Decline in drawing ability and cerebral perfusion in Parkinson's disease patients after subthalamic nucleus deep brain stimulation surgery

BackgroundSubthalamic nucleus deep brain stimulation (STN DBS) is an established therapy for alleviating motor symptoms in advanced Parkinson's disease (PD) patients; however, a postoperative decline in cognitive and speech function has become problematic although its mechanism remains unclear. The aim of the present study was to elucidate the properties of language and drawing ability and cerebral perfusion in PD patients after bilateral STN DBS surgery.MethodsWestern aphasia battery, including drawing as a subcategory, and perfusion (N-isopropyl-p-[¹²³I] iodoamphetamine) SPECT scan was conducted in 21 consecutive PD patients, before, and three to six months after, bilateral STN DBS surgery while on stimulation. Perfusion images were compared with those of 17 age- and gender-matched healthy volunteers. In the parametric image analysis, the statistical peak threshold was set at P < 0.001 uncorrected with a cluster threshold set at P < 0.05 uncorrected.ResultsAlthough motor symptoms were improved and general cognition was preserved in the patient group, 11 patients (52.4%) showed a decline in the drawing subcategory after surgery, which showed a reduction in Frontal Assessment Battery score in this group of patients. Statistical parametric analysis of the brain perfusion images showed a decrease of cerebral blood flow in the prefrontal and cingulate cortex after surgery. Patients whose drawing ability declined showed decreased perfusion in the middle cingulate cortex comparing before and after surgery.ConclusionPresent results show that some PD patients show a decline in drawing ability after bilateral STN DBS which may attributable by dysfunction in the cingulate network.     

Subthalamic nucleus deep brain stimulation improves deglutition in Parkinson's disease

Relatively little is known about the role of the basal ganglia in human deglutition. Deep brain stimulation (DBS) affords us a model for examining deglutition in humans with known impairment of the basal ganglia. The purpose of this study was to examine the effects of subthalamic nuclei (STN) DBS on the oral and pharyngeal stages of deglutition in individuals with Parkinson's Disease (PD). It was hypothesized that DBS would be associated with improved deglutition. Within participant, comparisons were made between DBS in the ON and OFF conditions using the dependent variables: pharyngeal transit time, maximal hyoid bone excursion, oral total composite score, and pharyngeal total composite score. Significant improvement occurred for the pharyngeal composite score and pharyngeal transit time in the DBS ON condition compared with DBS OFF. Stimulation of the STN may excite thalamocortical or brainstem targets to sufficiently overcome the bradykinesia/hypokinesia associated with PD and return some pharyngeal stage motor patterns to performance levels approximating those of “normal” deglutition. However, the degree of hyoid bone excursion and oral stage measures did not improve, suggesting that these motor acts may be under the control of different sensorimotor pathways within the basal ganglia. © 2007 Movement Disorder Society     

Improvement of sleep quality in patients with advanced Parkinson's disease treated with deep brain stimulation of the subthalamic nucleus.

Most Parkinson's patients complain about sleep problems. The subjective effect of deep brain stimulation (DBS) of the subthalamic nucleus (STN) on nocturnal disabilities and sleep quality was elucidated by the recently established Parkinson's disease sleep scale (PDSS). The DBS-treated group obtained significant improvement of motor function assessed by the Unified Parkinson's Disease Rating Scale. The mean total PDSS improved significantly after surgery whereas no change was found for the control group. Significant improvements of individual questions were obtained for overall sleep quality and motor symptoms whereas nocturia and daytime sleepiness did not change despite significant reduction of parkinsonian medication.     

