The comorbidity and co-medication profile of patients with progressive supranuclear palsy

Background: Progressive supranuclear palsy (PSP) is usually diagnosed in elderly. Currently, little is known about comorbidities and the co-medication in these patients. Objectives: To explore the pattern of comorbidities and co-medication in PSP patients according to the known different phenotypes and in comparison with patients without neurodegenerative disease. Methods: Cross-sectional data of PSP and patients without neurodegenerative diseases (non-ND) were collected from three German multicenter observational studies (DescribePSP, ProPSP and DANCER). The prevalence of comorbidities according to WHO ICD-10 classification and the prevalence of drugs administered according to WHO ATC system were analyzed. Potential drug–drug interactions were evaluated using AiDKlinik®. Results: In total, 335 PSP and 275 non-ND patients were included in this analysis. The prevalence of diseases of the circulatory and the nervous system was higher in PSP at first level of ICD-10. Dorsopathies, diabetes mellitus, other nutritional deficiencies and polyneuropathies were more frequent in PSP at second level of ICD-10. In particular, the summed prevalence of cardiovascular and cerebrovascular diseases was higher in PSP patients. More drugs were administered in the PSP group leading to a greater percentage of patients with polypharmacy. Accordingly, the prevalence of potential drug–drug interactions was higher in PSP patients, especially severe and moderate interactions. Conclusions: PSP patients possess a characteristic profile of comorbidities, particularly diabetes and cardiovascular diseases. The eminent burden of comorbidities and resulting polypharmacy should be carefully considered when treating PSP patients

Postsynaptic nigrostriatal dopamine receptors and their role in movement regulation

The article presents the hypothesis that nigrostriatal dopamine may regulate movement by modulation of tone and contraction in skeletal muscles through a concentration-dependent influence on the postsynaptic D1 and D2 receptors on the follow manner: nigrostriatal axons innervate both receptor types within the striatal locus somatotopically responsible for motor control in agonist/antagonist muscle pair around a given joint. D1 receptors interact with lower and D2 receptors with higher dopamine concentrations. Synaptic dopamine concentration increases immediately before movement starts. We hypothesize that increasing dopamine concentrations stimulate first the D1 receptors and reduce muscle tone in the antagonist muscle and than stimulate D2 receptors and induce contraction in the agonist muscle. The preceded muscle tone reduction in the antagonist muscle eases the efficient contraction of the agonist. Our hypothesis is applicable for an explanation of physiological movement regulation, different forms of movement pathology and therapeutic drug effects. Further, this hypothesis provides a theoretical basis for experimental investigation of dopaminergic motor control and development of new strategies for treatment of movement disorders

The comorbidity and co-medication profile of patients with progressive supranuclear palsy

Background Progressive supranuclear palsy (PSP) is usually diagnosed in elderly. Currently, little is known about comorbidities and the co-medication in these patients. Objectives To explore the pattern of comorbidities and co-medication in PSP patients according to the known different phenotypes and in comparison with patients without neurodegenerative disease. Methods Cross-sectional data of PSP and patients without neurodegenerative diseases (non-ND) were collected from three German multicenter observational studies (DescribePSP, ProPSP and DANCER). The prevalence of comorbidities according to WHO ICD-10 classification and the prevalence of drugs administered according to WHO ATC system were analyzed. Potential drug–drug interactions were evaluated using AiDKlinik®. Results In total, 335 PSP and 275 non-ND patients were included in this analysis. The prevalence of diseases of the circulatory and the nervous system was higher in PSP at first level of ICD-10. Dorsopathies, diabetes mellitus, other nutritional deficiencies and polyneuropathies were more frequent in PSP at second level of ICD-10. In particular, the summed prevalence of cardiovascular and cerebrovascular diseases was higher in PSP patients. More drugs were administered in the PSP group leading to a greater percentage of patients with polypharmacy. Accordingly, the prevalence of potential drug–drug interactions was higher in PSP patients, especially severe and moderate interactions. Conclusions PSP patients possess a characteristic profile of comorbidities, particularly diabetes and cardiovascular diseases. The eminent burden of comorbidities and resulting polypharmacy should be carefully considered when treating PSP patients

Proceedings of the 11th Annual Deep Brain Stimulation Think Tank: pushing the forefront of neuromodulation with functional network mapping, biomarkers for adaptive DBS, bioethical dilemmas, AI-guided neuromodulation, and translational advancements

The Deep Brain Stimulation (DBS) Think Tank XI was held on August 9–11, 2023 in Gainesville, Florida with the theme of “Pushing the Forefront of Neuromodulation”. The keynote speaker was Dr. Nico Dosenbach from Washington University in St. Louis, Missouri. He presented his research recently published in Nature inn a collaboration with Dr. Evan Gordon to identify and characterize the somato-cognitive action network (SCAN), which has redefined the motor homunculus and has led to new hypotheses about the integrative networks underpinning therapeutic DBS. The DBS Think Tank was founded in 2012 and provides an open platform where clinicians, engineers, and researchers (from industry and academia) can freely discuss current and emerging DBS technologies, as well as logistical and ethical issues facing the field. The group estimated that globally more than 263,000 DBS devices have been implanted for neurological and neuropsychiatric disorders. This year's meeting was focused on advances in the following areas: cutting-edge translational neuromodulation, cutting-edge physiology, advances in neuromodulation from Europe and Asia, neuroethical dilemmas, artificial intelligence and computational modeling, time scales in DBS for mood disorders, and advances in future neuromodulation devices

Spatio-temporal dynamics of cortical drive to human subthalamic nucleus neurons in Parkinson's disease

