Evolving concepts on bradykinesia Bologna, Matteo; Paparella, Giulia; Fasano, Alfonso ...
Brain (London, England : 1878),
03/2020, Letnik:
143, Številka:
3
Journal Article
Recenzirano
Odprti dostop
Bradykinesia is one of the cardinal motor symptoms of Parkinson's disease and other parkinsonisms. The various clinical aspects related to bradykinesia and the pathophysiological mechanisms ...underlying bradykinesia are, however, still unclear. In this article, we review clinical and experimental studies on bradykinesia performed in patients with Parkinson's disease and atypical parkinsonism. We also review studies on animal experiments dealing with pathophysiological aspects of the parkinsonian state. In Parkinson's disease, bradykinesia is characterized by slowness, the reduced amplitude of movement, and sequence effect. These features are also present in atypical parkinsonisms, but the sequence effect is not common. Levodopa therapy improves bradykinesia, but treatment variably affects the bradykinesia features and does not significantly modify the sequence effect. Findings from animal and patients demonstrate the role of the basal ganglia and other interconnected structures, such as the primary motor cortex and cerebellum, as well as the contribution of abnormal sensorimotor processing. Bradykinesia should be interpreted as arising from network dysfunction. A better understanding of bradykinesia pathophysiology will serve as the new starting point for clinical and experimental purposes.
Over the past few decades, abnormalities in sensory functions, such as tactile, proprioceptive and nociceptive processing, have been increasingly recognized in patients with focal dystonias. In this ...Review, we ask whether sensory system abnormalities are specific to particular types of dystonia, whether a causal link exists between sensory alterations and dystonic motor activity and how mechanisms underlying the sensory abnormalities fit in with the proposed 'network model' of dystonia. We suggest that alterations in the various sensory modalities participate at three different levels in the pathophysiological cascade that leads to dystonia: a background level that predisposes individuals to dystonia, a disease-related level that is evident only when dystonia becomes manifest and a causative level that triggers dystonia. We conclude that it is crucial to study sensory as well as motor pathophysiology to fully understand focal dystonias.
Changes in sensory function that have been described in patients with Parkinson disease (PD) can be either 'pure' disorders of conscious perception such as elevations in sensory threshold, or ...disorders of sensorimotor integration, in which the interaction between sensory input and motor output is altered. In this article, we review the extensive evidence for disrupted tactile, nociceptive, thermal and proprioceptive sensations in PD, as well as the influences exerted on these sensations by dopaminergic therapy and deep brain stimulation. We argue that abnormal spatial and temporal processing of sensory information produces incorrect signals for the preparation and execution of voluntary movement. Sensory deficits are likely to be a consequence of the dopaminergic denervation of the basal ganglia that is the hallmark of PD. A possible mechanism to account for somatosensory deficits is one in which disease-related dopaminergic denervation leads to a loss of response specificity, resulting in transmission of noisier and less-differentiated information to cortical regions. Changes in pain perception might have a different explanation, possibly involving disease-related effects outside the basal ganglia, including involvement of peripheral pain receptors, as well as structures such as the periaqueductal grey matter and non-dopaminergic neurotransmitter systems.
Parkinson's disease (PD) is a neurodegenerative disorder whose pathogenesis depends on a combination of genetic and environmental factors. The aim of the present review was to provide an updated ...description of the findings emerging from prospective longitudinal cohort studies on the possible risk/protective factors underlying the development, progression and clinical subtypes of PD. We reviewed all the environmental, lifestyle, dietary, comorbid and pharmacological factors that have been investigated as possible modifiable protective/risk factors for PD by longitudinal studies. Only a few factors have the epidemiological evidence and the biological plausibility to be considered risk (pesticides, dairy products, β2-adrenoreceptor antagonists) or protective (smoking, caffeine and tea intake, physical activity, gout, vitamin E intake, non-steroidal anti-inflammatory drugs and β2-adrenoreceptor agonists) factors for PD. Caffeine intake and physical activity also seem to slow down the progression of the disease, thus representing good candidates for primary prevention and disease modifying strategies in PD. Possible modifiable risk factors of PD subtypes is almost unknown and this might depend on the uncertain biological and neuropathological reliability of clinical subtypes. The results of the present review suggest that only eleven risk/protective factors may be associated with the risk of PD. It may be possible to target some of these factors for preventive interventions aimed at reducing the risk of developing and the rate of progression of PD.
