Cerebellar Volume and Disease Staging in Parkinson's Disease: An ENIGMA-PD Study.

BACKGROUND: Increasing evidence points to a pathophysiological role for the cerebellum in Parkinson's disease (PD). However, regional cerebellar changes associated with motor and non-motor functioning remain to be elucidated. OBJECTIVE: To quantify cross-sectional regional cerebellar lobule volumes using three dimensional T1-weighted anatomical brain magnetic resonance imaging from the global ENIGMA-PD working group. METHODS: Cerebellar parcellation was performed using a deep learning-based approach from 2487 people with PD and 1212 age and sex-matched controls across 22 sites. Linear mixed effects models compared total and regional cerebellar volume in people with PD at each Hoehn and Yahr (HY) disease stage, to an age- and sex- matched control group. Associations with motor symptom severity and Montreal Cognitive Assessment scores were investigated. RESULTS: Overall, people with PD had a regionally smaller posterior lobe (dmax = -0.15). HY stage-specific analyses revealed a larger anterior lobule V bilaterally (dmax = 0.28) in people with PD in HY stage 1 compared to controls. In contrast, smaller bilateral lobule VII volume in the posterior lobe was observed in HY stages 3, 4, and 5 (dmax = -0.76), which was incrementally lower with higher disease stage. Within PD, cognitively impaired individuals had lower total cerebellar volume compared to cognitively normal individuals (d = -0.17). CONCLUSIONS: We provide evidence of a dissociation between anterior "motor" lobe and posterior "non-motor" lobe cerebellar regions in PD. Whereas less severe stages of the disease are associated with larger motor lobe regions, more severe stages of the disease are marked by smaller non-motor regions. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

The role of laboratory investigations in the classification of tremors.

INTRODUCTION: Tremor is the most common movement disorder. Although clinical examination plays a significant role in evaluating patients with tremor, laboratory tests are useful to classify tremors according to the recent two-axis approach proposed by the International Parkinson and Movement Disorders Society. METHODS: In the present review, we will discuss the usefulness and applicability of the various diagnostic methods in classifying and diagnosing tremors. We will evaluate a number of techniques, including laboratory and genetic tests, neurophysiology, and neuroimaging. The role of newly introduced innovative tremor assessment methods will also be discussed. RESULTS: Neurophysiology plays a crucial role in tremor definition and classification, and it can be useful for the identification of specific tremor syndromes. Laboratory and genetic tests and neuroimaging may be of paramount importance in identifying specific etiologies. Highly promising innovative technologies are being developed for both clinical and research purposes. CONCLUSIONS: Overall, laboratory investigations may support clinicians in the diagnostic process of tremor. Also, combining data from different techniques can help improve understanding of the pathophysiological bases underlying tremors and guide therapeutic management.

Integrative Brain States Facilitate the Expression of Parkinson's Tremor.

BACKGROUND: Parkinson's disease (PD) rest tremor emerges from pathological activity in the basal ganglia and cerebello-thalamo-cortical circuits. A well-known clinical feature is the waxing and waning of PD tremor amplitude, but the mechanisms that drive this variability are unclear. Previous work has shown that arousal amplifies PD tremor by increasing between-network connectivity. Furthermore, brain states in PD are biased toward integration rather than segregation, a pattern that is also associated with increased arousal. OBJECTIVE: The aim was to test the hypothesis that fluctuations in integrative brain states and/or arousal drive spontaneous fluctuations in PD rest tremor. METHODS: We compared the temporal relationship between cerebral integration, the ascending arousal system, and tremor, both during cognitive load and in the resting state. In 40 tremor-dominant PD patients, we performed functional magnetic resonance imaging using concurrent tremor recordings and proxy measures of the ascending arousal system (pupil diameter, heart rate). We calculated whole-brain dynamic functional connectivity and used graph theory to determine a scan-by-scan measure of cerebral integration, which we related to the onset of tremor episodes. RESULTS: Fluctuations in cerebral integration were time locked to spontaneous changes in tremor amplitude: cerebral integration increased 13 seconds before tremor onset and predicted the amplitude of subsequent increases in tremor amplitude. During but not before tremor episodes, pupil diameter and heart rate increased and correlated with tremor amplitude. CONCLUSIONS: Integrative brain states are an important cerebral environment in which tremor-related activity emerges, which is then amplified by the ascending arousal system. New treatments focused on attenuating enhanced cerebral integration in PD may reduce tremor. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

The pathophysiology of Parkinson's disease tremor.

