Evoked resonant neural activity in subthalamic local field potentials reflects basal ganglia network dynamics.

Evoked resonant neural activity (ERNA) is induced by subthalamic deep brain stimulation (DBS) and was recently suggested as a marker of lead placement and contact selection in Parkinson's disease. Yet, its underlying mechanisms and how it is modulated by stimulation parameters are unclear. Here, we recorded local field potentials from 27 Parkinson's disease patients, while leads were externalised to scrutinise the ERNA. First, we show that ERNA in the time series waveform and spectrogram likely represent the same activity, which was contested before. Second, our results show that the ERNA has fast and slow dynamics during stimulation, consistent with the synaptic failure hypothesis. Third, we show that ERNA parameters are modulated by different DBS frequencies, intensities, medication states and stimulation modes (continuous DBS vs. adaptive DBS). These results suggest the ERNA might prove useful as a predictor of the best DBS frequency and lowest effective intensity in addition to contact selection. Changes with levodopa and DBS mode suggest that the ERNA may indicate the state of the cortico-basal ganglia circuit making it a putative biomarker to track clinical state in adaptive DBS.

Subthalamic Nucleus Stimulation-Induced Local Field Potential Changes in Dystonia.

BACKGROUND: Subthalamic nucleus (STN) stimulation is an effective treatment for Parkinson's disease and induced local field potential (LFP) changes that have been linked with clinical improvement. STN stimulation has also been used in dystonia although the internal globus pallidus is the standard target where theta power has been suggested as a physiomarker for adaptive stimulation. OBJECTIVE: We aimed to explore if enhanced theta power was also present in STN and if stimulation-induced spectral changes that were previously reported for Parkinson's disease would occur in dystonia. METHODS: We recorded LFPs from 7 patients (12 hemispheres) with isolated craniocervical dystonia whose electrodes were placed such that inferior, middle, and superior contacts covered STN, zona incerta, and thalamus. RESULTS: We did not observe prominent theta power in STN at rest. STN stimulation induced similar spectral changes in dystonia as in Parkinson's disease, such as broadband power suppression, evoked resonant neural activity (ERNA), finely-tuned gamma oscillations, and an increase in aperiodic exponents in STN-LFPs. Both power suppression and ERNA localize to STN. Based on this, single-pulse STN stimulation elicits evoked neural activities with largest amplitudes in STN, which are relayed to the zona incerta and thalamus with changing characteristics as the distance from STN increases. CONCLUSIONS: Our results show that STN stimulation-induced spectral changes are a nondisease-specific response to high-frequency stimulation, which can serve as placement markers for STN. This broadens the scope of STN stimulation and makes it an option for other disorders with excessive oscillatory peaks in STN. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Alpha-synuclein oligomers and small nerve fiber pathology in skin are potential biomarkers of Parkinson's disease.

The proximity ligation assay (PLA) is a specific and sensitive technique for the detection of αSyn oligomers (αSyn-PLA), early and toxic species implicated in the pathogenesis of PD. We aimed to evaluate by skin biopsy the diagnostic and prognostic capacity of αSyn-PLA and small nerve fiber reduction in PD in a longitudinal study. αSyn-PLA was performed in the ankle and cervical skin biopsies of PD (n = 30), atypical parkinsonisms (AP, n = 23) including multiple system atrophy (MSA, n = 12) and tauopathies (AP-Tau, n = 11), and healthy controls (HC, n = 22). Skin biopsy was also analyzed for phosphorylated αSyn (P-αSyn) and 5G4 (αSyn-5G4), a conformation-specific antibody to aggregated αSyn. Intraepidermal nerve fiber density (IENFD) was assessed as a measure of small fiber neuropathy. αSyn-PLA signal was more expressed in PD and MSA compared to controls and AP-Tau. αSyn-PLA showed the highest diagnostic accuracy (PD vs. HC sensitivity 80%, specificity 77%; PD vs. AP-Tau sensitivity 80%, specificity 82%), however, P-αSyn and 5G4, possible markers of later phases, performed better when considering the ankle site alone. A small fiber neuropathy was detected in PD and MSA. A progression of denervation not of pathological αSyn was detected at follow-up and a lower IENFD at baseline was associated with a greater cognitive and motor decline in PD. A skin biopsy-derived compound marker, resulting from a linear discrimination analysis model of αSyn-PLA, P-αSyn, αSyn-5G4, and IENFD, stratified patients with accuracy (77.8%), including the discrimination between PD and MSA (84.6%). In conclusion, the choice of pathological αSyn marker and anatomical site influences the diagnostic performance of skin biopsy and can help in understanding the temporal dynamics of αSyn spreading in the peripheral nervous system during the disease. Skin denervation, not pathological αSyn is a potential progression marker for PD.

Report of a Case of Creutzfeldt-Jakob Disease With an Unusual Clinical Presentation.

We describe the clinical features, neuropsychological tests, laboratory, electroencephalography (EEG), magnetic resonance imaging (MRI) and positron emission tomography (PET) findings of a 59-year-old woman who presented to our Centre for cognitive impairment since few months, with language disturbances, particularly anomia, dyscalculia, and memory loss. The clinical and neuropsychological features were non-specific and overlapping with those of other rapidly progressing neurodegenerative disorders. However, brain MRI played a pivotal role in the diagnosis, showing cortical diffusion restriction, particularly in the parietal lobes and posterior cingulum, with sparing of the perirolandic cortex, typical of Creutzfeldt-Jakob disease (CJD). Brain MRI abnormalities were visible since the first evaluation and remained stable at 2 and 6 weeks follow up. Basal ganglia and thalami were never involved. PET showed left lateralized reduced glucose metabolism, with partial overlap with MRI signal abnormalities. Despite MRI were strongly indicative of CJD, clinical, laboratory and EEG findings did not fulfill the diagnostic criteria for CJD which applied at the time of clinical assessment. Indeed, neither myoclonus, visual or cerebellar signs or akinetic mutism were present. Also, the characteristic periodic sharp wave complexes were absent at baseline EEG, and the CSF assay for 14-3-3 was negative. We, therefore, performed a real-time quaking-induced conversion (RT-QuIC) assay on a frozen sample of corticospinal fluid (CSF), which showed a positive result. RT-QuIC is a prion protein conversion assay that has shown high diagnostic sensitivity and specificity for the diagnosis of CJD. RT-QuIC has been recently incorporated in the National CJD Research and Surveillance Unit and Center for Disease Control and Prevention (CDC) diagnostic criteria for CJD. The fatal evolution of the disease brought the patient to death 13 months after symptoms onset. Pathology proved the diagnosis of sporadic CJD, subtype MM/MV 2C.