We report the case of a 27-year-old man with a history of speech delay and chronic, progressive movement disorder. He first developed gait difficulty at the age of 12. Given clinical signs of bradykinesia and resting tremor, he received a clinical diagnosis of childhood-onset parkinsonism. Treatment with oral levodopa initially improved symptoms, but after 2 years, he developed motor fluctuations and dyskinesias. Additional signs of spasticity and brain MRI showing a thin corpus callosum prompted genetic testing that identified a heterozygous pathogenic variant in the PRKN gene. However, he exhibited a progressive loss of response to chronic dopaminergic therapy, first with oral and later with continuous levodopa-carbidopa intestinal gel infusion, with disease progression over 7 years. This progression led to further genetic testing and the diagnosis of hereditary spastic paraplegia type 15 (SPG 15). Advancing motor symptoms prompted deep brain stimulation and botulinum toxin injections, although these had limited benefit. This case highlights the challenges of diagnosing and managing juvenile-onset parkinsonism and the value of comprehensive genetic analysis in evaluating genotypic-phenotypic correlations. Hereditary spastic paraplegias (HSPs) are a rare group of neurodegenerative disorders with diverse clinical and genetic features. They can be inherited in autosomal dominant, recessive, X-linked, or mitochondrial patterns. The SPG15 subtype (or HSP-ZFYVE26), caused by pathogenic variants in the ZFYVE26 gene, is a common form of autosomal recessive HSP. Presenting symptoms vary but commonly include cognitive impairment with a history of speech delay or learning disability and balance impairment or clumsiness from spasticity of the lower limbs.

Lipids are highly abundant in the brain and play key roles in membrane regulation, neurotransmission, neurogenesis, and inflammation. The same processes are involved in neuromodulation mechanisms. While neuromodulation therapies have shown promising outcomes for treatment-resistant psychiatric disorders, the factors determining individual variability in treatment response remain poorly understood. Furthermore, the potential impact of neurometabolic factors in predicting response has been largely overlooked. This narrative review aims to evaluate the role of lipids in psychiatric neuromodulation. Particularly glycerophospholipids, sphingolipids and polyunsaturated fatty acids (PUFAs) have been described as important mediators. Current evidence suggests a bidirectional relationship between lipids and neuromodulation therapies such as electroconvulsive therapy (ECT), and repetitive transcranial magnetic stimulation (rTMS). Neuromodulation effects are associated with lipid metabolism changes, including phospholipids, sphingolipids, and fatty acids. ECT is associated with an increase in lipid peroxidation and alterations of cholesterol and fatty acid levels, while rTMS is associated with normalization of sphingolipids and phospholipids levels. Solely one study investigated the relation between deep brain stimulation and lipids, showing an association with sphingolipid metabolism. To our knowledge, this is the first comprehensive review to consolidate findings on the relationship between lipids and neuromodulation. By mapping this emerging field, these findings might be a first step towards investigating whether lipids could be a potential biomarker for response prediction in the future. As most findings are preliminary, with variability across studies, further investigation is warranted and current findings should be interpreted in the context of their limitations.

Essential tremor (ET) is the most common cause of tremor worldwide and can become profoundly disabling in many patients, with pharmacological treatments often providing insufficient relief. Surgical interventions have emerged as effective strategies for long-term tremor control. This review summarizes the current evidence on surgical therapies, including deep brain stimulation (DBS), radiofrequency (RF) thalamotomy, magnetic resonance-guided focused ultrasound (MRgFUS), and Gamma Knife radiosurgery (GKSR) for ET and other tremor-inducing syndromes. These techniques demonstrate comparable efficacy. DBS offers the advantage of adjustable parameters, allowing optimization of the therapeutic window while minimizing adverse effects. MRgFUS is particularly attractive due to its minimally invasive nature, whereas RF thalamotomy and GKSR remain viable alternatives for patients who are ineligible for DBS or MRgFUS. Bilateral interventions are increasingly feasible, and treatment selection should be individualized, considering clinical characteristics and patient preference. Ongoing advances in magnetic resonance imaging (MRI) technology and neurostimulation are poised to further refine surgical management and improve outcomes for patients with tremor.