Tremor is one of the primary motor symptoms of Parkinson's disease (PD), and it is characterized by a highly phenomenological heterogeneity. Clinical and experimental observations suggest that tremor in PD cannot be interpreted merely as an expression of dopaminergic denervation of the basal ganglia. Accordingly, other neurotransmitter systems and brain areas are involved. We here review neurochemical, neurophysiological, and neuroimaging data as the basis of the presence of a dysfunctional network underlying tremor in PD. We will discuss the role of altered oscillations and synchronization in two partially overlapping central motor circuitries, e.g., the cerebello-thalamo-cortical and the basal ganglia-cortical loops. We will also emphasize the pathophysiological consequences of the abnormal interplay between the two systems. While there are many currently unknown and controversial aspects in the field, we will highlight the possible translational and practical implications of research advances in understanding tremor pathophysiology in PD. A better understanding of this issue is likely facilitating future therapeutic approaches to PD patients based on medications and invasive and non-invasive stimulation techniques. This article is part of the Special Issue "Tremor" edited by Daniel D. Truong, Mark Hallett, and Aasef Shaikh.

The clinical and electrophysiological investigation of tremor.

The various forms of tremor are now classified in two axes: clinical characteristics (axis 1) and etiology (axis 2). Electrophysiology is an extension of the clinical exam. Electrophysiologic tests are diagnostic of physiologic tremor, primary orthostatic tremor, and functional tremor, but they are valuable in the clinical characterization of all forms of tremor. Electrophysiology will likely play an increasing role in axis 1 tremor classification because many features of tremor are not reliably assessed by clinical examination alone. In particular, electrophysiology may be needed to distinguish tremor from tremor mimics, assess tremor frequency, assess tremor rhythmicity or regularity, distinguish mechanical-reflex oscillation from central neurogenic oscillation, determine if tremors in different body parts, muscles, or brain regions are strongly correlated, document tremor suppression or entrainment by voluntary movements of contralateral body parts, and document the effects of voluntary movement on rest tremor. In addition, electrophysiologic brain mapping has been crucial in our understanding of tremor pathophysiology. The electrophysiologic methods of tremor analysis are reviewed in the context of physiologic tremor and pathologic tremors, with a focus on clinical characterization and pathophysiology. Electrophysiology is instrumental in elucidating tremor mechanisms, and the pathophysiology of the different forms of tremor is summarized in this review.

Cerebello-thalamic activity drives an abnormal motor network into dystonic tremor.

Dystonic tremor syndromes are highly burdensome and treatment is often inadequate. This is partly due to poor understanding of the underlying pathophysiology. Several lines of research suggest involvement of the cerebello-thalamo-cortical circuit and the basal ganglia in dystonic tremor syndromes, but their role is unclear. Here we aimed to investigate the contribution of the cerebello-thalamo-cortical circuit and the basal ganglia to the pathophysiology of dystonic tremor syndrome, by directly linking tremor fluctuations to cerebral activity during scanning. In 27 patients with dystonic tremor syndrome (dystonic tremor: n = 23; tremor associated with dystonia: n = 4), we used concurrent accelerometery and functional MRI during a posture holding task that evoked tremor, alternated with rest. Using multiple regression analyses, we separated tremor-related activity from brain activity related to (voluntary) posture holding. Using dynamic causal modelling, we tested for altered effective connectivity between tremor-related brain regions as a function of tremor amplitude fluctuations. Finally, we compared grey matter volume between patients (n = 27) and matched controls (n = 27). We found tremor-related activity in sensorimotor regions of the bilateral cerebellum, contralateral posterior and anterior ventral lateral nuclei of the thalamus (VLp and VLa), contralateral primary motor cortex (hand area), contralateral pallidum, and the bilateral frontal cortex (laterality with respect to the tremor). Grey matter volume was increased in patients compared to controls in the portion of contralateral thalamus also showing tremor-related activity, as well as in bilateral medial and left lateral primary motor cortex, where no tremor-related activity was present. Effective connectivity analyses showed that inter-regional coupling in the cerebello-thalamic pathway, as well as the thalamic self-connection, were strengthened as a function of increasing tremor power. These findings indicate that the pathophysiology of dystonic tremor syndromes involves functional and structural changes in the cerebello-thalamo-cortical circuit and pallidum. Deficient input from the cerebellum towards the thalamo-cortical circuit, together with hypertrophy of the thalamus, may play a key role in the generation of dystonic tremor syndrome.

