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Rigidity was increased following MPTP administration. Kinematic measures (cross-session means) from pre-MPTP (black) and post-MPTP (gray) periods for flexion movements following torque perturbations. Cumulative distributions are shown at the bottom. Movement onsets (Mov), peak velocities (Velmax), and movement amplitudes (Joint angle) were compared between MPTP states (ANOVA; **p < 0.01, ***p < 0.001).
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Exaggeration of the long-latency stretch reflex (LLSR) is a characteristic neurophysiologic feature of Parkinson's disease (PD) that contributes to parkinsonian rigidity. To explore one frequently-hypothesized mechanism, we studied the effects of fast muscle stretches on neuronal activity in the macaque primary motor cortex (M1) before and after th...
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The influence of proprioceptive feedback on muscle activity during isometric tasks is the subject of conflicting studies. To better understand the relationship, we performed an isometric knee extension task experiment at four pre-set angles of the knee, recording from five muscles, and for two different hip positions. We applied muscle synergy anal...
Citations
... Consistent with our finding, a significantly decreased FC in the prefrontal cortex, motor area, and DMN was reported in both treated and drug-naïve patients and was enhanced after the levodopa challenge test (Michely et al., 2015;Wu et al., 2009;Zeng et al., 2022). Besides, lower activation in the motor area was significantly correlated with worse akinesia and rigidity symptoms in treated patients (Cao et al., 2020), and the neuronal response to muscle stretch was also reduced in the motor cortex of parkinsonian monkeys with severe rigidity (Pasquereau & Turner, 2013). The proper cooperation of these higher-order networks is fundamental for motor planning, initiation, coordination, and adjustment, therefore, lower connectivity between and within these networks may impair voluntary movements (Krajcovicova et al., 2012;Xu et al., 2019). ...
Dopamine replacement therapy (DRT) represents the standard treatment for Parkinson's disease (PD), however, instant and long-term medication influence on patients' brain function have not been delineated. Here, a total of 97 drug-naïve patients, 43 patients under long-term DRT, and 94 normal control (NC) were, retrospectively, enrolled. Resting-state functional magnetic resonance imaging data and motor symptom assessments were conducted before and after levodopa challenge test. Whole-brain functional connectivity (FC) matrices were constructed. Network-based statistics were performed to assess FC difference between drug-naïve patients and NC, and these significant FCs were defined as disease-related connectomes, which were used for further statistical analyses. Patients showed better motor performances after both long-term DRT and levodopa challenge test. Two disease-related connectomes were observed with distinct patterns. The FC of the increased connectome, which mainly consisted of the motor, visual, subcortical, and cerebellum networks, was higher in drug-naïve patients than that in NC and was normalized after long-term DRT (p-value <.050). The decreased connectome was mainly composed of the motor, medial frontal, and salience networks and showed significantly lower FC in all patients than NC (p-value <.050). The global FC of both increased and decreased connectome was significantly enhanced after levodopa challenge test (q-value <0.050, false discovery rate-corrected). The global FC of increased connectome in ON-state was negatively associated with levodopa equivalency dose (r = -.496, q-value = 0.007). Higher global FC of the decreased connectome was related to better motor performances (r = -.310, q-value = 0.022). Our findings provided insights into brain functional alterations under dopaminergic medication and its benefit on motor symptoms.
... The spinal component of the LLR is particularly relevant for the lower limbs, whereas the transcortical component has greater importance for the upper limbs. At the spinal level, alterations in stretch reflexes are likely implicated in the pathophysiology of rigidity with changes in interneuron (Ia and Ib) and spinal motoneuron excitability (Simonetta Moreau et al., 2002;Marchand-Pauvert et al., 2011;Pasquereau and Turner, 2013). The latter are thought to reflect, at least in part, neurodegeneration in the brainstem. ...
... The latter are thought to reflect, at least in part, neurodegeneration in the brainstem. For example, neurodegenerations in the reticulospinal system and various brainstem nuclei, particularly the locus coeruleus and raphe nucleus, result in the altered influence of descending noradrenergic and serotonergic systems on spinal circuits (Delwaide et al., 1993;Braak et al., 2006;Simonetta Moreau et al., 2002;Marchand-Pauvert et al., 2011;Pasquereau and Turner, 2013;Xia et al., 2016). Additional evidence has supported the possible role of brainstem dysfunction in the pathophysiology of rigidity in PD. ...
