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.

Free-water imaging in Parkinson's disease and atypical parkinsonism.

Conventional single tensor diffusion analysis models have provided mixed findings in the substantia nigra of Parkinson's disease, but recent work using a bi-tensor analysis model has shown more promising results. Using a bi-tensor model, free-water values were found to be increased in the posterior substantia nigra of Parkinson's disease compared with controls at a single site and in a multi-site cohort. Further, free-water increased longitudinally over 1 year in the posterior substantia nigra of Parkinson's disease. Here, we test the hypothesis that other parkinsonian disorders such as multiple system atrophy and progressive supranuclear palsy have elevated free-water in the substantia nigra. Equally important, however, is whether the bi-tensor diffusion model is able to detect alterations in other brain regions beyond the substantia nigra in Parkinson's disease, multiple system atrophy, and progressive supranuclear palsy and to accurately distinguish between these diseases. Free-water and free-water-corrected fractional anisotropy maps were compared across 72 individuals in the basal ganglia, midbrain, thalamus, dentate nucleus, cerebellar peduncles, cerebellar vermis and lobules V and VI, and corpus callosum. Compared with controls, free-water was increased in the anterior and posterior substantia nigra of Parkinson's disease, multiple system atrophy, and progressive supranuclear palsy. Despite no other changes in Parkinson's disease, we observed elevated free-water in all regions except the dentate nucleus, subthalamic nucleus, and corpus callosum of multiple system atrophy, and in all regions examined for progressive supranuclear palsy. Compared with controls, free-water-corrected fractional anisotropy values were increased for multiple system atrophy in the putamen and caudate, and increased for progressive supranuclear palsy in the putamen, caudate, thalamus, and vermis, and decreased in the superior cerebellar peduncle and corpus callosum. For all disease group comparisons, the support vector machine 10-fold cross-validation area under the curve was between 0.93-1.00 and there was high sensitivity and specificity. The regions and diffusion measures selected by the model varied across comparisons and are consistent with pathological studies. In conclusion, the current study used a novel bi-tensor diffusion analysis model to indicate that all forms of parkinsonism had elevated free-water in the substantia nigra. Beyond the substantia nigra, both multiple system atrophy and progressive supranuclear palsy, but not Parkinson's disease, showed a broad network of elevated free-water and altered free-water corrected fractional anisotropy that included the basal ganglia, thalamus, and cerebellum. These findings may be helpful in the differential diagnosis of parkinsonian disorders, and thereby facilitate the development and assessment of targeted therapies.

Distinct patterns of brain activity in progressive supranuclear palsy and Parkinson's disease.

The basal ganglia-thalamo-cortical and cerebello-thalamo-cortical circuits are important for motor control. Whether their functioning is affected in a similar or different way by progressive supranuclear palsy (PSP) and Parkinson's disease (PD) is not clear. A functional magnetic resonance imaging (fMRI) force production paradigm and voxel-based morphometry were used to assess differences in brain activity and macrostructural volumes between PSP, PD, and healthy age-matched controls. We found that PSP and PD share reduced functional activity of the basal ganglia and cortical motor areas, but this is more pronounced in PSP than in PD. In PSP the frontal regions are underactive, whereas the posterior parietal and occipital regions are overactive as compared with controls and PD. Furthermore, lobules I through IV, V, and VI of the cerebellum are hypoactive in PSP and PD, whereas Crus I and lobule IX are hyperactive in PSP only. Reductions in gray and white matter volume are specific to PSP. Finally, the functional status of the caudate as well as the volume of the superior frontal gyrus predict clinical gait and posture measures in PSP. PSP and PD share hypoactivity of the basal ganglia, motor cortex, and anterior cerebellum. These patients also display a unique pattern, such that anterior regions of the cortex are hypoactive and posterior regions of the cortex and cerebellum are hyperactive. Together, these findings suggest that specific structures within the basal ganglia, cortex, and cerebellum are affected differently in PSP relative to PD.

Longitudinal changes in free-water within the substantia nigra of Parkinson's disease.

