Different descending pathways mediate early and late portions of lower limb responses to transcranial magnetic stimulation.

Although recent studies in nonhuman primates have provided evidence that transcranial magnetic stimulation (TMS) activates cells within the reticular formation, it remains unclear whether descending brain stem projections contribute to the generation of TMS-induced motor evoked potentials (MEPs) in skeletal muscles. We compared MEPs in muscles with extensive direct corticomotoneuronal input (first dorsal interosseous) versus a prominent role in postural control (gastrocnemius) to determine whether the amplitudes of early and late MEPs were differentially modulated by cortical suppression. Suprathreshold TMS was applied with and without a preceding suprathreshold TMS pulse at two interstimulus intervals (50 and 80 ms). H reflexes in target muscles were also tested with and without TMS conditioning. Early and late gastrocnemius MEPs were differentially modulated by cortical inhibition, the amplitude of the early MEP being significantly reduced by cortical suppression and the late MEP facilitated. The amplitude of H reflexes in the gastrocnemius was reduced within the cortical silent period. Early MEPs in the first dorsal interosseous were also reduced during the silent period, but late MEPs were unaffected. Independent modulation of early and late MEPs in the gastrocnemius muscle supports the idea that the MEP is generated by multiple descending pathways. Suppression of the early MEP is consistent with transmission along the fast-conducting corticospinal tract, whereas facilitation of the late MEP suggests transmission along a corticofugal, potentially cortico-reticulospinal, pathway. Accordingly, differences in late MEP modulation between the first dorsal interosseous and gastrocnemius reflect an increased role of corticofugal pathways in the control of postural muscles.NEW & NOTEWORTHY Early and late portions of the response to transcranial magnetic stimulation (TMS) in a lower limb postural muscle are modulated independently by cortical suppression, late motor evoked potentials (MEPs) being facilitated during cortical inhibition. These results suggest a cortico-brain stem transmission pathway for late portions of the TMS-induced MEP.

Slow-wave sleep dysfunction in mild parkinsonism is associated with excessive beta and reduced delta oscillations in motor cortex.

Increasing evidence suggests slow-wave sleep (SWS) dysfunction in Parkinson's disease (PD) is associated with faster disease progression, cognitive impairment, and excessive daytime sleepiness. Beta oscillations (8-35 Hz) in the basal ganglia thalamocortical (BGTC) network are thought to play a role in the development of cardinal motor signs of PD. The role cortical beta oscillations play in SWS dysfunction in the early stage of parkinsonism is not understood, however. To address this question, we used a within-subject design in a nonhuman primate (NHP) model of PD to record local field potentials from the primary motor cortex (MC) during sleep across normal and mild parkinsonian states. The MC is a critical node in the BGTC network, exhibits pathological oscillations with depletion in dopamine tone, and displays high amplitude slow oscillations during SWS. The MC is therefore an appropriate recording site to understand the neurophysiology of SWS dysfunction in parkinsonism. We observed a reduction in SWS quantity (p = 0.027) in the parkinsonian state compared to normal. The cortical delta (0.5-3 Hz) power was reduced (p = 0.038) whereas beta (8-35 Hz) power was elevated (p = 0.001) during SWS in the parkinsonian state compared to normal. Furthermore, SWS quantity positively correlated with delta power (r = 0.43, p = 0.037) and negatively correlated with beta power (r = -0.65, p < 0.001). Our findings support excessive beta oscillations as a mechanism for SWS dysfunction in mild parkinsonism and could inform the development of neuromodulation therapies for enhancing SWS in people with PD.

Excessive cortical beta oscillations are associated with slow-wave sleep dysfunction in mild parkinsonism.

Increasing evidence associates slow-wave sleep (SWS) dysfunction with neurodegeneration. Using a within-subject design in the nonhuman primate model of Parkinson's disease (PD), we found that reduced SWS quantity in mild parkinsonism was accompanied by elevated beta and reduced delta power during SWS in the motor cortex. Our findings support excessive beta oscillations as a mechanism for SWS dysfunction and will inform development of neuromodulation therapies for enhancing SWS in PD.

