Case report: A novel CACNA1S mutation associated with hypokalemic periodic paralysis.

Background: Hypokalemic periodic paralysis (HypoKPP) is a rare neuromuscular genetic disorder causing recurrent episodes of flaccid paralysis. Most cases are associated with CACNA1S mutation, causing defect of calcium channel and subsequent impairment of muscle functions. Due to defined management approaches early diagnosis is crucial for promptly treatment and prevention new attacks. Materials and methods: We report a case of HypoKPP associated with previously unreported mutation in CACNA1S gene (p.R900M). Molecular modeling of CaV1.1 was applied to evaluate its pathogenicity. Results: As a patient referred between attacks neurological status, laboratory and neurophysiological examination were unremarkable. Molecular modeling predicted that the p.R900M mutation affects the process of calcium channels activation. Conclusion: Novel CACNA1S mutation, associated with HypoKPP was identified. Monte-Carlo energy minimization of the CaV1.1 model supported the association of this mutation with this disease.

Detecting the Potential for Consciousness in Unresponsive Patients Using the Perturbational Complexity Index.

The difficulties of behavioral evaluation of prolonged disorders of consciousness (DOC) motivate the development of brain-based diagnostic approaches. The perturbational complexity index (PCI), which measures the complexity of electroencephalographic (EEG) responses to transcranial magnetic stimulation (TMS), showed a remarkable sensitivity in detecting minimal signs of consciousness in previous studies. Here, we tested the reliability of PCI in an independently collected sample of 24 severely brain-injured patients, including 11 unresponsive wakefulness syndrome (UWS), 12 minimally conscious state (MCS) patients, and 1 emergence from MCS patient. We found that the individual maximum PCI value across stimulation sites fell within the consciousness range (i.e., was higher than PCI*, which is an empirical cutoff previously validated on a benchmark population) in 11 MCS patients, yielding a sensitivity of 92% that surpassed qualitative evaluation of resting EEG. Most UWS patients (n = 7, 64%) showed a slow and stereotypical TMS-EEG response, associated with low-complexity PCI values (i.e., ≤PCI*). Four UWS patients (36%) provided high-complexity PCI values, which might suggest a covert capacity for consciousness. In conclusion, this study successfully replicated the performance of PCI in discriminating between UWS and MCS patients, further motivating the application of TMS-EEG in the workflow of DOC evaluation.

Brain Activations and Functional Connectivity Patterns Associated with Insight-Based and Analytical Anagram Solving.

Insight is one of the most mysterious problem-solving phenomena involving the sudden emergence of a solution, often preceded by long unproductive attempts to find it. This seemingly unexplainable generation of the answer, together with the role attributed to insight in the advancement of science, technology and culture, stimulate active research interest in discovering its neuronal underpinnings. The present study employs functional Magnetic resonance imaging (fMRI) to probe and compare the brain activations occurring in the course of solving anagrams by insight or analytically, as judged by the subjects. A number of regions were activated in both strategies, including the left premotor cortex, left claustrum, and bilateral clusters in the precuneus and middle temporal gyrus. The activated areas span the majority of the clusters reported in a recent meta-analysis of insight-related fMRI studies. At the same time, the activation patterns were very similar between the insight and analytical solutions, with the only difference in the right sensorimotor region probably explainable by subject motion related to the study design. Additionally, we applied resting-state fMRI to study functional connectivity patterns correlated with the individual frequency of insight anagram solutions. Significant correlations were found for the seed-based connectivity of areas in the left premotor cortex, left claustrum, and left frontal eye field. The results stress the need for optimizing insight paradigms with respect to the accuracy and reliability of the subjective insight/analytical solution classification. Furthermore, the short-lived nature of the insight phenomenon makes it difficult to capture the associated neural events with the current experimental techniques and motivates complementing such studies by the investigation of the structural and functional brain features related to the individual differences in the frequency of insight-based decisions.

Accuracy of Estimating the Area of Cortical Muscle Representations from TMS Mapping Data Using Voronoi Diagrams.

Motor evoked potentials (MEPs) caused by transcranial magnetic stimulation (TMS) provide a possibility of noninvasively mapping cortical muscle representations for clinical and research purposes. The interpretation of such results is complicated by the high variability in MEPs and the lack of a standard optimal mapping protocol. Comparing protocols requires the determination of the accuracy of estimated representation parameters (such as the area), which is problematic without ground truth data. We addressed this problem and obtained two main results: (1) the development of a bootstrapping-based approach for estimating the within-session variability and bias of representation parameters and (2) estimations of the area and amplitude-weighted area accuracies for motor representations using this approach. The method consists in the simulation of TMS mapping results by subsampling MEPs from a single map with a large number of stimuli. We studied the extensor digitorum communis (EDC) and flexor digitorum superficialis (FDS) muscle maps of 15 healthy subjects processed using Voronoi diagrams. We calculated the (decreasing) dependency of the errors in the area and weighted area on the number of stimuli. This result can be used to choose a number of stimuli sufficient for studying the effects of a given size (e.g., the protocol with 150 stimuli leads to relative errors of 7% for the area and 11% for the weighted area in 90% of the maps). The approach is applicable to other parameters (e.g., the center of gravity) and other map processing methods, such as spline interpolation.

