The researchers used a bidirectional stimulation-and-recording design during the days after electrodes were implanted. Temporary subdural electrocorticography strips were placed over sensorimotor cortex, while directional deep brain stimulation leads targeted the subthalamic nucleus. Motor cortex was stimulated through a bipolar electrode configuration and responses were recorded from individual subthalamic contacts. In the opposite direction, the researchers stimulated the subthalamic lead and recorded cortical activity. Recordings were repeated with patients taking their usual dopaminergic medication and after withdrawal of dopaminergic medication for at least 12 hours. Clinically meaningful motor improvement accompanied the medication-on state: mean Movement Disorder Society–Unified Parkinson’s Disease Rating Scale Part III score was 25.9 ± 9.7 off medication and 16.6 ± 8.9 on medication.

Cortical stimulation elicited a reproducible series of subthalamic responses. The earliest appeared at 2.6 ± 0.7 milliseconds, followed by components at 10.1 ± 1.9, 23.9 ± 3.4 and 38.9 ± 3.5 milliseconds. The first deflection was significantly different from baseline activity across all patients, with p = 0.002, and its consistent shape and presence across nearly all recorded subthalamic channels supported its interpretation as fast orthodromic engagement of the cortex-to-subthalamus pathway. Its latency and reproducibility were consistent with the hyperdirect projection, which animal and tractography research has associated with a direct, monosynaptic route from cortex to the subthalamic nucleus. The human recordings were compatible with that mechanism, although stimulation artefact or volume conduction could not be excluded completely.

Several checks strengthened the physiological interpretation of the fast response. It occurred after the stimulation artefact ended, retained its form when bipolar stimulation polarity was reversed in one participant, and showed spatial specificity rather than appearing equally across the brain. The researchers excluded the first millisecond, during which the artefact was confined, and defined the earliest analyzable response after the signal returned to baseline. Subthalamic stimulation also produced an early cortical response at 3.2 ± 0.3 milliseconds, followed by later components at 6.4 ± 1.1, 11.5 ± 1.8 and 23.2 ± 2.4 milliseconds. That cortical response differed from baseline at p = 0.003 and was compatible with antidromic activation of cortico-subthalamic axons.

Medication state did not significantly modify these earliest responses. Among 10 paired datasets for cortical stimulation, the short-latency subthalamic response averaged −3.3 ± 1.7 microvolts with dopaminergic medication withdrawn and −2.6 ± 1.4 microvolts on medication, with p = 0.06. Its latency was 2.7 ± 0.6 milliseconds off medication and 2.6 ± 0.8 milliseconds on medication, with p = 0.36. In nine paired datasets for subthalamic stimulation, the short-latency cortical amplitude was −18.2 ± 9.7 microvolts off medication and −22.1 ± 9.8 microvolts on medication, with p = 0.367; latency was 3.1 ± 0.3 and 3.3 ± 0.6 milliseconds, respectively, with p = 0.288. These comparisons did not show significant dopaminergic modulation of the earliest responses in either direction.

The delayed subthalamic response was where the medication effect became clear. Following cortical stimulation, activity between 40 and 100 milliseconds differed significantly from baseline at p = 0.002, and its mean peak latency was 79.9 ± 8.9 milliseconds. With medication withdrawn, the peak was positive at 1.5 ± 1.2 microvolts; with medication present, it was negative at −2.2 ± 2.2 microvolts. The paired comparison in 10 patients yielded p = 0.002, while an unpaired comparison of 13 medication-off and 12 medication-on recordings yielded p < 0.001. A cluster-based permutation test with 1,000 iterations confirmed a more sustained negative response in the medication-on state, principally between 65 and 85 milliseconds. Peak latency itself did not differ significantly between conditions: 81.5 ± 10.2 milliseconds off medication and 73.6 ± 10.7 milliseconds on medication, with p = 0.09.

That effect was direction-specific. The researchers found no significant medication-related change in either early or late cortical responses evoked by subthalamic stimulation. For the late cortical component, amplitude was −3.9 ± 26.8 microvolts off medication and −0.2 ± 24.2 microvolts on medication, with p = 0.059 in the paired analysis of nine datasets; latency was 78.7 ± 10 and 75.5 ± 8 milliseconds, with p = 0.258. A temporally resolved cluster-based permutation test also found no significant effect, with p = 0.736 in the unpaired comparison. The observed asymmetry means that dopamine-sensitive modulation was detected in delayed cortical-to-subthalamic signalling but not in the tested cortical responses to subthalamic stimulation; it does not establish the precise synaptic or cellular mechanism responsible.