This review is part of the series on the clinical neurophysiology of movement disorders. It focuses on Parkinson’s disease and parkinsonism. The topics covered include the pathophysiology of
tremor, rigidity and bradykinesia, balance and gait disturbance and myoclonus in Parkinson’s disease. The use of electroencephalography, electromyography, long latency reflexes, cutaneous
silent period, studies of cortical excitability with single and paired transcranial magnetic stimulation, studies of plasticity, intraoperative microelectrode recordings and recording of local field potentials from deep brain stimulation, and electrocorticography are also reviewed. In
addition to advancing knowledge of pathophysiology, neurophysiological studies can be useful in refining the diagnosis, localization of surgical targets, and help to develop novel therapies for
Parkinson’s disease.
Keywords: tremor; bradykinesia; gait and balance; electroencephalography; electromyography; long latency reflexes; transcranial magnetic stimulation; local field potentials; microelectrode recording; deep brain stimulation.
... Much of the motor impairment associated with Parkinson's disease (PD) is presumed to arise from aberrant frequencyspecific oscillatory and/or neuronal single-unit activity across the cortico-basal ganglia-thalamocortical circuit West et al., 2018;Cagnan et al., 2019;Holt et al., 2019;Underwood and Parr-Brownlie, 2021). Profound aberrant discharge patterns and presence of exaggerated oscillatory activity across the basal ganglia (Avila et al., 2010;Brazhnik et al., 2012Brazhnik et al., , 2014Halje et al., 2012;Quiroga-Varela et al., 2013;Devergnas et al., 2014;Rossant et al., 2016), thalamic nuclei (Parr-Brownlie et al., 2009;Bosch-Bouju et al., 2014), and motor cortex (Parr-Brownlie et al., 2007;Pasquereau and Turner, 2013;Pasquereau et al., 2015;Hyland et al., 2019) have been observed. Dopamine depletion in PD triggers pathologic alterations not only among individual brain sites but also throughout the cortico-basal ganglia-thalamocortical circuit. ...
Parkinson’s disease (PD) is characterized by aberrant discharge patterns and exaggerated oscillatory activity within basal ganglia-thalamocortical circuits. We have previously observed substantial alterations in spike and local field potential (LFP) activities recorded in the thalamic parafascicular nucleus (PF) and motor cortex (M1), respectively, of hemiparkinsonian rats during rest or catching movements. This study explored whether the mutual effects of the PF and M1 depended on the amplitude and phase relationship in their identified neuron spikes or group rhythmic activities. Microwire electrode arrays were paired and implanted in the PF and M1 of rats with unilateral dopaminergic cell lesions. The results showed that the identified PF neurons exhibited aberrant cell type-selective firing rates and preferential and excessive phase-locked firing to cortical LFP oscillations mainly at 12–35 Hz (beta frequencies), consistent with the observation of identified M1 neurons with ongoing PF LFP oscillations. Experimental evidence also showed a decrease in phase-locking at 0.7–12 Hz and 35–70 Hz in the PF and M1 circuits in the hemiparkinsonian rats. Furthermore, anatomical evidence was provided for the existence of afferent and efferent bidirectional reciprocal connectivity pathways between the PF and M1 using an anterograde and retrograde neuroanatomical tracing virus. Collectively, our results suggested that multiple alterations may be present in regional anatomical and functional modes with which the PF and M1 interact, and that parkinsonism-associated changes in PF integrate M1 activity in a manner that varies with frequency, behavioral state, and integrity of the dopaminergic system.
... Direct dopaminergic denervation of M1 may also contribute to abnormal voluntary movements in PD (MacDonald and Halliday, 2002;Braak et al., 2003Braak et al., , 2006Lindenbach and Bishop, 2013). It has been reported that deficits in the M1 are associated with PD pathophysiology in PD patients and in animal models of PD (Parr-Brownlie and Hyland, 2005;Pasquereau and Turner, 2011;Li et al., 2012;de Hemptinne et al., 2013;Pasquereau and Turner, 2013). PD symptoms are accompanied by certain alterations, including abnormal firing rates and patterns, pathologic oscillatory activity, and increased synchronization throughout basal ganglia-cortical circuits (Walters et al., 2007;Ellens and Leventhal, 2013;Devergnas et al., 2014;Valencia et al., 2014;Galvan et al., 2015;Wang et al., 2015;Dupre et al., 2016). ...
... PD symptoms are accompanied by certain alterations, including abnormal firing rates and patterns, pathologic oscillatory activity, and increased synchronization throughout basal ganglia-cortical circuits (Walters et al., 2007;Ellens and Leventhal, 2013;Devergnas et al., 2014;Valencia et al., 2014;Galvan et al., 2015;Wang et al., 2015;Dupre et al., 2016). However, the available data are inconsistent regarding whether there is a decrease or an increase in the movement-related activity of M1 neurons (Parr-Brownlie and Hyland, 2005;Pasquereau and Turner, 2011;Pasquereau and Turner, 2013), and some studies have reported an increase (Lefaucheur, 2005) or no change in cortical neuron activity (Goldberg et al., 2002). ...