Pathological synchronisation of beta frequency (12-35Hz) oscillations between the subthalamic nucleus (STN) and cerebral cortex is thought to contribute to motor impairment in Parkinson's disease (PD). For this cortico-subthalamic oscillatory drive to be mechanistically important, it must influence the firing of STN neurons and, consequently, their downstream targets. Here, we examined the dynamics of synchronisation between STN LFPs and units with multiple cortical areas, measured using frontal ECoG, midline EEG and lateral EEG, during rest and movement. STN neurons lagged cortical signals recorded over midline (over premotor cortices) and frontal (over prefrontal cortices) with stable time delays, consistent with strong corticosubthalamic drive, and many neurons maintained these dynamics during movement. In contrast, most STN neurons desynchronised from lateral EEG signals (over primary motor cortices) during movement and those that did not had altered phase relations to the cortical signals. The strength of synchronisation between STN units and midline EEG in the high beta range (25-35Hz) correlated positively with the severity of akinetic-rigid motor symptoms across patients. Together, these results suggest that sustained synchronisation of STN neurons to premotor-cortical beta oscillations play an important role in disrupting the normal coding of movement in PD

Spatio-temporal dynamics of cortical drive to human subthalamic nucleus neurons in Parkinson's disease

Pathological synchronisation of beta frequency (12-35Hz) oscillations between the subthalamic nucleus (STN) and cerebral cortex is thought to contribute to motor impairment in Parkinson's disease (PD). For this cortico-subthalamic oscillatory drive to be mechanistically important, it must influence the firing of STN neurons and, consequently, their downstream targets. Here, we examined the dynamics of synchronisation between STN LFPs and units with multiple cortical areas, measured using frontal ECoG, midline EEG and lateral EEG, during rest and movement. STN neurons lagged cortical signals recorded over midline (over premotor cortices) and frontal (over prefrontal cortices) with stable time delays, consistent with strong corticosubthalamic drive, and many neurons maintained these dynamics during movement. In contrast, most STN neurons desynchronised from lateral EEG signals (over primary motor cortices) during movement and those that did not had altered phase relations to the cortical signals. The strength of synchronisation between STN units and midline EEG in the high beta range (25-35Hz) correlated positively with the severity of akinetic-rigid motor symptoms across patients. Together, these results suggest that sustained synchronisation of STN neurons to premotor-cortical beta oscillations play an important role in disrupting the normal coding of movement in PD

Parkinson’s disease uncovers an underlying sensitivity of subthalamic nucleus neurons to beta-frequency cortical input in vivo

Abnormally sustained beta-frequency synchronisation between the motor cortex and subthalamic nucleus (STN) is associated with motor symptoms in Parkinson's disease (PD). It is currently unclear whether STN neurons have a preference for beta-frequency input (12-35 Hz), rather than cortical input at other frequencies, and how such a preference would arise following dopamine depletion. To address this question, we combined analysis of cortical and STN recordings from awake human PD patients undergoing deep brain stimulation surgery with recordings of identified STN neurons in anaesthetised rats. In these patients, we demonstrate that a subset of putative STN neurons is strongly and selectively sensitive to magnitude fluctuations of cortical beta oscillations over time, linearly increasing their phase-locking strength with respect to the full range of instantaneous amplitude in the beta-frequency range. In rats, we probed the frequency response of STN neurons in the cortico-basal-ganglia-network more precisely, by recording spikes evoked by short bursts of cortical stimulation with variable frequency (4-40 Hz) and constant amplitude. In both healthy and dopamine-depleted rats, only beta-frequency stimulation led to a progressive reduction in the variability of spike timing through the stimulation train. This suggests, that the interval of beta-frequency input provides an optimal window for eliciting the next spike with high fidelity. We hypothesize, that abnormal activation of the indirect pathway, via dopamine depletion and/or cortical stimulation, could trigger an underlying sensitivity of the STN microcircuit to beta-frequency input

Impact of Combined Subthalamic Nucleus and Substantia Nigra Stimulation on Neuropsychiatric Symptoms in Parkinson’s Disease Patients

The goal of the study was to compare the tolerability and the effects of conventional subthalamic nucleus (STN) and combined subthalamic nucleus and substantia nigra (STN+SNr) high-frequency stimulation in regard to neuropsychiatric symptoms in Parkinson’s disease patients. In this single center, randomized, double-blind, cross-over clinical trial, twelve patients with advanced Parkinson’s disease (1 female; age: 61.3±7.3 years; disease duration: 12.3±5.4 years; Hoehn and Yahr stage: 2.2±0.39) were included. Apathy, fatigue, depression, and impulse control disorder were assessed using a comprehensive set of standardized rating scales and questionnaires such as the Lille Apathy Rating Scale (LARS), Modified Fatigue Impact Scale (MFIS), Becks Depression Inventory (BDI-I), Questionnaire for Impulsive-Compulsive Disorders in Parkinson’s Disease Rating Scale (QUIP-RS), and Parkinson’s Disease Questionnaire (PDQ-39). Three patients that were initially assigned to the STN+SNr stimulation mode withdrew from the study within the first week due to discomfort. Statistical comparison of data retrieved from patients who completed the study revealed no significant differences between both stimulation conditions in terms of mean scores of scales measuring apathy, fatigue, depression, impulse control disorder, and quality of life. Individual cases showed an improvement of apathy under combined STN+SNr stimulation. In general, combined STN+SNr stimulation seems to be safe in terms of neuropsychiatric side effects, although careful patient selection and monitoring in the short-term period after changing stimulation settings are recommended