Search Results (486)

Mastication is a fundamental rhythmic motor behavior controlled by a brainstem central pattern generator (CPG) located within the pontine and medullary reticular formations. Coordinated activation of jaw-opening and jaw-closing muscles is generated by this network and continuously refined through sensory feedback from periodontal mechanoreceptors and muscle spindles, together with descending inputs from the cortical masticatory area (CMA), basal ganglia, and cerebellum. Thus, mastication is regulated by distributed neural circuits rather than a single central locus. At the cellular level, the rhythmic activity of the masticatory CPG depends on the coordinated action of voltage-gated and ligand-gated ion channels. Recent electrophysiological and computational studies have identified candidate conductances that are proposed to underlie rhythm generation. Persistent sodium currents are proposed to facilitate burst initiation, whereas T-type calcium channels are thought to promote burst activation through post-inhibitory rebound. HCN channels may contribute to rhythmic timing, while calcium-activated potassium channels are thought to participate in burst termination. This review summarizes the hierarchical neural control of mastication and the biophysical mechanisms by which ion channels shape CPG rhythmogenesis. It also discusses the impact of channelopathies and neurodegenerative disorders on masticatory function, highlighting potential ion-channel-targeted therapeutic approaches for temporomandibular disorders, bruxism, and impaired mastication. Full article

Neurodegeneration with brain iron accumulation (NBIA) comprises a group of rare genetic movement disorders characterized by progressive neurological deterioration, dystonia, parkinsonism, spasticity, and abnormal iron deposition in the basal ganglia. Although iron accumulation is the shared neuroradiological hallmark, most NBIA genes do not directly regulate iron metabolism. Instead, major NBIA forms arise from disruption of distinct but converging cellular pathways, including coenzyme A (CoA) biosynthesis, lipid metabolism, mitochondrial function, and autophagy. This narrative review aims to examine the pathogenic mechanisms of major NBIA disorders, namely pantothenate kinase-associated neurodegeneration (PKAN), COASY protein-associated neurodegeneration (CoPAN), PLA2G6-associated neurodegeneration (PLAN), mitochondrial membrane protein-associated neurodegeneration (MPAN), and beta-propeller protein-associated neurodegeneration (BPAN), and how these insights are guiding therapeutic development. Preclinical strategies aimed at restoring CoA metabolism, improving mitochondrial function, limiting lipid peroxidation, modulating autophagy, or correcting the underlying genetic defect have shown encouraging results, although none have yet reached robust clinical validation. Clinical translation remains limited by disease rarity, clinical heterogeneity, absence of validated biomarkers, and preclinical models that only partially recapitulate human pathology. Advancing the field will depend on earlier molecular diagnosis, biomarkers capable of tracking disease stage, and trial designs suited to ultra-rare populations. NBIA thus offers a paradigm for how mechanistic classification of a genetically defined disease group can redirect therapeutic strategy away from a shared radiological feature and toward pathway-specific intervention. Full article

Huntington disease (HD) is a debilitating, genetic disorder with a prevalence of 2.7 per 100,000 people. It is neurodegenerative, leading to cognitive, behavioral, and motor symptoms from neuronal loss within the striatum of the basal ganglia and cortex. Currently, the treatments involve symptomatic management, instead of treating the pathophysiology of the disease. Grape seed extract (GSE) is a complex mixture of polyphenols, proteins, and lipids with antioxidant and anti-inflammatory properties. This literature review examines the possibility of using GSE as a potential adjunctive therapy for HD. Preclinical studies have shown a neuroprotective effect through biologically plausible mechanisms. Clinical research has shown that GSE works on redox and inflammatory pathways related to the pathogenesis of HD. Although there are not many clinical trials on GSE in HD patients directly, the overlap of mechanisms behind both GSE and HD and the favorable side effect profile make GSE a potential adjunctive therapy. Targeted clinical investigation is warranted to determine the full therapeutic potential of GSE. Full article

