Asha Kishore

Cerebellar Processing of Sensory Inputs Primes Motor Cortex Plasticity

Plasticity of the human primary motor cortex (M1) has a critical role in motor control and learning. The cerebellum facilitates these functions using sensory feedback. We investigated whether cerebellar processing of sensory afferent information influences the plasticity of the primary motor cortex (M1). Theta-burst stimulation protocols (TBS), both excitatory and inhibitory, were used to modulate the excitability of the posterior cerebellar cortex and to condition an ongoing M1 plasticity. M1 plasticity was subsequently induced in 2 different ways: by paired associative stimulation (PAS) involving sensory processing and TBS that exclusively involves intracortical circuits of M1. Cerebellar excitation attenuated the PAS-induced M1 plasticity, whereas cerebellar inhibition enhanced and prolonged it. Furthermore, cerebellar inhibition abolished the topography-specific response of PAS-induced M1 plasticity, with the effects spreading to adjacent motor maps. Conversely, cerebellar excitation had no effect on the TBS-induced M1 plasticity. This demonstrates the key role of the cerebellum in priming M1 plasticity, and we propose that it is likely to occur at the thalamic or olivo-dentate nuclear level by influencing the sensory processing. We suggest that such a cerebellar priming of M1 plasticity could shape the impending motor command by favoring or inhibiting the recruitment of several muscle representations.

Nigrostriatal dopamine system and motor lateralization.

The mechanism by which most people favor use of the right hand remains unknown. It has been proposed that asymmetries in the nigrostriatal dopamine system may be related to motor lateralization in humans. We explored this hypothesis in vivo by using [18F]fluorodopa positron emission tomography. Whereas the degree of right hand preference was found to correlate with left putamen dominance as assessed by asymmetry in fluorodopa uptake (K(i)), right caudate dominance was positively correlated with the level of performance during simultaneous bimanual movements in right-handed normal subjects. In addition, right-handed patients with Parkinsons disease with higher right than left caudate K(i) performed much better in bimanual movement tests than those in whom the K(i) value of the left caudate was higher than that of the right. These findings support the notion that the nigrostriatal dopaminergic system may play a role in motor lateralization, and suggest a functional model for bimanual movements. We propose that the skill for performing simultaneous bilateral hand movements in right-handed subjects might depend upon both the activation (through the dominant left putamen circuitry) of the left supplementary motor area (SMA), and the inhibition (through the right caudate circuitry) of motor programs stored in the right SMA.

Utility of susceptibility-weighted MRI in differentiating Parkinson's disease and atypical parkinsonism

IntroductionNeuropathological studies report varying patterns of brain mineralization in Parkinson’s diseases (PD), progressive supranuclear palsy (PSP), and Parkinson variant of multiple system atrophy (MSA-P). Susceptibility-weighted imaging (SWI) is the ideal magnetic resonance imaging (MRI) technique to detect mineralization of the brain. The purpose of this study was to test if SWI can differentiate PD, PSP, and MSA-P.MethodsEleven patients with PD, 12 with PSP, 12 with MSA-P, and 11 healthy controls underwent SWI of the brain. Hypointensity of putamen, red nucleus, substantia nigra, and dentate nucleus in all groups were measured using an objective grading scale and scored from 0 to 3.ResultsIn PSP, hypointensity score of red nucleus was higher than that in MSA-P (p = 0.001) and PD (p = 0.001), and a score of ≥2 differentiated the PSP group from the PD and MSA-P groups. Putaminal hypointensity score was higher in PSP when compared to that in PD (p = 0.003), and a score of ≥2 differentiated PSP from PD groups. SWI hypointensity scores of red nucleus and putamen had an excellent intrarater and interrater correlation. Substantia nigra hypointensity score of the PSP group was higher than that of the MSA-P (p = 0.004) and PD (p = 0.006) groups, but the scores had only a moderate intrarater and interrater correlation.ConclusionsSWI shows different patterns of brain mineralization in clinically diagnosed groups of PD, PSP, and MSA-P and may be considered as an additional MR protocol to help differentiate these conditions.

