Theta-Alpha Connectivity in the Hippocampal-Entorhinal Circuit Predicts Working Memory Load.

Working memory (WM) maintenance relies on multiple brain regions and inter-regional communications. The hippocampus and entorhinal cortex (EC) are thought to support this operation. Besides, EC is the main gateway for information between the hippocampus and neocortex. However, the circuit-level mechanism of this interaction during WM maintenance remains unclear in humans. To address these questions, we recorded the intracranial electroencephalography from the hippocampus and EC while patients (N = 13, six females) performed WM tasks. We found that WM maintenance was accompanied by enhanced theta/alpha band (2-12 Hz) phase synchronization between the hippocampus to the EC. The Granger causality and phase slope index analyses consistently showed that WM maintenance was associated with theta/alpha band-coordinated unidirectional influence from the hippocampus to the EC. Besides, this unidirectional inter-regional communication increased with WM load and predicted WM load during memory maintenance. These findings demonstrate that WM maintenance in humans engages the hippocampal-entorhinal circuit, with the hippocampus influencing the EC in a load-dependent manner.

Intrinsic Neural Timescales in the Temporal Lobe Support an Auditory Processing Hierarchy.

During rest, intrinsic neural dynamics manifest at multiple timescales, which progressively increase along visual and somatosensory hierarchies. Theoretically, intrinsic timescales are thought to facilitate processing of external stimuli at multiple stages. However, direct links between timescales at rest and sensory processing, as well as translation to the auditory system are lacking. Here, we measured intracranial EEG in 11 human patients with epilepsy (4 women), while listening to pure tones. We show that, in the auditory network, intrinsic neural timescales progressively increase, while the spectral exponent flattens, from temporal to entorhinal cortex, hippocampus, and amygdala. Within the neocortex, intrinsic timescales exhibit spatial gradients that follow the temporal lobe anatomy. Crucially, intrinsic timescales at baseline can explain the latency of auditory responses: as intrinsic timescales increase, so do the single-electrode response onset and peak latencies. Our results suggest that the human auditory network exhibits a repertoire of intrinsic neural dynamics, which manifest in cortical gradients with millimeter resolution and may provide a variety of temporal windows to support auditory processing.SIGNIFICANCE STATEMENT Endogenous neural dynamics are often characterized by their intrinsic timescales. These are thought to facilitate processing of external stimuli. However, a direct link between intrinsic timing at rest and sensory processing is missing. Here, with intracranial EEG, we show that intrinsic timescales progressively increase from temporal to entorhinal cortex, hippocampus, and amygdala. Intrinsic timescales at baseline can explain the variability in the timing of intracranial EEG responses to sounds: cortical electrodes with fast timescales also show fast- and short-lasting responses to auditory stimuli, which progressively increase in the hippocampus and amygdala. Our results suggest that a hierarchy of neural dynamics in the temporal lobe manifests across cortical and limbic structures and can explain the temporal richness of auditory responses.

A phase Ib/II randomized, open-label drug repurposing trial of glutamate signaling inhibitors in combination with chemoradiotherapy in patients with newly diagnosed glioblastoma: the GLUGLIO trial protocol.

