Reply to: Touchscreen Smartphone Interaction in Parkinson's Disease and Healthy Subjects on Out-Patient Clinics.

Objective: To analyze the content of α-synuclein oligomer(O-α-Syn) in erythrocytes in patients with Parkinson's disease (PD) and multiple system atrophy (MSA) and the correlation with clinical symptoms. Methods: Two hundred and ninety-six PD patients and 85 MSA patients were recruited from the Department of Functional Neurosurgery and Neurology of Xuanwu Hospital, Capital Medical University from July 2020 to October 2021. Four hundred and three healthy controls (HC) were recruited from the Beijing Longitudinal Study of Aging community cohort during the same period. The levels of RBC-O-α-Syn were measured by enzyme-linked immunosorbent assay (ELISA). Univariate linear regression model was used to analyze the correlation between the content of RBD-O-α-Syn and various motor and non-motor functional scores, such as Unified Parkinson Disease Rating Scale (UPDRS) Ⅲ, Unified Multiple System Atrophy Rating Scale (UMSARS) Ⅲ, Mini-Mental State Examination (MMSE), rapid eye movement sleep disorder questionnaire-HongKong(RBDQ-HK) and Montreal Cognitive Assessment (MoCA). Receiver operating characteristic (ROC) curves was used to evaluate the specificity, sensitivity, and the area under the curve (AUC) of RBC-O-α-Syn in distinguishing PD and MSA patients from HC subjects. Results: The average age of HC subjects was (70±8) years old, the average age of PD patients was (64±9) years old, including 115 (38.9%) cases with tremor dominant PD (TD-PD), 132 cases (44.6%) of postural instability disorder predominant PD (PIGD-PD), and 142 cases (48.0%) of patients with H-Y stage 2. UPDRS Ⅲ score was 31.2±17.8. The mean age of MSA patients was (64±9) years, with the mean UMSARS Ⅱ score of 18.9±10.3. The non-motor symptoms of PD and MSA patients were significantly different from those of HC subjects (P<0.001). The levels of RBC-O-α-Syn in PD [(50±17) ng/mg] and MSA [(52±19) ng/mg] were significantly higher than those in HC subjects [(21±10) ng/mg] (P<0.001). The sensitivity and specificity of RBC-O-α-Syn in distinguishing PD patients and HC subjects were 87.16% (95%CI: 82.87%-90.50%) and 86.10% (95%CI: 82.38%-89.14%), with an AUC of 0.933 (95%CI: 0.914-0.951), and the sensitivity and specificity in distinguishing MSA patients and HC subjects were 85.88% (95%CI: 76.93%-91.74%) and 81.39% (95%CI: 77.30%-84.89%), with an AUC of 0.921 (95%CI: 0.884-0.957). The levels of RBC-O-α-Syn in PD patients with rapid eye movement sleep behavior disorder (RBD) were higher than that in PD patients without RBD [(53±16) ng/mg vs (48±17) ng/mg, P=0.029].The content of RBC-O-α-Syn in female PD patients and HC subjects was higher than that in male, but there was no significant difference between subjects of different ages and disease duration (P>0.05). In addition, RBC-O-α-Syn content was positively correlated with UPDRS Ⅲ (r=0.18, P=0.002) and the score of rapid eye movement sleep behavior disorder questionnaire(Hong Kong) (RBDQ-HK)(r=0.19, P<0.001). But there was no correlation with H-Y stage, non-motor symptoms scale (NMSS), MMSE, Moca, Hamilton Depression Scale (HAMD), Hamilton Anxiety Scale (HAMA) scores (all P>0.05). There was no correlation between RBC-O-α-Syn content and UMSARS Ⅱ, NMSS, MMSE, MoCA, HAMD, HAMA in patients with MSA (all P>0.05). Conclusions: Levels of RBC-O-α-Syn are significantly increased in PD and MSA patients. There are positive correlations between levels of RBC-O-α-Syn and scores of UPDRS Ⅲ and RBDQ-HK.