Early, severe and bilateral loss of LTP and LTD-like plasticity in motor cortex (M1) in de novo Parkinson’s disease

OBJECTIVE To test the plasticity of bilateral motor cortices (M1) in treatment-naïve (de novo) Parkinsons disease (PD) patients and its response to single dose of L-DOPA. METHODS Twenty-one de novo PD patients with only unilateral motor symptoms were recruited to eliminate the effects of advanced disease and chronic treatment and were tested with intermittent (n=10) and continuous theta burst stimulation (iTBS and cTBS) (n=11) protocols to induce LTP and LTD-like plasticity on both M1 cortices. They were compared with two groups of 10 each, age-matched, healthy volunteers (HV). Severity of motor signs and effectiveness of TBS were measured bilaterally in the untreated state and after a uniform dose of L-DOPA in all patients. RESULTS iTBS and cTBS induced significant LTP and LTD- like plasticity in M1 of HV. In de novo patients, there was no plasticity in both M1. Acute L-DOPA challenge did not improve plasticity in either M1 cortices, though motor signs of PD improved. There was no correlation of motor signs with M1 plasticity. CONCLUSION The early, severe and bilateral loss of plasticity in M1 in de novo PD patients is a primary disease-related cortical dysfunction. The contrasting L-DOPA response of motor signs and M1 plasticity could arise from differences in neural circuits mediating them or differing effects of acute dopamine replacement on circuits recruited by specific plasticity-induction techniques, particularly in treatment naïve PD. SIGNIFICANCE M1 plasticity defect occurs early in PD and might affect motor learning. Acute vs. chronic dopamine replacement could have different effects on plasticity in PD or in the networks recruited by a specific plasticity induction technique.

Consensus Paper: Towards a Systems-Level View of Cerebellar Function: the Interplay Between Cerebellum, Basal Ganglia, and Cortex

Despite increasing evidence suggesting the cerebellum works in concert with the cortex and basal ganglia, the nature of the reciprocal interactions between these three brain regions remains unclear. This consensus paper gathers diverse recent views on a variety of important roles played by the cerebellum within the cerebello-basal ganglia-thalamo-cortical system across a range of motor and cognitive functions. The paper includes theoretical and empirical contributions, which cover the following topics: recent evidence supporting the dynamical interplay between cerebellum, basal ganglia, and cortical areas in humans and other animals; theoretical neuroscience perspectives and empirical evidence on the reciprocal influences between cerebellum, basal ganglia, and cortex in learning and control processes; and data suggesting possible roles of the cerebellum in basal ganglia movement disorders. Although starting from different backgrounds and dealing with different topics, all the contributors agree that viewing the cerebellum, basal ganglia, and cortex as an integrated system enables us to understand the function of these areas in radically different ways. In addition, there is unanimous consensus between the authors that future experimental and computational work is needed to understand the function of cerebellar-basal ganglia circuitry in both motor and non-motor functions. The paper reports the most advanced perspectives on the role of the cerebellum within the cerebello-basal ganglia-thalamo-cortical system and illustrates other elements of consensus as well as disagreements and open questions in the field.

Striatal D2 receptors in symptomatic and asymptomatic carriers of dopa-responsive dystonia measured with [11C]-raclopride and positron-emission tomography

We tested the hypothesis that asymptomatic carriers of dopa-responsive dystonia (DRD) have increased dopamine D2 receptors in the striatum that protect them from the clinical manifestations of dopaminergic deficiency. We examined striatal D2-receptor binding in (1) symptomatic subjects (treated and untreated) and (2) asymptomatic gene carriers. Using[11C]-raclopride PET, we found elevated striatal D2-receptor binding in both groups. In one of our drug-naive symptomatic subjects, 7 months of treatment with levodopa/carbidopa did not affect the receptor binding as measured on a second scan. We conclude that increased D2-receptor binding in DRD may be a homeostatic response to the dopaminergic deficit in subjects carrying the DRD gene, but is not the sole factor determining the clinical state of these individuals.