BACKGROUND: Glioblastoma is the most common and most aggressive malignant primary brain tumor in adults. Glioblastoma cells synthesize and secrete large quantities of the excitatory neurotransmitter glutamate, driving epilepsy, neuronal death, tumor growth and invasion. Moreover, neuronal networks interconnect with glioblastoma cell networks through glutamatergic neuroglial synapses, activation of which induces oncogenic calcium oscillations that are propagated via gap junctions between tumor cells. The primary objective of this study is to explore the efficacy of brain-penetrating anti-glutamatergic drugs to standard chemoradiotherapy in patients with glioblastoma. METHODS/DESIGN: GLUGLIO is a 1:1 randomized phase Ib/II, parallel-group, open-label, multicenter trial of gabapentin, sulfasalazine, memantine and chemoradiotherapy (Arm A) versus chemoradiotherapy alone (Arm B) in patients with newly diagnosed glioblastoma. Planned accrual is 120 patients. The primary endpoint is progression-free survival at 6 months. Secondary endpoints include overall and seizure-free survival, quality of life of patients and caregivers, symptom burden and cognitive functioning. Glutamate levels will be assessed longitudinally by magnetic resonance spectroscopy. Other outcomes of interest include imaging response rate, neuronal hyperexcitability determined by longitudinal electroencephalography, Karnofsky performance status as a global measure of overall performance, anticonvulsant drug use and steroid use. Tumor tissue and blood will be collected for translational research. Subgroup survival analyses by baseline parameters include segregation by age, extent of resection, Karnofsky performance status, O6-methylguanine DNA methyltransferase (MGMT) promotor methylation status, steroid intake, presence or absence of seizures, tumor volume and glutamate levels determined by MR spectroscopy. The trial is currently recruiting in seven centers in Switzerland. TRIAL REGISTRATION: NCT05664464. Registered 23 December 2022.

Functional network dynamics between the anterior thalamus and the cortex in deep brain stimulation for epilepsy.

Owing to its unique connectivity profile with cortical brain regions, and its suggested role in the subcortical propagation of seizures, the anterior nucleus of the thalamus (ANT) has been proposed as a key deep brain stimulation (DBS) target in drug-resistant epilepsy. However, the spatio-temporal interaction dynamics of this brain structure, and the functional mechanisms underlying ANT DBS in epilepsy remain unknown. Here, we study how the ANT interacts with the neocortex in vivo in humans and provide a detailed neurofunctional characterization of mechanisms underlying the effectiveness of ANT DBS, aiming at defining intraoperative neural biomarkers of responsiveness to therapy, assessed at 6 months post-implantation as the reduction in seizure frequency. A cohort of 15 patients with drug-resistant epilepsy (n = 6 males, age = 41.6 ± 13.79 years) underwent bilateral ANT DBS implantation. Using intraoperative cortical and ANT simultaneous electrophysiological recordings, we found that the ANT is characterized by high amplitude θ (4-8 Hz) oscillations, mostly in its superior part. The strongest functional connectivity between the ANT and the scalp EEG was also found in the θ band in ipsilateral centro-frontal regions. Upon intraoperative stimulation in the ANT, we found a decrease in higher EEG frequencies (20-70 Hz) and a generalized increase in scalp-to-scalp connectivity. Crucially, we observed that responders to ANT DBS treatment were characterized by higher EEG θ oscillations, higher θ power in the ANT, and stronger ANT-to-scalp θ connectivity, highlighting the crucial role of θ oscillations in the dynamical network characterization of these structures. Our study provides a comprehensive characterization of the interaction dynamic between the ANT and the cortex, delivering crucial information to optimize and predict clinical DBS response in patients with drug-resistant epilepsy.

Self-modulation of the sense of agency via neurofeedback enhances sensory-guided behavioral control.

The sense of agency is a fundamental aspect of human self-consciousness, whose neural correlates encompass widespread brain networks. Research has explored the neuromodulatory properties of the sense of agency with noninvasive brain stimulation, which induces exogenous manipulations of brain activity; however, it is unknown whether endogenous modulation of the sense of agency is also achievable. We investigated whether the sense of agency can be self-regulated with electroencephalography-based neurofeedback. We conducted 2 experiments in which healthy humans performed a motor task while their motor control was artificially disrupted, and gave agency statements on their perceived control. We first identified the electrophysiological response to agency processing, and then applied neurofeedback in a parallel, sham-controlled design, where participants learnt to self-modulate their sense of agency. We found that behavioral measures of agency and performance on the task decreased with the increasing disruption of control. This was negatively correlated with power spectral density in the theta band, and positively correlated in the alpha and beta bands, at central and parietal electrodes. After neurofeedback training of central theta rhythms, participants improved their actual control over the task, and this was associated with a significant decrease in the frequency band trained via neurofeedback. Thus, self-regulation of theta rhythms can improve sensory-guided behavior.