International Multicenter Analysis of Brain Structure Across Clinical Stages of Parkinson's Disease.

BACKGROUND: Brain structure abnormalities throughout the course of Parkinson's disease have yet to be fully elucidated. OBJECTIVE: Using a multicenter approach and harmonized analysis methods, we aimed to shed light on Parkinson's disease stage-specific profiles of pathology, as suggested by in vivo neuroimaging. METHODS: Individual brain MRI and clinical data from 2357 Parkinson's disease patients and 1182 healthy controls were collected from 19 sources. We analyzed regional cortical thickness, cortical surface area, and subcortical volume using mixed-effects models. Patients grouped according to Hoehn and Yahr stage were compared with age- and sex-matched controls. Within the patient sample, we investigated associations with Montreal Cognitive Assessment score. RESULTS: Overall, patients showed a thinner cortex in 38 of 68 regions compared with controls (dmax  = -0.20, dmin  = -0.09). The bilateral putamen (dleft  = -0.14, dright  = -0.14) and left amygdala (d = -0.13) were smaller in patients, whereas the left thalamus was larger (d = 0.13). Analysis of staging demonstrated an initial presentation of thinner occipital, parietal, and temporal cortices, extending toward rostrally located cortical regions with increased disease severity. From stage 2 and onward, the bilateral putamen and amygdala were consistently smaller with larger differences denoting each increment. Poorer cognition was associated with widespread cortical thinning and lower volumes of core limbic structures. CONCLUSIONS: Our findings offer robust and novel imaging signatures that are generally incremental across but in certain regions specific to disease stages. Our findings highlight the importance of adequately powered multicenter collaborations. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Effects of dopamine on reinforcement learning in Parkinson's disease depend on motor phenotype.

Parkinson's disease is clinically defined by bradykinesia, along with rigidity and tremor. However, the severity of these motor signs is greatly variable between individuals, particularly the presence or absence of tremor. This variability in tremor relates to variation in cognitive/motivational impairment, as well as the spatial distribution of neurodegeneration in the midbrain and dopamine depletion in the striatum. Here we ask whether interindividual heterogeneity in tremor symptoms could account for the puzzlingly large variability in the effects of dopaminergic medication on reinforcement learning, a fundamental cognitive function known to rely on dopamine. Given that tremor-dominant and non-tremor Parkinson's disease patients have different dopaminergic phenotypes, we hypothesized that effects of dopaminergic medication on reinforcement learning differ between tremor-dominant and non-tremor patients. Forty-three tremor-dominant and 20 non-tremor patients with Parkinson's disease were recruited to be tested both OFF and ON dopaminergic medication (200/50 mg levodopa-benserazide), while 22 age-matched control subjects were recruited to be tested twice OFF medication. Participants performed a reinforcement learning task designed to dissociate effects on learning rate from effects on motivational choice (i.e. the tendency to 'Go/NoGo' in the face of reward/threat of punishment). In non-tremor patients, dopaminergic medication improved reward-based choice, replicating previous studies. In contrast, in tremor-dominant patients, dopaminergic medication improved learning from punishment. Formal modelling showed divergent computational effects of dopaminergic medication as a function of Parkinson's disease motor phenotype, with a modulation of motivational choice bias and learning rate in non-tremor and tremor patients, respectively. This finding establishes a novel cognitive/motivational difference between tremor and non-tremor Parkinson's disease patients, and highlights the importance of considering motor phenotype in future work.

