The functional role of conscious sensation of movement.

This paper proposes a new framework for investigating neural signals sufficient for a conscious sensation of movement and their role in motor control. We focus on signals sufficient for proprioceptive awareness, particularly from muscle spindle activation and from primary motor cortex (M1). Our review of muscle vibration studies reveals that afferent signals alone can induce conscious sensations of movement. Similarly, studies employing peripheral nerve blocks suggest that efferent signals from M1 are sufficient for sensations of movement. On this basis, we show that competing theories of motor control assign different roles to sensation of movement. According to motor command theories, sensation of movement corresponds to an estimation of the current state based on afferent signals, efferent signals, and predictions. In contrast, within active inference architectures, sensations correspond to proprioceptive predictions driven by efferent signals from M1. The focus on sensation of movement provides a way to critically compare and evaluate the two theories. Our analysis offers new insights into the functional roles of movement sensations in motor control and consciousness.

Motor context modulates substantia nigra pars reticulata spike activity in patients with Parkinson's disease.

OBJECTIVE: The severity of motor symptoms in Parkinson's disease (PD) depends on environmental conditions. For example, the presence of external patterns such as a rhythmic tone can attenuate bradykinetic impairments. However, the neural mechanisms for this context-dependent attenuation (e.g., paradoxical kinesis) remain unknown. Here, we investigate whether context-dependent symptom attenuation is reflected in single-unit activity recorded in the operating room from the substantia nigra pars reticulata (SNr) of patients with PD undergoing deep brain stimulation surgery. The SNr is known to influence motor planning and execution in animal models, but its role in humans remains understudied. METHODS: We recorded SNr activity while subjects performed cued directional movements in response to auditory stimuli under interleaved 'patterned' and 'unpatterned' contexts. SNr localisation was independently confirmed with expert intraoperative assessment as well as post hoc imaging-based reconstructions. RESULTS: As predicted, we found that motor performance was improved in the patterned context, reflected in increased reaction speed and accuracy compared with the unpatterned context. These behavioural differences were associated with enhanced responsiveness of SNr neurons-that is, larger changes in activity from baseline-in the patterned context. Unsupervised clustering analysis revealed two distinct subtypes of SNr neurons: one exhibited context-dependent enhanced responsiveness exclusively during movement preparation, whereas the other showed enhanced responsiveness during portions of the task associated with both motor and non-motor processes. CONCLUSIONS: Our findings indicate the SNr participates in motor planning and execution, as well as warrants greater attention in the study of human sensorimotor integration and as a target for neuromodulatory therapies.

TDP-43 proteinopathies: a new wave of neurodegenerative diseases.

Inclusions of pathogenic deposits containing TAR DNA-binding protein 43 (TDP-43) are evident in the brain and spinal cord of patients that present across a spectrum of neurodegenerative diseases. For instance, the majority of patients with sporadic amyotrophic lateral sclerosis (up to 97%) and a substantial proportion of patients with frontotemporal lobar degeneration (~45%) exhibit TDP-43 positive neuronal inclusions, suggesting a role for this protein in disease pathogenesis. In addition, TDP-43 inclusions are evident in familial ALS phenotypes linked to multiple gene mutations including the TDP-43 gene coding (TARDBP) and unrelated genes (eg, C9orf72). While TDP-43 is an essential RNA/DNA binding protein critical for RNA-related metabolism, determining the pathophysiological mechanisms through which TDP-43 mediates neurodegeneration appears complex, and unravelling these molecular processes seems critical for the development of effective therapies. This review highlights the key physiological functions of the TDP-43 protein, while considering an expanding spectrum of neurodegenerative diseases associated with pathogenic TDP-43 deposition, and dissecting key molecular pathways through which TDP-43 may mediate neurodegeneration.

Postural sway correlates with cognition and quality of life in Parkinson's disease.

BACKGROUND: The severity of Parkinson's disease (PD) is difficult to assess objectively owing to the lack of a robust biological marker of underlying disease status, with consequent implications for diagnosis, treatment and prognosis. The current standard tool is the Unified Parkinson's Disease Rating Scale (MDS-UPDRS), but this is hampered by variability between observers and within subjects. Postural sway has been shown to correlate with complex brain functioning in other conditions. This study aimed to investigate the relationship between postural sway, MDS-UPDRS and other non-motor measures of disease severity in patients with PD. METHOD: 25 patients with PD and 18 age-matched controls participated in the study. All participants underwent assessment of postural sway using a force plate, with eyes open and closed. In addition, participants underwent tests of cognition and quality of life: Montreal Cognitive Assessment (MoCA), Neuropsychiatry Unit Cognitive Assessment (NUCOG) and, for the patients, the Parkinson's Disease Questionnaire (PDQ-39-1), and assessment of clinical status using the motor component of the MDS-UPDRS. RESULTS: Patients swayed significantly more than controls. This was most obvious in the eyes-closed condition. Sway path length showed strong correlations with PDQ-39-1, MoCA and the verbal fluency component of the NUCOG, and, to a lesser degree, with the UPDRS-III in patients with PD. CONCLUSION: These results suggest that motor and non-motor symptoms of PD are associated in patients, and, in particular, that postural sway shows potential as a possible measure of underlying disease status in PD, either alone or in combination with other measures.

Brain-Machine Interfaces: Powerful Tools for Clinical Treatment and Neuroscientific Investigations.

Brain-machine interfaces (BMIs) have exploded in popularity in the past decade. BMIs, also called brain-computer interfaces, provide a direct link between the brain and a computer, usually to control an external device. BMIs have a wide array of potential clinical applications, ranging from restoring communication to people unable to speak due to amyotrophic lateral sclerosis or a stroke, to restoring movement to people with paralysis from spinal cord injury or motor neuron disease, to restoring memory to people with cognitive impairment. Because BMIs are controlled directly by the activity of prespecified neurons or cortical areas, they also provide a powerful paradigm with which to investigate fundamental questions about brain physiology, including neuronal behavior, learning, and the role of oscillations. This article reviews the clinical and neuroscientific applications of BMIs, with a primary focus on motor BMIs.