Background/Objectives: Pediatric acute-onset neuropsychiatric syndrome (PANS) describes the rapid onset of obsessive–compulsive symptoms or severe food restriction, accompanied by neuropsychiatric or somatic features that are not better explained by another disorder. PANDAS (Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal infections) is a related, more narrowly defined construct in which symptoms are temporally associated with group A Streptococcus infection. This review examines clinical symptoms, infectious associations, proposed immune mechanisms, biomarker limitations, and treatment strategies for infection-associated PANS/PANDAS. Methods: A structured narrative search of PubMed/MEDLINE, Embase, the Cochrane Library, Google Scholar/publisher-indexed literature, ClinicalTrials.gov, and reference lists was performed up to 16 June 2026. Original cohorts, case series, systematic reviews, narrative reviews, consensus guidance, mechanistic studies, and registered prospective studies were prioritized. The review was not designed as a PRISMA-ScR scoping review; however, the methods were expanded to improve transparency and align with SANRA principles. Results: Group A Streptococcus remains the best characterized infectious association, although prospective studies have not uniformly demonstrated a consistent temporal relationship between streptococcal infection and neuropsychiatric exacerbations. Parent-reported surveys and case-based literature also describe temporal associations with Mycoplasma pneumoniae, influenza-like illnesses, upper respiratory infections, Borrelia burgdorferi, Epstein–Barr virus, and SARS-CoV-2. Proposed mechanisms include molecular mimicry, anti-D1R and anti-D2R antibodies, other antineuronal antibodies, calcium/calmodulin-dependent protein kinase II signaling, blood–brain barrier vulnerability, cytokine and Th17 effects, neuroinflammatory amplification, basal ganglia/CSTC circuit dysfunction, and gut–oral–brain immune interactions. None currently provides a definitive diagnostic biomarker. Conclusions: Infection-associated PANS is best approached as a clinically defined, heterogeneous neuroimmune presentation that requires rigorous differential diagnosis, multidisciplinary care, cautious treatment escalation, prospective biomarker validation, and large, multicenter treatment trials. Full article

Background/Aim: Motor skill acquisition is the foundation of athletic performance, from the novice learning a new technique to the elite athlete executing complex movements automatically under pressure. Although classical models have defined the neural substrates of motor control—the cerebellum for error correction, the basal ganglia for action selection, and the primary motor cortex (M1) for execution—emerging evidence suggests that motor learning is the result of the dynamic interaction of multiple parallel processes rather than a linear hierarchy. This narrative review integrates classical neuroanatomical knowledge with contemporary findings on multisite plasticity, with a particular focus on sport-specific adaptations. Methods: We examined three core learning mechanisms operating in parallel: error-based learning (cerebellar-dependent, driven by sensory prediction errors), reinforcement learning (striatal-dependent, driven by reward prediction errors and dopamine), and use-dependent learning (cortical-dependent, driven by mere repetition). We also summarize the biochemical pathways supporting these learning processes, including glutamatergic LTP-like cortical plasticity, cerebellar mGluR1–PKC–LTD signaling, dopaminergic corticostriatal plasticity, BDNF–TrkB-dependent neurotrophic mechanisms, growth-factor signaling, and exercise-induced muscle–brain communication. Results: We then propose a spatiotemporal model in which the relative contribution of each network shifts dynamically across the three stages of skill acquisition, from the early cognitive/strategic phase to the late automatic phase characteristic of elite performance. At the molecular level, these stage-dependent adaptations are supported by synaptic strengthening and weakening mechanisms, reward-dependent dopamine signaling, neurotrophic and growth-factor-mediated remodeling, and peripheral metabolic/myokine signals that modulate brain plasticity during training and recovery. Special attention is given to contextual and sport-specific adaptations, using the paradigmatic example of elite swimmers who demonstrate enhanced short-interval intracortical inhibition (SICI) selectively in the aquatic environment, reflecting long-term sport-induced neuroplasticity. Conclusions: Understanding these dynamic network mechanisms has direct implications for coaching, training periodization, and the development of targeted neuromodulatory interventions to accelerate skill acquisition and optimize athletic performance. Full article

