Direct subthalamic nucleus stimulation influences speech and voice quality in Parkinson's disease patients.

BACKGROUND: DBS of the subthalamic nucleus (STN) considerably ameliorates cardinal motor symptoms in PD. Reported STN-DBS effects on secondary dysarthric (speech) and dysphonic symptoms (voice), as originating from vocal tract motor dysfunctions, are however inconsistent with rather deleterious outcomes based on post-surgical assessments. OBJECTIVE: To parametrically and intra-operatively investigate the effects of deep brain stimulation (DBS) on perceptual and acoustic speech and voice quality in Parkinson's disease (PD) patients. METHODS: We performed an assessment of instantaneous intra-operative speech and voice quality changes in PD patients (n = 38) elicited by direct STN stimulations with variations of central stimulation features (depth, laterality, and intensity), separately for each hemisphere. RESULTS: First, perceptual assessments across several raters revealed that certain speech and voice symptoms could be improved with STN-DBS, but this seems largely restricted to right STN-DBS. Second, computer-based acoustic analyses of speech and voice features revealed that both left and right STN-DBS could improve dysarthric speech symptoms, but only right STN-DBS can considerably improve dysphonic symptoms, with left STN-DBS being restricted to only affect voice intensity features. Third, several subareas according to stimulation depth and laterality could be identified in the motoric STN proper and close to the associative STN with optimal (and partly suboptimal) stimulation outcomes. Fourth, low-to-medium stimulation intensities showed the most optimal and balanced effects compared to high intensities. CONCLUSIONS: STN-DBS can considerably improve both speech and voice quality based on a carefully arranged stimulation regimen along central stimulation features.

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.

Association of Mortality and Risk of Epilepsy With Type of Acute Symptomatic Seizure After Ischemic Stroke and an Updated Prognostic Model.

Importance: Acute symptomatic seizures occurring within 7 days after ischemic stroke may be associated with an increased mortality and risk of epilepsy. It is unknown whether the type of acute symptomatic seizure influences this risk. Objective: To compare mortality and risk of epilepsy following different types of acute symptomatic seizures. Design, Setting, and Participants: This cohort study analyzed data acquired from 2002 to 2019 from 9 tertiary referral centers. The derivation cohort included adults from 7 cohorts and 2 case-control studies with neuroimaging-confirmed ischemic stroke and without a history of seizures. Replication in 3 separate cohorts included adults with acute symptomatic status epilepticus after neuroimaging-confirmed ischemic stroke. The final data analysis was performed in July 2022. Exposures: Type of acute symptomatic seizure. Main Outcomes and Measures: All-cause mortality and epilepsy (at least 1 unprovoked seizure presenting >7 days after stroke). Results: A total of 4552 adults were included in the derivation cohort (2547 male participants [56%]; 2005 female [44%]; median age, 73 years [IQR, 62-81]). Acute symptomatic seizures occurred in 226 individuals (5%), of whom 8 (0.2%) presented with status epilepticus. In patients with acute symptomatic status epilepticus, 10-year mortality was 79% compared with 30% in those with short acute symptomatic seizures and 11% in those without seizures. The 10-year risk of epilepsy in stroke survivors with acute symptomatic status epilepticus was 81%, compared with 40% in survivors with short acute symptomatic seizures and 13% in survivors without seizures. In a replication cohort of 39 individuals with acute symptomatic status epilepticus after ischemic stroke (24 female; median age, 78 years), the 10-year risk of mortality and epilepsy was 76% and 88%, respectively. We updated a previously described prognostic model (SeLECT 2.0) with the type of acute symptomatic seizures as a covariate. SeLECT 2.0 successfully captured cases at high risk of poststroke epilepsy. Conclusions and Relevance: In this study, individuals with stroke and acute symptomatic seizures presenting as status epilepticus had a higher mortality and risk of epilepsy compared with those with short acute symptomatic seizures or no seizures. The SeLECT 2.0 prognostic model adequately reflected the risk of epilepsy in high-risk cases and may inform decisions on the continuation of antiseizure medication treatment and the methods and frequency of follow-up.

