Comparison of children and adults in deep brain stimulation for Tourette Syndrome: a large-scale multicenter study of 102 cases with long-term follow-up.

BACKGROUND: Deep brain stimulation (DBS) is a promising therapy for refractory Gilles de la Tourette syndrome (GTS). However, its long-term efficacy, safety, and recommended surgical age remain controversial, requiring evidence to compare different age categories. METHODS: This retrospective cohort study recruited 102 GTS patients who underwent DBS between October 2006 and April 2022 at two national centers. Patients were divided into two age categories: children (aged < 18 years; n = 34) and adults (aged ≥ 18 years; n = 68). The longitudinal outcomes as tic symptoms were assessed by the YGTSS, and the YBOCS, BDI, and GTS-QOL were evaluated for symptoms of obsessive-compulsive disorder (OCD), depression, and quality of life, respectively. RESULTS: Overall, these included patients who finished a median 60-month follow-up, with no significant difference between children and adults (p = 0.44). Overall, the YGTSS total score showed significant postoperative improvements and further improved with time (improved 45.2%, 51.6%, 55.5%, 55.6%, 57.8%, 61.4% after 6, 12, 24, 36, 48, and ≥ 60 months of follow-up compared to baseline, respectively) in all included patients (all p < 0.05). A significantly higher improvement was revealed in children than adults at ≥ 60 months of follow-up in the YGTSS scores (70.1% vs 55.9%, p = 0.043), and the time to achieve 60% improvement was significantly shorter in the children group (median 6 months vs 12 months, p = 0.013). At the last follow-up, the mean improvements were 45.4%, 48.9%, and 55.9% and 40.3%, 45.4%, and 47.9% in YBOCS, BDI, and GTS-QOL scores for children and adults, respectively, which all significantly improved compared to baseline (all p < 0.05) but without significant differences between these two groups (all p > 0.05), and the children group received significantly higher improvement in GTS-QOL scores than adults (55.9% vs. 47.9%, p = 0.049). CONCLUSIONS: DBS showed acceptable long-term efficacy and safety for both children and adults with GTS. Surgeries performed for patients younger than 18 years seemed to show acceptable long-term efficacy and safety and were not associated with increased risks of loss of benefit compared to patients older than 18 at the time of surgery. However, surgeries for children should also be performed cautiously to ensure their refractoriness and safety.

Contribution of basal ganglia activity to REM sleep disorder in Parkinson's disease.

BACKGROUND: Rapid eye movement (REM) sleep behaviour disorder (RBD) is one of the most common sleep problems and represents a key prodromal marker in Parkinson's disease (PD). It remains unclear whether and how basal ganglia nuclei, structures that are directly involved in the pathology of PD, are implicated in the occurrence of RBD. METHOD: Here, in parallel with whole-night video polysomnography, we recorded local field potentials from two major basal ganglia structures, the globus pallidus internus and subthalamic nucleus, in two cohorts of patients with PD who had varied severity of RBD. Basal ganglia oscillatory patterns during RBD and REM sleep without atonia were analysed and compared with another age-matched cohort of patients with dystonia that served as controls. RESULTS: We found that beta power in both basal ganglia nuclei was specifically elevated during REM sleep without atonia in patients with PD, but not in dystonia. Basal ganglia beta power during REM sleep positively correlated with the extent of atonia loss, with beta elevation preceding the activation of chin electromyogram activities by ~200 ms. The connectivity between basal ganglia beta power and chin muscular activities during REM sleep was significantly correlated with the clinical severity of RBD in PD. CONCLUSIONS: These findings support that basal ganglia activities are associated with if not directly contribute to the occurrence of RBD in PD. Our study expands the understanding of the role basal ganglia played in RBD and may foster improved therapies for RBD by interrupting the basal ganglia-muscular communication during REM sleep in PD.

A genome-wide transposon mutagenesis screening identifies LppB as a key factor associated with Mycoplasma bovis colonization and invasion into host cells.