Background: Acute carbon monoxide (CO) poisoning can cause delayed neuropsychiatric sequelae (DNS) after a latent period, yet its pathophysiology remains poorly understood because of the lack of reproducible experimental models. Methods: We established a rat model of DNS using acute CO poisoning (6500 ppm for 25 min). Behavioral assessments evaluated cognition, locomotion, sensorimotor function, exploratory behavior, and reward responsiveness. Histopathological analyses assessed brain injury, and regional monoamine concentrations were quantified using high-performance liquid chromatography. Results: CO-exposed rats developed delayed and progressive behavioral abnormalities, including impaired spatial working memory, reduced locomotor activity, sensorimotor dysfunction, and diminished exploratory behavior. At 4 weeks, CO-exposed rats showed reduced Y-maze alternation (49.3% vs. 72.2%, p < 0.0001), complete loss of tape-removal success (0% vs. 100%, p < 0.001), reduced digging behavior (10.1 ± 6.9 vs. 27.4 ± 3.9, p < 0.01), and decreased locomotor activity (330.5 ± 172.1 vs. 730.5 ± 139.5 cm, p < 0.01). In contrast, olfactory discrimination, sucrose preference, and grip strength were preserved. Histopathology demonstrated persistent neuronal and inflammatory alterations. Dopamine concentrations were significantly reduced in the cortex and basal ganglia, whereas thalamic serotonin levels were increased following CO poisoning. Conclusion: Acute CO poisoning induces a reproducible DNS characterized by progressive behavioral impairment, persistent histopathological abnormalities, and regional monoaminergic dysregulation. These findings support the concept that DNS is an evolving neuropathological process and identify dopaminergic pathways as potential therapeutic targets. Full article

Background: Basal ganglia calcifications (BGCs) are frequently detected on brain CT scans in older adults, but their clinical relevance for mobility and fall risk is unclear. This study investigated the association of BGCs with impaired mobility and recurrent falls. Methods: In this cross-sectional study, all consecutive patients referred to the mobility clinic of a regional teaching hospital between 2019 and 2021 were included. Mobility was assessed using the Performance-Oriented Mobility Assessment (POMA) for balance, gait and overall mobility, and the Timed Up and Go (TUG) test for functional mobility. All assessments were performed by a trained physiotherapist. Recurrent falls were defined as self-reported occurrence of more than one fall in the past 12 months. Brain CT scans were evaluated for BGCs by a trained senior radiologist and were scored by severity. Univariable and multivariable logistic regression analyses were performed, adjusting for age, sex, and history of cardiovascular events. Results: A total of 253 participants were included (median age 82 years; 58% female), of whom 31% had BGCs. Falls data were available for 246 participants, and 70% reported recurrent falls. In both univariable and multivariable analyses, there was no evidence of a statistically significant association between the presence of BGCs and impaired balance, gait, overall mobility, functional mobility, or recurrent falls. Conclusions: No evidence of a statistically significant association was found between incidentally detected BGCs and impaired mobility or recurrent falls in older adults. Further longitudinal research is needed to confirm these findings and clarify whether BGCs are clinically relevant for mobility and fall risk assessment. Full article

Background/Objectives: Atrial fibrillation (AF) is the most common supraventricular arrhythmia and one of the most commonly encountered heart conditions in clinical practice. Emerging evidence suggests a significant role of inflammation, endothelial disfunction and extracellular matrix (ECM) remodeling in the pathogenesis of AF. Population studies have also suggested an association between AF and cerebral small vessel disease (CSVD), with growing evidence indicating that the burden of certain markers of CSVD is greater in women. However, the association between female sex and CSVD remains poorly understood. The aim of this study was thus to investigate the role of female sex in the association between circulating biomarkers and the presence of CSVD in AF patients undergoing oral anticoagulant therapy. Methods: The Strat-AF study is an observational, prospective, single-center, hospital-based study enrolling elderly patients with AF. Results refer to 170 patients (59 women and 111 men). Recruited patients are evaluated by means of a comprehensive protocol, with clinical, cerebral magnetic resonance imaging (MRI) and circulating biomarker assessments. Results: From a multivariate logistic regression analysis adjusted for multiple confounders, independent predictors were: in women, elevated vWF levels for the presence of lacunar infarcts [OR 3.24 (1.23–8.55), p = 0.018], elevated MMP-12, TIMP-1, TIMP-2, and TIMP-4 levels for the presence of CMBs [OR 7.76 (1.60–37.69), p = 0.021; OR 1.90 (1.02–3.52), p = 0.042; OR 2.46 (1.27–4.80), p = 0.008; and OR 2.36 (1.12–4.95), p = 0.023, respectively], elevated IL-6 and MMP-2 levels for the presence of WMH [OR 10.65 (1.31–86.67), p = 0.027; OR 3.36 (1.23–9.15), p = 0.018, respectively] and elevated MMP-12 and TIMP-2 levels for the presence of bgEPVS [OR 2.57 (1.22–5.93), p = 0.027; OR 2.15 (1.03–4.53), p = 0.043, respectively]; and in men: elevated TIMP-1 levels for the presence of WMH [OR 2.10 (1.08–4.08), p = 0.030], elevated TIMP-1 levels for the presence of bgEPVS [OR 2.20 (1.11–4.38), p = 0.025] and elevated TIMP-1 levels for SVDs positivity [OR 7.25 (2.18–24.15), p = 0.001]. Conclusions: These results from the Strat-AF study demonstrated that a complete biohumoral and instrumental assessment can jointly identify female patients with AF at higher risk of CSVD. These findings pave the way for the implementation of clinical protocols incorporating brain MRI and circulating biomarkers as potential innovative tools for an increasingly refined—and sex-specific—stratification of cardiovascular risk in AF patients undergoing oral anticoagulant therapy. Full article