Recent transcranial magnetic stimulation studies have shown that the motor output pathway shows a profound inhibition during the preparation of an action. This phenomenon, called “preparatory inhibition”, remains incompletely understood, as it is still unclear which neural structures support it and what function it exactly serves during action preparation. In the current study, we tested this preparatory inhibition in Parkinson’s disease (PD) patients and matched healthy control subjects. The aim was to better understand the role of basal ganglia (which are dysfunctional in PD) and the influence of dopamine replacement therapy on motor inhibition during action preparation.

3. Perisaccadic EEG components in Parkinson disease patients

Prehension patterns in restless legs syndrome patients

P 256. Augmented set-shifting in Parkinson’s disease with noisy Galvanic Vestibular Stimulation

Background:Vitamin D insufficiency and serum calcium disturbance have been reported to be more common in Parkinson's disease (PD) patients than in healthy control subjects, which may be due to a chronic disease or reduced mobility contributes to these relatively disturbances. Because of the high-vitamin D insufficiency in our population, we aimed to compare a biochemical levels which are related to bone metabolism, in PD patients in comparison with age-matched healthy controls, for the 1st time in a Middle East population.Materials and Methods:This case-control study was involved 105 (20 were excluded) PD patients, who were age- and -sex matched with 112 controls. 25-hydroxyvitamin D (25OHD) and parathyroid hormone analyzed by enzyme immunoassay; another laboratory data including, calcium, phosphorous, and alkaline phosphatase were performed by spectrophotometric methods.Results:There was no significant difference in 25OHD between PD patients and control group (P = 0.071). 25OHD level was not significantly different in PD patients compared to controls {odds ratio 1.003, (confidence interval [CI], 0.98-1.02), P value 0.793}. None of the other biochemical levels did not induce more chance for PD, only we observed in men has more risk of PD than women (odds ratio 2.53, [CI, 1.27-5.03], P value 0.008).Conclusion:Our data do not support a possible role of vitamin D insufficiency in PD. Regarding to variable changes in biochemical markers in PD patients than in controls; further studies are suggested to determine any plausibility role of them as a causal relationship or as an outcome of PD.

Previous studies have revealed alteration of functional connectivity (FC) in Parkinson's disease patients with anxiety (PD-A), but local brain activities associated with anxiety in Parkinson's disease (PD) patients remain to be elucidated. Regional homogeneity (ReHo) analysis was employed to investigate alterations of regional brain activities in PD-A patients. Resting-state functional magnetic resonance imaging (rs-fMRI) data were acquired from 42 PD-A patients, 41 PD patients without anxiety (PD-NA), and 40 age-and gender-matched healthy control (HC) subjects. ReHo analysis was used to investigate the synchronization of neuronal activities in brain regions in the three groups. The relationship between ReHo value and anxiety score in the PD-A group was also investigated. Parkinson's disease patients with anxiety showed increased ReHo values in the bilateral frontal lobes, caudate nucleus, and anterior cingulate gyrus [Gaussian random field (GRF) correction, voxel size p < 0.01, cluster size p < 0.05], compared with PD-NA patients and HC subjects, but the ReHo values of the right cerebellar hemisphere and posterior cerebellar lobe decreased (GRF correction, voxel size p < 0.01, cluster size p < 0.05). The increased ReHo values of the right superior frontal gyrus (r = 0.633, p = 0.001) and anterior cingulate gyrus (r = 0.45, p = 0.01) were positively correlated with anxiety scores in PD-A patients. The development of PD-A may be associated with dysfunctional local activities in multiple brain regions, including the frontal cortex, cerebella, basal ganglia, and limbic system. Abnormal ReHo values in these brain regions may serve as neuroimaging markers for the early diagnosis of PD-A. The results suggest that using ReHo analysis to identify functional changes in core regions may advance our understanding of the pathophysiological mechanisms underlying PD-A.