Mycoplasma spp., the smallest self-replicating and genome-reduced organisms, have raised a great concern in both the medical and veterinary fields due to their pathogenicity. The molecular determinants of these wall-less bacterium efficiently use their limited genes to ensure successful infection of the host remain unclear. In the present study, we used the ruminant pathogen Mycoplasma bovis as a model to identify the key factors for colonization and invasion into host cells. We constructed a nonredundant fluorescent transposon mutant library of M. bovis using a modified transposon plasmid, and identified 34 novel adhesion-related genes based on a high-throughput screening approach. Among them, the ΔLppB mutant exhibited the most apparent decrease in adhesion to embryonic bovine lung (EBL) cells. The surface-localized lipoprotein LppB, which is highly conserved in Mycoplasma species, was then confirmed as a key factor for M. bovis adhesion with great immunogenicity. LppB interacted with various components (fibronectin, vitronectin, collagen IV, and laminin) of host extracellular matrix (ECM) and promoted plasminogen activation through tPA to degrade ECM. The 439-502 amino acid region of LppB is a critical domain, and F465 and Y493 are important residues for the plasminogen activation activity. We further revealed LppB as a key factor facilitating internalization through clathrin- and lipid raft-mediated endocytosis, which helps the Mycoplasma invade the host cells. Our study indicates that LppB plays a key role in Mycoplasma infection and is a potential new therapeutic and vaccine target for Mycoplasma species.

Pallidal activities during sleep and sleep decoding in dystonia, Huntington's, and Parkinson's disease.

BACKGROUND: Sleep disturbances are highly prevalent in movement disorders, potentially due to the malfunctioning of basal ganglia structures. Pallidal deep brain stimulation (DBS) has been widely used for multiple movement disorders and been reported to improve sleep. We aimed to investigate the oscillatory pattern of pallidum during sleep and explore whether pallidal activities can be utilized to differentiate sleep stages, which could pave the way for sleep-aware adaptive DBS. METHODS: We directly recorded over 500 h of pallidal local field potentials during sleep from 39 subjects with movement disorders (20 dystonia, 8 Huntington's disease, and 11 Parkinson's disease). Pallidal spectrum and cortical-pallidal coherence were computed and compared across sleep stages. Machine learning approaches were utilized to build sleep decoders for different diseases to classify sleep stages through pallidal oscillatory features. Decoding accuracy was further associated with the spatial localization of the pallidum. RESULTS: Pallidal power spectra and cortical-pallidal coherence were significantly modulated by sleep-stage transitions in three movement disorders. Differences in sleep-related activities between diseases were identified in non-rapid eye movement (NREM) and REM sleep. Machine learning models using pallidal oscillatory features can decode sleep-wake states with over 90% accuracy. Decoding accuracies were higher in recording sites within the internus-pallidum than the external-pallidum, and can be precited using structural (P < 0.0001) and functional (P < 0.0001) whole-brain neuroimaging connectomics. CONCLUSION: Our findings revealed strong sleep-stage dependent distinctions in pallidal oscillations in multiple movement disorders. Pallidal oscillatory features were sufficient for sleep stage decoding. These data may facilitate the development of adaptive DBS systems targeting sleep problems that have broad translational prospects.

Cortical phase-amplitude coupling is key to the occurrence and treatment of freezing of gait.

Freezing of gait is a debilitating symptom in advanced Parkinson's disease and responds heterogeneously to treatments such as deep brain stimulation. Recent studies indicated that cortical dysfunction is involved in the development of freezing, while evidence depicting the specific role of the primary motor cortex in the multi-circuit pathology of freezing is lacking. Since abnormal beta-gamma phase-amplitude coupling recorded from the primary motor cortex in patients with Parkinson's disease indicates parkinsonian state and responses to therapeutic deep brain stimulation, we hypothesized this metric might reveal unique information on understanding and improving therapy for freezing of gait. Here, we directly recorded potentials in the primary motor cortex using subdural electrocorticography and synchronously captured gait freezing using optoelectronic motion-tracking systems in 16 freely-walking patients with Parkinson's disease who received subthalamic nucleus deep brain stimulation surgery. Overall, we recorded 451 timed up-and-go walking trials and quantified 7073 s of stable walking and 3384 s of gait freezing in conditions of on/off-stimulation and with/without dual-tasking. We found that (i) high beta-gamma phase-amplitude coupling in the primary motor cortex was detected in freezing trials (i.e. walking trials that contained freezing), but not non-freezing trials, and the high coupling in freezing trials was not caused by dual-tasking or the lack of movement; (ii) non-freezing episodes within freezing trials also demonstrated abnormally high couplings, which predicted freezing severity; (iii) deep brain stimulation of subthalamic nucleus reduced these abnormal couplings and simultaneously improved freezing; and (iv) in trials that were at similar coupling levels, stimulation trials still demonstrated lower freezing severity than no-stimulation trials. These findings suggest that elevated phase-amplitude coupling in the primary motor cortex indicates higher probabilities of freezing. Therapeutic deep brain stimulation alleviates freezing by both decoupling cortical oscillations and enhancing cortical resistance to abnormal coupling. We formalized these findings to a novel 'bandwidth model,' which specifies the role of cortical dysfunction, cognitive burden and therapeutic stimulation on the emergence of freezing. By targeting key elements in the model, we may develop next-generation deep brain stimulation approaches for freezing of gait.