Introduction: Progressive supranuclear palsy (PSP) is an atypical Parkinsonian disorder characterized by a range of clinical phenotypes, reflecting its multiple subtypes. As a result, accurate diagnosis during life remains challenging, underscoring the need for reliable biomarkers. The present narrative review aims to evaluate whether dopamine transporter single-photon emission computed tomography (DaT-SPECT) can serve as a biomarker in the assessment of PSP. Methods: The database search identified 31 original research articles relevant to our study objective. Of these, 17 studies included PSP patients and utilized DaT-SPECT as the sole molecular imaging modality; 9 studies combined DaT-SPECT with at least one additional molecular imaging technique; and 5 studies integrated DaT-SPECT with a laboratory-based biomarker of neurodegenerative disease. Results: DaT-SPECT appears to demonstrate low specificity and variable sensitivity for PSP across studies. Discussion: Combining DaT-SPECT with other diagnostic biomarkers, especially brain magnetic resonance imaging and other nuclear imaging modalities, may improve diagnostic accuracy, especially given its relatively low specificity for PSP. Nevertheless, these initially promising findings need to be validated in large, multicenter studies that include and clearly define multiple, autopsy-confirmed PSP subtypes. Full article

Background: Parkinson’s Disease (PD) is a multisystem neurodegenerative disorder associated with cognitive and emotional disturbances, including visuospatial deficits and alexithymia, which may substantially affect quality of life (QoL). The metabolic underpinnings of non-motor and emotional features within deep basal ganglia nuclei remain poorly understood. This exploratory proof-of-concept study aimed to examine ¹H-MRS-derived metabolite ratios in the substantia nigra (SN) and globus pallidus (GP) and to explore their preliminary associations with visuospatial-attentional abilities and alexithymia. Methods: Fifteen individuals with PD and 15 healthy controls (HCs) underwent Proton Magnetic Resonance Spectroscopy (¹H-MRS) targeting the SN and GP bilaterally. Metabolite ratios were quantified with LCModel and analyzed as left, right, and hemisphere-averaged measures. PD participants completed a multidisciplinary assessment including motor severity, cognition, visuospatial abilities, mood and alexithymia. Multiple testing was controlled using false discovery rate (FDR). Given the between-group imbalance in age and education, exploratory covariate-adjusted sensitivity analyses were also performed. Results: PD participants were older, less educated, and showed lower global cognition than HCs, including significantly reduced MoCA scores (20.9 ± 6.6 vs. 28.7 ± 1.8; FDR-corrected p < 0.001). In uncorrected analyses, between-group metabolite comparisons showed lower myo-inositol (Ins) in the SN (p = 0.04) and higher glutamatergic signal in the right GP in PD relative to HCs (p = 0.03); however, these differences were not robust after adjustment for age, education and multiple testing. Within the PD group, an uncorrected right–left asymmetry was observed for pallidal Ins. Exploratory correlations suggested uncorrected associations between SN metabolites and alexithymia dimensions related to emotional awareness and verbalization, whereas GP metabolites were more frequently associated with selected visuospatial, attentional, language-related, and broader cognitive measures. None of these associations survived FDR correction. Conclusions: This exploratory proof-of-concept study provides preliminary feasibility data and effect-size estimates for future ¹H-MRS investigations of basal ganglia metabolites in PD. Given the small sample size, lack of cognitive matching, age and education imbalance, and absence of correction-surviving associations, the findings should not be interpreted as evidence of PD-specific neurometabolic markers. Larger, prospectively matched, and adequately powered studies are needed. Full article