Deep brain stimulation (DBS) is an established treatment for movement disorders and an expanding therapy for several neuropsychiatric conditions, yet its mechanisms of action remain incompletely understood. Early interpretations largely relied on linear and focal models, framing DBS as local excitation, inhibition, or a reversible lesion. Accumulating evidence, however, indicates that DBS reorganizes neural activity across multiple spatial and temporal scales, engaging distributed circuits and network-level dynamics. Here, we synthesize experimental, computational, and clinical findings supporting a nonlinear dynamical perspective on DBS. Within this framework, pathological brain states, such as excessive β synchrony in Parkinson’s disease or hypersynchronous epileptic activity, can be conceptualized as maladaptive network regimes. DBS perturbs these regimes in a state-dependent manner, disrupting pathological synchrony, modulating intrinsic oscillations, inducing threshold-like state transitions, and, in some contexts, altering temporal complexity. This perspective helps explain why DBS effects depend on ongoing brain state and why modest changes in stimulation timing or pattern can produce disproportionate clinical effects. Rather than prescribing specific technologies, nonlinear dynamics provides an integrative framework for interpreting diverse DBS phenomena and for understanding the principles underlying adaptive, temporally patterned, and individualized neuromodulation strategies. Together, these insights position DBS as a state-dependent, network-level intervention operating within a nonlinear brain, complementing classical mechanisms and offering a unified lens through which to interpret its diverse therapeutic effects.

Recently, the effectiveness of noninvasive brain stimulation (NIBS) techniques, such as transcranial direct current stimulation (tDCS), has been shown in psychiatric disorders. Here, a new, intensified protocol has been developed, which is suggested to induce late-phase long-term potentiation (LTP)-like plasticity, and increase efficacy of the intervention. In the present case report, we evaluated the effectiveness of a new intensified tDCS protocol (30 sessions, 2 mA for 20 min, 2 sessions daily with a 20 min interval between daily sessions, for 15d) applied to the left ventromedial prefrontal cortex (AF3 according to the EEG International 10 to 20 system), which is suggested to induce late-phase plasticity, and therefore is expected to have superior clinical effects, in a girl with severe cockroach phobia. Severity of phobia symptoms, the anxiety level to phobic stimuli (cockroach), general anxiety, depression, and emotional distress were measured before and immediately after intervention and at follow-up (3wk and 6wk after the last intervention). The results show a significant improvement in phobia symptoms postintervention, maintained for up to 6 weeks after the last intervention, and side effects, including burning sensations and skin redness, were mild. These findings suggest that an intensified tDCS stimulation protocol over the left vmPFC may effectively improve phobia symptoms. Moreover, the results showed that this intensified protocol is safe and tolerable. To substantiate the effects of the current protocol, further investigations in larger patient groups are required.

Commentary: Staged Versus Simultaneous Bilateral Deep Brain Stimulation: A Matched Comparison of Outcomes and Resource Utilization.

What is the future direction for the treatment of Parkinson's disease: Deep brain stimulation or stem cell transplantation therapy?

Background and PurposeUpper limb motor impairment after stroke is a leading cause of long-term disability. This single-center pilot randomized controlled trial (RCT) evaluated the safety, feasibility, and preliminary efficacy of intermittent theta-burst stimulation (iTBS) combined with task-oriented training (TOT) for upper limb rehabilitation. iTBS, a non-invasive brain stimulation technique, may enhance recovery when paired with task-oriented training (TOT), particularly in the subacute phase of heightened neuroplasticity.MethodsTwenty-nine patients with subacute stroke were randomized into three groups: (1) iTBS + TOT (n = 10), (2) sham iTBS + TOT (n = 9), and (3) traditional physiotherapy (n = 10). All underwent a 4-week intervention. Primary outcomes were safety and feasibility. Secondary outcomes included motor impairment (Fugl-Meyer Assessment for Upper Extremity, FMA-UE), functional independence (Modified Barthel Index, MBI), and neurological deficit (National Institutes of Health Stroke Scale, NIHSS), assessed at baseline, week 2, and week 4.ResultsTwenty-nine participants completed the trial without any adverse events, and one participant from Group 2 discontinued early due to discharge. At week 4, the iTBS + TOT group showed greater improvements in FMA-UE (22.9 points vs. 3.6 and 10.2; p = 0.013; p = 0.013), NIHSS (3.0 vs 6.6; p = 0.009), and MBI (90.7 vs 51.4; p < 0.001) compared with controls, indicating potential functional benefits.ConclusionsThis exploratory pilot RCT suggests that combining iTBS with TOT is safe and feasible, with preliminary evidence supporting its potential to improve upper limb recovery in subacute stroke. However, these findings should be interpreted with caution and validated in larger, adequately powered trials.