Low-frequency oscillations link frontal and parietal cortex with subthalamic nucleus in conflicts.

Low-frequency oscillations (LFOs, 28 Hz) in the subthalamic nucleus(STN) are known to reflect cognitive conflict. However, it is unclear if LFOs mediate communication and functional interactions among regions implicated in conflict processing, such as the motor cortex (M1), premotor cortex (PMC), and superior parietal lobule (SPL). To investigate the potential contribution of LFOs to cognitive conflict mediation, we recorded M1, PMC, and SPL activities by right subdural electrocorticography (ECoG) simultaneously with bilateral STN local field potentials (LFPs) by deep brain stimulation electrodes in 13 patients with Parkinson's disease who performed the arrow version of the Eriksen flanker task. Elevated cue-related LFO activity was observed across patients during task trials, with the earliest onset in PMC and SPL. At cue onset, LFO power exhibited a significantly greater increase or a trend of a greater increase in the PMC, M1, and STN, and less increase in the SPL during high-conflict (incongruent) trials than in low-conflict (congruent) trials. The local LFO power increases in PMC, SPL, and right STN were correlated with response time, supporting the notion that these structures are critical hubs for cognitive conflict processing. This power increase was accompanied by increased functional connectivity between the PMC and right STN, which was correlated with response time across subjects. Finally, ipsilateral PMC-STN Granger causality was enhanced during high-conflict trials, with direction from STN to PMC. Our study indicates that LFOs link the frontal and parietal cortex with STN during conflicts, and the ipsilateral PMC-STN connection is specifically involved in this cognitive conflict processing.

Effect of an artificial intelligence-based quality improvement system on efficacy of a computer-aided detection system in colonoscopy: a four-group parallel study.

BACKGROUND: Tandem colonoscopy studies have found that about one in five adenomas are missed at colonoscopy. It remains debatable whether the combination of a computer-aided polyp detection (CADe) system with a computer-aided quality improvement (CAQ) system for real-time monitoring of withdrawal speed results in additional benefits in adenoma detection or if the synergetic effect may be harmed due to excessive visual burden resulting from information overload. This study aimed to evaluate the interaction effect on improving the adenoma detection rate (ADR). METHODS: This single-center, randomized, four-group, parallel, controlled study was performed at Renmin Hospital of Wuhan University. Between 1 July and 15 October 2020, 1076 patients were randomly allocated into four treatment groups: control 271, CADe 268, CAQ 269, and CADe plus CAQ (COMBO) 268. The primary outcome was ADR. RESULTS: The ADR in the control, CADe, CAQ, and COMBO groups was 14.76 % (95 % confidence interval [CI] 10.54 to 18.98), 21.27 % (95 %CI 16.37 to 26.17), 24.54 % (95 %CI 19.39 to 29.68), and 30.60 % (95 %CI 25.08 to 36.11), respectively. The ADR was higher in the COMBO group compared with the CADe group (21.27 % vs. 30.6 %, P = 0.024, odds ratio [OR] 1.284, 95 %CI 1.033 to 1.596) but not compared with the CAQ group (24.54 % vs. 30.6 %, P = 0.213, OR 1.309, 95 %CI 0.857 to 2.000, respectively). CONCLUSIONS: CAQ significantly improved the efficacy of CADe in a four-group, parallel, controlled study. No significant difference in the ADR or polyp detection rate was found between CAQ and COMBO.