Low-frequency deep brain stimulation reveals resonant beta-band evoked oscillations in the pallidum of Parkinson's Disease patients.

Introduction: Evidence suggests that spontaneous beta band (11-35 Hz) oscillations in the basal ganglia thalamocortical (BGTC) circuit are linked to Parkinson's disease (PD) pathophysiology. Previous studies on neural responses in the motor cortex evoked by electrical stimulation in the subthalamic nucleus have suggested that circuit resonance may underlie the generation of spontaneous and stimulation-evoked beta oscillations in PD. Whether these stimulation-evoked, resonant oscillations are present across PD patients in the internal segment of the globus pallidus (GPi), a primary output nucleus in the BGTC circuit, is yet to be determined. Methods: We characterized spontaneous and stimulation-evoked local field potentials (LFPs) in the GPi of four PD patients (five hemispheres) using deep brain stimulation (DBS) leads externalized after DBS implantation surgery. Results: Our analyses show that low-frequency (2-4 Hz) stimulation in the GPi evoked long-latency (>50 ms) beta-band neural responses in the GPi in 4/5 hemispheres. We demonstrated that neural sources generating both stimulation-evoked and spontaneous beta oscillations were correlated in their frequency content and spatial localization. Discussion: Our results support the hypothesis that the same neuronal population and resonance phenomenon in the BGTC circuit generates both spontaneous and evoked pallidal beta oscillations. These data also support the development of closed-loop control systems that modulate the GPi spontaneous oscillations across PD patients using beta band stimulation-evoked responses.

Startle-induced rapid release of a gait initiation sequence in Parkinson's disease with freezing of gait.

OBJECTIVE: Freezing of gait (FOG) in Parkinson's disease (PD) is characterized by the inability to initiate stepping, despite the intention to do so. This study used a startling acoustic stimulus paradigm to examine if the capacity to select, prepare and initiate gait under simple and choice reaction time conditions are impaired in people with PD and FOG. METHODS: Thirty individuals (10 PD with FOG, 10 PD without FOG, and 10 controls) performed an instructed-delay gait initiation task under simple and choice reaction time conditions. In a subset of trials, a startle stimulus (124 dB) was presented 500 ms before the time of the imperative go-cue. Anticipatory postural adjustments preceding and accompanying gait initiation were quantified. RESULTS: The presentation of a startling acoustic stimulus resulted in the rapid initiation of an anticipatory postural adjustment sequence during both the simple and choice reaction time tasks in all groups. CONCLUSIONS: The neural capacity to prepare the spatial and temporal components of gait initiation remains intact in PD individuals with and without FOG. SIGNIFICANCE: The retained capacity to prepare anticipatory postural adjustments in advance may explain why external sensory cues are effective in the facilitation of gait initiation in people with PD with FOG.

Parkinsonian daytime sleep-wake classification using deep brain stimulation lead recordings.

Excessive daytime sleepiness is a recognized non-motor symptom that adversely impacts the quality of life of people with Parkinson's disease (PD), yet effective treatment options remain limited. Deep brain stimulation (DBS) of the subthalamic nucleus (STN) is an effective treatment for PD motor signs. Reliable daytime sleep-wake classification using local field potentials (LFPs) recorded from DBS leads implanted in STN can inform the development of closed-loop DBS approaches for prompt detection and disruption of sleep-related neural oscillations. We performed STN DBS lead recordings in three nonhuman primates rendered parkinsonian by administrating neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Reference sleep-wake states were determined on a second-by-second basis by video monitoring of eyes (eyes-open, wake and eyes-closed, sleep). The spectral power in delta (1-4 Hz), theta (4-8 Hz), low-beta (8-20 Hz), high-beta (20-35 Hz), gamma (35-90 Hz), and high-frequency (200-400 Hz) bands were extracted from each wake and sleep epochs for training (70% data) and testing (30% data) a support vector machines classifier for each subject independently. The spectral features yielded reasonable daytime sleep-wake classification (sensitivity: 90.68 ± 1.28; specificity: 88.16 ± 1.08; accuracy: 89.42 ± 0.68; positive predictive value; 88.70 ± 0.89, n = 3). Our findings support the plausibility of monitoring daytime sleep-wake states using DBS lead recordings. These results could have future clinical implications in informing the development of closed-loop DBS approaches for automatic detection and disruption of sleep-related neural oscillations in people with PD to promote wakefulness.