Disruption of the function of the primary motor cortex (M1) is thought to play a critical role in motor dysfunction in Parkinson’s disease (PD). Detailed information regarding the specific aspects of M1 circuits that become abnormal is lacking. We recorded single units and local field potentials (LFPs) of M1 neurons in unilateral 6-hydroxydopamine (6-OHDA) lesion rats and control rats to assess the impact of dopamine (DA) cell loss during rest and a forelimb reaching task. Our results indicated that M1 neurons can be classified into two groups (putative pyramidal neurons and putative interneurons) and that 6-OHDA could modify the activity of different M1 subpopulations to a large extent. Reduced activation of putative pyramidal neurons during inattentive rest and reaching was observed. In addition, 6-OHDA intoxication was associated with an increase in certain LFP frequencies, especially those in the beta range (broadly defined here as any frequency between 12 and 35 Hz), which become pathologically exaggerated throughout cortico-basal ganglia circuits after dopamine depletion. Furthermore, assessment of different spike-LFP coupling parameters revealed that the putative pyramidal neurons were particularly prone to being phase-locked to ongoing cortical oscillations at 12–35 Hz during reaching. Conversely, putative interneurons were neither hypoactive nor synchronized to ongoing cortical oscillations. These data collectively demonstrate a neuron type-selective alteration in the M1 in hemiparkinsonian rats. These alterations hamper the ability of the M1 to contribute to motor conduction and are likely some of the main contributors to motor impairments in PD.
... [21,22] Pasquereau and Turner concluded that segmental spinal circuits can be responsible for exaggeration of the long latency stretch reflex. [23] On the other hand, some studies suggest that an excessive corticospinal output and increased excitability of the primary motor cortex has been observed in PD. [24][25][26][27][28][29] In our patients, abnormalities in trapezius LLRs showed some discrepancies from those obtained from thenar LLRs as mentioned above. These differences between the behaviors of the reflexes suggested that the neural substrate or the generator of LLRs obtained from the trapezius is different from LLRs obtained from the distal hand muscle. ...
Objectives
Distal electrical stimulation of an upper extremity mixed nerve can generate a reflex response from the trapezius muscle. This reflex response may have a central neural pathway and can be affected by postural changes. Materials and Methods: In this study, long latency reflexes (LLRs) from both distal and trapezius muscle were evaluated in patients with Parkinson's disease (PD) with and without postural dysfunction and in patients with cerebellar ataxias. Thirty-three patients with PD, 10 patients with degenerative cerebellar ataxia and 22 healthy volunteers were included in the study. LLRs were recorded from ipsilateral thenar and trapezius muscles. Latencies and amplitudes of LLRs obtained from thenar (thenar LLR) and trapezius (trapezius LLR) muscles were analyzed. Results: In patients with PD, thenar LLRs showed significant shortening in the onset latencies and significant increase in the amplitudes in comparison with healthy controls. Trapezius LLRs did not show any significant difference in latencies or amplitudes; however, these responses showed a significant absence in one or two components in patients with Parkinson's disease with postural dysfunction. Additionally, this reflex was not recorded in patients with cerebellar ataxia.
Conclusion
Trapezius LLRs can give some information regarding the physiology of neural circuits responsible for postural arrangement. Cerebellar connections may have a major role in the generation of trapezius LLRs.
... The etiology of rigidity in PD is complex; the clinical impression of rigidity has been shown to correlate with long latency reflex characteristics, 41 and contributions have been proposed not only from failures to relax, abnormalities in stretch reflexes and the mechanical properties of muscle, 42,43 but also from potential contributions of abnormal basal ganglia activity on spinal reflexes. 41,44 Although an examiner is necessary to appreciate rigidity directly, its effects can be seen during gait, in which a reduction in the pendular movement of the arms (arm swing) throughout the phases of locomotion in patients with PD is observed. ...
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Abstract
The motor symptoms of Parkinson's disease are not limited to the cardinal symptoms of bradykinesia, rigidity, and resting tremor, but also include a variety of interrelated motor phenomena such as deficits in spatiotemporal planning and movement sequencing, scaling and timing of movements, and intermuscular coordination that can be clinically observed. Although many of these phenomena overlap, a review of the full breadth of the motor phenomenon can aid in the diagnosis and monitoring of disease progression.