Subthalamic nucleus deep brain stimulation for camptocormia associated with Parkinson's disease

Camptocormia becomes increasingly recognized as a disabling symptom associated with Parkinson's disease (PD). We here report six patients with advanced PD in whom continuous bilateral stimulation of the subthalamic nucleus produced substantial (mean 78% ± 9.1% of the thoracolumbar angle) improvement of camptocormia along with other motor symptoms. © 2009 Movement Disorder Society     

A ventromedial prefrontal dysrhythmia in obsessive-compulsive disorder is attenuated by nucleus accumbens deep brain stimulation

BackgroundObsessive-compulsive disorder (OCD) has consistently been linked to abnormal frontostriatal activity. The electrophysiological disruption in this circuit, however, remains to be characterized.Objective/hypothesisThe primary goal of this study was to investigate the neuronal synchronization in OCD patients. We predicted aberrant oscillatory activity in frontal regions compared to healthy control subjects, which would be alleviated by deep brain stimulation (DBS) of the nucleus accumbens (NAc).MethodsWe compared scalp EEG recordings from nine patients with OCD treated with NAc-DBS with recordings from healthy controls, matched for age and gender. Within the patient group, EEG activity was compared with DBS turned off vs. stimulation at typical clinical settings (3.5 V, frequency of stimulation 130 Hz, pulse width 60 μs). In addition, intracranial EEG was recorded directly from depth macroelectrodes in the NAc in four OCD patients.ResultsCross-frequency coupling between the phase of alpha/low beta oscillations and amplitude of high gamma was significantly increased over midline frontal and parietal electrodes in patients when stimulation was turned off, compared to controls. Critically, in patients, beta (16–25 Hz) -gamma (110–166 Hz) phase amplitude coupling source localized to the ventromedial prefrontal cortex, and was reduced when NAc-DBS was active. In contrast, intracranial EEG recordings showed no beta-gamma phase amplitude coupling. The contribution of non-sinusoidal beta waveforms to this coupling are reported.ConclusionWe reveal an increased beta-gamma phase amplitude coupling in fronto-central scalp sensors in patients suffering from OCD, compared to healthy controls, which may derive from ventromedial prefrontal regions implicated in OCD and is normalized by DBS of the nucleus accumbens. This aberrant cross-frequency coupling could represent a biomarker of OCD, as well as a target for novel therapeutic approaches.     

Neuromodulation effects of deep brain stimulation on beta rhythm: A longitudinal local field potential study

BackgroundDeep brain stimulation (DBS) holds great promise in treating various brain diseases but its chronic therapeutic mechanisms are unclear.ObjectiveTo explore the immediate and chronic effects of DBS on brain oscillations, and understand how different sub-bands of oscillations may be related to symptom improvement in Parkinson's patients.MethodsWe carried out a longitudinal study to examine the effects of DBS on local field potentials recorded by sensing-enabled neurostimulators in the subthalamic nuclei of Parkinson's patients, using a novel block-design stimulation paradigm.ResultsDBS significantly suppressed beta activity (13–35Hz) but the suppression effect appeared to gradually attenuate during a 6-month follow-up period after surgery (p = 0.002). However, beta suppression did not attenuate after repeated stimulation over several minutes (p > 0.110), suggesting that the changes in beta suppression may reflect a slow reconfiguration of neural pathways instead of habituation. Suppression of beta was also associated with clinical symptom improvement across subjects. Importantly, symptom-relevant features fell within the high beta band at month 1 but shifted to the low beta band at month 6, indicating that the high beta and the low beta oscillations may play different functional roles and respond differently to stimulation over the long-term treatment.ConclusionThese data may advance understanding of chronic DBS effects on beta oscillations and their association with clinical improvement, offering novel insights to the therapeutic mechanisms of DBS.     

High density microelectrode recording predicts span of therapeutic tissue activation volumes in subthalamic deep brain stimulation for Parkinson disease