Postural instability in Parkinson's disease assessed with clinical "pull test" and standardized postural perturbations: effect of medication and body weight support.

OBJECTIVE: This experiment tested if balance performance differed between a standardized treadmill surface perturbation task and a clinical pull test and was affected by medication or the presence of body weight support in people with Parkinson's disease (PD). METHODS: Twenty-seven individuals were tested (14 PD in both ON- and OFF-medication states). Clinical pull test and rapid forward (backward fall) translations of the support surface were applied to induce postural reactions requiring at least 1 step to restore balance. The effects of pull type (clinical vs. treadmill), partial bodyweight support (0 vs 20% body weight) and group (control, PD ON-meds and PD OFF-meds) on reactive stepping as well as practice/learning effect were examined. The number of steps taken and the first step duration were entered in linear repeated-measures mixed-effect models separately. RESULTS: The effects of pull type, group, and bodyweight support were all significant in both metrics, as was ON- vs. OFF-medication. A significant interaction term (group x pull type) was found in the first step duration, showing that the group difference was greater in treadmill compared to the clinical pull test. A significant practice effect was also observed within and across testing sessions. CONCLUSIONS: A standardized treadmill perturbation performed slightly better than the classical pull test in distinguishing between groups, and partial weight support did not substantially degrade the test's performance to detect the balance deficits in people with PD.

Basal ganglia engagement during REM sleep movements in Parkinson's disease.

To elucidate the role of the basal ganglia during REM sleep movements in Parkinson's disease (PD) we recorded pallidal neural activity from four PD patients. Unlike desynchronization commonly observed during wakeful movements, beta oscillations (13-35 Hz) synchronized during REM sleep movements; furthermore, high-frequency oscillations (150-350 Hz) synchronized during movement irrespective of sleep-wake states. Our results demonstrate differential engagement of the basal ganglia during REM sleep and awake movements.

Controlling pallidal oscillations in real-time in Parkinson's disease using evoked interference deep brain stimulation (eiDBS): Proof of concept in the human.

Approaches to control basal ganglia neural activity in real-time are needed to clarify the causal role of 13-35 Hz ("beta band") oscillatory dynamics in the manifestation of Parkinson's disease (PD) motor signs. Here, we show that resonant beta oscillations evoked by electrical pulses with precise amplitude and timing can be used to predictably suppress or amplify spontaneous beta band activity in the internal segment of the globus pallidus (GPi) in the human. Using this approach, referred to as closed-loop evoked interference deep brain stimulation (eiDBS), we could suppress or amplify frequency-specific (16-22 Hz) neural activity in a PD patient. Our results highlight the utility of eiDBS to characterize the role of oscillatory dynamics in PD and other brain conditions, and to develop personalized neuromodulation systems.

Modulation of Beta Oscillations in the Pallidum During Externally Cued Gait.

Freezing of gait (FOG) is a particularly debilitating symptom of Parkinson's disease (PD) and is often refractory to treatment. A striking feature of FOG is that external sensory cues can be used to overcome freezing and improve gait. Local field potentials (LFPs) recorded from the subthalamic nucleus (STN) and globus pallidus (GP) show that beta-band power modulates with gait phase. In the STN, beta-band oscillations are modulated by external cues, but it is unknown if this relationship holds in the globus pallidus (GP). Here we report LFP data recorded from the left GP, using a Medtronic PC + S device, in a 68-year-old man with PD and FOG during treadmill walking. A "stepping stone" task was used during which stepping was cued using visual targets of constant color or targets that unpredictably changed color, requiring a step length adjustment. Gait performance was quantified using measures of treadmill ground reaction forces and center of pressure and body kinematics from video monitoring. Beta-band power (12-30 Hz) and number of freezing episodes were measured. Cues which unpredictably changed color improved FOG more than conventional cues and were associated with greater modulation of beta-band power in phase with gait. This preliminary finding suggests that cueing-induced improvement of FOG may relate to beta-band modulation.