Dopamine-responsive and dopamine-resistant resting tremor in Parkinson disease.

OBJECTIVE: We tested the hypothesis that there are 2 distinct phenotypes of Parkinson tremor, based on interindividual differences in the response of resting tremor to dopaminergic medication. We also investigated whether this pattern is specific to tremor by comparing interindividual differences in the dopamine response of tremor to that of bradykinesia. METHODS: In this exploratory study, we performed a levodopa challenge in 76 tremulous patients with Parkinson tremor. Clinical scores (Movement Disorders Society-sponsored version of the Unified Parkinson's Disease Rating Scale part III) were collected "off" and "on" a standardized dopaminergic challenge (200/50 mg dispersible levodopa-benserazide). In both sessions, resting tremor intensity was quantified using accelerometry, both during rest and during cognitive coactivation. Bradykinesia was quantified using a speeded keyboard test. We calculated the distribution of dopamine-responsiveness for resting tremor and bradykinesia. In 41 patients, a double-blinded, placebo-controlled dopaminergic challenge was repeated after approximately 6 months. RESULTS: The dopamine response of resting tremor, but not bradykinesia, significantly departed from a normal distribution. A cluster analysis on 3 clinical and electrophysiologic markers of tremor dopamine-responsiveness revealed 3 clusters: dopamine-responsive, intermediate, and dopamine-resistant tremor. A repeated levodopa challenge after 6 months confirmed this classification. Patients with dopamine-responsive tremor had greater disease severity and tended to have a higher prevalence of dyskinesia. CONCLUSION: Parkinson resting tremor can be divided into 3 partially overlapping phenotypes, based on the dopamine response. These tremor phenotypes may be associated with different underlying pathophysiologic mechanisms, requiring a different therapeutic approach.

Cognitive load amplifies Parkinson's tremor through excitatory network influences onto the thalamus.

Parkinson's tremor is related to cerebral activity in both the basal ganglia and a cerebello-thalamo-cortical circuit. It is a common clinical observation that tremor markedly increases during cognitive load (such as mental arithmetic), leading to serious disability. Previous research has shown that this tremor amplification is associated with reduced efficacy of dopaminergic treatment. Understanding the mechanisms of tremor amplification and its relation to catecholamines might help to better control this symptom with a targeted therapy. We reasoned that, during cognitive load, tremor amplification might result from modulatory influences onto the cerebello-thalamo-cortical circuit controlling tremor amplitude, from the ascending arousal system (bottom-up), a cognitive control network (top-down), or their combination. We have tested these hypotheses by measuring concurrent EMG and functional MRI in 33 patients with tremulous Parkinson's disease, OFF medication, during alternating periods of rest and cognitive load (mental arithmetic). Simultaneous heart rate and pupil diameter recordings indexed activity of the arousal system (which includes noradrenergic afferences). As expected, tremor amplitude correlated with activity in a cerebello-thalamo-cortical circuit; and cognitive load increased tremor amplitude, pupil diameter, heart rate, and cerebral activity in a cognitive control network distributed over fronto-parietal cortex, insula, thalamus and anterior cingulate cortex. The novel finding, obtained through network analyses, indicates that cognitive load influences tremor by increasing activity in the cerebello-thalamo-cortical circuit in two different ways: by stimulating thalamic activity, likely through the ascending arousal system (given that this modulation correlated with changes in pupil diameter), and by strengthening connectivity between the cognitive control network and the cerebello-thalamo-cortical circuit. We conclude that both the bottom-up arousal system and a top-down cognitive control network amplify tremor when a Parkinson's patient experiences cognitive load. Interventions aimed at attenuating noradrenergic activity or cognitive demands may help to reduce Parkinson's tremor.