Keywords
Parkinson's disease - phenomenology - symptoms - signs
... Given that pathological activity in the motor cortex may translate into the motor symptoms observed in PD, the synaptic adaptations and neuronal activities involved in the PD motor cortex have begun to attract more and more attention in recent years 39,[108][109][110][111][112] . The study detailed above in which researchers examined the remodeling of the motor cortex neural circuits in a PD model through combining in vivo imaging of spine dynamics, electrophysiological analyses of synaptic functional plasticity, and behavioral investigation, provides evidence for abnormal remodeling in PD motor cortex and allows us to better understand the mechanisms underlying motor skill learning and memory deficits in PD 92 . ...
In Parkinson's disease (PD), dopamine depletion causes major changes in the brain, resulting in the typical cardinal motor features of the disease. PD neuropathology has been restricted to postmortem examinations, which are limited to only a single time of PD progression. Models of PD in which dopamine tone in the brain is chemically or physically disrupted are valuable tools in understanding the mechanisms of the disease. The basal ganglia have been well studied in the context of PD, and circuit changes in response to dopamine loss have been linked to the motor dysfunctions in PD. However, the etiology of the cognitive dysfunctions that are comorbid in PD patients has remained unclear until now. In this article, we review recent studies exploring how dopamine depletion affects the motor cortex at the synaptic level. In particular, we highlight our recent findings on abnormal spine dynamics in the motor cortex of PD mouse models through in vivo time-lapse imaging and motor skill behavior assays. In combination with previous studies, a role of the motor cortex in skill learning and the impairment of this ability with the loss of dopamine are becoming more apparent. Taken together, we conclude with a discussion on the potential role for the motor cortex in PD, with the possibility of targeting the motor cortex for future PD therapeutics. © 2017 International Parkinson and Movement Disorder Society
... Beta oscillations have a causal role in bradykinesia, as boosting beta power over motor cortex via transcranial magnetic stimulation (TMS) leads to movement slowing (Pogosyan et al., 2009). Although movement is impaired in Parkinson's, re exive responses of motor cortex to muscle stretch are preserved, and in fact exhibit a reduced latency compared to controls (Pasquereau and Turner, 2013). Consistent with this, Gilbertson et al. (2005) found that beta oscillations in healthy subjects correlate with slowed movement and potentiated long-latency stretch re exes which stabilize motor steady-states. ...
... In addition, there is growing recognition that different neuronal subtypes in M1 are affected differently in the parkinsonian state (Lefaucheur, 2005;Turner, 2011, 2013;Brazhnik et al., 2012;Shepherd, 2013). We have shown that lamina 5b pyramidal tracttype neurons (PTNs) are affected strongly by the induction of parkinsonism: PTN activity at rest is depressed, more bursty, and more likely to be rhythmic in the beta frequency range (Pasquereau and Turner, 2011), and PTNs respond to proprioceptive stimulation at shorter latencies with reduced directional specificity (Pasquereau and Turner, 2013). Surprisingly, nearby intratelencephalicprojecting corticostriatal neurons (CSNs; a distinct class of cortical pyramidal neuron; Shepherd, 2013) were largely unaffected by the induction of parkinsonism Turner, 2011, 2013). ...
... Procedures were approved by the Institutional Animal Care and Use Committee and complied with the Public Health Service Policy on the humane care and use of laboratory animals (amended 2002). Other data from the same animals were used in recent publications describing post-MPTP changes in resting M1 activity (Pasquereau and Turner, 2011) and in neuronal responses to muscle stretch (Pasquereau and Turner, 2013). Many aspects of the experimental approach are described in detail in those reports. ...
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How motor cortex activity is altered in Parkinson’s disease is poorly understood. Pasquereau et al. report abnormalities in modulation and timing of putative corticospinal neurons in the MPTP model of the disease, implying that dysfunction of such neurons plays a role in the pathophysiology of parkinsonism.
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How motor cortex activity is altered in Parkinson’s disease is poorly understood. Pasquereau et al. report abnormalities in modulation and timing of putative corticospinal neurons in the MPTP model of the disease, implying that dysfunction of such neurons plays a role in the pathophysiology of parkinsonism.
... There is also evidence that PD patients lose the ability to scale responses to features of the task [91]. However, recent work with a non-human primate model of PD found no overt change in M1 activity associated with the observed increase in reflex gain [92 ], which implicates subcortical circuits in goaldirected feedback responses. ...
Humans possess an impressive ability to generate goal-oriented motor actions to move and interact with the environment. The planning and initiation of these body movements is supported by highly distributed cortical and subcortical circuits. Recent studies, inspired by advanced control theory, highlight similar sophistication when we make online corrections to counter small disturbances of the limb or altered visual feedback. Such goal-directed feedback is likely generated by the same neural circuits associated with motor planning and initiation. These common neural substrates afford a highly responsive system to maintain goal-directed control and rapidly select new motor actions as required to deftly move and interact in a complex world.
Copyright © 2015. Published by Elsevier Ltd.