White matter microstructure in Parkinson's disease with and without elevated rapid eye movement sleep muscle tone.

People with Parkinson's disease who have elevated muscle activity during rapid eye movement sleep (REM sleep without atonia) typically have a worse motor and cognitive impairment compared with those with normal muscle atonia during rapid eye movement sleep. This study used tract-based spatial statistics to compare diffusion MRI measures of fractional anisotropy, radial, mean and axial diffusivity (measures of axonal microstructure based on the directionality of water diffusion) in white matter tracts between people with Parkinson's disease with and without rapid eye movement sleep without atonia and controls and their relationship to measures of motor and cognitive function. Thirty-eight individuals with mild-to-moderate Parkinson's disease and 21 matched control subjects underwent ultra-high field MRI (7 T), quantitative motor assessments of gait and bradykinesia and neuropsychological testing. The Parkinson's disease cohort was separated post hoc into those with and without elevated chin or leg muscle activity during rapid eye movement sleep based on polysomnography findings. Fractional anisotropy was significantly higher, and diffusivity significantly lower, in regions of the corpus callosum, projection and association white matter pathways in the Parkinson's group with normal rapid eye movement sleep muscle tone compared with controls, and in a subset of pathways relative to the Parkinson's disease group with rapid eye movement sleep without atonia. The Parkinson's disease group with elevated rapid eye movement sleep muscle tone showed significant impairments in the gait and upper arm speed compared with controls and significantly worse scores in specific cognitive domains (executive function, visuospatial memory) compared with the Parkinson's disease group with normal rapid eye movement sleep muscle tone. Regression analyses showed that gait speed and step length in the Parkinson's disease cohort were predicted by measures of fractional anisotropy of the anterior corona radiata, whereas elbow flexion velocity was predicted by fractional anisotropy of the superior corona radiata. Visuospatial memory task performance was predicted by the radial diffusivity of the posterior corona radiata. These findings show that people with mild-to-moderate severity of Parkinson's disease who have normal muscle tone during rapid eye movement sleep demonstrate compensatory-like adaptations in axonal microstructure that are associated with preserved motor and cognitive function, but these adaptations are reduced or absent in those with increased rapid eye movement sleep motor tone.

Overground versus treadmill walking in Parkinson's disease: Relationship between speed and spatiotemporal gait metrics.

BACKGROUND: Treadmills provide a safe and convenient way to study the gait of people with Parkinson's disease (PD), but outcome measures derived from treadmill gait may differ from overground walking. OBJECTIVE: To investigate how the relationships between gait metrics and walking speed vary between overground and treadmill walking in people with PD and healthy controls. METHODS: We compared 29 healthy controls to 27 people with PD in the OFF-medication state. Subjects first walked overground on an instrumented gait walkway, then on an instrumented treadmill at 85%, 100% and 115% of their overground walking speed. Average stride length and cadence were computed for each subject in both overground and treadmill walking. RESULTS: Stride length and cadence both differed between overground and treadmill walking. Regressions of stride length and cadence on gait speed showed a log-log relationship for both overground and treadmill gait in both PD and control groups. The difference between the PD and control groups during overground gait was maintained for treadmill gait, not only when treadmill speed matched overground speed, but also with ± 15% variation in treadmill speed from that value. SIGNIFICANCE: These results show that the impact of PD on stride length and cadence and their relationship to gait speed is preserved in treadmill as compared to overground walking. We conclude that a treadmill protocol is suitable for laboratory use in studies of PD gait therapeutics.

Can People with Parkinson's Disease Self-Trigger Gait Initiation? A Comparison of Cueing Strategies.