In this paper, we proposed Approximate Entropy (ApEn) measure for nonlinear analysis of patterns of two daily common movements, that is sit-to-stand and stand-to-sit, in patients with Parkinson's disease (PD) using deep brain stimulation (DBS). ApEn value of a signal indicates its complexity and irregularity, such that larger the ApEn measure is, more stochastic and less regular the signal is. Here, this nonlinear measure is used for classifying three groups of 1) healthy subjects, 2) PD patients with DBS off, and 3) the same PD patients with DBS on, based on their sit-to-stand and stand-to-sit patterns. To this end, the area under receiver operating characteristic (ROC) plots (AUC) is used to evaluate the capability of ApEn. For stand-to-sit patterns and for discrimination between two groups of normal vs. PD with DBS off, normal vs. PD with DBS on, and PD with DBS off vs. PD with DBS on, we achieved the AUC values of up to 0.9625, 0.9, and 0.9583, respectively. Also, there was high correlation between ApEn values of PD patients obtained from different sensors and the severity of their Parkinson's disease i.e. UPDRS scores (up to 0.7671 for PD with DBS off and 0.774 for PD with DBS on). For sit-to-stand patterns and to distinguish between normal vs. PD with DBS off, normal vs. PD with DBS on, and PD with DBS off vs. PD with DBS on, we achieved the AUC values of up to 1, 0.9778, and 0.9167, respectively. Moreover, for this pattern, there was higher correlation between ApEn values of PD patients and their UPDRS scores (up to 0.9573 for PD with DBS off and 0.7145 for PD with DBS on). Furthermore, in both sit-to-stand and stand-to-sit patterns, it was observed that PD patients have larger complexity values than healthy controls and PD subjects in DBS on state had smaller irregularity values than PD subjects in DBS off state. In general, we may conclude that sit-to-stand patterns can distinguish PD patients from healthy subjects and also be used to estimate the severity of Parkinson's disease better than stand-to-sit patterns.

Parkinson’s disease (PD) is the second most common neurodegenerative disorder. Early intervention/treatment relies on early diagnosis of PD. There is increasing interest in methods based on electromyography measurements of PD patients because of its noninvasiveness. Thus, this study was to investigate electromyographic (EMG) characteristics of the upper limb between PD patients and healthy control subjects using EMG, and to distinguish PD patients from healthy control subjects according to the EMG information using a support vector machine (SVM) classifier. Sixteen right-handed PD patients and 25 right-handed healthy subjects participated in experiments involving elbow flexion movement. The frequency power, duration, skewness, recurrence rate, and correlation dimension of EMG signals and success rate for the right hand and the skewness of EMG signals for the left hand were found to be significantly different between the two groups. This information was subsequently used to distinguish PD patients from healthy control subjects using the SVM classifier to obtain a mean accuracy of 87.02%. Although the results may not be immediately available to use in clinical applications, the safety, simplicity and speed of the system still merits further consideration. Enhancing performance accuracy and examining PD patients in different stages of disease are anticipated in future investigations.