BackgroundSubthalamic deep brain stimulation alleviates motor symptoms of Parkinson disease by activating precise volumes of neural tissue. While electrophysiological and anatomical correlates of clinically effective electrode sites have been described, therapeutic stimulation likely acts through multiple distinct neural populations, necessitating characterization of the full span of tissue activation. Microelectrode recordings have yet to be mapped to therapeutic tissue activation volumes and surveyed for predictive markers.ObjectiveCombine high-density, broadband microelectrode recordings with detailed computational models of tissue activation to describe and to predict regions of therapeutic tissue activation.MethodsElectrophysiological features were extracted from microelectrode recordings along 23 subthalamic deep brain stimulation implants in 16 Parkinson disease patients. These features were mapped in space against tissue activation volumes of therapeutic stimulation, modeled using clinically-determined stimulation programming parameters and fully individualized, atlas-independent anisotropic tissue properties derived from 3T diffusion tensor magnetic resonance images. Logistic LASSO was applied to a training set of 17 implants out of the 23 implants to identify predictors of therapeutic stimulation sites in the microelectrode recording. A support vector machine using these predictors was used to predict therapeutic activation. Performance was validated with a test set of six implants.ResultsAnalysis revealed wide variations in the distribution of therapeutic tissue activation across the microelectrode recording-defined subthalamic nucleus. Logistic LASSO applied to the training set identified six oscillatory predictors of therapeutic tissue activation: theta, alpha, beta, high gamma, high frequency oscillations (HFO, 200–400 Hz), and high frequency band (HFB, 500–2000 Hz), in addition to interaction terms: theta x HFB, alpha x beta, beta x HFB, and high gamma x HFO. A support vector classifier using these features predicted therapeutic sites of activation with 64% sensitivity and 82% specificity in the test set, outperforming a beta-only classifier. A probabilistic predictor achieved 0.87 area under the receiver-operator curve with test data.ConclusionsTogether, these results demonstrate the importance of personalized targeting and validate a set of microelectrode recording signatures to predict therapeutic activation volumes. These features may be used to improve the efficiency of deep brain stimulation programming and highlight specific neural oscillations of physiological importance.     

Mandibular advancement device in Parkinson's disease: a pilot study on efficacy and usability

Background/objectivesContinuous positive airway pressure (CPAP) is efficacious in the treatment of obstructive sleep apnea syndrome (OSAS) in patients with Parkinson's disease (PD). However, this treatment is often not well tolerated in this disabled population. We explored, in a pilot study, the efficacy, observance, and usability of mandibular advancement device (MAD) for the treatment of OSAS in this peculiar population.Patients/methodsTwenty patients with PD and moderate or severe OSAS were included in the study. Ten patients had refused or not tolerated the validated treatment with CPAP so that they were treated with MAD. The patients treated with MAD were matched for sex, age and body mass index (BMI) to 10 patients with PD treated with CPAP.We explored the efficacy of MAD on sleep disorders complaints (PDSS-2) and on sleep recordings. We compared adherence, tolerance and usability with MAD and with CPAP.ResultsMAD improved sleep complaints increasing PDSS-2 scores (85 [55–106] vs 106 [88–126], p < 0.005), and sleep respiratory measures reducing apnea/hypopnea index (AHI) (50.8 [30.0–76.4] vs 9.4 [5.0–45.2], <0.001) and oxygen desaturation index (22.9 [2.1–92.0] vs 3.8 [0.2–34.2], p < 0.05). Observance was higher with MAD than with CPAP. Usability and caregiver satisfaction were higher with MAD than with CPAP whereas side effects were similarly reported.ConclusionMandibular advancement device may be an noteworthy alternative treatment of OSAS in patients with PD.     

Subthalamic nucleus stimulation selectively improves motor and visual memory performance in Parkinson's disease

Although the treatment of Parkinson's disease via subthalamic stimulation yields remarkable improvements in motor symptoms, its effects on memory function are less clear. In this context, we previously demonstrated dissociable effects of levodopa therapy on parkinsonian performance in spatial and nonspatial visual working memory. Here we used the same protocol with an additional, purely motor task to investigate visual memory and motor performance in 2 groups of patients with Parkinson's disease with or without subthalamic stimulation. In each stimulation condition, subjects performed a simple motor task and 3 successive cognitive tasks: 1 conditional color‐response association task and 2 visual (spatial and nonspatial) working memory tasks. The Parkinson's groups were compared with a control group of age‐matched healthy subjects. Our principal results demonstrated that (1) in the motor task, stimulated patients were significantly improved with respect to nonstimulated patients and did not differ significantly from healthy controls, and (2) in the cognitive tasks, stimulated patients were significantly improved with respect to nonstimulated patients, but both remained significantly impaired when compared with healthy controls. These results demonstrate selective effects of subthalamic stimulation on parkinsonian disorders of motor and visual memory functions, with clear motor improvement for stimulated patients and a partial improvement for their visual memory processing. © 2011 Movement Disorder Society     