Systematic clinical approach for diagnosing upper limb tremor.

Tremor is the most common movement disorder worldwide, but diagnosis is challenging. In 2018, the task force on tremor of the International Parkinson and Movement Disorder Society published a consensus statement that proposes a tremor classification along two independent axes: a clinical tremor syndrome and its underlying aetiology. In line with this statement, we here propose a stepwise diagnostic approach that leads to the correct clinical and aetiological classification of upper limb tremor. We also describe the typical clinical signs of each clinical tremor syndrome. A key feature of our algorithm is the distinction between isolated and combined tremor syndromes, in which tremor is accompanied by bradykinesia, cerebellar signs, dystonia, peripheral neuropathy or brainstem signs. This distinction subsequently informs the selection of appropriate diagnostic tests, such as neurophysiology, laboratory testing, structural and dopaminergic imaging and genetic testing. We highlight treatable metabolic causes of tremor, as well as drugs and toxins that can provoke tremor. The stepwise approach facilitates appropriate diagnostic testing and avoids unnecessary investigations. We expect that the approach offered in this article will reduce diagnostic uncertainty and increase the diagnostic yield in patients with tremor.

GABAergic changes in the thalamocortical circuit in Parkinson's disease.

Parkinson's disease is characterized by bradykinesia, rigidity, and tremor. These symptoms have been related to an increased gamma-aminobutyric acid (GABA)ergic inhibitory drive from globus pallidus onto the thalamus. However, in vivo empirical evidence for the role of GABA in Parkinson's disease is limited. Some discrepancies in the literature may be explained by the presence or absence of tremor. Specifically, recent functional magnetic resonance imaging (fMRI) findings suggest that Parkinson's tremor is associated with reduced, dopamine-dependent thalamic inhibition. Here, we tested the hypothesis that GABA in the thalamocortical motor circuit is increased in Parkinson's disease, and we explored differences between clinical phenotypes. We included 60 Parkinson patients with dopamine-resistant tremor (n = 17), dopamine-responsive tremor (n = 23), or no tremor (n = 20), and healthy controls (n = 22). Using magnetic resonance spectroscopy, we measured GABA-to-total-creatine ratio in motor cortex, thalamus, and a control region (visual cortex) on two separate days (ON and OFF dopaminergic medication). GABA levels were unaltered by Parkinson's disease, clinical phenotype, or medication. However, motor cortex GABA levels were inversely correlated with disease severity, particularly rigidity and tremor, both ON and OFF medication. We conclude that cortical GABA plays a beneficial rather than a detrimental role in Parkinson's disease, and that GABA depletion may contribute to increased motor symptom expression.

Cerebral differences between dopamine-resistant and dopamine-responsive Parkinson's tremor.

Rest tremor in Parkinson's disease is related to cerebral activity in both the basal ganglia and a cerebello-thalamo-cortical circuit. Clinically, there is strong interindividual variation in the therapeutic response of tremor to dopaminergic medication. This observation casts doubt on the idea that Parkinson's tremor has a dopaminergic basis. An interesting alternative explanation is that interindividual differences in the pathophysiology of tremor may underlie this clinical heterogeneity. Previous work showed that dopaminergic medication reduces Parkinson's tremor by inhibiting tremulous activity in the pallidum and thalamus, and this may explain why some tremors are dopamine-responsive. Here we test the hypothesis that dopamine-resistant resting tremor may be explained by increased contributions of non-dopaminergic brain regions, such as the cerebellum. To test this hypothesis, we first performed a levodopa challenge test in 83 tremulous Parkinson's disease patients, and selected 20 patients with a markedly dopamine-responsive tremor (71% reduction) and 14 patients with a markedly dopamine-resistant tremor (6% reduction). The dopamine response of other core motor symptoms was matched between groups. Next, in all 34 patients, we used combined EMG-functional MRI to quantify tremor-related brain activity during two separate sessions (crossover, double-blind, counterbalanced design): after placebo, or after 200/50 mg dispersible levodopa/benserazide. We compared tremor-related brain activity between groups and medication sessions. Both groups showed tremor amplitude-related brain activity in a cerebello-thalamo-cortical circuit. Dopamine-resistant tremor patients showed increased tremor-related activity in non-dopaminergic areas (cerebellum), whereas the dopamine-responsive group showed increased tremor-related activity in the thalamus and secondary somatosensory cortex (across medication sessions). Levodopa inhibited tremor-related thalamic responses in both groups, but this effect was significantly greater in dopamine-responsive patients. These results suggest that dopamine-resistant tremor may be explained by increased cerebellar and reduced somatosensory influences onto the cerebellar thalamus, making this region less susceptible to the inhibitory effects of dopamine.