Feasibility of Non-Gaussian Diffusion Metrics in Chronic Disorders of Consciousness.

Diagnostic accuracy of different chronic disorders of consciousness (DOC) can be affected by the false negative errors in up to 40% cases. In the present study, we aimed to investigate the feasibility of a non-Gaussian diffusion approach in chronic DOC and to estimate a sensitivity of diffusion kurtosis imaging (DKI) metrics for the differentiation of vegetative state/unresponsive wakefulness syndrome (VS/UWS) and minimally conscious state (MCS) from a healthy brain state. We acquired diffusion MRI data from 18 patients in chronic DOC (11 VS/UWS, 7 MCS) and 14 healthy controls. A quantitative comparison of the diffusion metrics for grey (GM) and white (WM) matter between the controls and patient group showed a significant (p < 0.05) difference in supratentorial WM and GM for all evaluated diffusion metrics, as well as for brainstem, corpus callosum, and thalamus. An intra-subject VS/UWS and MCS group comparison showed only kurtosis metrics and fractional anisotropy differences using tract-based spatial statistics, owing mainly to macrostructural differences on most severely lesioned hemispheres. As a result, we demonstrated an ability of DKI metrics to localise and detect changes in both WM and GM and showed their capability in order to distinguish patients with a different level of consciousness.

Optimization of the Navigated TMS Mapping Algorithm for Accurate Estimation of Cortical Muscle Representation Characteristics.

Navigated transcranial magnetic stimulation (nTMS) mapping of cortical muscle representations allows noninvasive assessment of the state of a healthy or diseased motor system, and monitoring changes over time. These applications are hampered by the heterogeneity of existing mapping algorithms and the lack of detailed information about their accuracy. We aimed to find an optimal motor evoked potential (MEP) sampling scheme in the grid-based mapping algorithm in terms of the accuracy of muscle representation parameters. The abductor pollicis brevis (APB) muscles of eight healthy subjects were mapped three times on consecutive days using a seven-by-seven grid with ten stimuli per cell. The effect of the MEP variability on the parameter accuracy was assessed using bootstrapping. The accuracy of representation parameters increased with the number of stimuli without saturation up to at least ten stimuli per cell. The detailed sampling showed that the between-session representation area changes in the absence of interventions were significantly larger than the within-session fluctuations and thus could not be explained solely by the trial-to-trial variability of MEPs. The results demonstrate that the number of stimuli has no universally optimal value and must be chosen by balancing the accuracy requirements with the mapping time constraints in a given problem.

A Russian validation study of the Coma Recovery Scale-Revised (CRS-R).

INTRODUCTION: The aim of the study was to develop and validate a Russian adaptation of the Coma Recovery Scale-Revised (CRS-R). SUBJECTS AND METHODS: We evaluated 58 patients with chronic disorders of consciousness (> 4 weeks post-injury, DOC) of various etiology and two patients in a locked-in state at different stages after coma. We tested sensitivity for changes over 1 week, reliability, criterion validity and diagnostic sensitivity of the Russian adaptation of the CRS-R in comparison with the Russian adaptations of Full Outline of UnResponsiveness Score (FOUR), and Glasgow Coma Scale (GCS). RESULTS: We obtained good sensitivity for changes in neurological status over week (p < 0.0001) and good test-retest reliability (r = 0.997, p < 0.0001) of the CRS-R. Inter-rater reliability was good (κ = 0.99, p < 0.001). We showed high internal consistency (α = 0.87) of the scale and good criterion validity between other scales (r = 0.597 for GCS, and r = 0.900 for FOUR). CRS-R also demonstrated a higher sensitivity in differential diagnosis of DOC, as compared to GCS, and FOUR Score (p < 0.001). CONCLUSION: The results show that the Russian version of the CRS-R is a valid and sensitive tool for the evaluation of patients with chronic DOC, which can be used for differential diagnosis and for recovery assessment.

Degrees of functional connectome abnormality in disorders of consciousness.