Probabilistic maps for deep brain stimulation – Impact of methodological differences

BackgroundGroup analysis of patients with deep brain stimulation (DBS) has the potential to help understand and optimize the treatment of patients with movement disorders. Probabilistic stimulation maps (PSM) are commonly used to analyze the correlation between tissue stimulation and symptomatic effect but are applied with different methodological variations.ObjectiveTo compute a group-specific MRI template and PSMs for investigating the impact of PSM model parameters.MethodsImprovement and occurrence of dizziness in 68 essential tremor patients implanted in caudal zona incerta were analyzed. The input data includes the best parameters for each electrode contact (screening), and the clinically used settings. Patient-specific electric field simulations (n = 488) were computed for all DBS settings. The electric fields were transformed to a group-specific MRI template for analysis and visualization. The different comparisons were based on PSMs representing occurrence (N-map), mean improvement (M-map), weighted mean improvement (wM-map), and voxel-wise t-statistics (p-map). These maps were used to investigate the impact from input data (clinical/screening settings), clustering methods, sampling resolution, and weighting function.ResultsScreening or clinical settings showed the largest impacts on the PSMs. The average differences of wM-maps were 12.4 and 18.2% points for the left and right sides respectively. Extracting clusters based on wM-map or p-map showed notable variation in volumes, while positioning was similar. The impact on the PSMs was small from weighting functions, except for a clear shift in the positioning of the wM-map clusters.ConclusionThe distribution of the input data and the clustering method are most important to consider when creating PSMs for studying the relationship between anatomy and DBS outcome.     

α and θ oscillations in the subthalamic nucleus are potential biomarkers for Parkinson's disease with depressive symptoms

IntroductionAbnormal α oscillations in the bed nucleus of stria terminalis and subgenual cingulate of patients with depression correlate with symptom severity. Some Parkinson's disease (PD) patients also have abnormal θ-α oscillations in the subthalamic nucleus (STN). However, the relationship between abnormal θ-α oscillations and depressive symptoms in PD patients has not been determined. This study explored the correlation between α and θ oscillations of the STN and depressive symptoms in PD patients.MethodsWe conducted a retrospective case-control study on 36 PD patients with (dPD group) or without depressive symptoms (nPD group), analyzing the difference in the average power spectral density (PSD) of α and θ oscillations of the local field potential (LFP) recorded in the STN during deep brain stimulation (DBS), and their correlation with the Hamilton depression rating scale (HAMD) of PD patients during the same period.ResultsThe dPD group had a higher PSD of α oscillations and a lower PSD of θ oscillations in the left ventral STN. The PSD of α oscillations of the left ventral STN were positively correlated with the severity of depressive symptoms, whereas the PSD of θ oscillations of this location was negatively correlated with severity of depressive symptoms. The PSD of α and θ oscillations did not correlate with motor symptoms, sleep quality, or quality of life score.ConclusionAbnormal α and θ oscillations of the left ventral STN could be used as biomarkers of PD with depressive symptoms, which might guide STN-DBS treatment.     

A theoretical framework for the site-specific and frequency-dependent neuronal effects of deep brain stimulation