Acute dopamine boost has a negative effect on plasticity of the primary motor cortex in advanced Parkinson's disease

Plasticity of primary motor cortex is severely impaired in Parkinsons disease and chronic dopaminergic treatment is reported not to rescue it. The effect of an acute dose of levodopa on cortical plasticity reported so far is variable. In this study, it was hypothesized that cortical plasticity would be restored in Parkinsons disease as a long duration response to treatment in stable responders while those with motor complications would have a reduction or loss of plasticity similar to the decay of long duration response of motor signs. Patients were carefully stratified based on their motor response to levodopa into stable responders (n=17), fluctuating non-dyskinetics (n=18) and fluctuating dyskinetics (n=20). Theta burst stimulation was applied to the motor cortex to induce long-term potentiation and long-term depression-like plasticity in both OFF and ON conditions. In OFF, stable responders could express both types of plasticity, fluctuating non-dyskinetics had long-term potentiation, but no long-term depression and both types of plasticity were lost in fluctuating dyskinetics. This suggests the presence of a long duration response in early stages of levodopa treatment and a gradual loss of chronic treatment benefit on plasticity, particularly for long-term depression, when motor complications develop. An acute dose of levodopa led to a worsening of long-term potentiation in fluctuating non-dyskinetic patients, and it did not have any effect on the plasticity that was absent in OFF in the fluctuating dyskinetic patients. Acute dosing led to a worsening of long-term depression in all the groups. In the fluctuating dyskinetic patients, there was a paradoxical potentiation instead of depression. Our results suggest that an acute non-physiological dopamine boost has a negative effect on cortical plasticity as disease advances. We propose that the loss of long duration response and the negative effect of acute doses on cortical plasticity with progression of disease may contribute to the pathophysiology of motor complications. Repeated non-physiological surges in synaptic dopamine during acute levodopa dosing could potentially lead to persistent dysfunction of key enzymes of the intracellular signalling cascade that are involved in the induction and maintenance of both forms of plasticity.

Do nonmotor symptoms in Parkinson's disease differ from normal aging?

Nonmotor symptoms in Parkinsons disease are frequent and affect health‐related quality of life of patients. The severity and domains of nonmotor symptoms involved in Parkinsons disease and normal aging have not been compared before.

Cerebellar Sensory Processing Alterations Impact Motor Cortical Plasticity in Parkinson's Disease: Clues from Dyskinetic Patients

The plasticity of primary motor cortex (M1) in patients with Parkinsons disease (PD) and levodopa-induced dyskinesias (LIDs) is severely impaired. We recently reported in young healthy subjects that inhibitory cerebellar stimulation enhanced the sensorimotor plasticity of M1 that was induced by paired associative stimulation (PAS). This study demonstrates that the deficient sensorimotor M1 plasticity in 16 patients with LIDs could be reinstated by a single session of real inhibitory cerebellar stimulation but not sham stimulation. This was evident only when a sensory component was involved in the induction of plasticity, indicating that cerebellar sensory processing function is involved in the resurgence of M1 plasticity. The benefit of inhibitory cerebellar stimulation on LIDs is known. To explore whether this benefit is linked to the restoration of sensorimotor plasticity of M1, we conducted an additional study looking at changes in LIDs and PAS-induced plasticity after 10 sessions of either bilateral, real inhibitory cerebellar stimulation or sham stimulation. Only real and not sham stimulation had an antidyskinetic effect and it was paralleled by a resurgence in the sensorimotor plasticity of M1. These results suggest that alterations in cerebellar sensory processing function, occurring secondary to abnormal basal ganglia signals reaching it, may be an important element contributing to the maladaptive sensorimotor plasticity of M1 and the emergence of abnormal involuntary movements.

Long term outcome of unilateral pallidotomy: follow up of 15 patients for 3 years

OBJECTIVES With the advent of new antiparkinsonian drug therapy and promising results from subthalamic and pallidal stimulation, this study evaluated the long term efficacy of unilateral pallidotomy, a technique which has gained popularity over the past decade for the management of advanced Parkinsons disease. METHODS The 15 patients reported here are part of the original cohort of 24 patients who underwent posteroventral pallidotomy for motor fluctuations and disabling dyskinesias 3 years ago as part of a prospective study. Evaluation scales included the unified Parkinsons disease rating scale, the Goetz dyskinesia scale, and the Purdue pegboard test. RESULTS When compared with the prepallidotomy scores, the reduction in the limb dyskinesias and off state tremor scores persisted on the side contralateral to pallidotomy at the end of 3 years (dyskinesias were reduced by 64% (p<0.01) and tremor by 63% (p<0.05). Other measures tended to deteriorate. The dosage of antiparkinsonian medications did not change significantly from 3 months prepallidotomy to 3 years postpallidotomy. CONCLUSIONS Although unilateral pallidotomy is useful in controlling the contralateral dyskinesias and tremor 3 years after surgery, all other early benefits disappear and activities of daily living continue to worsen.