A deep learning-based system for real-time image reporting during esophagogastroduodenoscopy: a multicenter study.

BACKGROUND AND STUDY AIMS: Endoscopic reports are essential for the diagnosis and follow-up of gastrointestinal diseases. This study aimed to construct an intelligent system for automatic photo documentation during esophagogastroduodenoscopy (EGD) and test its utility in clinical practice. PATIENTS AND METHODS: Seven convolutional neural networks trained and tested using 210,198 images were integrated to construct the endoscopic automatic image reporting system (EAIRS). We tested its performance through man-machine comparison at three levels: internal, external, and prospective test. Between May 2021 and June 2021, patients undergoing EGD at Renmin Hospital of Wuhan University were recruited. The primary outcomes were accuracy for capturing anatomical landmarks, completeness for capturing anatomical landmarks, and detected lesions. RESULTS: The EAIRS outperformed endoscopists in retrospective internal and external test. A total of 161 consecutive patients were enrolled in the prospective test. The EAIRS achieved an accuracy of 95.2% in capturing anatomical landmarks in the prospective test. It also achieved higher completeness on capturing anatomical landmarks compared with endoscopists: (93.1% vs. 88.8%), and was comparable to endoscopists on capturing detected lesions: (99.0% vs. 98.0%). CONCLUSIONS: The EAIRS can generate qualified image reports and could be a powerful tool for generating endoscopic reports in clinical practice.

Neuromodulation in drug-resistant epilepsy: A review of current knowledge.

Nearly 1% of the global population suffers from epilepsy. Drug-resistant epilepsy (DRE) affects one-third of epileptic patients who are unable to treat their condition with existing drugs. For the treatment of DRE, neuromodulation offers a lot of potential. The background, mechanism, indication, application, efficacy, and safety of each technique are briefly described in this narrative review, with an emphasis on three approved neuromodulation therapies: vagus nerve stimulation (VNS), deep brain stimulation of the anterior nucleus of the thalamus (ANT-DBS), and closed-loop responsive neurostimulation (RNS). Neuromodulatory approaches involving direct or induced electrical currents have been developed to lessen seizure frequency and duration in patients with DRE since the notion of electrical stimulation as a therapy for neurologic diseases originated in the early nineteenth century. Although few people have attained total seizure independence for more than 12 months using these treatments, more than half have benefitted from a 50% drop in seizure frequency over time. Although promising outcomes in adults and children with DRE have been achieved, challenges such as heterogeneity among epilepsy types and etiologies, optimization of stimulation parameters, a lack of biomarkers to predict response to neuromodulation therapies, high-level evidence to aid decision-making, and direct comparisons between neuromodulatory approaches remain. To solve these existing gaps, authorize new kinds of neuromodulation, and develop personalized closed-loop treatments, further research is needed. Finally, both invasive and non-invasive neuromodulation seems to be safe. Implantation-related adverse events for invasive stimulation primarily include infection and pain at the implant site. Intracranial hemorrhage is a frequent adverse event for DBS and RNS. Other stimulation-specific side-effects are mild with non-invasive stimulation.

Local field potentials in Parkinson's disease: A frequency-based review.

Deep brain stimulation (DBS) surgery offers a unique opportunity to record local field potentials (LFPs), the electrophysiological population activity of neurons surrounding the depth electrode in the target area. With direct access to the subcortical activity, LFP research has provided valuable insight into disease mechanisms and cognitive processes and inspired the advent of adaptive DBS for Parkinson's disease (PD). A frequency-based framework is usually employed to interpret the implications of LFP signatures in LFP studies on PD. This approach standardizes the methodology, simplifies the interpretation of LFP patterns, and makes the results comparable across studies. Importantly, previous works have found that activity patterns do not represent disease-specific activity but rather symptom-specific or task-specific neuronal signatures that relate to the current motor, cognitive or emotional state of the patient and the underlying disease. In the present review, we aim to highlight distinguishing features of frequency-specific activities, mainly within the motor domain, recorded from DBS electrodes in patients with PD. Associations of the commonly reported frequency bands (delta, theta, alpha, beta, gamma, and high-frequency oscillations) to motor signs are discussed with respect to band-related phenomena such as individual tremor and high/low beta frequency activity, as well as dynamic transients of beta bursts. We provide an overview on how electrophysiology research in DBS patients has revealed and will continuously reveal new information about pathophysiology, symptoms, and behavior, e.g., when combining deep LFP and surface electrocorticography recordings.

