A widespread visually-sensitive functional network relates to symptoms in essential tremor.

Essential tremor is a neurological syndrome of heterogeneous pathology and aetiology that is characterized by tremor primarily in the upper extremities. This tremor is commonly hypothesized to be driven by a single or multiple neural oscillator(s) within the cerebello-thalamo-cortical pathway. Several studies have found an association of blood-oxygen level-dependent (BOLD) signal in the cerebello-thalamo-cortical pathway with essential tremor, but there is behavioural evidence that also points to the possibility that the severity of tremor could be influenced by visual feedback. Here, we directly manipulated visual feedback during a functional MRI grip force task in patients with essential tremor and control participants, and hypothesized that an increase in visual feedback would exacerbate tremor in the 4-12 Hz range in essential tremor patients. Further, we hypothesized that this exacerbation of tremor would be associated with dysfunctional changes in BOLD signal and entropy within, and beyond, the cerebello-thalamo-cortical pathway. We found that increases in visual feedback increased tremor in the 4-12 Hz range in essential tremor patients, and this increase in tremor was associated with abnormal changes in BOLD amplitude and entropy in regions within the cerebello-thalamo-motor cortical pathway, and extended to visual and parietal areas. To determine if the tremor severity was associated with single or multiple brain region(s), we conducted a birectional stepwise multiple regression analysis, and found that a widespread functional network extending beyond the cerebello-thalamo-motor cortical pathway was associated with changes in tremor severity measured during the imaging protocol. Further, this same network was associated with clinical tremor severity measured with the Fahn, Tolosa, Marin Tremor Rating Scale, suggesting this network is clinically relevant. Since increased visual feedback also reduced force error, this network was evaluated in relation to force error but the model was not significant, indicating it is associated with force tremor but not force error. This study therefore provides new evidence that a widespread functional network is associated with the severity of tremor in patients with essential tremor measured simultaneously at the hand during functional imaging, and is also associated with the clinical severity of tremor. These findings support the idea that the severity of tremor is exacerbated by increased visual feedback, suggesting that designers of new computing technologies should consider using lower visual feedback levels to reduce tremor in essential tremor.

The role of high-field magnetic resonance imaging in parkinsonian disorders: Pushing the boundaries forward.

Historically, magnetic resonance imaging (MRI) has contributed little to the study of Parkinson's disease (PD), but modern MRI approaches have unveiled several complementary markers that are useful for research and clinical applications. Iron- and neuromelanin-sensitive MRI detect qualitative changes in the substantia nigra. Quantitative MRI markers can be derived from diffusion weighted and iron-sensitive imaging or volumetry. Functional brain alterations at rest or during task performance have been captured with functional and arterial spin labeling perfusion MRI. These markers are useful for the diagnosis of PD and atypical parkinsonism, to track disease progression from the premotor stages of these diseases and to better understand the neurobiological basis of clinical deficits. A current research goal using MRI is to generate time-dependent models of the evolution of PD biomarkers that can help understand neurodegeneration and provide reliable markers for therapeutic trials. This article reviews recent advances in MRI biomarker research at high-field (3T) and ultra high field-imaging (7T) in PD and atypical parkinsonism. © 2017 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.

Free-water and BOLD imaging changes in Parkinson's disease patients chronically treated with a MAO-B inhibitor.

Rasagiline is a monoamine oxidase type B inhibitor that possesses no amphetamine-like properties, and provides symptomatic relief in early and late stages of Parkinson's disease (PD). Data in animal models of PD suggest that chronic administration of rasagiline is associated with structural changes in the substantia nigra, and raise the question whether the structure and function of the basal ganglia could be different in PD patients treated chronically with rasagiline as compared with PD patients not treated with rasagiline. Here, we performed a retrospective cross-sectional magnetic resonance imaging (MRI) study at 3 T that investigated nigrostriatal function and structure in PD patients who had taken rasagiline before testing (∼8 months), PD who had not taken rasagiline before testing, and age-matched controls. The two PD groups were selected a priori to not differ significantly in age, sex, disease duration, severity of symptoms, cognitive status, and total levodopa equivalent daily dose of medication. We evaluated percent signal change in the posterior putamen during force production using functional MRI, free-water in the posterior substantia nigra using diffusion MRI, and performance on a bimanual coordination task using a pegboard test. All patients were tested after overnight withdrawal from antiparkinsonian medication. The rasagiline group had greater percent signal change in the posterior putamen, less free-water in the posterior substantia nigra, and better performance on the coordination task than the group not taking rasagiline. These findings point to a possible chronic effect of rasagiline on the structure and function of the basal ganglia in PD. Hum Brain Mapp 37:2894-2903, 2016. © 2016 Wiley Periodicals, Inc.