The nature of postural tremor in Parkinson disease.

OBJECTIVE: To disentangle the different forms of postural tremors in Parkinson disease (PD). METHODS: In this combined observational and intervention study, we measured resting and postural tremor characteristics in 73 patients with tremulous PD by using EMG of forearm muscles. Patients were measured both "off" medication (overnight withdrawal) and after dispersible levodopa-benserazide 200/50 mg. We performed an automated 2-step cluster analysis on 3 postural tremor characteristics: the frequency difference with resting tremor, the degree of tremor suppression after posturing, and the dopamine response. RESULTS: The cluster analysis revealed 2 distinct postural tremor phenotypes: 81% had re-emergent tremor (amplitude suppression, frequency difference with resting tremor 0.4 Hz, clear dopamine response) and 19% had pure postural tremor (no amplitude suppression, frequency difference with resting tremor 3.5 Hz, no dopamine response). This finding was manually validated (accuracy of 93%). Pure postural tremor was not associated with clinical signs of essential tremor or dystonia, and it was not influenced by weighing. CONCLUSION: There are 2 distinct postural tremor phenotypes in PD, which have a different pathophysiology and require different treatment. Re-emergent tremor is a continuation of resting tremor during stable posturing, and it has a dopaminergic basis. Pure postural tremor is a less common type of tremor that is inherent to PD, but has a largely nondopaminergic basis.

Pathophysiology and Management of Parkinsonian Tremor.

Parkinson's tremor is one of the cardinal motor symptoms of Parkinson's disease. The pathophysiology of Parkinson's tremor is different from that of other motor symptoms such as bradykinesia and rigidity. In this review, the authors discuss evidence suggesting that tremor is a network disorder that arises from distinct pathophysiological changes in the basal ganglia and in the cerebellothalamocortical circuit. They also discuss how interventions in this circuitry, for example, deep brain surgery and noninvasive brain stimulation, can modulate or even treat tremor. Future research may focus on understanding sources for the large variability between patients in terms of treatment response, on understanding the contextual factors that modulate tremor (stress, voluntary movements), and on focused interventions in the tremor circuitry.

Dopamine controls Parkinson's tremor by inhibiting the cerebellar thalamus.

Parkinson's resting tremor is related to altered cerebral activity in the basal ganglia and the cerebello-thalamo-cortical circuit. Although Parkinson's disease is characterized by dopamine depletion in the basal ganglia, the dopaminergic basis of resting tremor remains unclear: dopaminergic medication reduces tremor in some patients, but many patients have a dopamine-resistant tremor. Using pharmacological functional magnetic resonance imaging, we test how a dopaminergic intervention influences the cerebral circuit involved in Parkinson's tremor. From a sample of 40 patients with Parkinson's disease, we selected 15 patients with a clearly tremor-dominant phenotype. We compared tremor-related activity and effective connectivity (using combined electromyography-functional magnetic resonance imaging) on two occasions: ON and OFF dopaminergic medication. Building on a recently developed cerebral model of Parkinson's tremor, we tested the effect of dopamine on cerebral activity associated with the onset of tremor episodes (in the basal ganglia) and with tremor amplitude (in the cerebello-thalamo-cortical circuit). Dopaminergic medication reduced clinical resting tremor scores (mean 28%, range -12 to 68%). Furthermore, dopaminergic medication reduced tremor onset-related activity in the globus pallidus and tremor amplitude-related activity in the thalamic ventral intermediate nucleus. Network analyses using dynamic causal modelling showed that dopamine directly increased self-inhibition of the ventral intermediate nucleus, rather than indirectly influencing the cerebello-thalamo-cortical circuit through the basal ganglia. Crucially, the magnitude of thalamic self-inhibition predicted the clinical dopamine response of tremor. Dopamine reduces resting tremor by potentiating inhibitory mechanisms in a cerebellar nucleus of the thalamus (ventral intermediate nucleus). This suggests that altered dopaminergic projections to the cerebello-thalamo-cortical circuit have a role in Parkinson's tremor.aww331media15307619934001.