PARP1 inhibition prevents oxidative stress in age-related hearing loss via PAR-Ca2+-AIF axis in cochlear strial marginal cells.

Studies have highlighted oxidative damage in the inner ear as a critical pathological basis for sensorineural hearing loss, especially the presbycusis. Poly(ADP-ribose) polymerase-1 (PARP1) activation responds to oxidative stress-induced DNA damage with pro-repair and pro-death effects resembling two sides of the same coin. PARP1-related cell death, known as parthanatos, whose underlying mechanisms are attractive research hotspots but remain to be clarified. In this study, we observed that aged rats showed stria vascularis degeneration and oxidative damage, and PARP1-dependent cell death was prominent in age-related cochlear disorganization and dysfunction. Based on oxidative stress model of primary cultured stria marginal cells (MCs), we revealed that upregulated PARP1 and PAR (Poly(ADP-ribose)) polymers are responsible for MCs oxidative death with high mitochondrial permeability transition pore (mPTP) opening and mitochondrial membrane potential (MMP) collapse, while inhibition of PARP1 ameliorated the adverse outcomes. Importantly, the PARylation of apoptosis-inducing factor (AIF) is essential for its conformational change and translocation, which subsequently causes DNA break and cell death. Concretely, the interaction of PAR and truncated AIF (tAIF) is the mainstream in the parthanatos pathway. We also found that the effects of AIF cleavage and release were achieved through calpain activity and mPTP opening, both of which could be regulated by PARP1 via mediation of mitochondria Ca2+ concentration. In conclusion, the PAR-Ca2+-tAIF signaling pathway in parthanatos contributes to the oxidative stress damage observed in MCs. Targeting PAR-Ca2+-tAIF might be a potential therapeutic strategy for the early intervention of presbycusis and other oxidative stress-associated sensorineural deafness.

Deep brain stimulation of the subthalamic nucleus for primary Meige syndrome: clinical outcomes and predictive factors.

OBJECTIVE: Deep brain stimulation (DBS) of the subthalamic nucleus (STN) has demonstrated efficacy against multiple types of dystonia, but only a few case reports and small-sample studies have investigated the clinical utility of STN-DBS for Meige syndrome, a rare but distressing form of craniofacial dystonia. Furthermore, the effects of DBS on critical neuropsychological sequelae, such as depression and anxiety, are rarely examined. In this study, the authors investigated the therapeutic efficacy of STN-DBS for both motor and psychiatric symptoms of Meige syndrome. METHODS: The authors retrospectively reviewed consecutive patients with Meige syndrome receiving bilateral STN-DBS at their institution from January 2016 to June 2023. Motor performance and nonmotor features including mood, cognitive function, and quality of life (QOL) were evaluated using standardized rating scales at baseline and at final postoperative follow-up. Clinical and demographic factors influencing postoperative motor outcome were evaluated by uni- and multivariable linear regression models. RESULTS: Fifty-one patients were ultimately included, with a mean ± SD follow-up duration of 27.3 ± 18.0 months. The mean Burke-Fahn-Marsden Dystonia Rating Scale (BFMDRS) movement score improved from 12.9 ± 5.2 before surgery to 5.3 ± 4.2 at the last follow-up (mean improvement 58.9%, p < 0.001) and the mean BFMDRS disability score improved from 5.6 ± 3.3 to 2.9 ± 2.9 (mean improvement 44.6%, p < 0.001). Hamilton Depression and Anxiety Rating Scale scores also improved by 35.3% and 34.2%, respectively, and the postoperative 36-item Short-Form Health Survey score indicated substantial QOL enhancement. Global cognition remained stable after treatment. Multiple linear regression analysis identified disease duration (ß = -0.241, p = 0.027), preoperative anxiety severity (ß = -0.386, p = 0.001), and volume of activated tissue within the dorsolateral (sensorimotor) STN (ß = 0.483, p < 0.001) as independent predictors of motor outcome. CONCLUSIONS: These findings support STN-DBS as an effective and promising therapy for both motor and nonmotor symptoms of Meige syndrome. Timely diagnosis, treatment of preoperative anxiety, and precise electrode placement within the dorsolateral STN are essential for optimal clinical outcome.