Effects of visual and auditory feedback on sensorimotor circuits in the basal ganglia.

Previous work using visual feedback has identified two distinct sensorimotor circuits in the basal ganglia (BG): one that scaled with the duration of force and one that scaled with the rate of change of force. The present study compared functional MRI signal changes in the BG during a grip force task using either visual or auditory feedback to determine whether the BG nuclei process auditory and visual feedback similarly. We confirmed the same two sensorimotor circuits in the BG. Activation in the striatum and external globus pallidus (GPe) scaled linearly with the duration of force under visual and auditory feedback conditions, with similar slopes and intercepts across feedback type. The pattern of signal change for the internal globus pallidus (GPi) and subthalamic nucleus (STN) was nonlinear and parameters of the exponential function were altered by feedback type. Specifically, GPi and STN activation decreased exponentially with the rate of change of force. The rate constant and asymptote of the exponential functions for GPi and STN were greater during auditory than visual feedback. In a comparison of the BOLD signal between BG regions, GPe had the highest percentage of variance accounted for and this effect was preserved for both feedback types. These new findings suggest that neuronal activity of specific BG nuclei is affected by whether the feedback is derived from visual or auditory inputs. Also, the data are consistent with the hypothesis that the GPe has a high level of information convergence from other BG nuclei, which is preserved across different sensory feedback modalities.

Role of individual basal ganglia nuclei in force amplitude generation.

The basal ganglia-thalamo-cortical loop is an important neural circuit that regulates motor control. A key parameter that the nervous system regulates is the level of force to exert against an object during tasks such as grasping. Previous studies indicate that the basal ganglia do not exhibit increased activity with increasing amplitude of force, although these conclusions are based mainly on the putamen. The present study used functional magnetic resonance imaging to investigate which regions in the basal ganglia, thalamus, and motor cortex display increased activity when producing pinch-grip contractions of increasing force amplitude. We found that the internal portion of the globus pallidus (GPi) and subthalamic nucleus (STN) had a positive increase in percent signal change with increasing force, whereas the external portion of the globus pallidus, anterior putamen, posterior putamen, and caudate did not. In the thalamus we found that the ventral thalamic regions increase in percent signal change and activation volume with increasing force amplitude. The contralateral and ipsilateral primary motor/somatosensory (M1/S1) cortices had a positive increase in percent signal change and activation volume with increasing force amplitude, and the contralateral M1/S1 had a greater increase in percent signal change and activation volume than the ipsilateral side. We also found that deactivation did not change across force in the motor cortex and basal ganglia, but that the ipsilateral M1/S1 had greater deactivation than the contralateral M1/S1. Our findings provide direct evidence that GPi and STN regulate the amplitude of force output. These findings emphasize the heterogeneous role of individual nuclei of the basal ganglia in regulating specific parameters of motor output.

Force control and disease severity in Parkinson's disease.