Anterior-Posterior Hippocampal Dynamics Support Working Memory Processing.

The hippocampus is a locus of working memory (WM) with anterior and posterior subregions that differ in their transcriptional and external connectivity patterns. However, the involvement and functional connections between these subregions in WM processing are poorly understood. To address these issues, we recorded intracranial EEG from the anterior and the posterior hippocampi in humans (seven females and seven males) who maintained a set of letters in their WM. We found that WM maintenance was accompanied by elevated low-frequency activity in both the anterior and posterior hippocampus and by increased theta/alpha band (3-12 Hz) phase synchronization between anterior and posterior subregions. Cross-frequency and Granger prediction analyses consistently showed that the correct WM trials were associated with theta/alpha band-coordinated unidirectional influence from the posterior to the anterior hippocampus. In contrast, WM errors were associated with bidirectional interactions between the anterior and posterior hippocampus. These findings imply that theta/alpha band synchrony within the hippocampus may support successful WM via a posterior to anterior influence. A combination of intracranial recording and a fine-grained atlas may be of value in understanding the neural mechanisms of WM processing.SIGNIFICANCE STATEMENT Working memory (WM) is crucial to everyday functioning. The hippocampus has been proposed to be a subcortical node involved in WM processes. Previous studies have suggested that the anterior and posterior hippocampi differ in their external connectivity patterns and gene expression. However, it remains unknown whether and how human hippocampal subregions are recruited and coordinated during WM tasks. Here, by recording intracranial electroencephalography simultaneously from both hippocampal subregions, we found enhanced power in both areas and increased phase synchronization between them. Furthermore, correct WM trials were associated with a unidirectional influence from the posterior to the anterior hippocampus, whereas error trials were correlated with bidirectional interactions. These findings indicate a long-axis specialization in the human hippocampus during WM processing.

Nonconvulsive status epilepticus in neurocritical care: A critical reappraisal of outcome prediction scores.

OBJECTIVE: Nonconvulsive status epilepticus (NCSE) is a frequent condition in the neurocritical care unit (NCCU) patient population, with high morbidity and mortality. We aimed to assess the validity of available outcome prediction scores for prognostication in an NCCU patient population in relation to their admission reason (NCSE vs. non-NCSE related). METHODS: All 196 consecutive patients diagnosed with NCSE during the NCCU stay between January 2010 and December 2020 were included. Demographics, Simplified Acute Physiology Score II (SAPS II), NCSE characteristics, and in-hospital and 3-month outcome were extracted from the electronic charts. Status Epilepticus Severity Score (STESS), Epidemiology-Based Mortality Score in Status Epilepticus (EMSE), and encephalitis, NCSE, diazepam resistance, imaging features, and tracheal intubation score (END-IT) were evaluated as previously described. Univariable and multivariable analysis and comparison of sensitivity/specificity/positive and negative predictive values/accuracy were performed. RESULTS: A total of 30.1% died during the hospital stay, and 63.5% of survivors did not achieve favorable outcome at 3 months after onset of NCSE. Patients admitted primarily due to NCSE had longer NCSE duration and were more likely to be intubated at diagnosis. The receiver operating characteristic (ROC) for SAPS II, EMSE, and STESS when predicting mortality was between .683 and .762. The ROC for SAPS II, EMSE, STESS, and END-IT when predicting 3-month outcome was between .649 and .710. The accuracy in predicting mortality/outcome was low, when considering both proposed cutoffs and optimized cutoffs (estimated using the Youden Index) as well as when adjusting for admission reason. SIGNIFICANCE: The scores EMSE, STESS, and END-IT perform poorly when predicting outcome of patients with NCSE in an NCCU environment. They should be interpreted cautiously and only in conjunction with other clinical data in this particular patient group.

Deep brain stimulation of the anterior nucleus of the thalamus increases slow wave activity in non-rapid eye movement sleep.

