Aim: The aim of this study was to describe the protocol of the longitudinal observational study "Biomarkers of Parkinson`s disease" (BIO-PD) and provide clinical characteristics of newly diagnosed Parkinson`s disease (PD) patients enrolled in the BIO-PD study to date. Methods: Treatment- naive PD patients diagnosed according to the Movement Disorders Society clinical diagnostic criteria with abnormal finding on dopamine transporter SPECT as well as healthy controls were enrolled in the study. Baseline examination included brain MRI, structured interview, Movement Disorders Society-Unified PD Rating Scale (MDS-UPDRS), video-polysomnography, transcranial sonography, olfactory testing, visual color sensitivity, a battery of neurophysiological tests, detailed cognitive testing, a comprehensive set of questionnaires as well as sampling of biofluids. Results: As of July 2020, 95 PD patients (37 females, mean age 61.0 [SD = 12.4] years, mean symptom duration 1.9 [1.7] years) and 57 healthy controls (15 females, mean age 62.2 [9.4] years) were included in the study. Compared to controls, PD patients were more likely to be never smokers (P = 0.02) and to have a history of anxiety or depression disorder (P = 0.02), and constipation (P = 0.002). In addition, PD patients had worse scores in the visual color sensitivity (Farnsworth-Munsell Hue 100) test (P = 0.002), MDS-UPDRS motor score, Beck depression inventory- II, State-Trait Anxiety Inventory X1/X2, Scales for Outcomes in PD-Autonomic questionnaire (SCOPA-AUT), University of Pennsylvania Smell Identifi cation Test, and more frequent substantia nigra hyperechogenicity on transcranial sonography (P < 0.001 for all tests). The frequencies of symptoms and abnormal findings in PD patients were as follows: hyposmia 82.4%, substantia nigra hyperechogenicity 75.4%, history of anxiety or depression disorder 29.5%, constipation 22.1%, and REM (rapid eye movement) sleep behavior disorder 22%. Conclusion: Baseline characteristics of patients enrolled in the BIO-PD study are comparable to other de novo PD cohorts, indicating that it is a representative sample of PD patients. Hyposmia is the most prevalent non-motor abnormality in newly diagnosed PD patients and is thus a suitable diagnostic marker for early PD.

Treatment efficacy of pallidal stimulation (GPi DBS) in dystonia varies and the benefit increases slowly, suggesting induction of slow plastic processes in regions involved with motor control. We examined 19 patients (mean age 48 ± (SD)18 years) with cervical (N = 7) or generalized dystonia (N = 12) of various origin by chronic GPi DBS for 57 ± 28 months. Voxel-based morphometry of postoperative T1-weighted images was calculated for gray matter (GM) density in every patient and compared with 20 matched controls. Paired TMS was applied to the motor cortex to elicit short-latency intracortical inhibition (SICI) of the motor evoked potential. The clinical effect of GPi DBS was expressed as a change in the dystonic score (BFMDS or TWSTRS) between actual GPi DBS ON condition and the preoperative state. Dystonia patients showed increased GM density in the SMA and middle cingulate in comparison with healthy controls (p < 0.05 corrected). The SICI was lower in patients than in controls regardless of the ON and OFF conditions (p < 0.001) and its mean amplitude correlated with GM density in both cerebellar hemispheres (p < 0.05 corrected). Brain changes of chronically GPi DBS treated patients possibly reflect “hardwire” rebuilding of motor regions associated with functional improvement. Supported by the grant GAČR 16-13323S.

Pallidal stimulation (GPi DBS) is an effective treatment of dystonic syndromes with a relatively high variability of clinical benefit. As patients with dystonia typically have a lower ability to suppress unwanted movements, we expected a decreased intracortical inhibition of motor cortex, which can be potentially reversed by GPi DBS. To distinguish between patients with dystonia according to the clinical outcome of GPi DBS using short-latency intracortical inhibition (SICI) of the motor cortex assessed by paired transcranial magnetic stimulation (TMS). We examined 22 patients (mean age 51 ± 17 years) with dystonia of various distribution and origin treated by GPi DBS in different time intervals from implantation. Paired TMS with subthreshold conditioning stimulus followed by a supratreshold testing stimulus 2.5 ms later were applied to the motor cortex to elicit SICI in GPi DBS ON and GPi DBS OFF condition two hours later. The clinical effect (CE) was expressed as a change in the dystonic score (Burke-Fahn-Marsden Dystonia rating Scale or Toronto Western Spasmodic Torticollis Scale) between actual GPi DBS ON condition and the preoperative state. The SICI was less effective in patients than in controls regardless of the ON and OFF conditions (p < 0.001) (Fig. 1aDownload : Download high-res image (206KB)Download : Download full-size image). Non-responders (n = 9; <25% CE) showed abnormally low SICI, partial responders (n = 5; 25%–50% CE) showed higher SICI and the highest SICI was in responders (n = 8; >50% CE, p < 0.05) (Fig. 1b). The MEP onset latency was shorter in patients in GPi DBS ON than in OFF condition (p < 0.001) (Download : Download high-res image (225KB)Download : Download full-size imageFig. 2a) and in addition, the shortest MEP onset latency was observed in non-responders (p < 0.001) (Fig. 2b). There was no correlation of the SICI or MEP onset latency with the position of the distal contact of the electrodes. Our results suggest that the best responders to GPi DBS treatment exhibited a similar level of SICI as in healthy controls. On the contrary, non-responders were unable to increase their reduced cortical inhibition and effectively suppressed dystonic symptoms. We speculate that decreased intracortical inhibition with abnormally fast transmission volley is underpinned by the poor complexity of the motor network. Supported by the grant IGA MZ ČR NT12282-5/2011.