There is a clear need to develop non-invasive markers of substantia nigra progression in Parkinson's disease. We previously found elevated free-water levels in the substantia nigra for patients with Parkinson's disease compared with controls in single-site and multi-site cohorts. Here, we test the hypotheses that free-water levels in the substantia nigra of Parkinson's disease increase following 1 year of progression, and that baseline free-water levels in the substantia nigra predict the change in bradykinesia following 1 year. We conducted a longitudinal study in controls (n = 19) and patients with Parkinson's disease (n = 25). Diffusion imaging and clinical data were collected at baseline and after 1 year. Free-water analyses were performed on diffusion imaging data using blinded, hand-drawn regions of interest in the posterior substantia nigra. A group effect indicated free-water values were increased in the posterior substantia nigra of patients with Parkinson's disease compared with controls (P = 0.003) and we observed a significant group × time interaction (P < 0.05). Free-water values increased for the Parkinson's disease group after 1 year (P = 0.006), whereas control free-water values did not change. Baseline free-water values predicted the 1 year change in bradykinesia scores (r = 0.74, P < 0.001) and 1 year change in Montreal Cognitive Assessment scores (r = -0.44, P = 0.03). Free-water in the posterior substantia nigra is elevated in Parkinson's disease, increases with progression of Parkinson's disease, and predicts subsequent changes in bradykinesia and cognitive status over 1 year. These findings demonstrate that free-water provides a potential non-invasive progression marker of the substantia nigra.

Increased free water in the substantia nigra of Parkinson's disease: a single-site and multi-site study.

Measures from diffusion magnetic resonance imaging reflect changes in the substantia nigra of Parkinson's disease. It is the case, however, that partial volume effects from free water can bias diffusion measurements. The bi-tensor diffusion model was introduced to quantify the contribution of free water and eliminates its bias on estimations of tissue microstructure. Here, we test the hypothesis that free water is elevated in the substantia nigra for Parkinson's disease compared with control subjects. This hypothesis was tested between large cohorts of Parkinson's disease and control participants in a single-site study and validated against a multisite study using multiple scanners. The fractional volume of free water was increased in the posterior region of the substantia nigra in Parkinson's disease compared with control subjects in both the single-site and multi-site studies. We did not observe changes in either cohort for free-water-corrected fractional anisotropy or free-water-corrected mean diffusivity. Our findings provide new evidence that the free-water index reflects alteration of the substantia nigra in Parkinson's disease, and this was evidenced across both single-site and multi-site cohorts.

Distinct functional and macrostructural brain changes in Parkinson's disease and multiple system atrophy.

Parkinson's disease (PD) and the parkinsonian variant of multiple system atrophy (MSAp) are neurodegenerative disorders that can be difficult to differentiate clinically. This study provides the first characterization of the patterns of task-related functional magnetic resonance imaging (fMRI) changes across the whole brain in MSAp. We used fMRI during a precision grip force task and also performed voxel-based morphometry (VBM) on T1 -weighted images in MSAp patients, PD patients, and healthy controls. All groups were matched on age, and the patient groups had comparable motor symptom durations and severities. There were three main findings. First, MSAp and PD had reduced fMRI activation in motor control areas, including the basal ganglia, thalamus, insula, primary sensorimotor and prefrontal cortices, and cerebellum compared with controls. Second, there were no activation differences among the disease groups in the basal ganglia, thalamus, insula, or primary sensorimotor cortices, but PD had more extensive activation deficits throughout the cerebrum compared with MSAp and controls. Third, VBM revealed reduced volume in the basal ganglia, middle and inferior cerebellar peduncles, pons, and throughout the cerebrum in MSAp compared with controls and PD, and additionally throughout the cerebellar cortex and vermis in MSAp compared with controls. Collectively, these results provide the first evidence that fMRI activation is abnormal in the basal ganglia, cerebellum, and cerebrum in MSAp, and that a key distinguishing feature between MSAp and PD is the extensive and widespread volume loss throughout the brain in MSAp.

Functional Brain Activity Relates to 0-3 and 3-8 Hz Force Oscillations in Essential Tremor.

It is well-established that during goal-directed motor tasks, patients with essential tremor have increased oscillations in the 0-3 and 3-8 Hz bands. It remains unclear if these increased oscillations relate to activity in specific brain regions. This study used task-based functional magnetic resonance imaging to compare the brain activity associated with oscillations in grip force output between patients with essential tremor, patients with Parkinson's disease who had clinically evident tremor, and healthy controls. The findings demonstrate that patients with essential tremor have increased brain activity in the motor cortex and supplementary motor area compared with controls, and this activity correlated positively with 3-8 Hz force oscillations. Brain activity in cerebellar lobules I-V was reduced in essential tremor compared with controls and correlated negatively with 0-3 Hz force oscillations. Widespread differences in brain activity were observed between essential tremor and Parkinson's disease. Using functional connectivity analyses during the task evidenced reduced cerebellar-cortical functional connectivity in patients with essential tremor compared with controls and Parkinson's disease. This study provides new evidence that in essential tremor 3-8 Hz force oscillations relate to hyperactivity in motor cortex, 0-3 Hz force oscillations relate to the hypoactivity in the cerebellum, and cerebellar-cortical functional connectivity is impaired.