OBJECTIVE: Previous studies suggest that intermittent deep brain stimulation (DBS) of the anterior nucleus of the thalamus (ANT) affects physiological sleep architecture. Here, we investigated the impact of continuous ANT DBS on sleep in epilepsy patients in a multicenter crossover study in 10 patients. METHODS: We assessed sleep stage distribution, delta power, delta energy, and total sleep time in standardized 10/20 polysomnographic investigations before and 12 months after DBS lead implantation. RESULTS: In contrast to previous studies, we found no disruption of sleep architecture or alterations of sleep stage distribution under active ANT DBS (p = .76). On the contrary, we observed more consolidated and deeper slow wave sleep (SWS) under continuous high-frequency DBS as compared to baseline sleep prior to DBS lead implantation. In particular, biomarkers of deep sleep (delta power and delta energy) showed a significant increase post-DBS as compared to baseline (36.67 ± 13.68 µV2 /Hz and 799.86 ± 407.56 µV2 *s, p < .001). Furthermore, the observed increase in delta power was related to the location of the active stimulation contact within the ANT; we found higher delta power and higher delta energy in patients with active stimulation in more superior contacts as compared to inferior ANT stimulation. We also observed significantly fewer nocturnal electroencephalographic discharges in DBS ON condition. In conclusion, our findings suggest that continuous ANT DBS in the most cranial part of the target region leads to more consolidated SWS. SIGNIFICANCE: From a clinical perspective, these findings suggest that patients with sleep disruption under cyclic ANT DBS could benefit from an adaptation of stimulation parameters to more superior contacts and continuous mode stimulation.

The role of neuronal antibodies in cryptogenic new onset refractory status epilepticus.

Most cases with new onset refractory status epilepticus (NORSE) remain cryptogenic despite extensive diagnostic workup. The aim of this study was to analyze the etiology and clinical features of NORSE and investigate known or potentially novel autoantibodies in cryptogenic NORSE (cNORSE). We retrospectively assessed the medical records of adults with status epilepticus at a Swiss tertiary referral center between 2010 and 2021. Demographic, diagnostic, therapeutic, and outcome parameters were characterized. We performed post hoc screening for known or potentially novel autoantibodies including immunohistochemistry (IHC) on rat brain with cerebrospinal fluid (CSF) and serum samples of cNORSE. Twenty patients with NORSE were identified. Etiologies included infections (n = 4), Creutzfeldt-Jakob disease (n = 1), CASPR2 autoimmune encephalitis (n = 1), and carotid artery stenosis with recurrent perfusion deficit (n = 1). Thirteen cases (65%) were cryptogenic despite detailed evaluation. A posteriori IHC for neuronal autoantibodies yielded negative results in all available serum (n = 11) and CSF (n = 9) samples of cNORSE. Our results suggest that neuronal antibodies are unlikely to play a major role in the pathogenesis of cNORSE. Future studies should rather focus on other-especially T-cell- and cytokine-mediated-mechanisms of autoinflammation in this devastating disease, which is far too poorly understood so far.

The modulatory effect of self-paced and cued motor execution on subthalamic beta-bursts in Parkinson's disease: Evidence from deep brain recordings in humans.

Deep brain stimulation (DBS) electrodes provide an unparalleled window to record and investigate neuronal activity right at the core of pathological brain circuits. In Parkinson's disease (PD), basal ganglia beta-oscillatory activity (13-35 Hz) seems to play an outstanding role. Conventional DBS, which globally suppresses beta-activity, does not meet the requirements of a targeted treatment approach given the intricate interplay of physiological and pathological effects of beta-frequencies. Here, we wanted to characterise the local field potential (LFP) in the subthalamic nucleus (STN) in terms of beta-burst prevalence, amplitude and length between movement and rest as well as during self-paced as compared to goal-directed motor control. Our electrophysiological recordings from externalised DBS-electrodes in nine patients with PD showed a marked decrease in beta-burst durations and prevalence during movement as compared to rest as well as shorter and less frequent beta-bursts during cued as compared to self-paced movements. These results underline the importance of beta-burst modulation in movement generation and are in line with the clinical observation that cued motor control is better preserved than self-paced movements. Furthermore, our findings motivate the use of adaptive DBS based on beta-bursts, which selectively trim longer beta-bursts, as it is more suitable and efficient over a range of motor behaviours than conventional DBS.

