Connecting the dots: Sensory cueing enhances functional connectivity between pre-motor and supplementary motor areas in Parkinson's disease.

People with Parkinson's disease often exhibit improvements in motor tasks when exposed to external sensory cues. While the effects of different types of sensory cues on motor functions in Parkinson's disease have been widely studied, the underlying neural mechanism of these effects and the potential of sensory cues to alter the motor cortical activity patterns and functional connectivity of cortical motor areas are still unclear. This study aims to compare changes in oxygenated haemoglobin, deoxygenated haemoglobin and correlations among different cortical regions of interest during wrist movement under different external stimulus conditions between people with Parkinson's disease and controls. Ten Parkinson's disease patients and 10 age- and sex-matched neurologically healthy individuals participated, performing repetitive wrist flexion and extension tasks under auditory and visual cues. Changes in oxygenated and deoxygenated haemoglobin in motor areas were measured using functional near-infrared spectroscopy, along with electromyograms from wrist muscles and wrist movement kinematics. The functional near-infrared spectroscopy data revealed significantly higher neural activity changes in the Parkinson's disease group's pre-motor area compared to controls (p = 0.006), and functional connectivity between the supplementary motor area and pre-motor area was also significantly higher in the Parkinson's disease group when external sensory cues were present (p = 0.016). These results indicate that external sensory cues' beneficial effects on motor tasks are linked to changes in the functional connectivity between motor areas responsible for planning and preparation of movements.

Circadian dysfunction and fluctuations in gait initiation impairment in Parkinson's disease.

In people with Parkinson's disease (PD), anticipatory postural adjustments may be prolonged, reduced in amplitude, or absent, contributing to impaired gait initiation. In addition to motor symptoms, disturbance of the circadian rhythm (CR) is one of the common non-motor symptoms of PD. The purpose of this study was to investigate whether time of day modulates the magnitude of gait initiation impairment, and furthermore, if there is any relationship between CR dysfunction and impaired postural control in PD. Seven consecutive 24-h periods of wrist actigraphy (as a measure of CR), and then gait initiation studies (at two different times, 9:00 a.m. and 2:30 p.m., of the same day) were conducted in two cohorts of ten subjects each: people with PD, and age-matched control subjects. We found that in the PD group, the amplitude of medial/lateral center of pressure (CoP) excursions were significantly reduced in the afternoon as compared with the morning session across all trials (p < 0.05). Actigraphy results showed that CR amplitude was significantly decreased (p < 0.05) in the PD group, which suggests that the PD group suffered from CR disruption. More importantly, changes in medial/lateral CoP displacement were correlated with abnormal CR amplitude in the PD group. These findings provide novel evidence that diurnal fluctuations in treatment-resistant motor symptoms of PD, such as postural and gait initiation deficits, are associated with CR dysfunction. This study supports the idea that therapeutic correction of circadian misalignment should be considered in combination with pharmaceutical and rehabilitation treatments of motor symptoms in PD.

Subliminal gait initiation deficits in rapid eye movement sleep behavior disorder: A harbinger of freezing of gait?

BACKGROUND: Muscle activity during rapid eye movement sleep is markedly increased in people with rapid eye movement sleep behavior disorder and people with Parkinson's disease (PD) who have freezing of gait. This study examined whether individuals with rapid eye movement sleep behavior disorder who do not have a diagnosis of PD show abnormalities in gait initiation that resemble the impairments observed in PD and whether there is a relationship between these deficits and the level of rapid eye movement sleep without atonia. METHODS: Gait initiation and polysomnography studies were conducted in 4 groups of 10 participants: rapid eye movement sleep behavior disorder, PD with and without freezing of gait, and controls. RESULTS: Significant reductions were seen in the posterior shift of the center of pressure during the propulsive phase of gait initiation in the groups with rapid eye movement sleep behavior disorder and PD with freezing of gait when compared with controls and PD nonfreezers. These reductions negatively correlated with the amount of rapid eye movement sleep without atonia. The duration of the initial dorsiflexor muscle burst during gait initiation was significantly reduced in both PD groups and the rapid eye movement sleep behavior disorder cohort. CONCLUSIONS: These results provide evidence that people with rapid eye movement sleep behavior disorder, prior to a diagnosis of a degenerative neurologic disorder, show alterations in the coupling of posture and gait similar to those seen in PD. The correlation between increased rapid eye movement sleep without atonia and deficits in forward propulsion during the push-off phase of gait initiation suggests that abnormities in the regulation of muscle tone during rapid eye movement sleep may be related to the pathogenesis of freezing of gait. © 2016 International Parkinson and Movement Disorder Society.