Several measures of isometric contractions reflect motor impairments in subjects with Parkinson's disease (PD), including long relaxation times and greater power in the 5 to 15 Hz electromyographic (EMG) bandwidth during the holding phase of contractions compared to those measures in healthy subjects. We sought to determine whether the impairments observed in subjects with PD in the performance of isometric contractions reflect disease severity. Twenty-eight subjects with PD performed isometric contractions at a torque level equal to 50% of the torque generated during a maximum voluntary contraction while off medication. Subjects were instructed to reach the target torque as fast as possible upon hearing the auditory "go" signal and to relax their muscles when a second auditory cue signaled the end of the hold phase. There was a significant positive correlation between torque relaxation time and Unified Parkinson's Disease Rating Scale (UPDRS)-Motor score. A significant positive correlation was also observed between the proportion of power in the 5 to 15 Hz frequency bin of the agonist EMG signal and UPDRS-Motor score, and a significant negative correlation between the proportion of power in the 15 to 30 Hz frequency bin and UPDRS-Motor score. These measures provide objective quantification of the severity of motor impairment that can be used to investigate the efficacy of different interventions in individuals with PD.

Effects of subthalamic nucleus stimulation and medication on resting and postural tremor in Parkinson's disease.

Deep brain stimulation (DBS) of the subthalamic nucleus (STN) and antiparkinsonian medication have proved to be effective treatments for tremor in Parkinson's disease. To date it is not known how and to what extent STN DBS alone and in combination with antiparkinsonian medication alters the pathophysiology of resting and postural tremor in idiopathic Parkinson's disease. The purpose of this study was to examine the effects of STN DBS and antiparkinsonian medication on the neurophysiological characteristics of resting and postural hand tremor in Parkinson's disease. Resting and postural hand tremor were recorded using accelerometry and surface electromyography (EMG) from 10 Parkinson's disease patients and 10 matched control subjects. The Parkinson's disease subjects were examined under four treatment conditions: (i) off treatment; (ii) STN DBS; (iii) medication; and (iv) medication plus STN DBS. The amplitude, EMG frequency, regularity, and 1-8 Hz tremor-EMG coherence were analysed. Both STN DBS and medication reduced the amplitude, regularity and tremor-EMG coherence, and increased the EMG frequency of resting and postural tremor in Parkinson's disease. STN DBS was more effective than medication in reducing the amplitude and increasing the frequency of resting and postural tremor to healthy physiological levels. These findings provide strong evidence that effective STN DBS normalizes the amplitude and frequency of tremor. The findings suggest that neural activity in the STN is an important modulator of the neural network(s) responsible for both resting and postural tremor genesis in Parkinson's disease.

Effects of deep brain stimulation and medication on bradykinesia and muscle activation in Parkinson's disease.

Deep brain stimulation (DBS) of the subthalamic nucleus (STN) and antiparkinsonian medication (Meds) have proved to be effective therapies for treating bradykinesia in Parkinson's disease. However, it is not currently known how or to what extent STN stimulation alters the control signals to agonist and antagonist muscles to change movement speed. Our objective was to investigate movement speed along with the amplitude and temporal features of EMG activity to determine how and to what extent these parameters are changed by DBS and medication. Nine patients with Parkinson's disease were studied following neurosurgery that implanted high-frequency stimulating electrodes in the STN. The experiments for the patients were performed in each of four treatment conditions: (i) OFF treatment; (ii) STN DBS; (iii) Meds; and (iv) Meds plus STN DBS. Also, a group of age- and gender-matched control subjects were examined. Medication and DBS had similar effects in that both treatments increased movement speed, increased the amplitude of the first agonist burst, increased burst duration, reduced the number of agonist bursts, reduced cocontraction, increased the size of the antagonist EMG, and reduced the centroid time of the antagonist EMG. When DBS and medication were combined, only temporal measures of burst duration and the number of agonist bursts were different from the medication alone condition. There was a positive association between the level of bradykinesia OFF treatment and the level of bradykinesia following DBS and medication. The movement speed of neurologically normal control subjects' was over 40% higher during both flexion and extension movements when compared with the patients during Meds plus STN DBS. The changes in the muscle activation patterns provide a mechanism of action for the pharmacological and surgical interventions used to treat bradykinesia in Parkinson's disease. However, despite the success of medication and DBS at improving bradykinesia in patients with Parkinson's disease, patients' movement speed was not restored to normal due to limitations in the amplitude and temporal scaling of the agonist and antagonist bursting pattern. These findings suggest a link between basal ganglia function in scaling both the amplitude and temporal parameters of the input to the motor neuron pool.