Search Results (109)

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

Background and Objectives: Parkinson’s disease (PD) is a neurodegenerative disorder marked by bradykinesia, rigidity, and tremor. While deep brain stimulation (DBS) of the subthalamic nucleus (STN) and globus pallidus internus (GPi) effectively alleviates motor symptoms, the potential of targeting the substantia nigra pars reticulata (SNr) is less understood. This study investigates the effects of mid-term DBS of the SNr on motor function and neuroplasticity in a 6-hydroxydopamine (6-OHDA) rat model of PD. Methods: Adult male Sprague-Dawley rats (280–300 g) were divided into healthy control (n = 10), PD (n = 9), sham-DBS (n = 7), and SNr-DBS (n = 7) groups. Bilateral striatal 6-OHDA lesions induced PD. High-frequency (130 Hz, 60 µs) SNr-DBS was delivered for 14 days. Locomotor activity (open-field), gait (footprint method), and motor coordination (rotarod) were assessed. Tyrosine hydroxylase (TH) expression in the SN and c-Fos and BDNF expression in the cerebellum, prefrontal cortex (PFC), and ventrolateral thalamus were analyzed histologically. Results: SNr-DBS significantly improved ambulation and horizontal activity compared to the PD group (p < 0.05). Gait analysis showed significant improvements in forelimb/hindlimb stride length and stance width, while rotarod performance indicated enhanced motor coordination (p < 0.05). Histology revealed increased TH expression in the SN and elevated c-Fos and BDNF levels in the cerebellum, PFC, and thalamus in the SNr-DBS group vs. PD rats (p < 0.05). Conclusions: Mid-term SNr-DBS produced significant functional gains in motor activity and coordination in a 6-OHDA PD model, together with molecular evidence of dopaminergic enhancement and neuroplastic activation. These translational findings suggest that targeting the SNr may offer a clinically relevant alternative for patients with PD, particularly for those who may not optimally respond to conventional STN or GPi stimulation. Full article

Parkinson’s disease (PD) is characterized by asymmetric motor symptoms (MSs), which may influence non-motor symptoms (NMSs). This study investigated the relationship between NMSs and the neurometabolic profile of the substantia nigra (SN) and globus pallidus (GP) of patients with PD, examining how these associations vary according to MS asymmetry. Forty-three PD patients (20 with right-predominant motor symptoms—RPD, and 23 with left-predominant motor symptoms—LPD) and 20 healthy controls (HCs) underwent single-voxel proton magnetic resonance spectroscopy, along with comprehensive clinical assessments of MSs and NMSs. Compared with HCs, PD patients showed higher N-acetylaspartate (NAA) levels in the SN, lower myo-inositol (Ins) levels in both sides of the SN, and higher glutamate/glutamine (Glx) levels in the right GP. Choline (Cho) in the left GP was positively associated with cognitive performance. In LPD patients, compared with HCs, NAA levels were increased in the right SN, whereas Ins levels were reduced in both hemispheres. These patients reported higher anxiety and exhibited marked hemispheric asymmetry of SN NAA. In this group, higher NAA levels in the right SN were associated with fewer sleep disturbances, while Ins in the right GP was related to both cognitive function and NMS severity. RPD patients showed elevated Glx levels in the right GP compared with HCs, with no significant hemispheric differences in metabolite levels. Nevertheless, Cho in the right SN was positively associated with sleep disturbances. Overall, these findings suggest that motor asymmetry in PD influences the neurometabolic correlates of NMSs, revealing distinct metabolic-clinical profiles in RPD and LPD patients. Full article