BACKGROUND: An external cue can markedly improve gait initiation in people with Parkinson's disease (PD) and is often used to overcome freezing of gait (FOG). It is unknown if the effects of external cueing are comparable if the imperative stimulus is triggered by the person receiving the cue (self-triggered) or an external source. OBJECTIVE: Two experiments were conducted to compare the effects of self- versus externally triggered cueing on anticipatory postural adjustments (APAs) during gait initiation in people with PD. METHODS: In experiment 1, 10 individuals with PD and FOG initiated gait without a cue or in response to a stimulus triggered by the experimenter or by the participant. Experiment 2 compared self- versus externally triggered cueing across three groups: healthy young adults (n = 16), healthy older adults (n = 11), and a group with PD (n = 10). RESULTS: Experiment 1: Externally triggered cues significantly increased APA magnitudes compared to uncued stepping, but not when the same cue was self-triggered. Experiment 2: APAs were not significantly improved with a self-triggered cue compared to un-cued stepping in both the PD and healthy older adult groups, but the young adults showed a significant facilitation of APA magnitude. CONCLUSION: The effectiveness of an external cue on gait initiation in people with PD and older adults is critically dependent upon whether the source of the trigger is endogenous (self-produced) or exogenous (externally-generated). These results may explain why cueing interventions that rely upon self-triggering of the stimulus are often ineffective in people with PD.

Tremor and Dysmetria in Multiple Sclerosis: A Neurophysiological Study.

Objective: The mechanisms contributing to the pathogenesis of tremor and/or dysmetria in multiple sclerosis (MS) are poorly understood. Abnormal oscillations within the olivo-cerebello-thalamo-cortical networks are believed to play an important part in tremor aetiology, but could also contribute to intention dysmetria due to disruptions in motor timing. Conversely, delayed central motor conduction times are a common feature of ataxias, but could also contribute to the expression of dysmetria in MS. This study examined the roles of central conduction delays in the manifestation of tremor and/or dysmetria in MS. Methods: Twenty-three individuals with MS participated: 8 with no movement disorder, 6 with tremor, 4 with pure dysmetria and 5 with both tremor and dysmetria. Median nerve somatosensory evoked potentials (SEPs), transcranial magnetic stimulation (TMS) over the motor cortex and cervical spine, stretch reflexes were used assess sensory and motor conduction times. Results: Central, but not peripheral, sensory conductions time were significantly delayed in participants with dysmetria, regardless of the presence of tremor. Similarly, the TMS evoked muscles responses and the long-latency component of stretch reflexes were significantly delayed in those with dysmetria, but not pure tremor. Conclusion: Dysmetria in MS is associated with delays in central conduction of sensory or motor pathways, or both, likely leading to disruption of muscle activation timing and terminal oscillations that contribute to dysmetria. Significance: The presence of dysmetria in MS is associated with decreased conduction velocities in central sensory and/or motor pathways likely reflects greater demyelination of these axons compared to those with no movement disorder or pure tremor.

Semi-automated approaches to optimize deep brain stimulation parameters in Parkinson's disease.

BACKGROUND: Deep brain stimulation (DBS) is a treatment option for Parkinson's disease patients when medication does not sufficiently manage their symptoms. DBS can be a highly effect therapy, but only after a time-consuming trial-and-error stimulation parameter adjustment process that is susceptible to clinician bias. This trial-and-error process will be further prolonged with the introduction of segmented electrodes that are now commercially available. New approaches to optimizing a patient's stimulation parameters, that can also handle the increasing complexity of new electrode and stimulator designs, is needed. METHODS: To improve DBS parameter programming, we explored two semi-automated optimization approaches: a Bayesian optimization (BayesOpt) algorithm to efficiently determine a patient's optimal stimulation parameter for minimizing rigidity, and a probit Gaussian process (pGP) to assess patient's preference. Quantified rigidity measurements were obtained using a robotic manipulandum in two participants over two visits. Rigidity was measured, in 5Hz increments, between 10-185Hz (total 30-36 frequencies) on the first visit and at eight BayesOpt algorithm-selected frequencies on the second visit. The participant was also asked their preference between the current and previous stimulation frequency. First, we compared the optimal frequency between visits with the participant's preferred frequency. Next, we evaluated the efficiency of the BayesOpt algorithm, comparing it to random and equal interval selection of frequency. RESULTS: The BayesOpt algorithm estimated the optimal frequency to be the highest tolerable frequency, matching the optimal frequency found during the first visit. However, the participants' pGP models indicate a preference at frequencies between 70-110 Hz. Here the stimulation frequency is lowest that achieves nearly maximal suppression of rigidity. BayesOpt was efficient, estimating the rigidity response curve to stimulation that was almost indistinguishable when compared to the longer brute force method. CONCLUSIONS: These results provide preliminary evidence of the feasibility to use BayesOpt for determining the optimal frequency, while pGP patient's preferences include more difficult to measure outcomes. Both novel approaches can shorten DBS programming and can be expanded to include multiple symptoms and parameters.

