury gives rise to a long-term disease, we address the relationship between evolving cortical and subcortical brain damage and measures of functional outcome and cognitive functioning at 6 months after injury. METHODS: For this longitudinal analysis, clinical and MRI data were collected in a tertiary neurointensive care setting in a continuous sample of 157 patients surviving moderate to severe traumatic brain injury between 2000 and 2018. For each patient, we collected T1- and T2-weighted MRI data acutely and at the 6-month follow-up, as well as acute measures of injury severity (Glasgow Coma Scale), follow-up measures of functional impairment (Glasgow Outcome Scale-extended), and, in a subset of patients, neuropsychological measures of attention, executive functions, and episodic memory. RESULTS: In the final cohort of 113 subcortical and 92 cortical datasets that survived (blind) quality control, extensive atrophy was observed over the first 6 months after injury across the brain. However, only atrophy within subcortical regions, particularly in the left thalamus, was associated with functional outcome and neuropsychological measures of attention, executive functions, and episodic memory. Furthermore, when brought together in an analytical model, longitudinal brain measurements could distinguish good from bad outcome with 90% accuracy, whereas acute brain and clinical measurements alone could achieve only 20% accuracy. CONCLUSION: Despite great injury heterogeneity, secondary thalamic pathology is a measurable minimum common denominator mechanism directly relating biology to clinical measures of outcome and cognitive functioning, potentially linking the acute event and the longer-term disease of traumatic brain injury.