Background: Deep brain stimulation (DBS) has traditionally followed diagnosis-driven, nucleus-centered targeting paradigms. Increasing evidence supports a circuit-based framework in which clinical outcomes depend on modulation of symptom-relevant networks rather than diagnostic labels alone. This approach is particularly relevant in mixed movement disorder phenotypes such as dystonic tremor, where the most disabling symptom may not align with the conventional surgical target. Methods: We report a clinically illustrative single case treated using a symptom-oriented, connectome-informed DBS strategy. Clinical phenotype, tremor severity, functional impairment, prior medical and botulinum toxin treatments, and longitudinal outcomes were systematically reviewed. DBS target selection prioritized the dominant, treatment-refractory symptom rather than the underlying dystonia diagnosis. Surgical planning incorporated high-resolution MRI with patient-specific thalamic segmentation using Brainlab Brain Elements^®, followed by postoperative lead localization and volume of tissue activated visualization with the SureTune™ platform. Results: A 54-year-old left-handed woman with long-standing cervical dystonia developed a severe, markedly asymmetric dystonic tremor predominantly affecting the left upper limb, resulting in profound functional disability. Instead of conventional bilateral globus pallidus internus DBS, unilateral right ventral intermediate nucleus (VIM) DBS was selected to engage tremor-related cerebellothalamic circuits. Rapid and marked improvement was observed, with tremor severity reduced to mild levels within 15 days after stimulation onset. At 6-month follow-up, overall tremor severity improved from 49 to 13 points on the Fahn–Tolosa–Marin Tremor Rating Scale, corresponding to a 73.5% reduction. This improvement was associated with restoration of legible handwriting, independent feeding and drinking, and recovery of bimanual fine motor function. Clinical benefit remained stable throughout follow-up, without stimulation-related adverse effects. Conclusions: This case illustrates the feasibility of a symptom-oriented, connectome-informed DBS strategy in selected patients with dystonic tremor. When symptom expression and network involvement are markedly asymmetric, selective unilateral modulation of the tremor-dominant circuit may achieve meaningful and durable functional improvement. Further studies are needed to assess the generalizability of this approach. Full article

Background: Gilles de la Tourette syndrome is a neurobehavioral disorder that typically begins in childhood, subsides during puberty, and may reappear in adolescence. Treatment is primarily conservative, involving psychological and pharmacological therapy. Patients who do not respond to conservative therapy may be treated with deep brain stimulation, although this remains an experimental treatment. Methods: In this two-case report we present the first two cases of patients with Gilles de la Tourette syndrome in Slovenia treated with deep brain stimulation of the anteromedial globus pallidus internus. Results: Over an 18-month follow-up period, we observed an improvement in both cases. In the first case, the Yale Global Tic Severity Scale score decreased from 71 (17 for motor tics, 14 for phonic tics, and 40 on the impairment scale) to 44 points (12 motor, 12 phonic, and 20 impairment). In the second case, the score decreased from 72 (16 motor, 16 phonic, and 40 impairment) to 38 points (8 motor, 10 phonic, and 20 impairment). Conclusions: Deep brain stimulation could be a promising treatment for this disorder. However, further research is needed to determine the most suitable patients and targets. Full article

Insomnia and depression are severe sequelae of COVID-19 and often occur simultaneously. Our study examined associations of insomnia and/or depression with cognitive impairments, white matter changes, and serum biomarkers. In total, 76 long COVID patients and 22 healthy controls were examined using neuropsychiatric (ISI, HADS, and HDRS) and cognitive (MoCA, Stroop, WMT, and TMT) tests, with their blood biomarkers (anti-SARS-CoV-2, BDNF, anti-S100, anti-MBP, and anti-PLP) investigated, and underwent MRI using macromolecular proton fraction (MPF) mapping to quantify myelination. The Insomnia (n = 14), Depression (n = 12), InsDep (comorbid insomnia–depression, n = 13), and PostCovid (long COVID without depression and insomnia, n = 32) groups were identified based on psychiatric/neurological diagnoses and neuropsychiatric assessment. Cognitive performance was most affected in the Insomnia group in the MoCA and CW Stroop tests. The Depression group underperformed in the TMT and W Stroop task; the InsDep group underperformed in the WMT. The Insomnia group showed the greatest demyelination, affecting commissural (CC and tapetum), projection (CR, IC, CST, cerebral peduncles, CP, and ML), and some association pathways (SLF, SFOF), as well as most juxtacortical regions, the thalamus, and the midbrain; these changes correlated with insomnia severity. The Depression and InsDep groups showed smaller but significant overall demyelination correlated with depression severity. The Depression group exhibited the highest MPF decrease in the globus pallidus, putamen, and external capsule, while the InsDep group demonstrated the highest demyelination of the association pathways IFOF, UF, and cingulum. The anti-PLP levels were the highest in the Insomnia group and correlated with both the persistence of insomnia/depression symptoms and demyelination. Demyelination in long COVID is associated with high levels of myelin-specific autoantibodies, but symptoms of insomnia and/or depression are associated with demyelination of a different set of brain structures. Full article