Motor Dysfunction in REM Sleep Behavior Disorder: A Rehabilitation Framework for Prodromal Synucleinopathy.

Parkinson disease (PD) and other related diseases with α-synuclein pathology are associated with a long prodromal or preclinical stage of disease. Predictive models based on diagnosis of idiopathic rapid eye movement (REM) sleep behavior disorder (iRBD) make it possible to identify people in the prodromal stage of synucleinopathy who have a high probability of future disease and provide an opportunity to implement neuroprotective therapies. However, rehabilitation providers may be unaware of iRBD and the motor abnormalities that indicate early motor system dysfunction related to α-synuclein pathology. Furthermore, there is no existing rehabilitation framework to guide early interventions for people with iRBD. The purpose of this work is to (1) review extrapyramidal signs of motor system dysfunction in people with iRBD and (2) propose a framework for early protective or preventive therapies in prodromal synucleinopathy using iRBD as a predictive marker. Longitudinal and cross-sectional studies indicate that the earliest emerging motor deficits in iRBD are bradykinesia, deficits performing activities of daily living, and abnormalities in speech, gait, and posture. These deficits may emerge up to 12 years before a diagnosis of synucleinopathy. The proposed rehabilitation framework for iRBD includes early exercise-based interventions of aerobic exercise, progressive resistance training, and multimodal exercise with rehabilitation consultations to address exercise prescription, progression, and monitoring. This rehabilitation framework may be used to implement neuroprotective, multidisciplinary, and proactive clinical care in people with a high likelihood of conversion to PD, dementia with Lewy bodies, or multiple systems atrophy.

REM Sleep Without Atonia and Gait Impairment in People with Mild-to-Moderate Parkinson's Disease.

BACKGROUND: Subtle gait deficits can be seen in people with idiopathic rapid eye movement (REM) sleep behavior disorder (RBD), a prodromal stage of Parkinson's disease (PD) and related alpha-synucleinopathies. It is unknown if the presence and level of REM sleep without atonia (RSWA, the electromyographic hallmark of RBD) is related to the severity of gait disturbances in people with PD. OBJECTIVE: We hypothesized that gait disturbances in people with mild-to-moderate PD would be greater in participants with RSWA compared to those without RSWA and matched controls, and that gait impairment would correlate with measures of RSWA. METHODS: Spatiotemporal characteristics of gait were obtained from 41 people with PD and 21 age-matched controls. Overnight sleep studies were used to quantify muscle activity during REM sleep and group participants with PD into those with RSWA (PD-RSWA+, n = 22) and normal REM sleep muscle tone (PD-RSWA-, n = 19). Gait characteristics were compared between groups and correlated to RSWA. RESULTS: The PD-RSWA+ group demonstrated significantly reduced gait speed and step lengths and increased stance and double support times compared to controls, and decreased speed and cadence and increased stride velocity variability compared to PD-RSWA- group. Larger RSWA scores were correlated with worse gait impairment in the PD group. CONCLUSION: The presence and level of muscle tone during REM sleep is associated with the severity of gait disturbances in PD. Pathophysiological processes contributing to disordered gait may occur earlier and/or progress more rapidly in people with PD and RBD.

Comparison of forward and backward postural perturbations in mild-to-moderate Parkinson's disease.

