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The mismatch negativity (MMN) is considered the electrophysiological change-detection response of the brain, and therefore a valuable clinical tool for monitoring functional changes associated with return to consciousness after severe brain injury. Using an auditory multi-deviant oddball paradigm, we tracked auditory MMN responses in seventeen healthy controls over a 12-h period, and in three comatose patients assessed over 24 h at two time points. We investigated whether the MMN responses show fluctuations in detectability over time in full conscious awareness, or whether such fluctuations are rather a feature of coma. Three methods of analysis were utilized to determine whether the MMN and subsequent event-related potential (ERP) components could be identified: traditional visual analysis, permutation t-test, and Bayesian analysis. The results showed that the MMN responses elicited to the duration deviant-stimuli are elicited and reliably detected over the course of several hours in healthy controls, at both group and single-subject levels. Preliminary findings in three comatose patients provide further evidence that the MMN is often present in coma, varying within a single patient from easily detectable to undetectable at different times. This highlights the fact that regular and repeated assessments are extremely important when using MMN as a neurophysiological predictor of coma emergence.

IntroductionPrevious case-control studies of sudden unexpected death in epilepsy (SUDEP) patients failed to identify ECG features (peri-ictal heart rate, heart rate variability, corrected QT interval, postictal heart rate recovery, and cardiac rhythm) predictive of SUDEP risk. This implied a need to derive novel metrics to assess SUDEP risk from ECG.MethodsWe applied Single Spectrum Analysis and Independent Component Analysis (SSA-ICA) to remove artifact from ECG recordings. Then cross-frequency phase-phase coupling (PPC) was applied to a 20-s mid-seizure window and a contour of −3 dB coupling strength was determined. The contour centroid polar coordinates, amplitude (alpha) and angle (theta), were calculated. Association of alpha and theta with SUDEP was assessed and a logistic classifier for alpha was constructed.ResultsAlpha was higher in SUDEP patients, compared to non-SUDEP patients (p < 0.001). Theta showed no significant difference between patient populations. The receiver operating characteristic (ROC) of a logistic classifier for alpha resulted in an area under the ROC curve (AUC) of 94% and correctly classified two test SUDEP patients.DiscussionThis study develops a novel metric alpha, which highlights non-linear interactions between two rhythms in the ECG, and is predictive of SUDEP risk.

BackgroundConducting clinical trials for traumatic spinal cord injury (tSCI) presents challenges due to patient heterogeneity. Identifying clinically similar subgroups using patient demographics and baseline injury characteristics could lead to better patient-centered care and integrated care delivery.PurposeWe sought to (1) apply an unsupervised machine learning approach of cluster analysis to identify subgroups of tSCI patients using patient demographics and injury characteristics at baseline, (2) to find clinical similarity within subgroups using etiological variables and outcome variables, and (3) to create multi-dimensional labels for categorizing patients.Study designRetrospective analysis using prospectively collected data from a large national multicenter SCI registry.MethodsA method of spectral clustering was used to identify patient subgroups based on the following baseline variables collected since admission until rehabilitation: location of the injury, severity of the injury, Functional Independence Measure (FIM) motor, and demographic data (age, and body mass index). The FIM motor score, the FIM motor score change, and the total length of stay were assessed on the subgroups as outcome variables at discharge to establish the clinical similarity of the patients within derived subgroups. Furthermore, we discussed the relevance of the identified subgroups based on the etiological variables (energy and mechanism of injury) and compared them with the literature. Our study also employed a qualitative approach to systematically describe the identified subgroups, crafting multi-dimensional labels to highlight distinguishing factors and patient-focused insights.ResultsData on 334 tSCI patients from the Rick Hansen Spinal Cord Injury Registry was analyzed. Five significantly different subgroups were identified (p-value ≤0.05) based on baseline variables. Outcome variables at discharge superimposed on these subgroups had statistically different values between them (p-value ≤0.05) and supported the notion of clinical similarity of patients within each subgroup.ConclusionUtilizing cluster analysis, we identified five clinically similar subgroups of tSCI patients at baseline, yielding statistically significant inter-group differences in clinical outcomes. These subgroups offer a novel, data-driven categorization of tSCI patients which aligns with their demographics and injury characteristics. As it also correlates with traditional tSCI classifications, this categorization could lead to improved personalized patient-centered care.

Background: Spinal and Bulbar Muscular Atrophy (SBMA) is caused by the extension of the polyglutamine tract within the androgen receptor (AR) gene, and results in a multisystem presentation, including the degeneration of lower motor neurons. The androgen receptor (AR) is known to modulate the expression of endogenous retrovirus-K (ERVK), a pathogenic viral genomic symbiont. Since ERVK is associated with motor neuron disease, such as Amyotrophic Lateral Sclerosis (ALS), we sought to determine if patients with SBMA exhibit evidence of ERVK reactivation. Results: Data from a pilot study demonstrate that peripheral blood mononuclear cell (PBMC) samples from controls and patients with SBMA were examined ex vivo for the expression of ERVK viral transcripts and proteins. No differences in ERVK RNA expression was observed between the clinical groups. In contrast, enhancement of processed ERVK Gag and integrase proteins were observed in SBMA-derived PBMC as compared to healthy control specimens. Increased ERVK protein maturation co-occurred with elevation in the expression of the pro-inflammatory transcription factor IRF1 in SBMA. Conclusions: Our findings indicate that ERVK viral protein maturation in SBMA is an unrecognized biomarker and facet of the disease. We discuss how our current understanding of ERVK-driven pathology may tie into key aspects of multi-system dysfunction in SBMA, with a focus on inflammation, proteinopathy, as well as DNA damage and repair.