MRI reveals brain abnormalities in drug-naive Parkinson's disease.

Most brain studies of Parkinson's disease (PD) focus on patients who are already taking antiparkinsonian medication. This makes it difficult to isolate the effects of disease from those of treatment. We review magnetic resonance imaging evidence supporting the hypothesis that early-stage untreated PD patients have structural and functional abnormalities in the brain, some of which are related to motor symptoms.

Diffusion tensor imaging of Parkinson's disease, atypical parkinsonism, and essential tremor.

Diffusion tensor imaging could be useful in characterizing movement disorders because it noninvasively examines multiple brain regions simultaneously. We report a multitarget imaging approach focused on the basal ganglia and cerebellum in Parkinson's disease, parkinsonian variant of multiple system atrophy, progressive supranuclear palsy, and essential tremor and in healthy controls. Seventy-two subjects were studied with a diffusion tensor imaging protocol at 3 Tesla. Receiver operating characteristic analysis was performed to directly compare groups. Sensitivity and specificity values were quantified for control versus movement disorder (92% sensitivity, 88% specificity), control versus parkinsonism (93% sensitivity, 91% specificity), Parkinson's disease versus atypical parkinsonism (90% sensitivity, 100% specificity), Parkinson's disease versus multiple system atrophy (94% sensitivity, 100% specificity), Parkinson's disease versus progressive supranuclear palsy (87% sensitivity, 100% specificity), multiple system atrophy versus progressive supranuclear palsy (90% sensitivity, 100% specificity), and Parkinson's disease versus essential tremor (92% sensitivity, 87% specificity). The brain targets varied for each comparison, but the substantia nigra, putamen, caudate, and middle cerebellar peduncle were the most frequently selected brain regions across classifications. These results indicate that using diffusion tensor imaging of the basal ganglia and cerebellum accurately classifies subjects diagnosed with Parkinson's disease, atypical parkinsonism, and essential tremor and clearly distinguishes them from control subjects.

Force control deficits in individuals with Parkinson's disease, multiple systems atrophy, and progressive supranuclear palsy.

OBJECTIVE: This study examined grip force and cognition in Parkinson's disease (PD), Parkinsonian variant of multiple system atrophy (MSAp), progressive supranuclear palsy (PSP), and healthy controls. PD is characterized by a slower rate of force increase and decrease and the production of abnormally large grip forces. Early-stage PD has difficulty with the rapid contraction and relaxation of hand muscles required for precision gripping. The first goal was to determine which features of grip force are abnormal in MSAp and PSP. The second goal was to determine whether a single variable or a combination of motor and cognitive measures would distinguish patient groups. Since PSP is more cognitively impaired relative to PD and MSAp, we expected that combining motor and cognitive measures would further distinguish PSP from PD and MSAp. METHODS: We studied 44 participants: 12 PD, 12 MSAp, 8 PSP, and 12 controls. Patients were diagnosed by a movement disorders neurologist and were tested off anti-Parkinsonian medication. Participants completed a visually guided grip force task wherein force pulses were produced for 2 s, followed by 1 s of rest. We also conducted four cognitive tests. RESULTS: PD, MSAp, and PSP were slower at contracting and relaxing force and produced longer pulse durations compared to controls. PSP produced additional force pulses during the task and were more cognitively impaired relative to other groups. A receiver operator characteristic analysis revealed that the combination of number of pulses and Brief Test of Attention (BTA) discriminated PSP from PD, MSAp, and controls with a high degree of sensitivity and specificity. CONCLUSIONS: Slowness in contracting and relaxing force represent general features of PD, MSAp, and PSP, whereas producing additional force pulses was specific to PSP. Combining motor and cognitive measures provides a robust method for characterizing behavioral features of PSP compared to MSAp and PD.

Differences in brain activation between tremor- and nontremor-dominant Parkinson disease.