Seizures after Ischemic Stroke: A Matched Multicenter Study.

OBJECTIVE: The purpose of this study was to identify risk factors for acute symptomatic seizures and post-stroke epilepsy after acute ischemic stroke and evaluate the effects of reperfusion treatment. METHODS: We assessed the risk factors for post-stroke seizures using logistic or Cox regression in a multicenter study, including adults from 8 European referral centers with neuroimaging-confirmed ischemic stroke. We compared the risk of post-stroke seizures between participants with or without reperfusion treatment following propensity score matching to reduce confounding due to treatment selection. RESULTS: In the overall cohort of 4,229 participants (mean age 71 years, 57% men), a higher risk of acute symptomatic seizures was observed in those with more severe strokes, infarcts located in the posterior cerebral artery territory, and strokes caused by large-artery atherosclerosis. Strokes caused by small-vessel occlusion carried a small risk of acute symptomatic seizures. 6% developed post-stroke epilepsy. Risk factors for post-stroke epilepsy were acute symptomatic seizures, more severe strokes, infarcts involving the cerebral cortex, and strokes caused by large-artery atherosclerosis. Electroencephalography findings within 7 days of stroke onset were not independently associated with the risk of post-stroke epilepsy. There was no association between reperfusion treatments in general or only intravenous thrombolysis or mechanical thrombectomy with the time to post-stroke epilepsy or the risk of acute symptomatic seizures. INTERPRETATION: Post-stroke seizures are related to stroke severity, etiology, and location, whereas an early electroencephalogram was not predictive of epilepsy. We did not find an association of reperfusion treatment with risks of acute symptomatic seizures or post-stroke epilepsy. ANN NEUROL 2021;90:808-820.

Postoperative progression of brain metastasis is associated with seizures.

Seizures in patients with brain metastases have an impact on morbidity and quality of life. The influence of tumor growth on the risk of seizures in these patients is not well defined. In this cohort study, we evaluated adult patients from the University Hospital of Zurich following resection of brain metastases from solid tumors, with or without preoperative seizures, at 3, 6, 9, and 12 months postoperatively. Brain magnetic resonance imaging was assessed for tumor progression using the Response Assessment in Neuro-Oncology criteria. The quarterly risk of unprovoked seizures was modeled with mixed effects logistic regression. We analyzed 444 time frames in 220 patients. Progression of brain metastases was independently associated with seizures during the respective quarterly follow-up period (odds ratio = 3.9, 95% confidence interval = 1.3-11.3, p = .014). Complete resection of brain metastases was associated with a lower risk of seizures (odds ratio = .2, 95% confidence interval = .04-.7, p = .015). Postoperative progression of brain metastases quadrupled the risk of seizures; therefore, vigorous follow-up may be useful to identify tumor progression and gauge the risk of seizures. The identification of patients at high seizure risk may have implications for treatment decisions and influence aspects of daily life. Breakthrough seizures may indicate brain metastases progression.

Survival of brain tumour patients with epilepsy.