Parkinson's disease (PD), a complex neurodegenerative disease, is characterized by the loss of dopamine neurons in the substantia nigra of the midbrain. PD patients have varying degrees of cognitive impairment (CI)1 that we term PD-CI. However, the etiology of these changes remains unexplained. We chose three Uygur male patients with PD-CI and three healthy controls of the same of nationality and sex to explore the pathogenesis of Xinjiang Uygur PD-CI using microarray-based gene expression profiling of monocytes. METHODS Subjects The cases were three Uygur men with PD-CI (sporadic) diagnosed by doctors of the First Affiliated Hospital of Xinjiang Medical University between November 2012 and January 2013. They were 65, 72, and 75 years old and were screened using the BrainBank diagnostic criteria (United Kingdom).2 When necessary, diagnosis was confirmed using a head MRI or CT scan. Secondary PD, Parkinson's syndrome, hyperthyroidism and other genetic or neural diseases were excluded. The three healthy individuals in the control group were selected from a survey population about the incidence of PD in Urumqi and were of identical gender and ethnicity as the PD patients, but were not genetically related to the patient group. Their ages were 62, 67, and 70 years. These six subjects were used for microarray-based analyzes. We also collected 31 cases of Uygur men with PD-CI (sporadic) and 35 healthy Uygur subjects for qRT-PCR verification of the microarray experiments. To investigate cognitive function, we used Mini-Mental State Examination (MMSE). MMSE scores of junior high school level ≤24 are considered to indicate cognitive disorders. This study was conducted in accordance with the Declaration of Helsinki and with approval from the Ethics Committee of the First Affiliated Hospital of Xinjiang Medical University. Written informed consent was obtained from all participants. RNA extraction Monocytes from venous blood (4.0 ml) were isolated using Histopaque-1077 Lymphocyte Separation Medium (Sigma, Louis, MO, USA) and total RNA was extracted with Trizol (Invitrogen, Carlsbad, CA, USA) according to the manufacturer's instructions. RNA quality was determined spectrophotometrically and by using the RNA 6000 NanoChip kit with an Agilent 2100 Bioanalyzer (Agilent, Santa Clara, CA, USA), with sample acceptance limits 28S/18S ≥1.0; A260/A230 ≥1.0; A260/A280 ≥1.8. Microarray-based analysis cDNA was synthesized from 200 ng of total RNA. The cDNA was then purified using the Illumina TotalPrep RNA Amplification Kit (Ambion, Carlsbad, CA, USA) and then reverse transcribed to generate cRNA according to the manufacturer's instructions. The 1.5 μg cRNA, 10 μl RNase-free water (Ambion), and 20 μl HYB (Illumina, San Diego, CA, USA) were then added to each hybridization tube. The 30-μl sample was then added via the inlet port onto the center of each HumanHT-12 v4.0 Expression BeadChip (Illumina) and hybridization was performed at 58°C for 14–20 hours in an Illumina hybridization oven. Washes were performed in 250-ml E1BC solution (Illumina) at 55°C for 10 minutes and at room temperature for 5 minutes. BeadChip data were collected using the iScan System and BeadArray Reader and then analyzed using Illumina's GenomeStudio Gene Expression Module. This work was completed by Genergy Biotech (Shanghai, China). QuantiFast SYBR Green PCR One subset comes from 3 PD-CI and 3 healthy control subjects tested in the microarray. The other subset is a group of 31 additional Chinese Uygur patients with PD-CI and 35 healthy control subjects. Four genes, including SNCA, DNAJB4, HIPK4, and FBXW8, were selected for analysis by qRT-PCR. All primers were designed and synthesized by Genergy Biotech (Shanghai). Two-Step RT-PCR was carried out using a Funglyn FTC-3000 real-time PCR instrument (Funglyn Biotech, Toronto, Canada). Reaction Setup: 12.5 μl 2× QuantiFast SYBR Green PCR Master Mix, 2.5 μl Primer F/R and cDNA, 5.0 μl RNase-free water. Total reaction volume was 25 μl. The PCR initial activation step was 95°C, 5 minutes; denaturation was 95°C, 10 seconds; the annealing temperature for DNAJB4, HIPK4, and FBXW8 was 59°C, and for SNCA 61°C. The number of cycles was 40. Statistical analysis Background normalization was used for minimizing the amount of variation in background signals between arrays and the expected signal for unexpressed targets is equal to zero. Illumina Custom (self-developed algorithm) was used for assessing differential expression (http://supportres.illumina.com/documents/myillumina/c94519f7–9348–4308-a32f-b66ff3959e99/genomestudio_gx_module_v1.0_ug_11319121_reva.pdf). Data were analyzed by t test function in R software (Lucent Technologies, USA). Fold difference was calculated as 2-ΔΔCT. ΔΔCT(control) = CT(control) - CT(mean); ΔΔCT(case)= (CT(case) - CT(gapdh in case)) - (CT(control) - CT(gapdh in control)). A P value less than 0.05 was statistically significant. Ranksum test was used for comparing two samples 2-ΔΔCT. RESULTS MMSE assessment showed that one of the three PD-CI patients had mild cognitive disorder and that the other two cases had moderate cognitive disorder. Cluster analysis indicated that 177 genes were up-regulated and 97 were down-regulated in PD-CI subjects compared with control subjects (fold-change >2.0) (Figure 1).Figure 1.: Partial genes were up-regulated. 1–3 indicates the case group, 4–6 the control group, and red signifies over-expression of a gene.The top 10 functional pathways identified using the KEGG (Kyoto Encyclopedia of Genes and Genomes) pathway maps that were affected by the observed changes in gene expression were cholinergic synapse, small cell lung cancer, transcriptional misregulation in cancer, GABAergic synapse, D-glutamine and D-glutamate metabolism, circadian entrainment, chemokine signaling pathway, glutamatergic synapse, dopaminergic synapse, arginine and proline metabolism. The most significantly affected pathway was for the cholinergic synapse (P <0.01). Up-regulation of SNCA, DNAJB and down-regulation of FBXW8 (P <0.05) was validated by qRT-PCR on the same 3 PD-CI subjects and 3 controls that were used for the microarray experiment and on another 31 PD-CI cases and 35 controls. Up-regulation of HIPK4 (P <0.05) was validated by qRT-PCR in the 3 cases and 3 controls but there was no statistically significant difference in expression levels of HIPK4 between 31 cases and 35 controls (P >0.05). DISCUSSION In this study, we identified three biomarkers (SNCA, DNAJB4, and FBXW8) that can distinguish patients with PD-CI from controls. One of the biomarkers, SNCA, which encodes alpha-synuclein, is over-expressed in peripheral monocytes of the three Chinese Uygur patients with PD-CI. Previous studies investigating the role of SNCA in cognitive impairment show that parahippocampus/transentorhinal cortex homogenates from dementia with Lewy bodies (DLB) cases accumulate significantly greater amounts of insoluble alpha-synuclein and contribute to cognitive impairment in DLB. Pathway analysis of our microarray data shows that, of the top 10 functional pathways affected by differential gene expression, four are related to synapse function: cholinergic synapse, GABAergic synapse, glutamatergic synapse, and dopaminergic synapse. The involvement of alpha-synuclein in these pathways in PD-CI is consistent with the disrupted synaptic activity seen in dopaminergic neurons of the substantia nigra and glutamatergic neurons of the hippocampus that result in global cognitive impairment.3 FBXW8 encodes an E3 ubiquitin ligase that is implicated in neuronal survival and differentiation as well as in synaptic transmission in mammalian nervous systems. The level of FBXW8 in synapses is also closely correlated with cognitive decline in Alzheimer's disease (AD). The different E3 ligase complexes can target alpha-synuclein for polyubiquitination leading to degradation by the proteosome in the endosomallysosomal pathway. In the KEGG cholinergic synapse pathway, FBXW8 has been confirmed to contribute to clearing potentially toxic hyperphosphorylated tau aggregates, the presence of which might result in a loss of cholinergic synapses and cholinergic disconnection.4 Interestingly, the dentate nucleus of the cerebellum has an extensive projection to the hippocampus, part of the brain's limbic system, indicating that it is involved in the cognitive functions of the cerebellum. When FBXW8 is up-regulated, it can significantly alleviate the abnormal accumulation of toxic proteins in the cerebellar dentate nucleus, such as insoluble ATXN2. In addition, the T allele of rs7294919, a single nucleotide polymorphism in the FBXW8 gene, is associated with lower hippocampal volume.5 Therefore, FBXW8 involvement in PD-CI is associated with the above synaptic functions, degradation of alpha-synuclein and tau, the cerebellar-hippocampal pathway, and genetic polymorphisms. DNAJB4 is a member of DNAJ/heat shock protein 40 family. Over-expression of DNAJB4 via enhancer activator protein-1 binding to promoter Yin Yang-1 and the coactivator, p300 promotes apoptosis through the JNK/JunD and caspase-3 pathway in lung cancer and AD. In this study, the second-ranking KEGG functional pathway was smallcell lung cancer. Further studies are required to determine whether the apoptosis pathway in PD-CI is similar to that in the above two diseases. The other differentially expressed gene, HIPK4, is a novel mouse homeodomain-interacting protein kinase-like gene. Over-expression of HIPK4 could contribute to the phosphorylation of p53 at serine 9, which could induce apoptosis. Although our study indicates that HIPK4 is over-expressed in Uygur PD-CI, this difference was not confirmed in the additional subjects (P >0.05). The association between HIPK4 and apoptotic mechanisms of PD-CI needs further study. Our study shows that PD-CI affects gene expression in peripheral monocytes and that SNCA, FBXW8, and DNAJB4 may be potential biomarkers of Chinese Uygur patients with PD-CI.