Recordings from different contacts added a spatial dimension. Strongest negative responses were concentrated in the dorsolateral subthalamic nucleus, and response amplitude became progressively less negative as distance from a previously defined dorsolateral motor “sweet spot” increased. For the early response, that relationship was supported by a Pearson correlation of r = 0.527 and p = 3.981 × 10⁻⁶. The contact producing the largest short-latency response was also on the same contact level selected for chronic DBS in 12 of 15 patients, or 80% of cases. This exceeded the study’s chance model, which assigned equal probability to four contact levels, with two-sided binomial p < 0.001. The comparison was simplified, individual segment agreement was variable, and the researchers said the finding would require prospective validation before it could guide contact selection.

Motor activity offered another check on the central recordings. Five patients showed peripheral muscle activation after cortical stimulation, detected by surface electromyography and visible contraction. Responses mainly involved contralateral distal upper-limb muscles, especially wrist extension, and began at 24.1 ± 7.1 milliseconds on medication and 28.9 ± 16.4 milliseconds off medication in four paired datasets, with p = 0.75. Their presence did not correspond to systematic changes in the amplitude, morphology or medication modulation of subthalamic potentials, and subthalamic amplitude and latency did not correlate with electromyographic amplitude or latency. This dissociation supports interpreting the subthalamic signals as central cortico-subthalamic responses, but the small motor-response subgroup limits conclusions about anatomical specificity. Overall, the findings distinguish a comparatively dopamine-insensitive fast pathway from dopamine-sensitive delayed network activity in the patients studied, while leaving the routes responsible for the delayed component unresolved.

Subject of Research: Dopaminergic modulation of fast and delayed cortico-subthalamic communication in people with Parkinson’s disease

Article Title: Dopamine amplifies subthalamic long-latency responses to cortical stimulation in patients with Parkinson’s disease

Article References: Beyer, J.-C., Cavallo, A., Vanhoecke, J., Köhler, R. M., Al-Fatly, B., Schneider, G.-H., Faust, K., Brandt, G. A., Kühn, A. A., & Neumann, W.-J. (2026). Dopamine amplifies subthalamic long-latency responses to cortical stimulation in patients with Parkinson’s disease. npj Parkinson's Disease, 12(1), Article 254. https://doi.org/10.1038/s41531-026-01567-6

Image Credits: AI Generated

DOI: 10.1038/s41531-026-01567-6

Keywords: Parkinson’s disease, dopamine, subthalamic nucleus, motor cortex, deep brain stimulation, electrocorticography, basal ganglia, hyperdirect pathway, levodopa, intracranial recordings, amplifies, subthalamic

The study followed 30 consecutive patients, 17 of them women, who underwent deep brain stimulation targeting the nucleus accumbens and the anterior limb of the internal capsule, a combined target abbreviated NAcc/ALIC, between 2004 and 2022. All of them had severe, functionally disabling OCD that had failed to respond adequately to established pharmacological and psychotherapeutic treatments, and all had been approved for surgery by a multidisciplinary team. The researchers assessed symptom severity with the Yale-Brown Obsessive Compulsive Scale, or Y-BOCS, at three time points: before surgery, one year after implantation, and at a final follow-up at least three years after the operation, which in some cases stretched to 21 years.

The technical logic of the procedure is rooted in the cortico-striato-thalamo-cortical circuits, the looping networks that connect the prefrontal cortex to deep gray-matter structures and are thought to be pathologically overactive in OCD. By placing electrodes so that one contact sits within the nucleus accumbens, one at the transition to the internal capsule, and the two most dorsal contacts within the capsule itself, surgeons can modulate activity across this circuit with millimeter-scale precision. In this cohort, leads were implanted bilaterally in 25 patients and unilaterally on the right side in five, using Medtronic model 3387 or SenSight leads with 1.5-millimeter contact spacing. Standard stereotactic coordinates were individualized to each patient’s anatomy, with trajectories planned to avoid blood vessels, cortical sulci, and the ventricular system.