•Eleven risk/protective factors may affect Parkinson's disease development.•Caffeine and physical activity may improve Parkinson's disease progression.•Risk factors for Parkinson's disease subtypes are unknown.
Key points
We explored the large variability in motor skill acquisition‐related effects on the primary and sensory cortices. Namely, we tested whether this variability depends on interindividual ...variance or the type of motor task investigated.
We compared different motor‐learning tasks, i.e. model‐free vs. model‐based learning tasks, and their possible differential effects on the primary motor and sensory cortices by using transcranial magnetic stimulation techniques.
The model‐free learning task induced an increase in corticospinal excitability and a reduction in the amplitude of somatosensory‐evoked potentials. Conversely, the model‐based learning tasks induced a decrease in intracortical inhibition.
No correlations were found between neurophysiological changes and motor performance, indicating that this differential modulation may be secondary to the motor skill acquisition.
The study results suggest differential motor skill acquisition‐related effects on cortical parameters, possibly due to the engagement of specific neurophysiological substrates.
A large variability in learning‐related neurophysiological changes in the primary motor and sensory cortices has been observed. It is unclear whether these differential effects are due to the different tasks investigated or to interindividual variance. Only a few studies have assessed different motor‐learning tasks and their effects on neurophysiological features within the same group of participants, and several issues are unclear. Here, we compared the effects of different tasks within each individual. We investigated the effects on motor and sensory cortex parameters after a model‐free learning task, i.e. a ballistic motor task, compared with model‐based learning tasks, i.e. visuomotor‐learning tasks. Motor‐ and sensory‐evoked potentials, intracortical excitability as assessed by short‐interval intracortical inhibition, and sensorimotor interaction, i.e. short‐latency afferent inhibition, were recorded from 15 healthy subjects before and after the tasks. The ballistic motor task induced an increase in corticospinal excitability but did not change motor cortex intracortical inhibition or sensorimotor integration. In addition, it decreased the amplitude of cortical components of the somatosensory‐evoked potentials. The visuomotor‐learning tasks induced a reduction in motor cortex intracortical inhibition but did not modulate corticospinal and sensory cortex excitability or sensorimotor integration. This differential modulation is likely to be secondary to the motor skill acquisition, since no correlation was observed between neurophysiological changes and motor performance. Our results demonstrate differential motor skill acquisition‐related effects on cortical parameters, possibly reflecting the engagement of specific neurophysiological substrates, and contribute in‐depth knowledge of the mechanisms involved in different types of motor skill acquisition in humans.
Key points
We explored the large variability in motor skill acquisition‐related effects on the primary and sensory cortices. Namely, we tested whether this variability depends on interindividual variance or the type of motor task investigated.
We compared different motor‐learning tasks, i.e. model‐free vs. model‐based learning tasks, and their possible differential effects on the primary motor and sensory cortices by using transcranial magnetic stimulation techniques.
The model‐free learning task induced an increase in corticospinal excitability and a reduction in the amplitude of somatosensory‐evoked potentials. Conversely, the model‐based learning tasks induced a decrease in intracortical inhibition.
No correlations were found between neurophysiological changes and motor performance, indicating that this differential modulation may be secondary to the motor skill acquisition.
The study results suggest differential motor skill acquisition‐related effects on cortical parameters, possibly due to the engagement of specific neurophysiological substrates.
Despite previous functional MRI studies on alterations within the cerebello-thalamo-cortical circuit in patients with essential tremor (ET), the specific role of disconnection of the dentate nucleus ...(DN), the main output cerebellar pathway, still needs clarification. In this study, we evaluated DN functional connectivity (FC) changes and their relationship with motor and non-motor symptoms in ET. We studied 25 ET patients and 26 healthy controls. Tremor severity was assessed using the Fahn–Tolosa–Marin tremor rating scale (FTM-TRS) and tremor amplitude and frequency were evaluated using kinematic techniques. Cognitive profile was assessed by montreal cognitive assessment (MoCA) and frontal assessment battery (FAB). All participants underwent a 3 T MRI protocol including resting-state blood oxygenation level dependent and diffusion tensor sequences. We used a seed-based approach to investigate DN FC and to explore the diffusion properties of cerebellar peduncles. There was significantly decreased DN FC with cortical, subcortical, and cerebellar areas in ET patients compared with healthy controls. Correlation analysis showed that: (1) the DN FC with the supplementary motor area, pre and postcentral gyri, and prefrontal cortex negatively correlated with FTM-TRS score and disease duration; (2) DN FC changes in the thalamus and caudate negatively correlated with peak tremor frequency, changes in the cerebellum positively correlated with tremor amplitude, and changes in the bilateral thalamus negatively correlated with tremor amplitude, and (3) DN FC with the associative prefrontal and parietal cortices, basal ganglia, and thalamus positively correlated with the MoCA score. Diffusion abnormalities were found in the three cerebellar peduncles, which did not correlate with clinical scores.