Major depressive disorder (MDD) is the most common non-motor manifestation of Parkinson’s disease (PD) affecting 50% of patients. However, little is known about the cognitive correlates of MDD in PD. Using a computer-based cognitive task that dissociates learning from positive and negative feedback, we tested four groups of subjects: (1) patients with PD with comorbid MDD, (2) patients with PD without comorbid MDD, (3) matched patients with MDD alone (without PD), and (4) matched healthy control subjects. Furthermore, we used a mathematical model of decision-making to fit both choice and response time data, allowing us to detect and characterize differences between the groups that are not revealed by cognitive results. The groups did not differ in learning accuracy from negative feedback, but the MDD groups (PD patients with MDD and patients with MDD alone) exhibited a selective impairment in learning accuracy from positive feedback when compared to the non-MDD groups (PD patients without MDD and healthy subjects). However, response time in positive feedback trials in the PD groups (both with and without MDD) was significantly slower than the non-PD groups (MDD and healthy groups). While faster response time usually correlates with poor learning accuracy, it was paradoxical in PD groups, with PD patients with MDD having impaired learning accuracy and PD patients without MDD having intact learning accuracy. Mathematical modeling showed that both MDD groups (PD with MDD and MDD alone) were significantly slower than non-MDD groups in the rate of accumulation of information for stimuli trained by positive feedback, which can lead to lower response accuracy. Conversely, modeling revealed that both PD groups (PD with MDD and PD alone) required more evidence than other groups to make responses, thus leading to slower response times. These results suggest that PD patients with MDD exhibit cognitive profiles with mixed traits characteristic of both MDD and PD, furthering our understanding of both PD and MDD and their often-complex comorbidity. To the best of our knowledge, this is the first study to examine feedback-based learning in PD with MDD while controlling for the effects of PD and MDD.