Pro-tumorigenic electrochemical synapses between neurons and brain tumour cells in preclinical studies suggest unfavourable effects of epilepsy on patient survival. We investigated associations of epilepsy and survival in three cohorts of brain tumour patients (meningioma, glioblastoma and brain metastases). Cohorts were segregated into three groups for comparative analyses: (i) no epilepsy; (ii) epilepsy without status epilepticus; and (iii) status epilepticus. Status epilepticus was considered a surrogate of extensive neuronal hyperexcitability. The main outcome was progression-free survival (meningioma) and overall survival (glioblastoma and brain metastases), adjusted for established prognostic factors and onset of epilepsy by time-dependent multivariate Cox modelling. The primary analysis population comprised 1792 patients (742 meningioma, 249 glioblastoma, 801 brain metastases). Epilepsy was associated with favourable prognostic factors. However, on multivariate analyses, status epilepticus was associated with inferior overall survival of patients with glioblastoma [status epilepticus versus no epilepsy multivariate hazard ratio (HR) 3.72, confidence interval (CI) 1.78-7.76, P < 0.001] and brain metastases (status epilepticus versus no epilepsy HR 2.30, CI 1.10-4.79, P = 0.026). Among brain metastases patients, but not among patients with meningioma or glioblastoma, epilepsy was similarly associated with inferior overall survival (epilepsy versus no epilepsy HR 2.16, CI 1.60-2.93, P < 0.001). We conclude that epilepsy may convey inferior survival of patients with malignant brain tumours.

Impact of Seizures and Status Epilepticus on Outcome in Patients with Aneurysmal Subarachnoid Hemorrhage.

BACKGROUND: We aimed to evaluate the association between seizures as divided by timing and type (seizures or status epilepticus) and outcome in patients with aneurysmal subarachnoid hemorrhage (aSAH). METHODS: All consecutive patients with aSAH admitted to the neurocritical care unit of the University Hospital Zurich between 2016 and 2020 were included. Seizure type and frequency were extracted from electronic patient files. RESULTS: Out of 245 patients, 76 experienced acute symptomatic seizures, with 39 experiencing seizures at onset, 18 experiencing acute seizures, and 19 experiencing acute nonconvulsive status epilepticus (NCSE). Multivariate analysis revealed that acute symptomatic NCSE was an independent predictor of unfavorable outcome (odds ratio 14.20, 95% confidence interval 1.74-116.17, p = 0.013) after correction for age, Hunt-Hess grade, Fisher grade, and delayed cerebral ischemia. Subgroup analysis showed a significant association of all seizures/NCSE with higher Fisher grade (p < 0.001 for acute symptomatic seizures/NCSE, p = 0.031 for remote symptomatic seizures). However, although acute seizures/NCSE (p = 0.750 and 0.060 for acute seizures/NCSE respectively) were not associated with unfavorable outcome in patients with a high Hunt-Hess grade, they were significantly associated with unfavorable outcome in patients with a low Hunt-Hess grade (p = 0.019 and p < 0.001 for acute seizures/NCSE, respectively). CONCLUSIONS: Acute symptomatic NCSE independently predicts unfavorable outcome after aSAH. Seizures and NCSE are associated with unfavorable outcome, particularly in patients with a low Hunt-Hess grade. We propose that NCSE and the ictal or postictal reduction of Glasgow Coma Scale may hamper close clinical evaluation for signs of delayed cerebral ischemia, and thus possibly leading to delayed diagnosis and therapy thereof in patients with a low Hunt-Hess grade.

Intracerebral endotheliitis and microbleeds are neuropathological features of COVID-19.

Coronavirus disease 19 (COVID-19) is a rapidly evolving pandemic caused by the coronavirus Sars-CoV-2. Clinically manifest central nervous system symptoms have been described in COVID-19 patients and could be the consequence of commonly associated vascular pathology, but the detailed neuropathological sequelae remain largely unknown. A total of six cases, all positive for Sars-CoV-2, showed evidence of cerebral petechial hemorrhages and microthrombi at autopsy. Two out of six patients showed an elevated risk for disseminated intravascular coagulopathy according to current criteria and were excluded from further analysis. In the remaining four patients, the hemorrhages were most prominent at the grey and white matter junction of the neocortex, but were also found in the brainstem, deep grey matter structures and cerebellum. Two patients showed vascular intramural inflammatory infiltrates, consistent with Sars-CoV-2-associated endotheliitis, which was associated by elevated levels of the Sars-CoV-2 receptor ACE2 in the brain vasculature. Distribution and morphology of patchy brain microbleeds was clearly distinct from hypertension-related hemorrhage, critical illness-associated microbleeds and cerebral amyloid angiopathy, which was ruled out by immunohistochemistry. Cerebral microhemorrhages in COVID-19 patients could be a consequence of Sars- CoV-2-induced endotheliitis and more general vasculopathic changes and may correlate with an increased risk of vascular encephalopathy.