Stimulation began within days of implantation and was titrated over the first two weeks to therapeutic amplitudes, typically between 1.5 and 3.0 volts or milliamperes. Parameters were adjusted every four to six weeks during the first three months, then roughly every three months until the first postoperative year, after which follow-up intervals were individualized. The response criterion was a reduction of at least 35 percent in Y-BOCS score from baseline, in line with international consensus definitions, although the retrospective design meant that the companion Clinical Global Impression ratings required for the full consensus categories were not systematically available.

The statistical picture was unambiguous. Repeated-measures analysis of variance showed that Y-BOCS scores fell significantly across all three time points, with a large effect size, and every Bonferroni-adjusted pairwise comparison, from baseline to one year, from one year to final follow-up, and from baseline to final follow-up, reached significance. Mean scores dropped from roughly 30 at baseline to about 20 at one year and about 14 at the latest assessment. Expressed as percentages, the average reduction was 32.4 percent at one year and 51.6 percent at final follow-up, meaning that on average patients continued to improve well beyond the first anniversary of their surgery.

At the final follow-up, 22 of 30 patients, or 73.3 percent, met the response criterion. That figure exceeds the pooled response rates of 66 percent and 57.9 percent reported in earlier meta-analyses, although the authors caution that excluding four operated patients who lacked complete follow-up data may have inflated the proportion. Response was seen across all baseline severity categories: 80 percent of patients whose symptoms had been rated extreme at baseline, 66.7 percent of those rated severe, and two of the three patients with moderate total scores, whose eligibility rested on severe, disabling obsessions despite minimal compulsions.

Perhaps the most clinically consequential finding concerns timing. Eight patients, 26.7 percent of the cohort, were delayed responders: they had not crossed the 35 percent threshold at one year but did so later, sometimes years later. One patient with extreme baseline symptoms showed only a 12.5 percent reduction at one year but a 95 percent reduction at 21 years. Conversely, among the 15 patients who responded by one year, 14 retained their response and only one lost it. The authors suggest that delayed improvement could reflect gradual neural adaptation, long-term optimization of stimulation settings, changes in concomitant treatment, psychosocial shifts, or natural fluctuation in OCD severity, and the retrospective data cannot distinguish among these explanations. But the practical implication is clear: judging a patient a non-responder at the one-year mark may be premature.

The study is candid about its limits. It is retrospective, uncontrolled, and single-center, which precludes causal conclusions about DBS itself or about the temporal course of improvement. Follow-up duration varied enormously, from 3 to 21 years, and was treated as a categorical assessment rather than a continuous variable, so the analysis cannot estimate a yearly rate of change. Medication and psychotherapy histories were not systematically recorded, adverse events were not captured with a standardized framework, and the inclusion period spanned 18 years, during which surgical techniques, hardware, and programming practices inevitably evolved. The researchers also note that some patients experienced transient symptom worsening during transitions between voltage-controlled and current-controlled devices, particularly around generator replacements, observations documented mainly in narrative clinical notes rather than standardized assessments.

Those caveats notwithstanding, the trajectory data add an important dimension to a field that has often been judged on one-year outcomes. Long-term cohorts from Amsterdam and other centers have previously shown sustained benefit, but a dataset extending over two decades, with individual stimulation parameters and Y-BOCS scores documented for every patient, is rare. The finding that improvement continued to accrue between the first year and the final assessment, and that the cumulative reduction exceeded either interval-specific reduction, suggests that the therapeutic effect of NAcc/ALIC stimulation may mature slowly, in a way that shorter trials cannot capture.

For the roughly one in four people with OCD who do not respond to conventional treatment, the study offers a measured but meaningful message. Deep brain stimulation remains a last-resort intervention reserved for highly selected patients treated in specialized multidisciplinary centers, and no one should read these results as a guarantee. But they do provide descriptive evidence that clinically meaningful improvement can persist, and in some cases deepen, over very long follow-up, and that patience with the therapy, and with the patients, may itself be part of the treatment. The authors call for prospective studies with standardized follow-up intervals, systematic recording of concomitant treatments and adverse events, and analyses that incorporate exact follow-up duration to confirm what this two-decade cohort so strongly hints at.