Deep brain stimulation (DBS) is effective for treating neurological and psychiatric disorders. However, its tethered configuration, invasiveness, and limited tissue compatibility motivate wireless, minimally invasive alternatives. Here, we develop an in situ-gelled injectable conductive hydrogel (ICH), enabling wireless neuromodulation via electric-field localization under volume conduction. The ICH forms in vivo through bio-catalyzed polymerization and electrostatic self-assembly, yielding a stable, highly conductive, tissue-soft, and biocompatible network. Under high-frequency capacitive coupling, impedance difference between the ICH and surrounding brain tissue induces interfacial polarization and charge accumulation, locally concentrating the electric field to activate nearby neurons. This mechanism is supported by enhanced calcium signaling, increased c-Fos expression, and electrophysiological evidence of balanced basal ganglia-cortical activity. In a Parkinson's disease rat model, ICH-mediated stimulation improved locomotor behavior, preserved dopaminergic neurons, and restored functional connectivity and structural integrity as revealed by fMRI. This injectable hydrogel bioelectronics provides a platform for minimally invasive, wireless neuromodulation therapies.

Focused ultrasound is rapidly emerging as a novel technology for the development of symptomatic therapies and supporting disease-modifying treatments for Parkinson's disease (PD). At the forefront of this development is thermoablation using high-intensity focused ultrasound, an incisionless treatment that has been extensively tested in clinical trials and so far has received clinical approval for the treatment of essential tremor and PD patients. At the other end of the spectrum, low-intensity focused ultrasound has been demonstrated in both neuromodulation and blood-brain barrier opening to allow the entry of therapeutic molecules into the central nervous system. The aim of this review is both to provide an overview of the current and future roles of focused ultrasound in disease-modifying treatments for PD with a special focus on outlining the full complexity of the disease beyond dopaminergic cell loss and to bridge clinical and preclinical research. First, we establish PD as a disease including both circuit dysfunctions and molecular pathology. Second, we discuss focused ultrasound state-of-the-art clinically and when relevant in relation to other similar treatment strategies (ie, deep brain stimulation). Third, we highlight preclinical advances and the potential of focused ultrasound to become a disease-modifying treatment. Understanding the therapeutic effects of focused ultrasound in a complex disease like PD is necessary to harness the full potential of the technology. © 2026 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Dystonia due to loss-of-function variants in the GNAL gene in DYT-GNAL and 18p-deletion (18pdel) syndrome has been reported to respond well to pallidal deep brain stimulation (GPi-DBS) occasionally, but long-term data is scarce. GNAL is implicated in dopamine receptor function, which may explain anecdotal reports of hypokinesia in DYT-GNAL and 18pdel-associated dystonia, a phenomenon that has not yet been systematically reviewed. We retrospectively evaluated a cohort of three patients with GNAL variants treated with GPi-DBS, documenting individual long-term outcomes spanning up to 25 years. Dystonia severity was assessed using the Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS) and the Burke - Fahn - Marsden Dystonia Rating Scale (BFMDRS). We also documented bradykinetic symptoms and levodopa response. A literature review was added focusing on DBS outcomes and the effects of levodopa in DYT-GNAL and 18pdel-associated dystonia. In our patients, TWSTRS severity subscale I was reduced by 63% in early (≤ 12months; 20.7 to 7.7 points) and 81% in late follow-up (> 12months; 20.7 to 4 points) after GPi-DBS χ. BFMDRS decreased by 67% and 44%; each with a Kendall's coefficient of 0.78, indicating a high degree of concordance in improvement trajectories. Two patients exhibited bradykinesia, which was levodopa-responsive in one. GPi-DBS responses have been reported for another ten DYT-GNAL and two 18pdel-patients. Bradykinesia prompted levodopa challenges in 15 patients, resulting in improvement in five. Long-term follow-up data from three DYT-GNAL patients treated with DBS showed sustained improvement in dystonia, particularly in cervical symptoms. Bradykinesia may be an inherent clinical feature of GNAL-related dystonia, warranting further investigation.