BackgroundDeep brain stimulation is an established therapy for several neurological disorders; however, its effects on neuronal activity vary across brain regions and depend on stimulation settings. Understanding these variable responses can aid in the development of physiologically-informed stimulation paradigms in existing or prospective indications.ObjectiveProvide experimental and computational insights into the brain-region-specific and frequency-dependent effects of extracellular stimulation on neuronal activity.MethodsIn patients with movement disorders, single-neuron recordings were acquired from the subthalamic nucleus, substantia nigra pars reticulata, ventral intermediate nucleus, or reticular thalamus during microstimulation across various frequencies (1–100 Hz) to assess single-pulse and frequency-response functions. Moreover, a biophysically-realistic computational framework was developed which generated postsynaptic responses under the assumption that electrical stimuli simultaneously activated all convergent presynaptic inputs to stimulation target neurons. The framework took into consideration the relative distributions of excitatory/inhibitory afferent inputs to model site-specific responses, which were in turn embedded within a model of short-term synaptic plasticity to account for stimulation frequency-dependence.ResultsWe demonstrated microstimulation-evoked excitatory neuronal responses in thalamic structures (which have predominantly excitatory inputs) and inhibitory responses in basal ganglia structures (predominantly inhibitory inputs); however, higher stimulation frequencies led to a loss of site-specificity and convergence towards neuronal suppression. The model confirmed that site-specific responses could be simulated by accounting for local neuroanatomical/microcircuit properties, while suppression of neuronal activity during high-frequency stimulation was mediated by short-term synaptic depression.ConclusionsBrain-region-specific and frequency-dependant neuronal responses could be simulated by considering neuroanatomical (local microcircuitry) and neurophysiological (short-term plasticity) properties.     

Subthalamic nucleus deep brain stimulation for parkinson's disease after successful pallidotomy: clinical and electrophysiological observations.

Unilateral pallidotomy is an effective treatment for contralateral parkinsonism and dyskinesia, yet symptoms progress in many patients. Little is known about whether such patients obtain a useful response to subsequent bilateral subthalamic nucleus deep brain stimulation (STN DBS). Changes in Unified Parkinson's Disease Rating Scale (UPDRS) Motor and Activities of Daily Living (ADL) scores, medication requirements, and dyskinesias were measured. Clinical outcomes were compared to patients with de novo STN DBS. Neuronal recordings were performed. STN DBS resulted in a significant reduction in UPDRS Motor scores (42.1%; 95% confidence interval [CI], 26.9-57.4; P = 0.03), comparable with de novo STN DBS surgery (41%; 95% CI, 26-46%; P < 0.001). There was also less change in dyskinesia duration and disability scores (P = 0.017, 0.005). There were no side-to-side differences clinically or in the STN neuronal firing rates and patterns. Bilateral STN DBS is safe and efficacious in improving motor symptoms in patients with prior pallidotomy.     

The prevalence of sleep problems among children in mainland China: a meta-analysis and systemic-analysis

BackgroundWe conducted a meta-analysis and systematic review to identify a reliable estimate of sleep problems prevalence among children in mainland China and to describe its epidemiological characteristics.MethodsRelevant studies were searched thoroughly via electronic databases included China National Knowledge Infrastructure, Wanfang, Weipu, PubMed, Embase and Medline databases from inception until December 2020. Prevalence estimates were calculated by random-effects models. The sources of heterogeneity were explored using subgroup analyses and Meta-regression analysis, and publication bias was estimated by funnel plots and Egger's Test.ResultsOverall, 66 studies were included in this meta-analysis, which revealed that the pooled prevalence of sleep problems was 37.6% (95%CI: 34.3–40.9%) with high heterogeneity (I² = 99.6%,P < 0.001). The incidence of snoring was 7.7%, choking or gasping was 0.9%, apnea was 1.5%, restless sleep was 11.3%, mouth breathing was 4.7%, hyperhidrosis was 17.2%, leg movements was 2.7%, bruxism was 9.6%, sleep talking was 0.7%, sleep-walking was 0.8%, nightmare was 5.1%, enuresis was 3.4%, night awakening was 6.7% and trouble falling asleep was 11.1%. The prevalence rate of sleep problems among males was higher than females (OR:1.01,95%CI:1.05–1.13). In all age groups, the prevalence rates of sleep problems increased with age, including infancy or early childhood group (33.3%), pre-school group (38.9%), school-age group (43.7%). The prevalence rate in South China (30.4%, 95%CI: 23.9–36.8%) was the lowest, and the highest prevalence rate was in West China (47.4%,95%CI:35.9–58.9%), which than any other region in China. The point estimate for sleep disorders prevalence obtained using the CSHQ criterion was higher than other criteria. Meta-regression indicated that age group could influence prevalence estimation (P = 0.011).ConclusionsOver the past two decades, the prevalence rate of sleep problems among children in mainland China has increased, significantly affecting two-fifth of the school-age children. The incidence of hyperhidrosis, restless sleep and trouble falling asleep were significantly higher than other sleep prombles. The prevalence rate of sleep problems in west China was significantly higher than in any other area. There is still a lack of guidelines on children's sleep problems in mainland China, so future research should pay special attention to the sleep problems of school-age children and children in economically backward areas.     

