Multimodal Assessment of the Motor System in Patients With Chronic Ischemic Stroke.

BACKGROUND AND PURPOSE: Despite continuing efforts in the multimodal assessment of the motor system after stroke, conclusive findings on the complementarity of functional and structural metrics of the ipsilesional corticospinal tract integrity and the role of the contralesional hemisphere are still lacking. This research aimed to find the best combination of motor system metrics, allowing the classification of patients into 3 predefined groups of upper limb motor recovery. METHODS: We enrolled 35 chronic ischemic stroke patients (mean 47 [26-66] years old, 29 [6-58] months poststroke) with a single supratentorial lesion and unilateral upper extremity weakness. Patients were divided into 3 groups, depending on upper limb motor recovery: good, moderate, and bad. Nonparametric statistical tests and regression analysis were used to investigate the relationships among microstructural (fractional anisotropy (FA) ratio of the corticospinal tracts at the internal capsule (IC) level (classic method) and along the length of the tracts (Fréchet distance), and of the corpus callosum) and functional (motor evoked potentials [MEPs] for 2 hand muscles) motor system metrics. Stratification rules were also tested using a decision tree classifier. RESULTS: IC FA ratio in the IC and MEP absence were both equally discriminative of the bad motor outcome (96% accuracy). For the 3 recovery groups' classification, the best parameter combination was IC FA ratio and the Fréchet distance between the contralesional and ipsilesional corticospinal tract FA profiles (91% accuracy). No other metrics had any additional value for patients' classification. MEP presence differed for 2 investigated muscles. CONCLUSIONS: This study demonstrates that better separation between 3 motor recovery groups may be achieved when considering the similarity between corticospinal tract FA profiles along its length in addition to region of interest-based assessment and lesion load calculation. Additionally, IC FA ratio and MEP absence are equally important markers for poor recovery, while for MEP probing it may be important to investigate more than one hand muscle.

Action in auctions: neural and computational mechanisms of bidding behaviour.

Competition for resources is a fundamental characteristic of evolution. Auctions have been widely used to model competition of individuals for resources, and bidding behaviour plays a major role in social competition. Yet, how humans learn to bid efficiently remains an open question. We used model-based neuroimaging to investigate the neural mechanisms of bidding behaviour under different types of competition. Twenty-seven subjects (nine male) played a prototypical bidding game: a double action, with three "market" types, which differed in the number of competitors. We compared different computational learning models of bidding: directional learning models (DL), where the model bid is "nudged" depending on whether it was accepted or rejected, along with standard reinforcement learning models (RL). We found that DL fit the behaviour best and resulted in higher payoffs. We found the binary learning signal associated with DL to be represented by neural activity in the striatum distinctly posterior to a weaker reward prediction error signal. We posited that DL is an efficient heuristic for valuation when the action (bid) space is continuous. Indeed, we found that the posterior parietal cortex represents the continuous action space of the task, and the frontopolar prefrontal cortex distinguishes among conditions of social competition. Based on our findings, we proposed a conceptual model that accounts for a sequence of processes that are required to perform successful and flexible bidding under different types of competition.

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.

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.

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.

Navigated transcranial magnetic stimulation in amyotrophic lateral sclerosis.

INTRODUCTION: Amyotrophic lateral sclerosis (ALS) is a set of disorders associated with preferential degeneration of both upper and lower motor neurons. Navigated transcranial magnetic stimulation (nTMS) is a tool used to perform noninvasive functional brain mapping. We aimed to assess function of upper motor neurons in ALS. METHODS: nTMS was performed on 30 patients with ALS (mean age 54.4 ± 12.1 years) and 24 healthy volunteers (mean age 32.7 ± 13.3 years). RESULTS: The resting motor threshold (MT) was significantly higher in ALS patients compared with controls (P < 0.001). The mean map areas were smaller in patients with ALS than in healthy individuals, although some patients with short disease duration had extended maps. CONCLUSIONS: Motor area maps serve as markers of upper motor neuron damage in ALS. Further research may elucidate the pathogenic mechanisms of the neurodegenerative process and aid in development of diagnostic and prognostic markers.