Bilateral staged magnetic resonance-guided focused ultrasound thalamotomy for the treatment of essential tremor: a case series study.

BACKGROUND: Unilateral magnetic resonance-guided focused ultrasound (FUS) thalamotomy is efficacious for the treatment of medically refractory essential tremor (ET). Viability of bilateral FUS ablation is unexplored. METHODS: Patients diagnosed with medically refractory ET and previously treated with unilateral FUS thalamotomy at least 5 months before underwent bilateral treatment. The timepoints were baseline (before first thalamotomy) and FUS1 and FUS2 (4 weeks before and 6 months after second thalamotomy, respectively). The primary endpoint was safety. Efficacy was assessed through the Clinical Rating Scale for Tremor (CRST), which includes subscales for tremor examination (part A), task performance (part B) and tremor-related disability (part C). RESULTS: Nine patients were treated. No permanent adverse events were registered. Six patients presented mild gait instability and one dysarthria, all resolving within the first few weeks. Three patients reported perioral hypoesthesia, resolving in one case. Total CRST score improved by 71% from baseline to FUS2 (from 52.3±12 to 15.5±9.4, p<0.001), conveying a 67% reduction in bilateral upper limb A+B (from 32.3±7.8 to 10.8±7.3, p=0.001). Part C decreased by 81% (from 16.4±3.6 to 3.1±2.9, p<0.001). Reduction in head and voice tremor was 66% (from 1.2±0.44 to 0.4±0.54, p=0.01) and 45% (from 1.8±1.1 to 1±0.8, p=0.02), respectively. CONCLUSION: Bilateral staged FUS thalamotomy for ET is feasible and might be safe and effective. Voice and head tremor might also improve. A controlled study is warranted.

Large and Small Cerebral Vessel Involvement in Severe COVID-19: Detailed Clinical Workup of a Case Series.

BACKGROUND AND PURPOSE: Case series indicating cerebrovascular disorders in coronavirus disease 2019 (COVID-19) have been published. Comprehensive workups, including clinical characteristics, laboratory, electroencephalography, neuroimaging, and cerebrospinal fluid findings, are needed to understand the mechanisms. METHODS: We evaluated 32 consecutive critically ill patients with COVID-19 treated at a tertiary care center from March 9 to April 3, 2020, for concomitant severe central nervous system involvement. Patients identified underwent computed tomography, magnetic resonance imaging, electroencephalography, cerebrospinal fluid analysis, and autopsy in case of death. RESULTS: Of 32 critically ill patients with COVID-19, 8 (25%) had severe central nervous system involvement. Two presented with lacunar ischemic stroke in the early phase and 6 with prolonged impaired consciousness after termination of analgosedation. In all but one with delayed wake-up, neuroimaging or autopsy showed multiple cerebral microbleeds, in 3 with additional subarachnoid hemorrhage and in 2 with additional small ischemic lesions. In 3 patients, intracranial vessel wall sequence magnetic resonance imaging was performed for the first time to our knowledge. All showed contrast enhancement of vessel walls in large cerebral arteries, suggesting vascular wall pathologies with an inflammatory component. Reverse transcription-polymerase chain reactions for SARS-CoV-2 in cerebrospinal fluid were all negative. No intrathecal SARS-CoV-2-specific IgG synthesis was detectable. CONCLUSIONS: Different mechanisms of cerebrovascular disorders might be involved in COVID-19. Acute ischemic stroke might occur early. In a later phase, microinfarctions and vessel wall contrast enhancement occur, indicating small and large cerebral vessels involvement. Central nervous system disorders associated with COVID-19 may lead to long-term disabilities. Mechanisms should be urgently investigated to develop neuroprotective strategies.