Subject of Research: Long-term outcomes of deep brain stimulation for treatment-resistant obsessive-compulsive disorder

Article Title: Long-term outcomes of nucleus accumbens/anterior limb of the internal capsule deep brain stimulation in treatment-resistant obsessive-compulsive disorder

Article References: Cid-Rodríguez, F. X., Schmahl, R., Márquez-Franco, R., Heiden, P., Soriano-Ursúa, M. A., Wagemann, W., Huys, D., Baldermann, J. C., Kuhn, J., Visser-Vandewalle, V., & Andrade, P. (2026). Long-term outcomes of nucleus accumbens/anterior limb of the internal capsule deep brain stimulation in treatment-resistant obsessive-compulsive disorder. Frontiers in Psychiatry, 17, Article 1905823. https://doi.org/10.3389/fpsyt.2026.1905823

Image Credits: AI Generated

DOI: 10.3389/fpsyt.2026.1905823

Keywords: deep brain stimulation, obsessive-compulsive disorder, nucleus accumbens, anterior limb of the internal capsule, Y-BOCS, neuromodulation, treatment-resistant OCD, neurosurgery, psychiatry, long-term follow-up, cortico-striato-thalamo-cortical circuits, Frontiers in Psychiatry

Disorders of consciousness, or DoC, arise when insults—traumatic brain injury, anoxic damage, hemorrhage, infection—disrupt the distributed neural networks that generate awareness and arousal. Clinicians classify patients along a spectrum from coma through vegetative state or unresponsive wakefulness syndrome to the minimally conscious state, which is itself subdivided by whether language responses persist. Diagnosis is notoriously error-prone: the review cites a 37 percent misdiagnosis rate, and while the global incidence remains unknown, estimates hover around 201 cases per 100,000 annually. Because the mechanisms underlying consciousness are still poorly understood, and because spontaneous recovery can mimic therapeutic effects, the field has struggled to establish whether neurostimulation genuinely works. The Coma Recovery Scale-Revised remains the reference behavioral measure, tracking the two core components of consciousness—awareness and arousal—through standardized clinical assessment.

The review’s methodology was deliberately strict. Following the PRISMA extension for scoping reviews, the researchers searched PubMed, SCOPUS and Web of Science, with a final search performed in March 2026. Crucially, they only included studies with more than one participant, a quantitative measure of consciousness recovery, and a control or comparator group—a restriction designed to separate stimulation effects from the natural recovery that confounds uncontrolled reports. The initial search generated 1,318 records; after duplicate removal, dual screening and full-text review, nineteen studies met the criteria. An updated search in March 2026 added three more, bringing the final tally to twenty-two. Eighteen were randomized controlled trials, most employing sham controls, with healthy controls used in four studies. All subjects were adults with mixed etiologies—traumatic, anoxic, infective, hemorrhagic—with a mean age of 48.1 years, 43.7 percent female, and an average of 16.9 months since the inciting event.

The anatomical map that emerged is strikingly lopsided. Thirteen of the twenty-two studies targeted the frontoparietal network, the circuit spanning the dorsolateral prefrontal cortex and posterior parietal regions that supports executive function, attention and working memory—often called the central executive network. The dorsolateral prefrontal cortex alone was the primary target in fourteen studies, suggesting a pronounced research bias toward this single region. Three studies engaged the default mode network, integral to internal awareness, via the posterior parietal cortex and precuneus; one combined frontoparietal and default mode stimulation; one targeted the salience network through transcutaneous auricular vagal nerve stimulation of the bilateral auricles; two stimulated the sensorimotor network via the primary motor cortex; and two used invasive deep brain stimulation—one to the thalamocortical pathway through the bilateral centromedian-parafascicular nuclei, one to the medial pallidum. Transcranial direct current stimulation and repetitive transcranial magnetic stimulation tied as the most frequent modalities, each used in eight studies, with stimulation durations typically ranging from five to fourteen days—though the pallidal deep brain stimulation protocol extended up to eleven months.