Understanding the neuronal basis of disorders of consciousness can help improve the accuracy of their diagnosis, indicate potential targets for therapeutic interventions, and provide insights into the organization of normal conscious information processing. Measurements of brain activity have been used to find associations of the levels of consciousness with brain complexity, topological features of functional connectomes, and disruption of resting-state networks. However, obtainment of a detailed picture of activity patterns underlying the vegetative state/unresponsive wakefulness syndrome and the minimally conscious state remains a work in progress. We here aimed at finding the aspects of fMRI-based functional connectivity that differentiate these states from each other and from the normal condition. A group of 22 patients was studied (9 minimally conscious state and 13 vegetative state/unresponsive wakefulness syndrome). Patients were shown to have reduced connectivity in most resting-state networks and disrupted patterns of relative connection strengths as compared to healthy subjects. Differences between the unresponsive wakefulness syndrome and the minimally conscious state were found in the patterns formed by a relatively small number of strongest positive correlations selected by thresholding. These differences were captured by measures of functional connectivity disruption that integrate area-specific abnormalities over the whole brain. The results suggest that the strong positive correlations between the functional activities of specific brain areas observed in healthy individuals may be critical for consciousness and be an important target of disruption in disorders of consciousness.

Effects of Navigated Repetitive Transcranial Magnetic Stimulation After Stroke.

PURPOSE: The purpose of this study was to test the effects of navigated repetitive transcranial magnetic stimulation, delivered in different modes, on motor impairments and functional limitations after stroke. METHODS: The study sample included 42 patients (58.5 ± 10.7 years; 26 males) who experienced a single unilateral stroke (1-12 months previously) in the area of the middle cerebral artery. Patients completed a course of conventional rehabilitation, together with 10 sessions of navigated repetitive transcranial magnetic stimulation or sham stimulation. Stimulation was scheduled five times a week over two consecutive weeks in an inpatient clinical setting. Patients were randomly assigned to one of four groups and received sham stimulation (n = 10), low-frequency (1-Hz) stimulation of the nonaffected hemisphere (n = 11), high-frequency (10-Hz) stimulation of the affected hemisphere (n = 13), or sequential combination of low- and high-frequency stimulations (n = 8). Participants were evaluated before and after stimulation with clinical tests, including the arm and hand section of the Fugl-Meyer Assessment Scale, modified Ashworth Scale of Muscle Spasticity, and Barthel Index of Activities of Daily Living. RESULTS: Participants in the three groups receiving navigated repetitive transcranial magnetic stimulation showed improvements in arm and hand functions on the Fugl-Meyer Stroke Assessment Scale. Ashworth Scale of Muscle Spasticity and Barthel Index scores were significantly reduced in groups receiving low- or high-frequency stimulation alone. CONCLUSIONS: Including navigated repetitive transcranial magnetic stimulation in a conventional rehabilitation program positively influenced motor and functional recovery in study participants, demonstrating the clinical potential of the method. The results of this study will be used for designing a large-scale clinical trial.

The Pathogenesis of the Demyelinating Form of Guillain-Barre Syndrome (GBS): Proteo-peptidomic and Immunological Profiling of Physiological Fluids.

Acute inflammatory demyelinating polyneuropathy (AIDP) - the main form of Guillain-Barre syndrome-is a rare and severe disorder of the peripheral nervous system with an unknown etiology. One of the hallmarks of the AIDP pathogenesis is a significantly elevated cerebrospinal fluid (CSF) protein level. In this paper CSF peptidome and proteome in AIDP were analyzed and compared with multiple sclerosis and control patients. A total protein concentration increase was shown to be because of even changes in all proteins rather than some specific response, supporting the hypothesis of protein leakage from blood through the blood-nerve barrier. The elevated CSF protein level in AIDP was complemented by activization of protein degradation and much higher peptidome diversity. Because of the studies of the acute motor axonal form, Guillain-Barre syndrome as a whole is thought to be associated with autoimmune response against neurospecific molecules. Thus, in AIDP, autoantibodies against cell adhesion proteins localized at Ranvier's nodes were suggested as possible targets in AIDP. Indeed, AIDP CSF peptidome analysis revealed cell adhesion proteins degradation, however no reliable dependence on the corresponding autoantibodies levels was found. Proteome analysis revealed overrepresentation of Gene Ontology groups related to responses to bacteria and virus infections, which were earlier suggested as possible AIDP triggers. Immunoglobulin blood serum analysis against most common neuronal viruses did not reveal any specific pathogen; however, AIDP patients were more immunopositive in average and often had polyinfections. Cytokine analysis of both AIDP CSF and blood did not show a systemic adaptive immune response or general inflammation, whereas innate immunity cytokines were up-regulated. To supplement the widely-accepted though still unproven autoimmunity-based AIDP mechanism we propose a hypothesis of the primary peripheral nervous system damaging initiated as an innate immunity-associated local inflammation following neurotropic viruses egress, whereas the autoantibody production might be an optional complementary secondary process.