Background/Objectives: Subcortical local field potentials (LFPs) provide a valuable in vivo window into the neurophysiology of the dystonia network. These signals can be recorded through Deep Brain Stimulation (DBS) devices and combined with whole-head techniques such as magnetoencephalography (MEG) to study cortical–subcortical interactions. However, simultaneous LFP-MEG acquisition poses challenges, including interference from the DBS device and synchronization issues. We present preliminary data on the feasibility and signal quality of concurrent LFP and MEG recordings in dystonia patients. Methods: We assessed simultaneous MEG-LFP recordings in 11 patients with inherited or idiopathic dystonia who underwent bilateral DBS lead implantation in the Globus Pallidus Internus (GPi). Two synchronization strategies were tested: (1) the Tapping method, using an accelerometer placed on the DBS device, and (2) the Stimulation method, which generated detectable artifacts during sham stimulation. Results: Both methods successfully aligned MEG and LFP signals with a mean temporal delay of 91 ± 22 ms for the Tapping method and 288 ± 166 ms for the Stimulation method. Post-implantation signal-to-noise ratio analysis revealed slight degradation but no significant impact on MEG quality (gradiometers: −0.12 ± 1.85 dB; magnetometers: −0.47 ± 2.03 dB). Conclusions: Simultaneous MEG-LFP recordings in dystonic patients are feasible, yielding high-quality signals, and reliable synchronization. Temporal alignment improved with practice, suggesting a short learning curve. This method opens new opportunities to study cortical-subcortical dynamics and strengthens the potential of combining MEG-LFP approaches for investigating dystonia. Full article

Objective: The genetic causes of obesity are complex and include diabetes and obesity monogenic syndromes like autosomal recessive Bardet–Biedl syndrome (BBS). Other clinical manifestations of this syndrome include metabolic disorders, polydactyly, retinal dystrophy, and endocrine, urological, and neurological abnormalities. Moreover, isolated clinical manifestations have been described in carriers of heterozygous mutations in BBS genes. On the other hand, Fahr’s disease is characterized by the accumulation of calcium deposits in various areas within the brain, leading to neurodegeneration, and the course of the disease is variable. Case presentation: We present the case of a 21-year-old female with severe obesity, diagnosed at the age of six years. The patient also experienced hypertension, hyperlipidemia, insulin resistance, and polycystic ovarian syndrome. During an MRI examination, hyperintensity in the region of the dentate nuclei and hyperintensity in the globus pallidus were described. NGS (next-generation sequencing) results showed a heterozygous variant in the TMEM67 gene, which revealed the patient to be a carrier of BBS, and a homozygotic variant in the MYORG gene, leading to a Fahr’s disease diagnosis. However, due to an insufficient number of phenotypic criteria and only one causative variant in the TMEM67 gene, the diagnosis of BBS could not be established. Conclusions: Attempts to identify the cause of obesity can lead to unexpected results, which can be resolved through collaboration between clinicians of different specialties and the use of NGS molecular testing. The status of being a BBS carrier, which coexists with Fahr’s disease, may be a potential contributing factor to severe obesity and metabolic disorders in the patient. Full article

Background/Objectives: Deep brain stimulation (DBS) of the globus pallidus interna (GPi) is a safe and established therapy for management of refractory motor fluctuations and dyskinesia in Parkinson’s disease (PD). However, the relationship between stimulation site connectivity and improvement of axial gait symptoms remains poorly understood, particularly when stimulating in the GPi. This study investigated functional and structural connectivity patterns specifically associated with axial symptom outcomes following bilateral GPi-DBS, and, as a secondary exploratory analysis, examined whether Volumes of tissue activated (VTAs)-based connectivity related to overall UPDRS-III change. Methods: We retrospectively analyzed 19 PD patients who underwent bilateral GPi-DBS at the University of Florida (2002–2017). Unified Parkinson’s Disease Rating Scale (UPDRS-III) axial gait subscores were assessed at baseline and 36-month follow-up. VTAs were reconstructed using Lead-DBS and coregistered to Montreal Neurological Institute (MNI) space. Structural connectivity was evaluated with diffusion tractography, and functional connectivity was estimated using normative resting-state fMRI datasets. Correlations between VTA connectivity and clinical improvement were examined using Spearman correlation and voxelwise analyses. Results: Patients with axial improvement in motor scales demonstrated specific VTA connectivity to sensorimotor and supplementary motor networks, particularly lobule V and lobules I–IV of the cerebellum. These associations were specific to axial gait subscores. In contrast, worsening axial gait symptoms correlated with connectivity to cerebellar Crus II, cerebellum VIII, calcarine cortex, and thalamus (p < 0.05). Total UPDRS-III scores did not show a significant positive correlation with supplementary motor area or primary motor cortex connectivity; a non-significant trend was observed for VTA–M1 connectivity (R = 0.41, p = 0.078). Worsening total motor scores were associated with cerebellar Crus II and frontal–parietal networks. These findings suggest that distinct connectivity patterns underlie differential trajectories in axial and global motor outcomes following GPi-DBS. Conclusions: Distinct connectivity profiles might underlie axial gait symptom outcomes following GPi-DBS. Connectivity to motor and sensorimotor pathways supports improvement, whereas involvement of Crus II and occipital networks predicts worsening. Additional studies to confirm and expand on these findings are needed, but our results highlight the value of connectomic mapping for refining patient-specific targeting and developing future programming strategies. Full article