Technically, the two dominant modalities work in fundamentally different ways. Transcranial direct current stimulation delivers weak, subthreshold currents through scalp electrodes, subtly biasing cortical neuronal membrane potentials toward excitation or inhibition depending on polarity. Repetitive transcranial magnetic stimulation uses rapidly alternating magnetic fields to induce electric currents that depolarize cortical neurons directly, with stimulation frequency determining whether the net effect is excitatory or inhibitory. Both are non-invasive and, across the review, maintained good safety profiles. The review also catalogued newer variants—transcranial pulsed current, alternating current, random noise, and intermittent theta burst stimulation—reflecting a field experimenting with how best to entrain residual network activity.

Here is where the story gets genuinely interesting. Among the twelve studies that also used electroencephalography and the two that used functional imaging, improvements in functional connectivity—particularly increased alpha-band coherence—were observed after stimulation, and these electrophysiological shifts often correlated with individual-level gains in clinical consciousness. In other words, when the stimulation worked at the level of the person, the brain’s networks visibly reorganized in parallel. Yet when the reviewers aggregated results across cohorts, the picture fractured: only six of the twenty-two studies reported significant group-level improvement in consciousness-related behavioral outcomes on the Coma Recovery Scale-Revised. Those six responders spanned the frontoparietal network, the default mode network, a combined frontoparietal-default mode cross-network approach, and the salience network—with no common stimulation modality, no concentration at the most frequently studied network, and median time from injury ranging from roughly 1.5 to 43 months. Four used repetitive transcranial magnetic stimulation, one used direct current stimulation, and one used auricular vagal nerve stimulation.

Why the disconnect between individual and group results? The review’s authors argue that heterogeneity is the culprit. Cohort sizes ranged from 3 to 50 participants. Etiologies varied from traumatic brain injury, which can follow prolonged recovery trajectories, to anoxic injury, which follows more predictable patterns. Clinical subtypes varied from minimally conscious state-only cohorts to mixed populations including unresponsive wakefulness syndrome and vegetative state. Stimulation protocols were applied uniformly despite these differences, neglecting critical individual variations in structural cerebral integrity and baseline functional connectivity that can be identified through functional MRI or electrophysiology. One study even used EEG electrode landmarks to determine stimulation targets—a practical but error-prone approach given individual anatomical variability, particularly in patients whose brains may have structurally altered. The reviewers also note that brief stimulation durations, limited prospective follow-up, and absent dose-response data further confound interpretation, since cerebral recovery is optimized by sustained, repetitive stimulation that drives lasting synaptic reorganization.

Safety, at least, is encouraging. Neurostimulation modalities generally demonstrated favorable profiles, though adverse event reporting was inconsistent, with eleven studies not formally reporting any. Only one study—an invasive deep brain stimulation to the medial pallidum—reported an adverse event attributable to the intervention: one participant developed a bronchopulmonary infection and died fifteen months after electrode implantation, with no acute neurological signs beforehand. Participants receiving auricular vagal nerve stimulation reported seizures, pneumonitis and deep vein thrombosis in both treatment and sham groups, with no significant difference between them and no attribution to stimulation effects.

The deeper conceptual problem the review surfaces is that consciousness is not the product of any single network. Neural networks share overlapping anatomical regions, and it is their complex interplay that gives rise to awareness. Studies classed as engaging the default mode network via the parietal hub likely co-modulated the frontoparietal network through shared parietal nodes. The positive outcomes observed across studies may therefore reflect wider coordinated restoration of neuronal activity across multiple networks rather than the effect of any isolated target. The absence of a network-specific response pattern is not evidence that chosen targets were irrelevant, the authors caution—rather, the small number of responders and the heterogeneity of modality, etiology and protocol limit the dataset’s power to detect network-specific effects. The network classifications should be read as an organizing framework, not proof of selective engagement.

Where does this leave the field? Network-targeted neurostimulation is promising but remains investigational. The review’s authors propose a clear roadmap: future trials should employ individualized structural and functional mapping guided by residual network integrity rather than anatomical landmarks, stratify participants by baseline connectivity and clinical subtype, apply standardized outcome definitions, and explore dual-network or dual-modality stimulation—approaches that have not yet been investigated. A shift toward tailored, patient-specific neuromodulation strategies, they argue, may finally move the field toward precision neurorehabilitation, optimizing therapeutic outcomes for consciousness recovery in ways that uniform protocols never could.