Spinal cord and brain atrophy patterns in neuromyelitis optica spectrum disorder and multiple sclerosis.

BACKGROUND: Spinal cord and brain atrophy are common in neuromyelitis optica spectrum disorder (NMOSD) and relapsing-remitting multiple sclerosis (RRMS) but harbor distinct patterns accounting for disability and cognitive impairment. METHODS: This study included 209 NMOSD and 304 RRMS patients and 436 healthy controls. Non-negative matrix factorization was used to parse differences in spinal cord and brain atrophy at subject level into distinct patterns based on structural MRI. The weights of patterns were obtained using a linear regression model and associated with Expanded Disability Status Scale (EDSS) and cognitive scores. Additionally, patients were divided into cognitive impairment (CI) and cognitive preservation (CP) groups. RESULTS: Three patterns were observed in NMOSD: (1) Spinal Cord-Deep Grey Matter (SC-DGM) pattern was associated with high EDSS scores and decline of visuospatial memory function; (2) Frontal-Temporal pattern was associated with decline of language learning function; and (3) Cerebellum-Brainstem pattern had no observed association. Patients with CI had higher weights of SC-DGM pattern than CP group. Three patterns were observed in RRMS: (1) DGM pattern was associated with high EDSS scores, decreased information processing speed, and decreased language learning and visuospatial memory functions; (2) Frontal-Temporal pattern was associated with overall cognitive decline; and (3) Occipital pattern had no observed association. Patients with CI trended to have higher weights of DGM and Frontal-Temporal patterns than CP group. CONCLUSION: This study estimated the heterogeneity of spinal cord and brain atrophy patterns in NMOSD and RRMS patients at individual level, and evaluated the clinical relevance of these patterns, which may contribute to stratifying participants for targeted therapy.

Advances in Understanding the Notch Signaling Pathway in the Cochlea.

The cochlear structure is highly complex and specific, and its development is regulated by multiple signaling pathways. Abnormalities in cochlear development can lead to different degrees of loss of function. Hair cells (HCs), which are difficult to regenerate in the mature mammalian cochlea, are susceptible to damage from noise and ototoxic drugs, and damage to HCs can cause hearing loss to varying degrees. Notch, a classical developmental signaling molecule, has been shown to be closely associated with embryonic cochlear development and plays an important role in HC regeneration in mammals, suggesting that the Notch signaling pathway may be a potential therapeutic target for cochlear development and hearing impairment due to HC damage. In recent years, the important role of the Notch signaling pathway in the cochlea has received increasing attention. In this paper, we review the role of Notch signaling in cochlear development and HC regeneration, with the aim of providing new research ideas for the prevention and treatment of related diseases.

Premature drug reduction after subthalamic nucleus deep brain stimulation leading to worse depression in patients with Parkinson's disease.

Background: Reduction of medication in Parkinson's disease (PD) following subthalamic nucleus deep brain stimulation (STN-DBS) has been recognized, but the optimal timing for medication adjustments remains unclear, posing challenges in postoperative patient management. Objective: This study aimed to provide evidence for the timing of medication reduction post-DBS using propensity score matching (PSM). Methods: In this study, initial programming and observation sessions were conducted over 1 week for patients 4-6 weeks postoperatively. Patients were subsequently categorized into medication reduction or non-reduction groups based on their dyskinesia evaluation using the 4.2-item score from the MDS-UPDRS-IV. PSM was employed to maintain baseline comparability. Short-term motor and neuropsychiatric symptom assessments for both groups were conducted 3-6 months postoperatively. Results: A total of 123 PD patients were included. Baseline balance in motor and non-motor scores was achieved between the two groups based on PSM. Short-term efficacy revealed a significant reduction in depression scores within the non-reduction group compared to baseline (P < 0.001) and a significant reduction compared to the reduction group (P = 0.037). No significant differences were observed in UPDRS-III and HAMA scores between the two groups. Within-group analysis showed improvements in motor symptoms, depression, anxiety, and subdomains in the non-reduction group, while the reduction group exhibited improvements only in motor symptoms. Conclusion: This study provides evidence for the timing of medication reduction following DBS. Our findings suggest that early maintenance of medication stability is more favorable for improving neuropsychiatric symptoms.