Directional stimulation of subthalamic nucleus sweet spot predicts clinical efficacy: Proof of concept

BackgroundDirectional deep brain stimulation (dDBS) of the subthalamic nucleus for Parkinson's disease (PD) increases the therapeutic window. However, empirical programming of the neurostimulator becomes more complex given the increasing number of stimulation parameters. A better understanding of dDBS is needed to improve therapy and help guide postoperative programming.ObjectiveTo determine whether clinical effects of dDBS can be predicted in individual patients based on lead location and volume of tissue activated (VTA) modelling.MethodsWe analysed a prospective series of 28 PD patients. Imaging analysis and systematic clinical testing performed 4–6 months postoperatively yielded location, clinical efficacy and corresponding therapeutic windows for 272 directional contacts. We calculated the corresponding VTAs to build a probabilistic stimulation map using voxel-wise statistical analysis.ResultsWe found a positive and statistically significant correlation between the overlap ratio of a patient's individual stimulation volume and the probabilistic map's sweet spot –defined as the 10% voxels with the highest clinical efficacy values (average Spearman's rho = 0.43, average p ≤ 0.036). Patients who had a larger therapeutic window with directional compared to omnidirectional stimulation had a larger distance between the electrode and the sweet spot centroid (average distances 2.3 vs. 1.5 mm, p = 0.0019).ConclusionOur analysis provides new insights into how the definition of a probabilistic sweet spot based on directional stimulation data and individual VTA modelling can be applied to predict clinically effective directional stimulation and help guide clinicians with the intricate postoperative DBS programming.     

No enhanced (p-) α-synuclein deposition in gastrointestinal tissue of Parkinson's disease patients

BackgroundNeuronal alpha-synuclein (α-Syn) aggregation in the brain is believed to be a central component of the pathogenesis of Parkinson's disease (PD). α-Syn aggregates in the gastrointestinal tract have been suggested as a potential biomarker of PD that may even signal an early event of the Parkinsonian molecular pathology. However, studies further investigating this hypothesis have produced mixed results.ObjectiveTo determine whether the prevalence of α-Syn- and serine 129-phosphorylated α-Syn (Ser129p-α-Syn) depositions detected in intestine from PD patients differed from that of non-Parkinsonian controls.MethodsIn this retrospective study, we examined post-mortem small and large intestine samples of 25 PD patients and 20 age- and sex-matched controls without PD. Specimens were taken from archived paraffin-embedded tissue blocks. Immunohistochemical techniques were applied to detect α-Syn and Ser129p-α-Syn aggregates in situ. Immunoreactivity was quantified by a new approach that employed the detailed assessment of α-Syn- and Ser129p-α-Syn-positive morphological structures of the enteric nervous system (i.e., nerve fibers, myenteric and submucous plexus as well as ganglion cells).Resultsα-Syn immunoreactivity was a common finding in intestinal tissues from PD patients and controls. Importantly, α-Syn and Ser129p-α-Syn immunoreactivity were significantly reduced in PD patients compared to controls in each of the morphological structures examined.ConclusionsImmunohistochemical detection of intestinal α-Syn and Ser129p-α-Syn seems to be a frequent and potentially normal finding. Neither α-Syn nor Ser129p-α-Syn immunoreactivity may, therefore, be regarded as a molecular intestinal biomarker of PD pathology. Reduced intestinal α-Syn and Ser129p-α-Syn immunoreactivity in PD patients rather reflect PD-related neuronal degeneration.