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.

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.

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.

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.

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.

Variability of Neuronal Responses: Types and Functional Significance in Neuroplasticity and Neural Darwinism.

HIGHLIGHTS We suggest classifying variability of neuronal responses as follows: false (associated with a lack of knowledge about the influential factors), "genuine harmful" (noise), "genuine neutral" (synonyms, repeats), and "genuine useful" (the basis of neuroplasticity and learning).The genuine neutral variability is considered in terms of the phenomenon of degeneracy.Of particular importance is the genuine useful variability that is considered as a potential basis for neuroplasticity and learning. This type of variability is considered in terms of the neural Darwinism theory. In many cases, neural signals detected under the same external experimental conditions significantly change from trial to trial. The variability phenomenon, which complicates extraction of reproducible results and is ignored in many studies by averaging, has attracted attention of researchers in recent years. In this paper, we classify possible types of variability based on its functional significance and describe features of each type. We describe the key adaptive significance of variability at the neural network level and the degeneracy phenomenon that may be important for learning processes in connection with the principle of neuronal group selection.

Possible Mechanisms Underlying the Therapeutic Effects of Transcranial Magnetic Stimulation.

Transcranial magnetic stimulation (TMS) is an effective method used to diagnose and treat many neurological disorders. Although repetitive TMS (rTMS) has been used to treat a variety of serious pathological conditions including stroke, depression, Parkinson's disease, epilepsy, pain, and migraines, the pathophysiological mechanisms underlying the effects of long-term TMS remain unclear. In the present review, the effects of rTMS on neurotransmitters and synaptic plasticity are described, including the classic interpretations of TMS effects on synaptic plasticity via long-term potentiation and long-term depression. We also discuss the effects of rTMS on the genetic apparatus of neurons, glial cells, and the prevention of neuronal death. The neurotrophic effects of rTMS on dendritic growth and sprouting and neurotrophic factors are described, including change in brain-derived neurotrophic factor concentration under the influence of rTMS. Also, non-classical effects of TMS related to biophysical effects of magnetic fields are described, including the quantum effects, the magnetic spin effects, genetic magnetoreception, the macromolecular effects of TMS, and the electromagnetic theory of consciousness. Finally, we discuss possible interpretations of TMS effects according to dynamical systems theory. Evidence suggests that a rTMS-induced magnetic field should be considered a separate physical factor that can be impactful at the subatomic level and that rTMS is capable of significantly altering the reactivity of molecules (radicals). It is thought that these factors underlie the therapeutic benefits of therapy with TMS. Future research on these mechanisms will be instrumental to the development of more powerful and reliable TMS treatment protocols.

Clinical and experimental studies of multiple sclerosis in Russia: experience of the leading national research centers.

Mechanisms of axonal damage and adaptive capacity in multiple sclerosis (MS), including cortical reorganization, have been actively studied in recent years. The lack of regenerative capabilities and the irreversibility of neurodegeneration in MS are critical factors for the optimization of MS treatment. In this study, we present the results of clinical and basic studies in the field of MS by two leading Russian centers. Clinical and neuroimaging correlations show that spinal damage in MS is accompanied by functional reorganization of the cerebral cortex, which is determined not only by the efferent component but also by the afferent component. Comparative analysis of MS treatment with both interferon ß1b (IFN-ß1b) and IFN-ß1a at a dosage of 22 µg for 3 years through subcutaneous administration and glatiramer acetate showed equally high efficiency in reducing the number of exacerbations in relapsing-remitting MS and secondary-progressive MS. We demonstrate a reduced risk of disability in relapsing-remitting MS and secondary-progressive MS patients in all groups treated with IFN-ß1 and glatiramer acetate. MS appears to be a disease that would greatly benefit from the development of personalized therapy; thus, adequate molecular predictors of myelin degradation are greatly needed. Therefore, novel ideas related to the viral hypothesis of the etiology of MS and new targets for therapeutic intervention are currently being developed. In this manuscript, we discuss findings of both clinical practice and fundamental research reflecting challenges and future directions of MS treatment in the Russian Federation.