To evaluate the anatomy of the substantia nigra (SN) in healthy subjects by performing 7-T magnetic resonance (MR) imaging of the SN, and to prospectively define the accuracy of 7-T MR imaging in distinguishing Parkinson disease (PD) patients from healthy subjects on an individual basis. The 7-T MR imaging protocol was approved by the Italian Ministry of Health and by the local competent ethics committee. SN anatomy was described ex vivo on a gross brain specimen by using highly resolved proton-density (spin-echo proton density) and gradient-recalled-echo (GRE) images, and in vivo in eight healthy subjects (mean age, 40.1 years) by using GRE three-dimensional multiecho susceptibility-weighted images. After training on appearance of SN in eight healthy subjects, the SN anatomy was evaluated twice by two blinded observers in 13 healthy subjects (mean age, 54.7 years) and in 17 PD patients (mean age, 56.9 years). Deviations from normal SN appearance were described and indicated as abnormal, and both diagnostic accuracy and intra- and interobserver agreement for diagnosis of PD with 7-T MR imaging were calculated. Three-dimensional multiecho susceptibility-weighted 7-T MR imaging reveals a three-layered organization of the SN allowing readers to distinguish pars compacta ventralis and dorsalis from pars reticulata. The abnormal architecture of the SN allowed a discrimination between PD patients and healthy subjects with sensitivity and specificity of 100% and 96.2% (range, 92.3%-100%), respectively. Intraobserver agreement (κ = 1) and interobserver agreement (κ = 0.932) were excellent. MR imaging at 7-T allows a precise characterization of the SN and visualization of its inner organization. Three-dimensional multiecho susceptibility-weighted images can be used to accurately differentiate healthy subjects from PD patients, which provides a novel diagnostic opportunity.