OBJECTIVE To compare differences in functional brain activity between tremor- and nontremor-dominant subtypes of Parkinson disease (PD) using functional magnetic resonance imaging. DESIGN In our study, patients with tremor-dominant PD and those with nontremor-dominant PD performed a grip task, and the results obtained were compared using voxelwise analysis. Areas of the brain that were significantly different were then examined using a region-of-interest analysis to compare these patients with healthy controls. Voxel-based morphometry was used to determine macroscopic differences in gray and white matter volume between patient groups. SETTING University-affiliated research institution. PARTICIPANTS A total of 20 drug-naive patients with PD (10 with tremor-dominant PD and 10 with nontremor-dominant PD) and a total of 20 healthy controls. MAIN OUTCOME MEASURES Blood oxygenation level-dependent activation and percent signal change. RESULTS Robust findings across both voxelwise and region-of-interest analyses showed that, compared with patients with tremor-dominant PD, patients with nontremor-dominant PD had reduced activation in the ipsilateral dorsolateral prefrontal cortex, the globus pallidus interna, and the globus pallidus externa. Region-of-interest analyses confirmed that patients with nontremor-dominant PD had reduced activity in the ipsilateral dorsolateral prefrontal cortex, the globus pallidus interna, and the globus pallidus externa compared with patients with tremor-dominant PD and healthy controls. Patients with tremor-dominant PD had increased activity in the contralateral dorsolateral prefrontal cortex compared with patients with nontremor-dominant PD and healthy controls. These results could not be explained by differences in gray or white matter volume. CONCLUSIONS Reduced brain activity occurs in the prefrontal cortex and globus pallidus of patients with nontremor-dominant PD compared with both patients with tremor-dominant PD and healthy controls, which suggests that functional magnetic resonance imaging is a promising technique to understand differences in brain activation between subtypes of PD.

Segregated and overlapping neural circuits exist for the production of static and dynamic precision grip force.

A central topic in sensorimotor neuroscience is the static-dynamic dichotomy that exists throughout the nervous system. Previous work examining motor unit synchronization reports that the activation strategy and timing of motor units differ for static and dynamic tasks. However, it remains unclear whether segregated or overlapping blood-oxygen-level-dependent (BOLD) activity exists in the brain for static and dynamic motor control. This study compared the neural circuits associated with the production of static force to those associated with the production of dynamic force pulses. To that end, healthy young adults (n = 17) completed static and dynamic precision grip force tasks during functional magnetic resonance imaging (fMRI). Both tasks activated core regions within the visuomotor network, including primary and sensory motor cortices, premotor cortices, multiple visual areas, putamen, and cerebellum. Static force was associated with unique activity in a right-lateralized cortical network including inferior parietal lobe, ventral premotor cortex, and dorsolateral prefrontal cortex. In contrast, dynamic force was associated with unique activity in left-lateralized and midline cortical regions, including supplementary motor area, superior parietal lobe, fusiform gyrus, and visual area V3. These findings provide the first neuroimaging evidence supporting a lateralized pattern of brain activity for the production of static and dynamic precision grip force.

The postcentral gyrus shows sustained fMRI activation during the tactile motion aftereffect.

The tactile motion aftereffect (tMAE) is a perceptual illusion in which a stationary stimulus feels as though it is moving when presented following adaptation to a unidirectionally moving tactile stimulus. Using functional magnetic resonance imaging (fMRI), we localized the brain areas responsive to tactile motion and then investigated whether these areas underlie the tMAE. Tactile stimulation was delivered to the glabrous surface of the right hand by means of a plastic cylinder with a square-wave patterned surface. In the tactile motion localizer, we contrasted periods in which the cylinder rotated at 15 rpm with periods of rest (stationary contact). Activation was observed in the contralateral (left) thalamus, postcentral gyrus, and parietal operculum. In the tMAE experiment, the cylinder rotated at 15 or 60 rpm for 2 min. The 60-rpm speed induced reliable tMAEs, whereas the 15-rpm speed did not. Of the areas activated by the tactile motion localizer, only the postcentral gyrus showed a sustained fMRI response following the offset of 60-rpm (but not 15-rpm) stimulation, presumably reflecting the illusory perception of motion.

The effect of adapting speed, duration, and distance on the tactile motion aftereffect.

We investigated the effect of adapting speed, duration, and distance on the frequency of occurrence, duration, and vividness of the tactile motion aftereffect (tMAE). Using a cylindrical drum with a patterned surface we adapted the glabrous surface of the right hand at two speeds (14 and 28 cm/s) and three durations (60, 120, and 240 s). Distance was explored in the interaction of adapting speed and duration. The results showed that the frequency of occurrence, duration, and vividness of the tMAE increased with adapting speed. There was also a positive relationship between adapting duration and the frequency of occurrence, but not the duration or vividness, of the illusion. Distance was only a factor when it came to the duration of the tMAE. Taken together, these results show the importance of adapting parameters, particularly speed, on the tMAE.

Site of stimulation effects on the prevalence of the tactile motion aftereffect.