Cognitive Stress Reduces the Effect of Levodopa on Parkinson's Resting Tremor.

AIMS: Resting tremor in Parkinson's disease (PD) increases markedly during cognitive stress. Dopamine depletion in the basal ganglia is involved in the pathophysiology of resting tremor, but it is unclear whether this contribution is altered under cognitive stress. We test the hypothesis that cognitive stress modulates the levodopa effect on resting tremor. METHODS: Tremulous PD patients (n = 69) were measured in two treatment conditions (OFF vs. ON levodopa) and in two behavioral contexts (rest vs. cognitive co-activation). Using accelerometry, we tested the effect of both interventions on tremor intensity and tremor variability. RESULTS: Levodopa significantly reduced tremor intensity (across behavioral contexts), while cognitive co-activation increased it (across treatment conditions). Crucially, the levodopa effect was significantly smaller during cognitive co-activation than during rest. Resting tremor variability increased after levodopa and decreased during cognitive co-activation. CONCLUSION: Cognitive stress reduces the levodopa effect on Parkinson's tremor. This effect may be explained by a stress-related depletion of dopamine in the basal ganglia motor circuit, by stress-related involvement of nondopaminergic mechanisms in tremor (e.g., noradrenaline), or both. Targeting these mechanisms may open new windows for treatment. Clinical tremor assessments under evoked cognitive stress (e.g., counting tasks) may avoid overestimation of treatment effects in real life.

The patient's perspective: The effect of levodopa on Parkinson symptoms.

BACKGROUND: Dopaminergic medication adjustments in Parkinson's disease are often solely based on patient reports. However, it is unclear how well patient-based ratings of the levodopa response correlate with clinician-based ratings, and whether this correlation differs between motor symptoms. Here we compare patient-clinician agreement for the effect of levodopa on resting tremor and bradykinesia/rigidity. Furthermore, given patients' reports that tremor is most troublesome during stress, we test for differences in patient-clinician agreement between tremor at rest and stress-induced tremor. METHODS: We included 42 tremulous Parkinson patients, who were clinically rated (using the MDS-UPDRS) in a practically defined OFF-state and after levodopa-benserazide 200/50 mg. Using accelerometry, we quantified the effect of dopaminergic medication and behavioral context (rest vs. cognitive stress) on tremor intensity. Patients rated medication effects on tremor and bradykinesia/rigidity using visual analogue scales. RESULTS: There was only moderate patient-clinician agreement for the effect of levodopa on bradykinesia/rigidity (R2 = 0.18; p < 0.01), and a tendency towards larger agreement for tremor (R2 = 0.44; p < 0.001; difference between correlation coefficients: z = 1.64; p = 0.051). Patient ratings of tremor changes correlated significantly better with accelerometry for tremor during cognitive stress (R2 = 0.35; p < 0.001) vs. tremor at rest (R2 = 0.12; p < 0.05; difference: z = -2.35, p < 0.01). CONCLUSION: The moderate correlations between patient ratings and clinical/accelerometry changes indicate the need for methods to better monitor symptom severity and impairments in daily life, for example wearable sensors. Our findings also suggest that context matters: Parkinson patients' subjective experience of levodopa effectiveness on tremor was largely based on the ability of levodopa to reduce tremor during cognitive stress.

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.