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.

Dynamic causal modeling of reorganization of memory and language networks in temporal lobe epilepsy.

OBJECTIVE: To evaluate the alterations of language and memory functions using dynamic causal modeling, in order to identify the epileptogenic hemisphere in temporal lobe epilepsy (TLE). METHODS: Twenty-two patients with left TLE and 13 patients with right TLE underwent functional magnetic resonance imaging (fMRI) during four memory and four language mapping tasks. Dynamic causal modeling (DCM) was employed on fMRI data to examine effective directional connectivity in memory and language networks and the alterations in people with TLE compared to healthy individuals. RESULTS: DCM analysis suggested that TLE can influence the memory network more widely compared to the language network. For memory mapping, it demonstrated overall hyperconnectivity from the left hemisphere to the other cranial regions in the picture encoding, and from the right hemisphere to the other cranial regions in the word encoding tasks. On the contrary, overall hypoconnectivity was seen from the brain hemisphere contralateral to the seizure onset in the retrieval tasks. DCM analysis further manifested hypoconnectivity between the brain's hemispheres in the language network in patients with TLE compared to controls. The CANTAB® neuropsychological test revealed a negative correlation for the left TLE and a positive correlation for the right TLE cohorts for the connections extracted by DCM that were significantly different between the left and right TLE cohorts. INTERPRETATION: In this study, dynamic causal modeling evidenced the reorganization of language and memory networks in TLE that can be used for a better understanding of the effects of TLE on the brain's cognitive functions.

The early release of planned movement by acoustic startle can be delayed by transcranial magnetic stimulation over the motor cortex.

Previous studies have shown that preplanned movements can be rapidly released when a startling acoustic stimulus (SAS) is presented immediately prior to, or coincident with, the imperative signal to initiate movement. Based on the short latency of the onset of muscle activity (typically in less than 90 ms) and the frequent co-expression of startle responses in the neck and eye muscles, it has been proposed that the release of planned movements by a SAS is mediated by subcortical, possibly brainstem, pathways. However, a role for cortical structures in mediating these responses cannot be ruled out based on timing arguments alone. We examined the role of the cortex in the mediation of these responses by testing if a suprathreshold transcranial magnetic stimulation applied over the primary motor cortex, which suppresses voluntary drive and is known to delay movement initiation, could delay the release of movement by a SAS. Eight subjects performed an instructed-delay task requiring them to make a ballistic wrist movement to a target in response to an acoustic tone (control task condition). In a subset of trials subjects received one of the following: (1) suprathreshold TMS over the contralateral primary motor cortex 70 ms prior to their mean response time on control trials (TMS(CT)), (2) SAS 200 ms prior to the go cue (SAS), (3) suprathreshold TMS 70 ms prior to the mean SAS-evoked response time (TMS(SAS)), or (4) TMS(SAS) and SAS presented concurrently (TMS+SAS). Movement kinematics and EMG from the wrist extensors and flexors and sternocleidomastoid muscles were recorded. The application of TMS(CT) prior to control voluntary movements produced a significant delay in movement onset times (P < 0.001) (average delay = 37.7 ± 12.8 ms). The presentation of a SAS alone at -200 ms resulted in the release of the planned movement an average of 71.7 ± 2.7 ms after the startling stimulus. The early release of movement by a SAS was significantly delayed (P < 0.001, average delay = 35.0 ± 12.9 ms) when TMS(SAS) and SAS were presented concurrently. This delay could not be explained by a prolonged suppression of motor unit activity at the spinal level. These findings provide evidence that the release of targeted ballistic wrist movements by SAS is mediated, in part, by a fast conducting transcortical pathway via the primary motor cortex.