Subject of Research: Neuroscience

Article Title: What are the neural networks that have been modulated by anatomically targeted therapies to promote recovery of consciousness? A scoping review

Article References: Thakker, R. D., Karabacak, M., Aydin, S., Budihal, B. R., Cummins, D. D., Panov, F., & Margetis, K. (2026). What are the neural networks that have been modulated by anatomically targeted therapies to promote recovery of consciousness? A scoping review. Frontiers in Neurology, 17, Article 1882395. https://doi.org/10.3389/fneur.2026.1882395

Image Credits: AI Generated

DOI: 10.3389/fneur.2026.1882395

Keywords: neurostimulation, disorders of consciousness, neuromodulation, tDCS, rTMS, deep brain stimulation, neurorehabilitation, neural, networks, been, modulated, anatomically

The case, published in Frontiers in Neuroscience by neurosurgeons at Nara Medical University and collaborators at the Montreal Neurological Institute, describes a 29-year-old woman whose epilepsy had resisted every conventional therapy. Her medical history was extraordinarily complex. At age seven she was diagnosed with a suprasellar germ cell tumor, a rare growth near the pituitary region, and underwent craniotomy for resection, high-dose chemotherapy, whole-brain radiation totaling 50 Gy with a local boost, and stereotactic radiation to the anterior spinal cord at 24 Gy. The tumor went into remission, but the aggressive treatment left her with panhypopituitarism and severe intellectual disability, with a full-scale intelligence quotient of 42 measured at age 16. A ventriculoperitoneal shunt was later inserted to manage secondary hydrocephalus, a buildup of cerebrospinal fluid, but the device caused intracranial hemorrhage from overshunting and had to be ligated.

Seizures emerged at age 22 after an episode of nonconvulsive status epilepticus triggered by severe hyponatremia, a sodium level of 123 mmol/L against a reference range of 135 to 145. Magnetic resonance imaging revealed abnormal lesions in both temporal lobes, and recurrent seizures followed. Over the next seven years she tried levetiracetam, carbamazepine, perampanel, lacosamide, valproic acid, topiramate, and brivaracetam, with either no benefit or intolerable side effects. Vagus nerve stimulation, implanted at age 23, reduced dramatic falls from several per week to one or two, but daily seizures persisted at a rate of roughly ten per day. By the time she reached the Nara epilepsy clinic at 29, her team faced a patient whose brain had been reshaped by tumor, surgery, radiation, and shunt hardware, and whose seizures continued unabated.

The diagnostic workup was exhaustive. Neurological examination showed right-sided hemiparesis with manual muscle strength of grade 3, no meaningful speech, and an inability to follow verbal commands, which ruled out formal neuropsychological testing. Her seizures followed a distinctive pattern: asymmetric tonic posturing lasting 10 to 30 seconds, with eyes deviating to the left, the left arm extending, and the right arm flexing, followed by a flaccid atonic phase in which all four limbs went limp and the trunk tilted leftward. Computed tomography revealed brain atrophy, hydrocephalus, calcifications in both basal ganglia, and post-craniotomy changes in the right frontal region. Magnetic resonance imaging showed marked atrophy of the left hemisphere, so severe that the left anterior thalamic nucleus could not be identified at all.

Video-electroencephalography over three days, using scalp electrodes placed according to the International 10-20 system, painted a detailed electrical portrait. Between seizures, the awake recording showed a disorganized posterior dominant rhythm of 6 to 7 hertz, frequent slow and sharp waves over the F4 and C4 electrode positions on the right, and spikes with high-amplitude fast activity at sleep onset. Sleep architecture was disrupted, without obvious slow-wave sleep, and intermixed abnormal theta and delta activity was maximal over the left frontal region, with independent interictal epileptiform discharges also appearing in the right frontotemporal region. Crucially, the team captured around ten habitual seizures, and ictal recordings showed high-amplitude bursts of spiky fast waves originating at F4 and spreading across the right hemisphere. Frequent subclinical electrographic seizures occurred during sleep. The diagnosis: focal epilepsy arising from a widespread epileptogenic network centered on the right frontal and temporal lobes.