The subthalamic nucleus (STN) is an important motor and non-motor hub. Animal studies suggest that the STN is also involved in perception, however evidence in humans is missing. We analyzed the visuo-attentional activity of STN neurons in Parkinson‘s disease (PD) patients. Extracellular neuronal activity and electrooculography was recorded during deep brain stimulation surgery from 12 awake PD patients (mean age 54.4 (SD 8.1) years) during presentation of 24 photographs, each shown for 2 s and preceded by a black screen. The action potentials elicited by watching photographs vs. black screen were compared using bootstrap. Of the 122 neurons detected, 34 were eye movement-related and excluded. The activity of 45 (51%) of the remaining 88 neurons was stimulus-specific (P < 0.05): the photographs decreased activity in 14 neurons (which were in the dorsal STN), and increased activity in 31 neurons (with no spatial preference). The STN contains a surprisingly high ratio of neurons possibly involved in visuo-attentional processes. Neurons of the STN are involved in visual perception and processing.

Considering the functional organization of the subthalamic nucleus (STN), we hypothesized that STN-DBS might have a differential impact on emotional reactivity in relation to the electrode position within the STN. We aimed to assess this objectively using affective modulation of the acoustic blink reflex (ABR). ABR elicited during the viewing of rewarding, fearful and neutral pictures was recorded in 10 off-medicated PD patients with the STN-DBS switched ON and OFF. The active electrode contact positions in the STN were determined on T1-weighted MRI. The relation of ABR magnitude on DBS electrode position was assessed using linear regression. The ABR magnitude from all picture categories was related to the electrode position in both the ON (p < 0.01) and OFF-conditions (p < 0.05) with larger ABRs associated with more anterior position. The ABR magnitude increase was present in the ON-condition even when adjusting for the OFF-condition (p < 0.05), but not vice versa. The STN-DBS probably drove the electrode-position related effect on emotional activation along the anterio-posterior direction. This effect, however, was not stimulus category specific suggesting rather general increase in emotional arousal. Emotional reactivity changes due to DBS showed anterio-posterior gradient within the STN.

Deep brain stimulation (DBS) of the globus pallidus interna (GPi) is widely used in treatment of pharmacoresistant dystonic syndromes. In our study, we analyzed functional connectivity change derived from resting state fMRI in two conditions: with the DBS chronically switched on (ON condition) and two hours after switching the DBS off (OFF condition). We used a graph theory utilizing the degree of centrality (DC) based on mapping links at the voxel level in each condition. We examined 21 patients (13 women, 8 men, aged 46 ± (SD)18 years) with dystonia of various origin (14 idiopathic, 2 DYT-1, 2 PKAN, 2 with parkinsonism, 1 post-anoxic) treated with GPi DBS bilaterally (10–102 months after implantation). The clinical state of patients with generalized dystonia (N = 13) was assessed by the Burke Fahn Marsden Dystonia Scale and patients with cervical dystonia (N = 8) were rated by the Toronto Western Spasmodic Torticollis Rating Scale one week before surgery and on the day of the fMRI session in the ON condition. Each subject was instructed to watch a cross while lying motionless in the supine position for 10 minutes during fMRI acquisition (1.5 T, T2*-weighted gradient-echo echo-planar imaging: FA/TR/TE = 90°/3000/51 ms, 200 repetitions). Group analysis of connectivity change was based on voxel-wise comparison between the DC maps in the ON and OFF conditions and on comparison with age-matched healthy subjects and displayed with FWE correction (P<0.05) at cluster level. In ON compared with OFF condition, a significant increase of DC was found in the thalamus bilaterally, in the right accumbens and subthalamus, in the upper and posterior brainstem and the left cerebellum (Fig. 1). Patients in OFF condition when compared to healthy controls showed lower DC in the thalamus and putamen bilaterally, in the mesial region involving SMA, pre-SMA, middle cingulate and precuneus, as well as in the left premotor cortex and parieto-occipital cortex bilaterally (Fig. 2). In the ON condition, DC was found to be lower than healthy controls only in the precuneus and left parietal cortex. Chronic GPi DBS in patients regardless of the type and etiology of dystonia caused an increase of resting state functional connectivity in the thalamus, subthalamic nucleus and brainstem, which are the key structures where the GPi directly or indirectly projects to. This observation is in agreement with the comparison of patients with healthy controls: in OFF condition, patients showed lower connectivity in the basal ganglia and motor network, while in the ON condition, functional connectivity in these regions became similar like in the healthy subjects. Supported by the projects IGA MZ ČR NT12282-5/2011 and PRVOUK P26/LF1/4.