In humans, gamma (γ) oscillations in cortical motor areas reflect asynchronous synaptic activity and contribute to plasticity processes. In Parkinson's disease (PD), γ oscillatory activity in the ...basal ganglia-thalamo-cortical network is altered and the long-term potentiation (LTP)-like plasticity elicited by intermittent theta burst stimulation (iTBS) is reduced in the primary motor cortex (M1). In this study, we tested whether transcranial alternating current stimulation (tACS) delivered at γ frequency promotes iTBS-induced LTP-like plasticity in M1 in PD patients. Sixteen patients ('OFF' condition) and 16 healthy subjects (HS) underwent iTBS during γ-tACS (iTBS-γ tACS) and during sham-tACS (iTBS-sham tACS) in two sessions. Motor-evoked potentials (MEPs) evoked by single-pulse TMS and short-interval intracortical inhibition (SICI) were recorded before and after the co-stimulation. A subgroup of patients also underwent iTBS during β tACS. iTBS-sham tACS facilitated single-pulse MEPs in HS, but not in patients. iTBS-γ tACS induced a larger MEPs facilitation than iTBS-sham tACS in both groups, with similar values in patients and HS. In patients, SICI improved after iTBS-γ tACS. The effect produced by iTBS-γ tACS on single-pulse MEPs correlated with disease duration, while changes in SICI correlated with UPDRS-III scores. The effect of iTBS-β tACS on both single-pulse MEPs and SICI was similar to that obtained in the iTBS-sham tACS session. Our data suggest that γ oscillations have a role in the pathophysiology of the abnormal LTP-like plasticity in PD. Entraining M1 neurons at the γ rhythm through tACS may be an effective method to restore impaired plasticity.
In Parkinson's disease, the LTP-like plasticity of the primary motor cortex is impaired, and gamma oscillations are altered in the basal ganglia-thalamo-cortical network. Using a combined TMS-tACS approach (iTBS-γ tACS co-stimulation), we demonstrate that driving gamma oscillations restores the LTP-like plasticity in patients with Parkinson's disease. The effects correlate with clinical characteristics of patients, being more evident in less affected patients and weaker in patients with longer disease duration. These findings suggest that cortical gamma oscillations play a beneficial role in modulating the LTP-like plasticity of M1 in Parkinson's disease. The iTBS-γ tACS approach may be potentially useful in rehabilitative settings in patients.
In Parkinson's disease (PD), alpha-synuclein (a-syn) can be detected in biological fluids including saliva. Although previous studies found reduced a-syn total (a-syntotal) concentration in saliva of ...PD patients, no studies have previously examined salivary a-syn oligomers (a-synolig) concentrations or assessed the correlation between salivary a-syntotal, a-synolig and clinical features in a large cohort of PD patients. Is well known that a-synolig exerts a crucial neurotoxic effect in PD. We collected salivary samples from 60 PD patients and 40 age- and sex-comparable healthy subjects. PD was diagnosed according to the United Kingdom Brain Bank Criteria. Samples of saliva were analyzed by specific anti-a-syn and anti-oligomeric a-syn ELISA kits. A complete clinical evaluation of each patient was performed using MDS-Unified Parkinson's Disease Rating Scale, Beck Depression Inventory, Montreal Cognitive Assessment and Frontal Assessment Battery. Salivary a-syntotal was lower, whereas a-synolig was higher in PD patients than healthy subjects. The a-synolig/a-syntotal ratio was also higher in patients than in healthy subjects. Salivary a-syntotal concentration negatively correlated with that of a-synolig and correlated with several patients' clinical features. In PD, decreased salivary concentration of a-syntotal may reflect the reduction of a-syn monomers (a-synmon), as well as the formation of insoluble intracellular inclusions and soluble oligomers. The combined detection of a-syntotal and a-synolig in the saliva might help the early diagnosis of PD.