The motion aftereffect (MAE) refers to the apparent motion of a stationary stimulus following adaptation to a continuously moving stimulus. There is a growing consensus that the fast adapting (FA) rather than the slowly adapting (SA) afferent units mediate the tactile version of the MAE. The present study investigated which FA units underlie the tactile MAE by measuring its prevalence, duration, and vividness on different skin areas that vary in their composition of FA units. Specifically, the right cheek, volar surface of the forearm, and volar surface of the hand were adapted using a ridged cylindrical drum, which rotated at 60 rpm for 120 s. Although there was no difference in duration or vividness between the skin surfaces tested, the tactile MAE was reported twice as often on the hand compared to the cheek and forearm, which did not differ significantly from one another. This suggests that the FA I units in the glabrous skin and the hair follicle and/or the FA I and field units in the hairy skin contribute to the tactile MAE.

On the signals underlying conscious awareness of action.

To investigate whether conscious judgments of movement onset are based solely on pre-movement signals (i.e., premotor or efference copy signals) or whether sensory feedback (i.e., reafferent) signals also play a role, participants judged the onset of finger and toe movements that were either active (i.e., self initiated) or passive (i.e., initiated by the experimenter). Conscious judgments were made by reporting the position of a rotating clock hand presented on a computer screen and were then compared to the actual measured time of movement onset. In line with previous studies, judgment errors were found to be anticipatory for both finger and toe movements. There was a significant difference between judgment errors for active and passive movements, with judgments of active movements being more anticipatory than judgments of passive movements. This is consistent with a pre-movement (from here on referred to as an "efferent") account of action awareness because premotor and efference copy signals are only present in active movements, whereas the main source of movement information in passive movements is sensory feedback which is subject to time delays of conduction (and hence predicts later judgment times for passive movements). However, judgments of active toe movement onset time were less anticipatory than judgments of active finger movement onset time. This pattern of results is not consistent with a pure efferent account of conscious awareness of action onset - as this account predicts more anticipatory judgments for toe movements compared to finger movements. Instead, the data support the idea that conscious judgments of movement onset are based on efferent (i.e., premotor, efference copy) and reafferent (i.e., feedback from the movement) components.

Somatosensory temporal discrimination learning generalizes to motor interval production.

The present study investigated whether a common timing mechanism underlies the ability to analyze incoming sensory information and control outgoing motor commands. Participants were presented with two pairs of air puffs on the ventral surface of the right forearm. One pair (the standard interval) was separated by 500 ms on every trial for half of the participants ("500 group") and 800 ms on every trial for the other half ("800 group"). The duration of the comparison interval was always longer but varied adaptively to determine discrimination thresholds. Participants indicated which of the two intervals was longer. Both groups performed two motor interval production tasks (pressing a button twice in succession with the right thumb) before and again after somatosensory training. The target inter-press interval was 500 ms in one task and 800 ms in the other. A critical feature of the design was that only one of the motor tasks for each of the groups shared temporal properties with the somatosensory discrimination task. The results showed that somatosensory discrimination learning generalizes to motor interval production when the two tasks share temporal properties. Specifically, the 500 group showed a greater reduction in motor timing variability on the 500 ms task than the 800 ms task, whereas the 800 group showed a greater reduction in motor timing variability on the 800 ms task than the 500 ms task. The possible neural basis of temporal learning generalization is discussed.

The tactile motion aftereffect revisited.

In two experiments, we measured the direction, duration, frequency, and vividness of the tactile motion aftereffect (MAE) induced by a rotating drum with a ridged surface. In Experiment 1, we adapted the: (1) fingers and palm, including the thumb, (2) fingers and palm, excluding the thumb, and (3) fingers only, excluding the thumb. In each condition the drum rotated at 60 rpm for 120 s. There was no difference in duration, frequency, or vividness between the skin surfaces tested. In Experiment 2, we tested several adapting speeds: 15, 30, 45, 60, and 75 rpm. At each speed the fingers and palm, excluding the thumb, were adapted for 120 s. The duration, frequency, and vividness of the tactile MAE increased linearly with adapting speed. Overall, the tactile MAE was reported on approximately half of the trials, suggesting that it is not as robust as its visual counterpart.

Recognizing partially visible objects.

In two experiments we measured object recognition performance as a function of delay. In Experiment 1 we presented half of an image of an object, and then the other half after a variable delay. Objects were subdivided into top versus bottom halves, left versus right halves, or vertical strips. In Experiment 2 we separated the low (LSF) and high spatial frequency (HSF) components of an image, and presented one component followed by the other after a variable delay. For both experiments, performance was worse with a 105ms delay between the presentations of the object components than when the two components were presented simultaneously. These results are consistent with predictions made by models that combine information at a relatively early stage in processing. In addition, the results revealed that object recognition performance is significantly better when the LSF sub-image preceded the HSF sub-image than when the HSF sub-image preceded the LSF sub-image, consistent with previous work suggesting that LSF information is processed prior to HSF in object recognition.