Prefrontal association of subthalamic deep brain stimulation with rapid eye movement sleep behavior disorder in Parkinson's disease.

OBJECTIVE: Subthalamic nucleus (STN)-deep brain stimulation (DBS) in Parkinson's disease (PD) patients affects not just focused target areas but also diffuse brain networks. The effect of this network modulation on nonmotor DBS effects is not fully understood. By concentrating on the sleep domain, the authors comprehensively determined the influence of electrode location and related structural/functional connections on changes in probable rapid eye movement (REM) sleep behavior disorder (pRBD) symptoms after STN-DBS, which has been reported to ameliorate, deteriorate, or remain constant. METHODS: Preoperative and postoperative pRBD symptoms were documented in 60 PD patients. The volumes of tissue activated (VTAs) were assessed on the basis of individual electrode reconstructions and merged with normative connectome data to identify structural/functional connections associated with VTAs. The entire cohort was used to construct connection models that explained changes in pRBD symptoms, as well as to perform cross-validations. RESULTS: Structural/functional connectivity was associated with pRBD symptom changes during STN-DBS. Changes in pRBD symptoms were predicted using an ideal structural connection map. Prefrontal connection was related with improved pRBD symptoms, whereas sensorimotor connectivity was associated with deterioration. CONCLUSIONS: Recovery of pRBD symptoms was predicted on the basis of the fibers connecting the STN electrode to prefrontal regions. These findings implied that the placement of STN-DBS leads influences the fibers to prefrontal regions and may be used to enhance treatment of pRBD symptoms; however, further prospective studies are needed to validate these findings.

Subthalamic nucleus stimulation attenuates motor seizures via modulating the nigral orexin pathway.

Background: Focal motor seizures that originate in the motor region are a considerable challenge because of the high risk of permanent motor deficits after resection. Deep brain stimulation of the subthalamic nucleus (STN-DBS) is a potential treatment for motor epilepsy that may enhance the antiepileptic actions of the substantia nigra pars reticulata (SNr). Orexin and its receptors have a relationship with both STN-DBS and epilepsy. We aimed to investigate whether and how STN inputs to the SNr regulate seizures and the role of the orexin pathway in this process. Methods: A penicillin-induced motor epileptic model in adult male C57BL/6 J mice was established to evaluate the efficacy of STN-DBS in modulating seizure activities. Optogenetic and chemogenetic approaches were employed to regulate STN-SNr circuits. Selective orexin receptor type 1 and 2 antagonists were used to inhibit the orexin pathway. Results: First, we found that high-frequency ipsilateral or bilateral STN-DBS was effective in reducing seizure activity in the penicillin-induced motor epilepsy model. Second, inhibition of STN excitatory neurons and STN-SNr projections alleviates seizure activities, whereas their activation amplifies seizure activities. In addition, activation of the STN-SNr circuits also reversed the protective effect of STN-DBS on motor epilepsy. Finally, we observed that STN-DBS reduced the elevated expression of orexin and its receptors in the SNr during seizures and that using a combination of selective orexin receptor antagonists also reduced seizure activity. Conclusion: STN-DBS helps reduce motor seizure activity by inhibiting the STN-SNr circuit. Additionally, orexin receptor antagonists show potential in suppressing motor seizure activity and may be a promising therapeutic option in the future.

Profiling the low-beta characteristics of the subthalamic nucleus in early- and late-onset Parkinson's disease.