Whether neurophysiological abnormalities in the primary motor cortex (M1) contribute to bradykinesia in patients with Parkinson's disease is unclear. Bologna et al. show that M1 excitability and ...plasticity abnormalities correlate with various bradykinesia features, objectively assessed with kinematic techniques. However, additional mechanisms sensitive to dopamine levels may also play a role.
Abstract
Many neurophysiological abnormalities have been described in the primary motor cortex of patients with Parkinson's disease. However, it is unclear whether there is any relationship between them and bradykinesia, one of the cardinal motor features of the condition. In the present study we aimed to investigate whether objective measures of bradykinesia in Parkinson's disease have any relationship with neurophysiological measures in primary motor cortex as assessed by means of transcranial magnetic stimulation techniques. Twenty-two patients with Parkinson's disease and 18 healthy subjects were enrolled. Objective measurements of repetitive finger tapping (amplitude, speed and decrement) were obtained using a motion analysis system. The excitability of primary motor cortex was assessed by recording the input/output curve of the motor-evoked potentials and using a conditioning-test paradigm for the assessment of short-interval intracortical inhibition and facilitation. Plasticity-like mechanisms in primary motor cortex were indexed according to the amplitude changes in motor-evoked potentials after the paired associative stimulation protocol. Patients were assessed in two sessions, i.e. OFF and ON medication. A canonical correlation analysis was used to test for relationships between the kinematic and neurophysiological variables. Patients with Parkinson's disease tapped more slowly and with smaller amplitude than normal, and displayed decrement as tapping progressed. They also had steeper input/output curves, reduced short-interval intracortical inhibition and a reduced response to the paired associative stimulation protocol. Within the patient group, bradykinesia features correlated with the slope of the input/output curve and the after-effects of the paired associative stimulation protocol. Although dopaminergic therapy improved movement kinematics as well as neurophysiological measures, there was no relationship between them. In conclusion, neurophysiological changes in primary motor cortex relate to bradykinesia in patients with Parkinson's disease, although other mechanisms sensitive to dopamine levels must also play a role.
Although current knowledge attributes movement disorders to a dysfunction of the basal ganglia–motor cortex circuits, abnormalities in the peripheral afferent inputs or in their central processing ...may interfere with motor program execution. We review the abnormalities of sensorimotor integration described in the various types of movement disorders. Several observations, including those of parkinsonian patients' excessive reliance on ongoing visual information during movement tasks, suggest that proprioception is defective in Parkinson's disease (PD). The disturbance of proprioceptive regulation, possibly related to the occurrence of abnormal muscle‐stretch reflexes, might be important for generating hypometric or bradykinetic movements. Studies with somatosensory evoked potentials (SEPs), prepulse inhibition, and event‐related potentials support the hypothesis of central abnormalities of sensorimotor integration in PD. In Huntington's disease (HD), changes in SEPs and long‐latency stretch reflexes suggest that a defective gating of peripheral afferent input to the brain might impair sensorimotor integration in cortical motor areas, thus interfering with the processing of motor programs. Defective motor programming might contribute to some features of motor impairment in HD. Sensory symptoms are frequent in focal dystonia and sensory manipulation can modify the dystonic movements. In addition, specific sensory functions (kinaesthesia, spatial–temporal discrimination) can be impaired in patients with focal hand dystonia, thus leading to a “sensory overflow.” Sensory input may be abnormal and trigger focal dystonia, or defective “gating” may cause an input–output mismatch in specific motor programs. Altogether, several observations strongly support the idea that sensorimotor integration is impaired in focal dystonia. Although elemental sensation is normal in patients with tics, tics can be associated with sensory phenomena. Some neurophysiological studies suggest that an altered “gating” mechanism also underlies the development of tics. This review underlines the importance of abnormal sensorimotor integration in the pathophysiology of movement disorders. Although the physiological mechanism remains unclear, the defect is of special clinical relevance in determining the development of focal dystonia.
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