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.

EEG-Delta brushes in DPPX encephalitis - Welcome to the club.

Background: Extreme Delta Brushes are a rare interictal EEG pattern that was first described in NMDA-R encephalitis and has been considered a pathognomonic pattern for this subtype of autoimmune encephalitis. Recently, extreme delta brushes have been described as a rare EEG phenomenon in other forms of encephalitis. Case report: We describe to our knowledge the first occurrence of EEG Delta brushes in DPPX encephalitis. In this article, we present a comprehensive case report and discuss clinical differential diagnosis with special emphasis on the diagnostic value of the EEG, leading the way to the correct diagnosis. We also present current diagnostic criteria and clinical screening scales for initial evaluation for patients with suspected autoimmune encephalitis.

Sleep spindle and slow wave activity in Parkinson disease with excessive daytime sleepiness.

STUDY OBJECTIVES: Excessive daytime sleepiness (EDS) is a common and devastating symptom in Parkinson disease (PD), but surprisingly most studies showed that EDS is independent from nocturnal sleep disturbance measured with polysomnography. Quantitative electroencephalography (EEG) may reveal additional insights by measuring the EEG hallmarks of non-rapid eye movement (NREM) sleep, namely slow waves and spindles. Here, we tested the hypothesis that EDS in PD is associated with nocturnal sleep disturbance revealed by quantitative NREM sleep EEG markers. METHODS: Patients with PD (n = 130) underwent polysomnography followed by spectral analysis to calculate spindle frequency activity, slow-wave activity (SWA), and overnight SWA decline, which reflects the dissipation of homeostatic sleep pressure. We used the Epworth Sleepiness Scale (ESS) to assess subjective daytime sleepiness and define EDS (ESS > 10). All examinations were part of an evaluation for deep brain stimulation. RESULTS: Patients with EDS (n = 46) showed reduced overnight decline of SWA (p = 0.036) and reduced spindle frequency activity (p = 0.032) compared with patients without EDS. Likewise, more severe daytime sleepiness was associated with reduced SWA decline (ß= -0.24 p = 0.008) and reduced spindle frequency activity (ß= -0.42, p < 0.001) across all patients. Reduced SWA decline, but not daytime sleepiness, was associated with poor sleep quality and continuity at polysomnography. CONCLUSIONS: Our data suggest that daytime sleepiness in PD patients is associated with sleep disturbance revealed by quantitative EEG, namely reduced overnight SWA decline and reduced spindle frequency activity. These findings could indicate that poor sleep quality, with incomplete dissipation of homeostatic sleep pressure, may contribute to EDS in PD.

Stimulus Induced Rhythmic, Periodic, or Ictal Discharges (SIRPIDs) and its Association with Non-convulsive Status Epilepticus in Critically Ill Patients.

Stimulus induced repetitive periodic or ictal discharges (SIRPIDs) are a commonly observed EEG pattern in critically ill patients. However, the epileptic significance of SIRPIDs remain unclear. We identified and reviewed 55 cases with SIRPIDs according to the ACNS criteria. SIRPIDs occurred after standardized painful stimuli during a standard 20-minute EEG. These cases were investigated regarding their relation to non-convulsive status epilepticus (NCSE) according to Salzburg Consensus Criteria and in-hospital mortality. In 37/55 patients (67.3%), SIRPIDs were associated with NCSE. In most patients (26/37 cases, 70.3%) with concurrent status epilepticus, SIRPIDs occurred after status epilepticus (on average 4.8 days later), but in 3/37 patients (8.1%) they were observed before a later status epilepticus. In four cases (4/37 cases, 10.8%), SIRPIDs appeared both before and after an episode of NCSE and in other four cases the two patterns coexisted in the same EEG. In 50% of the patients, status epilepticus was refractory, super-refractory or the patient died before its resolution. The overall mortality in the cohort was high at 58.2%. These findings corroborate the hypothesis that SIRPIDs might represent a state with increased epileptogenic potential, commonly co-occurring with NCSE. Furthermore, SIRPIDs are associated with therapy-refractory course of status epilepticus and high mortality.