ObjectiveVascular comorbidities are associated with reduced cognitive performance and with changes in brain structure in people with multiple sclerosis (MS). Understanding causal pathways is necessary to support the design of interventions to mitigate the impacts of comorbidities, and to monitor their effectiveness. We assessed the inter-relationships among vascular comorbidity, cognition and brain structure in people with MS.MethodsAdults with neurologist-confirmed MS reported comorbidities, and underwent assessment of their blood pressure, HbA1c, and cognitive functioning (i.e., Symbol Digit Modalities Test, California Verbal Learning Test, Brief Visuospatial Memory Test-Revised, and verbal fluency). Test scores were converted to age-, sex-, and education-adjusted z-scores. Whole brain magnetic resonance imaging (MRI) was completed, from which measures of thalamic and hippocampal volumes, and mean diffusivity of gray matter and normal-appearing white matter were converted to age and sex-adjusted z-scores. Canonical correlation analysis was used to identify linear combinations of cognitive measures (cognitive variate) and MRI measures (MRI variate) that accounted for the most correlation between the cognitive and MRI measures. Regression analyses were used to test whether MRI measures mediated the relationships between the number of vascular comorbidities and cognition measures.ResultsOf 105 participants, most were women (84.8%) with a mean (SD) age of 51.8 (12.8) years and age of symptom onset of 29.4 (10.5) years. Vascular comorbidity was common, with 35.2% of participants reporting one, 15.2% reporting two, and 8.6% reporting three or more. Canonical correlation analysis of the cognitive and MRI variables identified one pair of variates (Pillai's trace = 0.45, p = 0.0035). The biggest contributors to the cognitive variate were the SDMT and CVLT-II, and to the MRI variate were gray matter MD and thalamic volume. The correlation between cognitive and MRI variates was 0.50; these variates were used in regression analyses. On regression analysis, vascular comorbidity was associated with the MRI variate, and with the cognitive variate. After adjusting for the MRI variate, vascular comorbidity was not associated with the cognitive variate.ConclusionVascular comorbidity is associated with lower cognitive function in people with MS and this association is partially mediated via changes in brain macrostructure and microstructure.

BackgroundFifty-one percent of individuals with multiple sclerosis (MS) develop cognitive impairment (CI) in information processing speed (IPS). Although IPS scores are associated with health and well-being, neural changes that underlie IPS impairments in MS are not understood. Resting state fMRI can provide insight into brain function changes underlying impairment in persons with MS.ObjectivesWe aimed to assess functional connectivity (FC) differences in (i) persons with MS compared to healthy controls (HC), (ii) persons with both MS and CI (MS-CI) compared to HC, (iii) persons with MS that are cognitively preserved (MS-CP) compared to HC, (iv) MS-CI compared to MS-CP, and (v) in relation to cognition within the MS group.MethodsWe included 107 participants with MS (age 49.5 ± 12.9, 82% women), and 94 controls (age 37.9 ± 15.4, 66% women). Each participant was administered the Symbol Digit Modalities Test (SDMT) and underwent a resting state fMRI scan. The MS-CI group was created by applying a z-score cut-off of ≤−1.5 to locally normalized SDMT scores. The MS-CP group was created by applying a z-score of ≥0. Control groups (HCMS-CI and HCMS-CP) were based on the nearest age-matched HC participants. A whole-brain ROI-to-ROI analysis was performed followed by specific contrasts and a regression analysis.ResultsIndividuals with MS showed FC differences compared to HC that involved the cerebellum, visual and language-associated brain regions, and the thalamus, hippocampus, and basal ganglia. The MS-CI showed FC differences compared to HCMS-CI that involved the cerebellum, visual and language-associated areas, thalamus, and caudate. SDMT scores were correlated with FC between the cerebellum and lateral occipital cortex in MS. No differences were observed between the MS-CP and HCMS-CP or MS-CI and MS-CP groups.ConclusionOur findings emphasize FC changes of cerebellar, visual, and language-associated areas in persons with MS. These differences were apparent for (i) all MS participants compared to HC, (ii) MS-CI subgroup and their matched controls, and (iii) the association between FC and SDMT scores within the MS group. Our findings strongly suggest that future work that examines the associations between FC and IPS impairments in MS should focus on the involvement of these regions.

Children and adolescents have the highest rates of traumatic brain injury (TBI), with mild TBI (mTBI) accounting for most of these injuries. This demographic also often suffers from post-injury symptomologies that may persist for months. Telomere length (TL) has previously been used as a marker for outcomes following repetitive mild TBI (RmTBI) and it may be possible that telomere elongation can reduce post-traumatic behavioral impairments. Telomerase activator-65 (TA-65) is a telomerase small-molecule activator purified from the root of Chinese herbs that has been anecdotally reported to have anti-aging and life-extending potential. We hypothesized that RmTBI would shorten TL but administration of TA-65 would reverse RmTBI-induced telomere shortening and behavioral deficits. Male and female Sprague-Dawley rats were orally administered TA-65 or a placebo substance for 30 consecutive days [postnatal day (P) 25-55]. Following the injury protocol (mTBIs on P33, 36, and 40), rats went through a behavioral test battery designed to examine symptomologies commonly associated with mTBI (balance and motor coordination, exploratory behavior, short-term working memory, and anxiety- and depressive-like behaviors). TL in ear and brain tissue (prefrontal cortex and hippocampus) and relative expression of