Impaired muscle phasing systematically adapts to varied relative angular relationships during locomotion in people poststroke.

After stroke, hemiparesis will result in impairments to locomotor control. Specifically, muscle coordination deficits, in the form of inappropriately phased muscle-activity patterns, occur in both the paretic and nonparetic limbs. These dysfunctional paretic muscle-coordination patterns can adapt to somatosensory inputs, and also the sensorimotor state of nonparetic limb can influence paretic limb. However, the relative contribution of interlimb pathways for improving paretic muscle-activation patterns in terms of phasing remains unknown. In this study, we investigated whether the paretic muscle-activity phasing can be influenced by the relative angular-spatial relationship of the nonparetic limb by using a split-crank ergometer, where the cranks could be decoupled. Eighteen participants with chronic stroke were asked to pedal bilaterally during each task while surface electromyogram signals were recorded bilaterally from four lower extremity muscles (vastus medialis, rectus femoris, tibialis anterior, and soleus). During each experiment, the relative angular crank positions were manipulated by increasing or decreasing their difference by randomly ordered increments of 30° over the complete cycle [0° (in phase pedaling), 30°, 60°, 90°, 120°, 150°, 180° (standard pedaling), 210°, 240°, 270°, 300°, 330° (out of phase pedaling)]. We found that the paretic and nonparetic muscle phasing in the cycle systematically adapted to varied relative angular relationships, and this systematic relationship was well modeled by a sinusoidal relationship. Also, the paretic uniarticular muscle (vastus medialis) showed larger phase shifts compared with biarticular muscle (rectus femoris). More importantly, for each stroke subject, we demonstrated an exclusive crank-angular relation that resulted in the generation of more appropriately phased paretic muscle activity. These findings provide new evidence to better understand the capability of impaired nervous system to produce a more normalized muscle-phasing pattern poststroke.

Relative temporal leading or following position of the contralateral limb generates different aftereffects in muscle phasing following adaptation training post-stroke.

Locomotor coordination depends on precise and appropriate adjustments of intra- and interlimb muscle activity phasing. Muscle coordination deficits, in the form of inappropriately phased muscle activity patterns, are well recognized in both the paretic and non-paretic limbs of stroke survivors. Our recent work demonstrated that muscle phasing can be systematically influenced by changing the relative angular positions of limbs in both neurologically intact individuals and people post-stroke. However, it is still unknown whether the observed transient changes in adjusted muscle phasing can be adapted following a short-bout of training on the split-crank ergometer. To explore the extent to which the non-paretic and paretic limbs of people with stroke can adapt to new muscle activity phasing changes, we examined the adaptation of muscle phasing following a short-bout of pedaling training at two specific relative spatial angular positions of limbs that had caused the greatest phasing changes in our previous studies. Twelve individuals with post-cerebral stroke and twelve age- and gender-matched control subjects participated in this study. We demonstrated that both intact and cerebrally impaired nervous systems are capable of adapting new muscle phasing patterns and producing aftereffects that persisted for at least 10 min. However, we observed a completely different trend of aftereffects in post-stroke subjects compared with controls. Specifically, in controls, the aftereffects were observed only in the leg that was in the following position during the adaptation training whereas in post-stroke subjects, aftereffects were observed only in the leg that acted as the leading leg during adaptation, regardless of the limb being paretic or non-paretic. These findings suggest that adapting a new muscle activity pattern during a bilateral locomotor task depends mainly on the relative temporal position of contralateral limb.

Bilateral limb phase relationship and its potential to alter muscle activity phasing during locomotion.