Differentiation of Parkinson's disease tremor and essential tremor based on a novel hand posture.

Background: Tremor is one of the most common movement disorders but the correct diagnosis of tremor disorders, especially the differentiation between Parkinson's disease tremor (PT) and essential tremor (ET) remains a challenge for clinicians. Method: We examined a novel hand position to distinguish PT from ET. We prospectively collected accelerometric tremor data in 14 ET patients and 14 PT patients with arms and hands fully stretched against arms stretched and hands relaxed, i. e. hanging down. The total acceleration from the three pairwise-perpendicular accelerometric axes during the 1-minute blocks of the two hand positions were computed and high-passed filtered at 2 Hz. The power spectral density during each hand position was calculated and summed up over the frequency domain. Results: Our results showed a significantly higher occurrence of tremor in the hands hanging down position in PT patients compared to ET patients (p = 0.0262). Moreover, in PT patients the tremor intensity significantly increased when transitioning from the stretched hand position to the hanging-down position (83 % of cohort) and vice versa in ET patients (75 % of cohort). Conclusion: In conclusion, the new hand posture can differentiate between PT and ET with high accuracy (sensitivity 83 %, specificity 75 % for PT) and may be a helpful tool in the clinical assessment of tremor.

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.

Dissociation of motor control from motor awareness in awake sleepwalkers: An EEG study in virtual reality.

Recent behavioral evidence from a virtual reality (VR) study indicates that awake sleepwalkers show dissociation of motor control and motor awareness. This dissociation resembles the nocturnal disintegration of motor awareness and movement during episodes of sleepwalking. Here, we set out to examine the neural underpinnings of altered motor awareness in sleepwalkers by measuring EEG modulation during redirected walking in VR. To this end, we measured scalp EEG during ongoing motor behavior to provide information on motor processing and its modulation in VR. Using this approach, we discovered distinct EEG patterns associated to dual tasking and sub-threshold motor control in sleepwalkers compared to control subjects. These observations provide further electrophysiological evidence for the proposed brain-body dissociation in awake sleepwalkers. This study shows proof-of-principle that EEG biomarkers of movement in a VR setting add to the understanding of altered motor awareness in sleepwalkers. In a broader perspective, we confirm the feasibility of using the additional dimensionality in VR providing novel diagnostic biomarkers not accessible to conventional clinical investigations. In future studies, this approach could contribute to the diagnostic work-up of patients with a broad spectrum of neurological diseases.

Slow-wave sleep affects synucleinopathy and regulates proteostatic processes in mouse models of Parkinson's disease.

Slow-wave sleep (SWS) modulation in rodent models of Alzheimer's disease alters extracellular amyloid burden. In Parkinson's disease (PD), SWS appears to be closely linked with disease symptoms and progression. PD is characterized by damaging intracellular α-synuclein (αSyn) deposition that propagates extracellularly, contributing to disease spread. Intracellular αSyn is sensitive to degradation, whereas extracellular αSyn may be eliminated by glymphatic clearance, a process increased during SWS. Here, we explored whether long-term slow-wave modulation in murine models of PD presenting αSyn aggregation alters pathological protein burden and, thus, might constitute a valuable therapeutic target. Sleep-modulating treatments showed that enhancing slow waves in both VMAT2-deficient and A53T mouse models of PD reduced pathological αSyn accumulation compared to control animals. Nonpharmacological sleep deprivation had the opposite effect in VMAT2-deficient mice, severely increasing the pathological burden. We also found that SWS enhancement was associated with increased recruitment of aquaporin-4 to perivascular sites, suggesting a possible increase of glymphatic function. Furthermore, mass spectrometry data revealed differential and specific up-regulation of functional protein clusters linked to proteostasis upon slow wave­enhancing interventions. Overall, the beneficial effect of SWS enhancement on neuropathological outcome in murine synucleinopathy models mirrors findings in models of Alzheimer. Modulating SWS might constitute an effective strategy for modulating PD pathology in patients.