Background/Objectives: Parkinson’s disease (PD) is associated with alterations in resting-state Electroencephalogram (EEG) biomarkers. Identifying stimulation protocols that reliably shift these biomarkers toward healthy-like patterns is essential for developing personalized neuromodulation strategies. This study introduces a rapid, biomarker-driven framework for screening the EEG effects of diverse Galvanic Vestibular Stimulation (GVS) waveforms in PD. Methods: More than 300 subthreshold GVS stimuli were delivered during resting-state EEG to PD (n = 5) subjects and Healthy Controls (n = 5). A composite biomarker score that included spectral, cross-frequency, aperiodic, and complexity measures quantified stimulation-related changes. A linear classifier and multi-criteria decision analysis were used to evaluate and rank stimuli. Results: Stimulation produced consistent improvements in the composite biomarker score, with the strongest effects observed for beta-range sinusoids, multisine waveforms, frequency-modulated stimuli with a 75 Hz carrier, and PAC-modulated signals. No significant post-stimulation carryover effects were detected. Conclusions: While preliminary, this exploratory framework enables rapid, interpretable profiling of EEG responses to non-invasive stimulation in PD. By prioritizing candidate GVS protocols based on biomarker shifts rather than behavioural endpoints, the approach provides a practical foundation for future personalized neuromodulation strategies.

Deep brain stimulation for Parkinson's disease in India: an expert consensus on availability, affordability, and eligibility by the Parkinson's research alliance India (PRAI).

Motor overflow phenomenon has been described in a variety of neurodegenerative conditions. Often referred to in the literature as "mirror" movements, this phenomenon actually represents a motor overflow, typically involving the contralateral limbs. This phenomenon has not been previously characterized in the facial or jaw muscles. We aim to describe the motor overflow phenomenon in orofacial muscles. We examined videos of patients with Parkinson's disease (PD) from our video library who were undergoing standard OFF and ON assessments for deep brain stimulation evaluation for any evidence of involuntary movements in the face or mouth. Of the evaluated patients, 32% showed evidence of mouth motor overflow movements upon activation by rapid sequential movements (RSM) in the limbs. In this study designed to systematically evaluate patients with PD for mouth motor overflow movements, we found that a third of the patients exhibited this phenomenon.

Deep brain stimulation (DBS) targeting the subthalamic nucleus (STN) is an effective treatment for patients with refractory neuropsychiatric disorders such as Parkinson's disease and obsessive-compulsive disorder. The mechanisms of DBS are not well understood and may involve adjacent structures. They are also associated with many side effects. The medial subthalamic region (MSR) has been characterized in humans as an anatomical target of the hyperdirect pathway originating in limbic cortical areas. However, no clearly identified cell clusters or nuclei have been described. In contrast, the rodent MSR receives inputs from the limbic cortex but contains well-defined nuclei, including the so-called para-STN. Comparison of neurochemical and hodological data suggests that the MSR is homologous in rodents and humans. In addition, nuclei of the rodent MSR are involved in functions that are compatible with many of the side effects associated with DBS of the STN in humans. These observations underscore the need for additional investigation of this region in both humans and rodents, which should prove beneficial in the treatment of neurological and neuropsychiatric disorders.

ABSTRACTThis study examined the effect of brain hemisphere stimulation on effort intensity. We applied high‐definition transcranial direct current stimulation (HD‐tDCS) to the dorsolateral prefrontal cortex (dlPFC) to manipulate left or right hemispheric activity and assess its impact on cardiovascular responses reflecting effort. In total, 102 participants (65 women, 37 men) performed a mental concentration task under right cathodal, left cathodal, or sham stimulation conditions. We recorded cardiovascular responses, including pre‐ejection period (PEP), systolic blood pressure (SBP), heart rate (HR), and diastolic blood pressure (DBP). Preregistered hypotheses predicted right cathodal stimulation to lead to greater left frontal hemispheric activity. This should result in higher effort during a mental concentration task of unclear difficulty by increasing approach motivation and thus success importance. As predicted, right cathodal stimulation increased PEP and SBP reactivity, indicating higher effort compared to the left cathodal and sham stimulation conditions. However, this effect was only evident in women, with men exhibiting a contrasting pattern. Our findings highlight the sex‐specific effects of brain stimulation on cardiovascular responses reflecting effort, with the anticipated effects appearing in women.

Efficacy of transcranial direct current stimulation in children and adolescents with autism spectrum disorder: A systematic review and meta-analysis.

Deep Brain Stimulation Response Circuits in Obsessive-Compulsive Disorder.

A brief history of electrical brain stimulation in humans.

Predictors of Response to Deep Brain Stimulation for Depression.