Objectives: Low-beta oscillation (13-20 Hz) has rarely been studied in patients with early-onset Parkinson's disease (EOPD, age of onset ≤50 years). We aimed to explore the characteristics of low-beta oscillation in the subthalamic nucleus (STN) of patients with EOPD and investigate the differences between EOPD and late-onset Parkinson's disease (LOPD). Methods: We enrolled 31 EOPD and 31 LOPD patients, who were matched using propensity score matching. Patients underwent bilateral STN deep brain stimulation (DBS). Local field potentials were recorded using intraoperative microelectrode recording. We analyzed the low-beta band parameters, including aperiodic/periodic components, beta burst, and phase-amplitude coupling. We compared low-beta band activity between EOPD and LOPD. Correlation analyses were performed between the low-beta parameters and clinical assessment results for each group. Results: We found that the EOPD group had lower aperiodic parameters, including offset (p = 0.010) and exponent (p = 0.047). Low-beta burst analysis showed that EOPD patients had significantly higher average burst amplitude (p = 0.016) and longer average burst duration (p = 0.011). Furthermore, EOPD had higher proportion of long burst (500-650 ms, p = 0.008), while LOPD had higher proportion of short burst (200-350 ms, p = 0.007). There was a significant difference in phase-amplitude coupling values between low-beta phase and fast high frequency oscillation (300-460 Hz) amplitude (p = 0.019). Conclusion: We found that low-beta activity in the STN of patients with EOPD had characteristics that varied when compared with LOPD, and provided electrophysiological evidence for different pathological mechanisms between the two types of PD. These differences need to be considered when applying adaptive DBS on patients of different ages.

Fronto-parieto-subthalamic activity decodes motor status in Parkinson's disease.

AIMS: Patients with Parkinson's disease (PD) have various motor difficulties, including standing up, gait initiation and freezing of gait. These abnormalities are associated with cortico-subthalamic dysfunction. We aimed to reveal the characteristics of cortico-subthalamic activity in PD patients during different motor statuses. METHODS: Potentials were recorded in the superior parietal lobule (SPL), the primary motor cortex (M1), premotor cortex (PMC), and the bilateral subthalamic nucleus (STN) in 18 freely walking patients while sitting, standing, walking, dual-task walking, and freezing in medication "off" (Moff) and "on" (Mon) states. Different motor status activities were compared in band power, and a machine learning classifier was used to differentiate the motor statuses. RESULTS: SPL beta power was specifically inhibited from standing to walking, and negatively correlated with walking speed; M1 beta power reflected the degree of rigidity and was reversed by medication; XGBoost algorithm classified the five motor statuses with acceptable accuracy (68.77% in Moff, 60.58% in Mon). SPL beta power ranked highest in feature importance in both Moff and Mon states. CONCLUSION: SPL beta power plays an essential role in walking status classification and could be a physiological biomarker for walking speed, which would aid the development of adaptive DBS.

Optimal subthalamic stimulation sites and related networks for freezing of gait in Parkinson's disease.

Freezing of gait is a common and debilitating symptom in Parkinson's disease. Although high-frequency subthalamic deep brain stimulation is an effective treatment for Parkinson's disease, post-operative freezing of gait severity has been reported to alleviate, deteriorate or remain constant. We conducted this study to explore the optimal stimulation sites and related connectivity networks for high-frequency subthalamic deep brain stimulation treating freezing of gait in Parkinson's disease. A total of 76 Parkinson's disease patients with freezing of gait who underwent bilateral high-frequency subthalamic stimulation were retrospectively included. The volumes of tissue activated were estimated based on individual electrode reconstruction. The optimal and sour stimulation sites were calculated at coordinate/voxel/mapping level and mapped to anatomical space based on patient-specific images and stimulation settings. The structural and functional predictive connectivity networks for the change of the post-operative Freezing of Gait-Questionnaire were also identified based on normative connectomes derived from the Parkinson's Progression Marker Initiative database. Leave-one-out cross-validation model validated the above results, and the model remained significant after including covariates. The dorsolateral two-thirds of the subthalamic nucleus was identified as the optimal stimulation site, while the ventrocentral portion of the right subthalamic nucleus and internal capsule surrounding the left central subthalamic nucleus were considered as the sour stimulation sites. Modulation of the fibre tracts connecting to the supplementary motor area, pre-supplementary motor area and pedunculopontine nucleus accounted for the alleviation of freezing of gait, whereas tracts connecting to medial and ventrolateral prefrontal cortices contributed to the deterioration of freezing of gait. The optimal/sour stimulation sites and structural/functional predictive connectivity networks for high-frequency subthalamic deep brain stimulation treating freezing of gait are identified and validated through sizable Parkinson's disease patients in this study. With the growing understanding of stimulation sites and related networks, individualized deep brain stimulation treatment with directional leads will become an optimal choice for Parkinson's disease patients with freezing of gait in the future.