Parkinson’s disease (PD) is the second most prevalent neurodegenerative disorder worldwide, and its early diagnosis remains a major challenge due to reliance on subjective clinical assessments. This study proposes a bio-inspired computational framework for automatic PD detection that draws explicit architectural inspiration from two biological systems: the hierarchical tonotopic organization of the human auditory cortex, which motivates the design of a 1D Convolutional Neural Network (CNN) for vocal biomarker analysis, and the basal ganglia–cerebellar motor control circuit, which motivates the selection and design of features extracted from Archimedean spiral drawing tasks. Unlike previous studies that apply standard machine learning techniques without grounding architectural choices in biological mechanisms, the proposed framework establishes a direct mapping between neural processing pathways and model design decisions. A Support Vector Machine (SVM) classifier evaluated on the Kaggle vocal dataset achieved 87% test accuracy with no overfitting, outperforming AdaBoost, Random Forest, KNN, XGBoost, and Decision Trees in terms of generalization. The 1D CNN applied to UCI spiral drawing data achieved 85% test accuracy, with overfitting behavior addressed through architectural regularization strategies including early stopping. A conceptual multimodal fusion architecture integrating both modalities is proposed as a direction for future experimental validation; it was not implemented or experimentally validated within the present study. The primary novelty of the framework resides in this explicit biomimetic grounding, which distinguishes it from existing performance-driven approaches. Results confirm that biologically grounded computational models constitute promising objective decision-support tools for early PD diagnosis. Full article

The hypothesis that Group A beta-haemolytic Streptococcus (GAS) triggers an autoimmune cascade targeting basal ganglia dopaminergic circuits—producing obsessive–compulsive disorder (OCD), tic disorders, or chorea depending on the receptor subtype involved—is biologically compelling and supported by emerging molecular evidence. Yet PANDAS has remained a diagnostic conundrum since its original description in 1998, with ongoing uncertainty surrounding diagnostic criteria, the interpretation of streptococcal serology, and the distinction from primary neurodevelopmental disorders. This study aimed to review the diagnostic challenges of PANDAS, with focus on streptococcal serology interpretation, advances in dopamine receptor autoantibody biology, the genetic epidemiology of primary tic disorders, and the differential diagnosis of acute neuropsychiatric presentations in children. A structured narrative review was conducted using PubMed, MEDLINE, EMBASE, and the Cochrane Library for publications from 1998 to early 2025 addressing PANDAS, PANS, streptococcal antibodies, childhood movement disorders, autoimmune encephalitis, and the genetics of tic disorders. No currently available biomarker—including ASO, anti-DNase B, anti-basal-ganglia antibodies, or the Cunningham Panel—has demonstrated adequate individual-level diagnostic accuracy for PANDAS. Emerging molecular evidence identifies anti-D1R autoantibodies, acting via G protein-and beta-arrestin-mediated signalling, as candidate biomarkers for PANDAS/PANS neuropsychiatric phenotypes, and anti-D2R autoantibodies for Sydenham chorea movement phenotypes; independent replication in unselected populations is required. Primary tic disorders carry heritability estimates of 50–80% and first-degree familial risk ratios of approximately 18-fold in large population-based cohorts. Prospective blinded studies have not demonstrated a consistent population-level association between GAS infections and tic or OCD exacerbations: PANDAS and PANS remain diagnoses of exclusion. The high background prevalence of both GAS exposure and primary neurodevelopmental disorders in overlapping paediatric age ranges creates conditions for incidental temporal co-occurrence. In the absence of validated molecular biomarkers, diagnostic imprecision carries direct clinical consequences: children may be exposed to treatments with significant risk profiles—including IVIG, plasma exchange, and prolonged antibiotic prophylaxis—while evidence-based therapies are delayed. A stepwise diagnostic approach incorporating the full differential diagnosis is both an epistemological and a patient safety imperative. Full article