It is well established that the sensorimotor state of one limb can influence another limb and therefore bilateral somatosensory inputs make an important contribution to interlimb coordination patterns. However, the relative contribution of interlimb pathways for modifying muscle activation patterns in terms of phasing is less clear. Here we studied adaptation of muscle activity phasing to the relative angular positions of limbs using a split-crank ergometer, where the cranks could be decoupled to allow different spatial angular position relationships. Twenty neurologically healthy individuals performed the specified pedaling tasks at different relative angular positions while surface electromyographic (EMG) signals were recorded bilaterally from eight lower extremity muscles. During each experiment, the relative angular crank positions were altered by increasing or decreasing their difference by randomly ordered increments of 30 degrees over the complete cycle [0 degrees (in phase pedaling); 30, 60, 90, 120, 150, and 180 degrees (standard pedaling); and 210, 240, 270, 300, and 330 degrees out of phase pedaling]. We found that manipulating the relative angular positions of limbs in a pedaling task caused muscle activity phasing changes that were either delayed or advanced, dependent on the relative spatial position of the two cranks and this relationship is well-explained by a sine curve. Further, we observed that the magnitude of phasing changes in biarticular muscles (like rectus femoris) was significantly greater than those of uniarticular muscles (like vastus medialis). These results are important because they provide new evidence that muscle phasing can be systematically influenced by interlimb pathways.

Muscle and reflex changes with varying joint angle in hemiparetic stroke.

BACKGROUND: Despite intensive investigation, the origins of the neuromuscular abnormalities associated with spasticity are not well understood. In particular, the mechanical properties induced by stretch reflex activity have been especially difficult to study because of a lack of accurate tools separating reflex torque from torque generated by musculo-tendinous structures. The present study addresses this deficit by characterizing the contribution of neural and muscular components to the abnormally high stiffness of the spastic joint. METHODS: Using system identification techniques, we characterized the neuromuscular abnormalities associated with spasticity of ankle muscles in chronic hemiparetic stroke survivors. In particular, we systematically tracked changes in muscle mechanical properties and in stretch reflex activity during changes in ankle joint angle. Modulation of mechanical properties was assessed by applying perturbations at different initial angles, over the entire range of motion (ROM). Experiments were performed on both paretic and non-paretic sides of stroke survivors, and in healthy controls. RESULTS: Both reflex and intrinsic muscle stiffnesses were significantly greater in the spastic/paretic ankle than on the non-paretic side, and these changes were strongly position dependent. The major reflex contributions were observed over the central portion of the angular range, while the intrinsic contributions were most pronounced with the ankle in the dorsiflexed position. CONCLUSION: In spastic ankle muscles, the abnormalities in intrinsic and reflex components of joint torque varied systematically with changing position over the full angular range of motion, indicating that clinical perceptions of increased tone may have quite different origins depending upon the angle where the tests are initiated.Furthermore, reflex stiffness was considerably larger in the non-paretic limb of stroke patients than in healthy control subjects, suggesting that the non-paretic limb may not be a suitable control for studying neuromuscular properties of the ankle joint. Our findings will help elucidate the origins of the neuromuscular abnormalities associated with stroke-induced spasticity.

The relation between Ashworth scores and neuromechanical measurements of spasticity following stroke.

BACKGROUND: Spasticity is a common impairment that follows stroke, and it results typically in functional loss. For this reason, accurate quantification of spasticity has both diagnostic and therapeutic significance. The most widely used clinical assessment of spasticity is the modified Ashworth scale (MAS), an ordinal scale, but its validity, reliability and sensitivity have often been challenged. The present study addresses this deficit by examining whether quantitative measures of neural and muscular components of spasticity are valid, and whether they are strongly correlated with the MAS. METHODS: We applied abrupt small amplitude joint stretches and Pseudorandom Binary Sequence (PRBS) perturbations to both paretic and non-paretic elbow and ankle joints of stroke survivors. Using advanced system identification techniques, we quantified the dynamic stiffness of these joints, and separated its muscular (intrinsic) and reflex components. The correlations between these quantitative measures and the MAS were investigated. RESULTS: We showed that our system identification technique is valid in characterizing the intrinsic and reflex stiffness and predicting the overall net torque. Conversely, our results reveal that there is no significant correlation between muscular and reflex torque/stiffness and the MAS magnitude. We also demonstrate that the slope and intercept of reflex and intrinsic stiffnesses plotted against the joint angle are not correlated with the MAS. CONCLUSION: Lack of significant correlation between our quantitative measures of stroke effects on spastic joints and the clinical assessment of muscle tone, as reflected in the MAS suggests that the MAS does not provide reliable information about the origins of the torque change associated with spasticity, or about its contributing components.