Digitized spiral analysis may be a potential biomarker for brachial dystonia.

INTRODUCTION: Objective measures for detection and quantification of dystonic movements may guide both diagnosis and clinical monitoring. Digitized spiral analysis is a non-invasive method used to assess upper limb motor control in movement disorders and may have utility in dystonia. We aimed to determine if digitized spiral analysis can distinguish dystonia subjects from controls, and evaluated correlation with a validated clinical rating scale. METHODS: Kinematic, dynamic, and spatial attributes of Archimedean spirals drawn with an inking pen on a digitizing tablet were compared for participants with brachial dystonia and either Tor1A (DYT1) (n = 15) or THAP1 (DYT6) mutations (n = 12) and age and gender matched controls (n = 27) using Receiver Operator Characteristics (ROC) analysis. Spiral indices including an overall degree of severity (DoS) were also calculated and correlated with clinical severity ratings as measured by the Burke-Fahn-Marsden scale. RESULTS: Dystonia spirals had significantly higher severity scores as well as higher measures of spiral irregularity compared to controls. ROC analysis demonstrated that the DoS score had good discriminative ability to distinguish dystonia spirals from controls, with an Area Under the Curve (AUC) of 0.87. Measures of spiral irregularity correlated with validated clinical rates of dystonia severity in the analyzed arm, with one particular index, Residue of Theta vs R, showing the highest correlation (r = 0.55, p = 0.005). CONCLUSION: Digitized spiral analysis may be a promising non-invasive method to objectively quantify brachial dystonia. It may also be a useful way to monitor subtle changes in dystonia severity over time not captured with current clinical rating scales.

Non-invasive Brain Stimulation for Essential Tremor.

BACKGROUND: There is increasing interest in the use of non-invasive brain stimulation to characterize and potentially treat essential tremor (ET). Studies have used a variety of stimulation coils, paradigms, and target locations to make these observations. We reviewed the literature to compare prior studies and to evaluate the rationale and the methods used in these studies. METHODS: We performed a systematic literature search of the PubMed database using the terms "transcranial," "noninvasive," "brain stimulation," "transcranial magnetic stimulation (TMS)," "transcranial direct current stimulation (tDCS)," "transcranial alternating current stimulation (tACS)," and "essential tremor." RESULTS: Single pulses of TMS to the primary motor cortex have long been known to reset tremor. Although there are relatively few studies showing alterations in motor cortical physiology, such as motor threshold, short and long intracortical inhibition, and cortical silent period, there may be some evidence of altered intracortical facilitation and cerebello-brain inhibition in ET. Repetitive TMS, theta burst stimulation, tDCS, and tACS have been applied to human subjects with tremor with some preliminary signs of tremor reduction, particularly in those studies that employed consecutive daily sessions. DISCUSSION: A variety of stimulation paradigms and targets have been explored, with the increasing rationale an interest in targeting the cerebellum. Rigorous assessment of coil geometry, stimulation paradigm, rationale for selection of the specific anatomic target, and careful phenotypic and physiologic characterization of the subjects with ET undergoing these interventions may be critical in extending these preliminary findings into effective stimulation therapies.

Facial bradykinesia.

The aim of this paper is to summarise the main clinical and pathophysiological features of facial bradykinesia in Parkinson's disease (PD) and in atypical parkinsonism. Clinical observation suggests that reduced spontaneous and emotional facial expressions are features of facial bradykinesia in PD and atypical parkinsonism. In atypical parkinsonism, facial bradykinesia is complicated by additional dystonic features. Experimental studies evaluating spontaneous and emotional facial movements demonstrate that PD is characterised by a reduction in spontaneous blinking and emotional facial expression. In PD, neurophysiological studies show that voluntary orofacial movements are smaller in amplitude and slower in velocity. In contrast, movements of the upper face (eg, voluntary blinking) are normal in terms of velocity and amplitude but impaired in terms of switching between the closing and opening phases. In progressive supranuclear palsy (PSP), voluntary blinking is not only characterised by a severely impaired switching between the closing and opening phases of voluntary blinking, but is also slow in comparison with PD. In conclusion, in PD, facial bradykinesia reflects abnormalities of spontaneous, emotional and voluntary facial movements. In PSP, spontaneous and voluntary facial movements are abnormal but experimental studies on emotional facial movements are lacking. Data on facial bradykinesia in other atypical parkinsonism diseases, including multiple system atrophy and corticobasal degeneration, are limited. In PD, facial bradykinesia is primarily mediated by basal ganglia dysfunction whereas in PSP, facial bradykinesia is a consequence of a widespread degeneration involving the basal ganglia, cortical and brainstem structures.

Tremor: clinical phenomenology and assessment techniques.

BACKGROUND: Tremors are among the most common movement disorders. As there can be considerable variability in the manner in which clinicians assess tremor, objective quantitative tools such as electromyography, accelerometry, and computerized, spiral analysis can be very useful in establishing a clinical diagnosis and in research settings. METHODS: In this review, we discuss the various methods of quantitative tremor analysis and the classification and pathogenesis of tremor. The most common pathologic tremors and an approach to the diagnosis of tremor etiology are described. CONCLUSIONS: Pathologic tremors are common, and the diagnosis of underlying etiology is not always straightforward. Computerized quantitative tremor analysis is a valuable adjunct to careful clinical evaluation in distinguishing tremulous diseases from physiologic tremors, and can also help shed light on their pathogenesis.