Slow-wave sleep and motor progression in Parkinson disease.

Growing evidence from Alzheimer disease supports a potentially beneficial role of slow-wave sleep in neurodegeneration. However, the importance of slow-wave sleep in Parkinson disease is unknown. In 129 patients with Parkinson disease, we retrospectively tested whether sleep slow waves, objectively quantified with polysomnography, relate to longitudinal changes in Unified Parkinson's Disease Rating Scale motor scores. We found that higher accumulated power of sleep slow waves was associated with slower motor progression, particularly of axial motor symptoms, over a mean time of 4.6 ± 2.3 years. This preliminary finding suggests that deeper sleep relates to slower motor progression in Parkinson disease. Ann Neurol 2019;85:765-770.

Functionally separated networks for self-paced and externally-cued motor execution in Parkinson's disease: Evidence from deep brain recordings in humans.

Spatially segregated cortico-basal ganglia networks have been proposed for the control of goal-directed and habitual behavior. In Parkinson's disease, selective loss of dopaminergic neurons regulating sensorimotor (habitual) behavior might therefore predominantly cause deficits in habitual motor control, whereas control of goal-directed movement is relatively preserved. Following this hypothesis, we examined the electrophysiology of cortico-basal ganglia networks in Parkinson patients emulating habitual and goal-directed motor control during self-paced and externally-cued finger tapping, respectively, while simultaneously recording local field potentials in the subthalamic nucleus (STN) and surface EEG. Only externally-cued movements induced a pro-kinetic event-related beta-desynchronization, whereas beta-oscillations were continuously suppressed during self-paced movements. Connectivity analysis revealed higher synchronicity (phase-locking value) between the STN and central electrodes during self-paced and higher STN to frontal phase-locking during externally-cued movements. Our data provide direct electrophysiological support for the existence of functionally segregated cortico-basal ganglia networks controlling motor behavior in Parkinson patients, and corroborate the assumption of Parkinson patients being shifted from habitual towards goal-directed behavior.

Electrophysiological Evidence for Alternative Motor Networks in REM Sleep Behavior Disorder.

Patients with Parkinson's disease (PD) and REM sleep behavior disorder (RBD) show mostly unimpaired motor behavior during REM sleep, which contrasts strongly to coexistent nocturnal bradykinesia. The reason for this sudden amelioration of motor control in REM sleep is unknown, however. We set out to determine whether movements during REM sleep are processed by different motor networks than movements in the waking state. We recorded local field potentials in the subthalamic nucleus (STN) and scalp EEG (modified 10/20 montage) during sleep in humans with PD and RBD. Time-locked event-related ß band oscillations were calculated during movements in REM sleep compared with movements in the waking state and during NREM sleep. Spectral analysis of STN local field potentials revealed elevated ß power during REM sleep compared with NREM sleep and ß power in REM sleep reached levels similar as in the waking state. Event-related analysis showed time-locked ß desynchronization during WAKE movements. In contrast, we found significantly elevated ß activity before and during movements in REM sleep and NREM sleep. Corticosubthalamic coherence was reduced during REM and NREM movements. We conclude that sleep-related movements are not processed by the same corticobasal ganglia network as movements in the waking state. Therefore, the well-known seemingly normal motor performance during RBD in PD patients might be generated by activating alternative motor networks for movement initiation. These findings support the hypothesis that pathological movement-inhibiting basal ganglia networks in PD patients are bypassed during sleep. SIGNIFICANCE STATEMENT: This study provides evidence that nocturnal movements during REM sleep in Parkinson's disease (PD) patients are not processed by the same corticobasal ganglia network as movements in the waking state. This implicates the existence of an alternative motor network that does not depend directly on the availability of l-Dopa in the basal ganglia. These findings further indicate that some PD patients are able to perform movements in the dopamine depleted state, possibly by bypassing the pathological basal ganglia network. The existence and direct activation of such alternative motor networks might finally have potential therapeutic effects for PD patients.