Objective assessments of Parkinson's disease (PD) patients' motor state using motion capture techniques are still rarely used in clinical practice, even though they may improve clinical management. One major obstacle relates to the large dimensionality of motor abnormalities in PD. We aimed to extract global motor performance measures covering different everyday motor tasks, as a function of a clinical intervention, i.e., deep brain stimulation (DBS) of the subthalamic nucleus. We followed a data-driven, machine-learning approach and propose performance measures that employ Random Forests with probability distributions. We applied this method to 14 PD patients with DBS switched-off or -on, and 26 healthy control subjects performing the Timed Up and Go Test (TUG), the Functional Reach Test (FRT), a hand coordination task, walking 10-m straight, and a 90° curve. For each motor task, a Random Forest identified a specific set of metrics that optimally separated PD off DBS from healthy subjects. We noted the highest accuracy (94.6%) for standing up. This corresponded to a sensitivity of 91.5% to detect a PD patient off DBS, and a specificity of 97.2% representing the rate of correctly identified healthy subjects. We then calculated performance measures based on these sets of metrics and applied those results to characterize symptom severity in different motor tasks. Task-specific symptom severity measures correlated significantly with each other and with the Unified Parkinson's Disease Rating Scale (UPDRS, part III, correlation of r2 = 0.79). Agreement rates between different measures ranged from 79.8 to 89.3%. The close correlation of PD patients' various motor abnormalities quantified by different, task-specific severity measures suggests that these abnormalities are only facets of the underlying one-dimensional severity of motor deficits. The identification and characterization of this underlying motor deficit may help to optimize therapeutic interventions, e.g., to "automatically" adapt DBS settings in PD patients.

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Precise knowledge about limb position and orientation is essential for the ability of the nervous system to plan and control voluntary movement. While it is well established that proprioceptive signals from peripheral receptors are necessary for sensing limb position and motion, it is less clear which supraspinal structures mediate the signals that ultimately lead to the conscious awareness of limb position (kinaesthesia). Recent functional imaging studies have revealed that the cerebellum, but not the basal ganglia, are involved in sensory processing of proprioceptive information induced by passive and active movements. Yet psychophysical studies have suggested a prominent role of the basal ganglia in kinaesthesia. This study addresses this apparent dichotomy by investigating the contributions of the cerebellum and the basal ganglia to the perception of limb position. Using a passive movement task, we examined the elbow position sense in patients with a dysfunction of the basal ganglia (Parkinson's disease, n = 9), patients with cerebellar degeneration [spinocerebellar ataxia (SCA) types 6 and 8, n = 6] and age-matched healthy control subjects (n = 11). In comparison with healthy control subjects, Parkinson's disease patients, but not SCA patients, were significantly impaired in the ability to detect displacements correctly. A 1 degrees forearm displacement was correctly recognized in >75% of trials by control subjects and SCA patients, but only in 55% of Parkinson's disease patients. Only at 6 degrees displacement did Parkinson's disease patients exhibit a response rate similar to those of the two other groups. Thresholds for 75% correct responses were 1.03 degrees for controls, 1.15 degrees for cerebellar patients and 2.10 degrees for Parkinson's disease patients. This kinaesthetic impairment significantly correlated with the severity of disease in Parkinson's disease patients, as determined by the Unified Parkinson's Disease Rating Scale (r = -0.7, P = 0.03) and duration of disease (r = -0.7, P = 0.05). In contrast, there was no significant correlation between performance and the daily levodopa equivalent dose. These results imply that an intact cerebro-basal ganglia loop is essential for awareness of limb position and suggest a selective role of the basal ganglia but not the cerebellum in kinaesthesia.