In less than 30 years, Deep Brain Stimulation (DBS) has evolved from an antiparkinsonian rescue intervention into a flexible neuromodulatory therapy with the potential for personalized, adaptive, and enhancement-focused interventions. In this review we collected evidence from seven areas: (i) modern eligibility criteria, and ways to practically improve on these, outside of ‘Core Assessment Program of Surgical Interventional Therapies in Parkinson’s Disease’ (CAPSIT-PD); (ii) cost-effectiveness, where long-horizon models now show positive incremental net monetary benefit for Parkinson’s disease, and rechargeable-devices lead the way in treatment-resistant depression and obsessive–compulsive disorder; (iii) anatomical targets, from canonical subthalamic nucleus (STN) / globus pallidus internus (GPi) sites, to new dual-node and cortical targets; (iv) mechanistic theories from informational lesions, antidromic cortical drive, and state-dependent network modulation made possible by optogenetics and computational modeling; (v) psychiatric and metabolic indications, and early successes in subcallosal and nucleus-accumbens stimulation for depression, obsessive–compulsive disorder (OCD), anorexia nervosa, and schizophrenia; (vi) procedure- and hardware-related safety, summarized through five reviews, showing that the risks were around 4% for infection, 4–5% for revision surgery, 3% for lead malposition or fracture, and 2% for intracranial hemorrhage; and (vii) future directions in connectomics, closed-loop sensing, and explainable machine learning pipelines, which may change patient selection, programming, and long-term stewardship. Overall, the DBS is entering a “third wave” focused on a better understanding of neural circuits, the integration of AI-based adaptive technologies, and an emphasis on cost-effectiveness, in order to extend the benefits of DBS beyond the treatment of movement disorders, while remaining sustainable for healthcare systems. Full article

Deep brain stimulation (DBS) is an established neurosurgical treatment for Parkinson’s disease (PD), mainly targeting motor symptoms resistant to pharmacological therapy. This review examines strategies to optimize DBS using advanced anatomical, functional, and imaging approaches. The subthalamic nucleus (STN) remains the principal target for alleviating bradykinesia and rigidity, while recent evidence highlights the dentato-rubro-thalamic tract (DRTt) as an additional promising target, especially for tremor control. Clinical data demonstrate that co-stimulation of both STN and DRTt via electrode electric fields results in superior motor outcomes, including greater reductions in UPDRS-III scores and lower levodopa requirements. The review highlights the use of high-resolution MRI and diffusion tensor imaging tractography in visualizing STN and DRTt with high precision. These methods support accurate targeting and individualized treatment planning. Electric field modelling is discussed as a tool to quantify stimulation overlap with target structures and predict clinical efficacy. Anatomical variability in DRTt positioning relative to the STN is emphasized, supporting the need for patient-specific DBS approaches. Alternative and emerging DBS targets—including the pedunculopontine nucleus, zona incerta, globus pallidus internus, and nucleus basalis of Meynert—are discussed for their potential in treating axial and cognitive symptoms. The review concludes with a forward-looking discussion on network-based DBS paradigms, the integration of adaptive stimulation technologies, and the potential of multimodal imaging and electrophysiological biomarkers to guide therapy. Together, these advances support a paradigm shift from focal to network-based neuromodulation in PD management. Full article

Metals are essential for the physiological and biochemical processes in the human brain. However, their accumulation can cause neurotoxic effects, including the generation of reactive oxygen species and structural changes in biomolecules. This study aimed to assess the presence and distribution of metals in the human globus pallidus internus using Particle-Induced X-ray Emission (PIXE) and Scanning Electron Microscopy with Energy-Dispersive X-ray (SEM-EDX). Post-mortem brain tissue samples from six individuals without clinical neuropathological findings were analysed. PIXE analysis revealed the presence of Fe, Cr, Al, Zn, Pb, and Ca. SEM-EDX analysis provided the qualitative elemental composition of an observed aggregate, revealing C, N, O, Na, Ca, Al, Si, S, K, Mg, Cl, Fe, Ni, and Cr. Our findings suggest that metal accumulation in the brain can result from environmental pollution and protein aggregation, as well as biomineralisation processes that sequester metal ions to mitigate their harmful effects. A deeper understanding of these accumulation pathways could contribute to improved therapeutic strategies for neurological diseases associated with metal toxicity. Full article