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.

Sensitivity of long-term EEG monitoring as a second diagnostic step in the initial diagnosis of epilepsy.

In this retrospective study, we aimed to evaluate the sensitivity and negative predictive value of long-term EEG (L-EEG) in patients being assessed for epilepsy, who had already undergone non-specific standard EEG(s) (S-EEG). Secondary endpoints of this study were: (1) the correlation of non-specific changes on EEG with epileptiform patterns on L-EEG; and (2) the correlation of clinical parameters such as subjective frequency of seizures or epileptogenic lesions on cerebral imaging with epileptiform changes on L-EEG. We retrospectively analysed clinical and electrophysiological data of 75 patients, assessed for epilepsy at the University Hospital Zurich, who had undergone an L-EEG for at least 48 hours, between 2010 and 2015. All patients had already undergone S-EEG(s) before L-EEG, which showed no epileptic changes. Furthermore, the association with clinical parameters, such as frequency of presumptive seizures, abnormalities on standard-EEG, AED intake and cerebral imaging with the final diagnosis, was analysed. Out of 75 patients, 14 (19%) patients were finally diagnosed with epilepsy. In eight of these patients, L-EEGs showed typical ictal/interictal patterns, with a sensitivity of 57% and negative predictive value of 91%. Neither the subjective frequency of seizures nor potentially epileptogenic lesions on cerebral imaging were associated with a positive epilepsy diagnosis. In this preselected cohort of patients, who had already undergone a non-diagnostic S-EEG, the sensitivity of L-EEG remained considerable. Nonetheless, our study also revealed a significant false-negative rate. Based on the high negative predictive value in this study, L-EEG appears to be most useful at excluding epilepsy. Nevertheless, thorough evaluation of seizure history and clinical findings remain crucial for a reliable diagnosis.

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.

Deep brain electrical neurofeedback allows Parkinson patients to control pathological oscillations and quicken movements.

Parkinsonian motor symptoms are linked to pathologically increased beta-oscillations in the basal ganglia. While pharmacological treatment and deep brain stimulation (DBS) reduce these pathological oscillations concomitantly with improving motor performance, we set out to explore neurofeedback as an endogenous modulatory method. We implemented real-time processing of pathological subthalamic beta oscillations through implanted DBS electrodes to provide deep brain electrical neurofeedback. Patients volitionally controlled ongoing beta-oscillatory activity by visual neurofeedback within minutes of training. During a single one-hour training session, the reduction of beta-oscillatory activity became gradually stronger and we observed improved motor performance. Lastly, endogenous control over deep brain activity was possible even after removing visual neurofeedback, suggesting that neurofeedback-acquired strategies were retained in the short-term. Moreover, we observed motor improvement when the learnt mental strategies were applied 2 days later without neurofeedback. Further training of deep brain neurofeedback might provide therapeutic benefits for Parkinson patients by improving symptom control using strategies optimized through neurofeedback.

Reduced Regional NREM Sleep Slow-Wave Activity Is Associated With Cognitive Impairment in Parkinson Disease.