Parkinson’s disease (PD) is traditionally defined by dopaminergic loss in the substantia nigra, yet its heterogeneous phenotypes and prodromal trajectories challenge a linear, dopamine-centered model. The α-synuclein origin and connectome (SOC) model proposes two major trajectories: a brain-first pathway, with the pathology initiating in limbic and brainstem structures and spreading ipsilaterally to the nigrostriatal system, and a body-first pathway, with the pathology originating in enteric and peripheral autonomic nerves before ascending to the brain. In this review, we integrate the SOC model into a broader framework, reconceptualizing PD as a progressive disorder of spatial–temporal symmetry. Spatial symmetry encompasses left–right and cranio-caudal balance of neural and musculoskeletal systems, whereas temporal symmetry denotes the coherence of biological rhythms from circadian and autonomic cycles, coupled with metabolic health and mitochondrial function, to sub-second timing governed by dopaminergic and basal ganglia–cortical network dynamics. We outline how systemic insulin resistance and mitochondrial stress erode temporal symmetry, while cranio-cervical malalignment and temporomandibular disorders perturb spatial symmetry. We discuss the neurobiological implementation of these symmetry axes via large-scale networks and dopaminergic modulation of spatial–temporal sensorimotor dynamics, framing PD as a multiscale symmetry-breaking process, and explore the implications for symmetry-oriented biomarkers, subtyping, and future interventions. Full article

Background and Clinical Significance: CTC1-related cerebroretinal microangiopathy with calcifications and cysts (CRMCC), or Coats-plus syndrome, is an extremely rare autosomal recessive telomere-dysfunction disorder. A total of 29 cases in 15 reports have been reported in the English literature. The primary imaging characteristics include leukoencephalopathy, intracranial calcifications, and parenchymal cysts. Case Presentation: We describe a patient with CRMCC, who presented with a large intracranial cystic mass and basal ganglia calcifications, with imaging findings strongly mimicking a primary CNS tumor. The patient underwent multiple surgeries with inconclusive biopsies. Ultimately, it took five years and the collaboration of several specialists to arrive at the final diagnosis. Furthermore, we present dedicated clinical 7T orbit MRI findings on the patient’s brother, who has the same disease. Conclusions: We present a rare case of CRMCC with lack of overt leukoencephalopathy at presentation and absence of characteristic extracranial/extraocular manifestations, significantly complicating diagnosis. Furthermore, to the best of our knowledge, we share the first reported clinical 7T orbital MRI in the pediatric population. Full article

Background: Essential tremor (ET) is a clinically heterogeneous disorder involving motor and non-motor features. Voluntary movement abnormalities, including movement slowness (bradykinesia), have been frequently described in ET. Among non-motor symptoms, insomnia is also frequently reported, raising the possibility of shared underlying mechanisms with bradykinesia (e.g., brainstem noradrenergic dysfunction involving the locus coeruleus due to Lewy body pathology). We investigated the relationship between movement abnormalities, as objectively quantified using finger-tapping kinematic analysis, and sleep disturbances in ET. Methods: A subsample of 29 ET patients included in a previous study underwent kinematic analysis of finger-tapping. Insomnia was evaluated using the Insomnia Severity Index (ISI). Patients were stratified according to the presence of bradykinesia (e.g, movement slowness during finger-tapping) and insomnia (ISI ≥ 8). Group comparisons and correlational analyses were performed to assess the association between kinematic measures of bradykinesia, insomnia severity and other clinical features. Results: Fourteen subjects (48.3%) exhibited bradykinesia on kinematic analysis, and eleven patients (37.9%) met the criteria for insomnia. The prevalence of insomnia was similar between patients with and without bradykinesia. Likewise, no significant differences in finger-tapping kinematics were observed between ET patients with and without insomnia. Kinematic measures of bradykinesia did not correlate with ISI scores (all p > 0.05), whereas ISI scores were significantly positively correlated with clinical tremor severity. Conclusions: The current kinematic analysis suggests no relationship between movement abnormalities and sleep disturbances in ET. While bradykinesia in ET possibly relies on the dysfunction of cerebellar–basal ganglia circuits, insomnia in ET may reflect prominent brainstem dysfunction. Larger studies integrating kinematic assessments, neuroimaging, and longitudinal designs are needed to clarify the relationship between movement and sleep disturbances in ET Full article