BACKGROUND: Assessing postural stability in Parkinson's disease (PD) often relies on measuring the stepping response to an imposed postural perturbation. The standard clinical technique relies on a brisk backwards pull at the shoulders by the examiner and judgement by a trained rater. In research settings, various quantitative measures and perturbation directions have been tested, but it is unclear which metrics and perturbation direction differ most between people with PD and controls. OBJECTIVES: (1) Use standardized forward vs. backward perturbations of a support surface to evaluate reactive stepping performance between PD and control participants. (2) Evaluate the utility of using principal components analysis to capture the dynamics of the reactive response and differences between groups. METHODS: Sixty-two individuals participated (40 mild-to-moderate PD, off medication). Standardized rapid translations of the support surface were applied, requiring at least one step, backward or forward, to restore balance. The number of steps taken and the projection of the first principal component (PC1) of the center of pressure (COP) time series were entered in linear repeated-measures mixed effect models. RESULTS: Forward falls required significantly fewer steps to recover than backward falls. PC1 captured more than half of the variance in the COP trajectory. Analysis of the PC1 projection revealed a significant interaction effect of group (PD vs. controls) by direction, such that there was a group difference in forward stepping, but not backward. SIGNIFICANCE: Forward reactive stepping in PD differed from controls more than backward-stepping. PC1 projections of the COP trajectory capture the dynamics of the postural response and differ between PD and controls.

Motor Unit Discharge Variability Is Increased in Mild-To-Moderate Parkinson's Disease.

Individuals with Parkinson's disease (PD) demonstrate deficits in muscle activation such as decreased amplitude and inappropriate bursting. There is evidence that some of these disturbances are more pronounced in extensor vs. flexor muscles. Surface EMG has been used widely to quantify muscle activation deficits in PD, but analysis of discharge of the underlying motor units may provide greater insight and be more sensitive to changes early in the disease. Of the few studies that have examined motor unit discharge in PD, the majority were conducted in the first dorsal interosseous, and no studies have measured motor units from extensor and flexor muscles within the same cohort. The objective of this study was to characterize the firing behavior of single motor units in the elbow flexor and extensor muscles during isometric contractions in people with mild-to-moderate PD. Ten individuals with PD (off-medication) and nine healthy controls were tested. Motor unit spike times were recorded via intramuscular EMG from the biceps and triceps brachii muscles during 30-s isometric contractions at 10% maximum voluntary elbow flexion and elbow extension torque, respectively. We selected variables of mean motor unit discharge rate, discharge variability, and torque variability to evaluate motor abnormalities in the PD group. The effects of group, muscle, and group-by-muscle on each variable were determined using separate linear mixed models. Discharge rate and torque variability were not different between groups, but discharge variability was significantly higher in the PD group for both muscles combined (p < 0.0001). We also evaluated the asymmetry in these motor variables between the triceps and biceps for each individual participant with PD to evaluate whether there was an association with disease severity. The difference in torque variability between elbow flexion and extension was significantly correlated with both the Hoehn and Yahr scale (rho = 0.71) and UPDRS (rho = 0.62). Our findings demonstrate that variability in motor output, rather than decreased discharge rates, may contribute to motor dysfunction in people with mild-to-moderate PD. Our findings provide insight into altered neural control of movement in PD and demonstrate the importance of measuring from multiple muscles within the same cohort.

REM sleep without atonia is associated with increased rigidity in patients with mild to moderate Parkinson's disease.

OBJECTIVE: Increased muscle activity during rapid eye movement (REM) sleep (i.e. REM sleep without atonia) is common in people with Parkinson's disease (PD). This study tested the hypotheses that people with PD and REM sleep without atonia (RSWA) would present with more severe and symmetric rigidity compared to individuals with PD without RSWA and age-matched controls. METHODS: Sixty-one individuals participated in this study (41 PD, 20 controls). An overnight sleep study was used to classify participants with PD as having either elevated (PD-RSWA+) or normal muscle activity (PD-RSWA-) during REM sleep. Quantitative measures of rigidity were obtained using a robotic manipulandum that passively pronated and supinated the forearm. RESULTS: Quantitative measures of forearm rigidity were significantly higher in the PD-RSWA+ group compared to the control group. Rigidity was significantly more asymmetric between limbs in the PD-RSWA- group compared with controls, while there was no significant difference in symmetry between the control and PD-RSWA+ groups. CONCLUSION: In people with mild to moderate PD, RSWA is associated with an increased and more symmetric presentation of upper limb rigidity. SIGNIFICANCE: Dysfunction of brainstem systems that control muscle tone during REM sleep may contribute to increased rigidity during wakefulness in people with PD.