Growing evidence implicates a distinct role of disturbed slow-wave sleep in neurodegenerative diseases. Reduced non-rapid eye movement (NREM) sleep slow-wave activity (SWA), a marker of slow-wave sleep intensity, has been linked with age-related cognitive impairment and Alzheimer disease pathology. However, it remains debated if SWA is associated with cognition in Parkinson disease (PD). Here, we investigated the relationship of regional SWA with cognitive performance in PD. In the present study, 140 non-demented PD patients underwent polysomnography and were administered the Montréal Cognitive Assessment (MoCA) to screen for cognitive impairment. We performed spectral analysis of frontal, central, and occipital sleep electroencephalography (EEG) derivations to measure SWA, and spectral power in other frequency bands, which we compared to cognition using linear mixed models. We found that worse MoCA performance was associated with reduced 1-4 Hz SWA in a region-dependent manner (F 2, 687 =11.67, p < 0.001). This effect was driven by reduced regional SWA in the lower delta frequencies, with a strong association of worse MoCA performance with reduced 1-2 Hz SWA (F 2, 687 =18.0, p < 0.001). The association of MoCA with 1-2 Hz SWA (and 1-4 Hz SWA) followed an antero-posterior gradient, with strongest, weaker, and absent associations over frontal (rho = 0.33, p < 0.001), central (rho = 0.28, p < 0.001), and occipital derivations, respectively. Our study shows that cognitive impairment in PD is associated with reduced NREM sleep SWA, predominantly in lower delta frequencies (1-2 Hz) and over frontal regions. This finding suggests a potential role of reduced frontal slow-wave sleep intensity in cognitive impairment in PD.

Sleep electroencephalographic asymmetry in Parkinson's disease patients before and after deep brain stimulation.

OBJECTIVE: Unilateral manifestation of motor dysfunction is a prominent hallmark of Parkinson's disease (PD). We investigated how the motor laterality of the disorder affects sleep neural asymmetry before and after Deep Brain Stimulation (DBS). METHODS: Twenty-seven PD patients of the akinetic-rigid subtype were studied; 11 with right dominant (RD) and 16 with left dominant (LD) motor symptoms. Neuronal sleep asymmetry was computed as the difference of sleep slow-wave energy (SWE) between left and right hemispheres. We used linear mixed models to assess the relationship between symptomatic profile and SWE asymmetry. RESULTS: LD PD patients exhibited frontal electroencephalographic (EEG) asymmetry and motor laterality pre-DBS with increased SWE contralateral to their affected body side, which diminished post-DBS. The RD group did not exhibit neither neural asymmetry nor motor laterality pre- and post-DBS. There was a significant negative correlation between the motor laterality and sleep EEG asymmetry. CONCLUSIONS: Our results suggest evidence for a local use-dependent modulation of SWE as a result of the lateralized pathological motor profile. More bilateral motor symptoms and optimized treatment contribute to diminished sleep EEG asymmetry. SIGNIFICANCE: These novel findings about the association between symptomatic motor laterality and sleep neural asymmetry may provide targeted therapeutic insights.

Personalised therapeutic management of epileptic patients guided by pathway-driven breath metabolomics.

Background: Therapeutic management of epilepsy remains a challenge, since optimal systemic antiseizure medication (ASM) concentrations do not always correlate with improved clinical outcome and minimal side effects. We tested the feasibility of noninvasive real-time breath metabolomics as an extension of traditional therapeutic drug monitoring for patient stratification by simultaneously monitoring drug-related and drug-modulated metabolites. Methods: This proof-of-principle observational study involved 93 breath measurements of 54 paediatric patients monitored over a period of 2.5 years, along with an adult's cohort of 37 patients measured in two different hospitals. Exhaled breath metabolome of epileptic patients was measured in real time using secondary electrospray ionisation-high-resolution mass spectrometry (SESI-HRMS). Results: We show that systemic ASM concentrations could be predicted by the breath test. Total and free valproic acid (VPA, an ASM) is predicted with concordance correlation coefficient (CCC) of 0.63 and 0.66, respectively. We also find (i) high between- and within-subject heterogeneity in VPA metabolism; (ii) several amino acid metabolic pathways are significantly enriched (p < 0.01) in patients suffering from side effects; (iii) tyrosine metabolism is significantly enriched (p < 0.001), with downregulated pathway compounds in non-responders. Conclusions: These results show that real-time breath analysis of epileptic patients provides reliable estimations of systemic drug concentrations along with risk estimates for drug response and side effects.