Background/Objectives: The most prevalent form of neurodegeneration with brain iron accumulation (NBIA) is pantothenate kinase-associated neurodegeneration (PKAN), caused by mutations in the PANK2 gene. The hallmark of PKAN is the “eye-of-the-tiger” sign, which is characterized by a bilateral region of central hyperintense signal surrounded by a hypointense signal in the medial globus pallidus on T2-weighted brain magnetic resonance imaging (MRI). Methods: Whole-exome sequencing (WES) was performed in four patients who presented with dystonia, cognitive impairment and abnormalities of the globus pallidus. All patients underwent comprehensive clinical and instrumental evaluations. Results: Molecular analysis using WES revealed PANK2 variants in all four cases. Two patients were homozygous for the known pathogenic variant c.1169A > T (p.N390I). The remaining two patients displayed compound heterozygotes, each carrying the novel splicing variant c.906-1G > A on one allele, combined with a different second variant on the other allele: the new missense variant c.617G > A (p.G206D) in one case and the known pathogenic variant c.1231G > A (p.G411R) in the other. In one case, brain imaging documented the transition from initial hyperintensity of the globus pallidus to the development of the “eye-of-the-tiger” sign. In two cases, MRI findings clearly demonstrated the characteristic “eye-of-the-tiger” appearance. Ultimately, in one case, the imaging likely captured a later disease stage, in which the “eye-of-the-tiger” sign was no longer visible, and only the residual hypointensity remained. Conclusions: This study describes two novel likely pathogenic variants and documents the full MRI progression of globus pallidus involvement in PKAN. The sequence starts with early T2 hyperintensity, followed by the emergence of the typical “eye-of-the-tiger” sign, and culminates in marked hypointensity in advanced stages. Since the initial clinical presentation may mimic mitochondrial disorders or other neurometabolic conditions, these imaging features are crucial for guiding differential diagnosis and enabling accurate disease identification. Full article

Dystonia-myoclonus syndrome is a rare neurological condition characterized by involuntary muscle contractions and myoclonic jerks, significantly impairing daily functioning. Pharmacological management is often ineffective, prompting consideration of alternative therapeutic interventions such as deep brain stimulation (DBS). This report describes a novel clinical case involving a 38-year-old female with severe dystonic and myoclonic symptoms associated with a pathogenic mutation in the KCNN2 gene (DYT34). Bilateral DBS targeting the internal segment of the globus pallidus (GPi) resulted in marked and sustained symptom improvement, notably reducing dystonic posturing and myoclonic movements over the 24-month follow-up period. Neuropsychological and neurologopedic assessments revealed no adverse effects on cognition or speech. This represents the first sufficient effect of GPi-DBS in a patient with a genetically confirmed KCNN2 mutation, highlighting its potential efficacy and underscoring the need for genetic testing in patients presenting with dystonia-myoclonus syndromes. Full article

Background: Dystonic cerebral palsy (DCP) is a complex, disabling manifestation of secondary dystonia, which significantly impacts motor function, quality of life, and well-being. Conventional pharmacologic therapies frequently do not relieve symptoms sufficiently. Deep brain stimulation (DBS) of the globus pallidus internal segment (GPi) has gained increasing attention as a neuromodulatory therapy for refractory dystonia. Still, the experience of the effect of GPi DBS treatment in adults with DCP has, until recently, been limited. Methods: We performed a retrospective, two-center case series of 11 adult patients with medically refractory DCP who underwent bilateral GPi-DBS. The clinical outcomes were evaluated based on the Burke–Fahn–Marsden Dystonia Rating Scale (BFMDRS), the Functional Independence Measure (FIM), the Gross Motor Function Classification System (GMFCS), and the Caregiver Burden Scale (CBS). The assessments were done preoperatively and at 1-year follow-up. Changes in continuous variables were analyzed using paired t-tests. Results: At the 1-year follow-up, the mean BFMDRS score improved from 69.6 ± 27.6 to 54.3 ± 36.5 (p = 0.001), indicating a significant reduction in overall dystonia severity. Functional independence also improved, demonstrated by the rise in FIM scores from 65.3 ± 33.9 to 79.2 ± 43.4 (p = 0.006). Although GMFCS levels did not change in most patients (p = 0.125), the burden on caregivers decreased significantly, with CBS scores falling from 35.7 ± 18.8 to 32.0 ± 17.1 (p = 0.015). There were no surgical complications. Conclusions: In adults, bilateral GPi-DBS is a safe and effective intervention for DCP, improving motor control and increasing functional independence while decreasing caregiver burden. These findings lend support to its role in the multidisciplinary management of DCP. Full article