That network localization shaped the surgical decision. Because the epileptogenic zone was distributed rather than confined to a resectable focus, focal removal was not indicated; resective surgery can render roughly two-thirds of medial temporal lobe epilepsy patients seizure-free and about half of those with neocortical epilepsy, but only when the abnormal tissue can be cleanly delineated. Deep brain stimulation of the anterior thalamic nucleus was chosen instead. The original plan was conventional bilateral implantation, but anatomy intervened. The left nucleus could not be visualized on imaging, even when compared against ultrahigh-resolution 200-micrometer sections from the BigBrain human atlas. Severe left hemispheric atrophy had widened the subdural space excessively, and a shunt valve sat at the anticipated burr-hole site beneath thinned scalp. With the epileptiform abnormalities predominantly right-sided, and with prior animal studies and human responsive neurostimulation cases suggesting unilateral thalamic stimulation could work, the team implanted a single electrode in the right anterior nucleus alone.

Stimulation began seven days after surgery at an intensity of 2 milliamperes, and the results were striking. Seizure frequency plummeted from roughly ten per day to about one, an early drop the authors attribute largely to a microlesioning effect, the temporary suppression that often follows electrode implantation itself rather than the stimulation. Once that effect settled, sustained stimulation produced a stable seizure reduction of approximately 60 percent, maintained throughout nine months of follow-up. Antiseizure medications were left unchanged, isolating the stimulation as the variable. Seizure duration also shortened by about half, reducing interruptions to daily life, and the patient showed improved daytime alertness, possibly reflecting better nighttime sleep quality, which in turn eased the burden on her caregivers. Final stimulation parameters were set at 2 mA, 145 pulses per second, 90-microsecond pulse width, and a duty cycle of one minute on and five minutes off, while vagus nerve stimulation was reduced to 1 mA. Routine postoperative electroencephalography showed a measurable reduction in interictal epileptiform discharges, and no surgery- or stimulation-related adverse events occurred.

The result fits a broader pattern in neuromodulation. In movement disorders such as Parkinson’s disease, unilateral deep brain stimulation of the subthalamic nucleus or internal globus pallidus improves contralateral symptoms by up to 75 percent but ipsilateral symptoms by only about 28 percent, and a recent systematic review found unilateral stimulation improved Unified Parkinson’s Disease Rating Scale Part III scores by 37 percent compared with up to 66 percent for bilateral approaches. The principle is that one electrode primarily treats the hemisphere in which it sits. Epilepsy complicates this logic, because seizures can propagate through the thalamus to widespread networks on both sides, which is precisely why bilateral anterior thalamic stimulation became standard. Yet animal work supports the one-sided approach in the right circumstances: in rats with unilateral amygdala kindling, high-frequency stimulation of the ipsilateral anterior nucleus significantly reduced seizure frequency and duration, while contralateral stimulation did not, although in a pilocarpine model of secondarily generalized seizures only bilateral stimulation or lesioning suppressed seizures.

Human case reports of responsive neurostimulation, a closed-loop device that fires only when it detects seizure activity, point the same way. One patient with refractory genetic generalized epilepsy achieved a 90 to 95 percent seizure reduction over two years with stimulation of the right anterior nucleus and prefrontal cortex, and three patients with multifocal epilepsy treated with unilateral thalamic responsive neurostimulation improved by 50 to 56 percent over 33 to 35 months. Although closed-loop and open-loop stimulation differ mechanistically, both experiences underscore the importance of targeting the hub of the epileptogenic network. The Nara case strengthens that hypothesis because open-loop stimulation alone, delivered continuously between seizures, achieved meaningful control, and its effects may continue to evolve over longer periods. The authors also note that the anterior nucleus and medial temporal structures are both components of the limbic system, and that stronger functional connectivity between the thalamus and the seizure onset zone has been linked to better stimulation outcomes, which may explain why unilateral stimulation worked when the network was predominantly ipsilateral.

The team is careful about the limits of a single case. The follow-up was only nine months, so durability remains unknown, and the pre-existing vagus nerve stimulator complicates attribution, since a synergistic effect between the two devices cannot be excluded. Still, the clinical message is concrete: when the predominant epileptogenic network is confined to one hemisphere, and especially when anatomical constraints such as atrophy, shunt hardware, or distorted anatomy prevent placing electrodes on both sides, unilateral anterior thalamic stimulation is a reasonable and potentially worthwhile option. The authors caution that bilateral stimulation remains necessary when seizures arise from or spread through both hemispheres, as in post-encephalitic epilepsy, and that larger cohorts with longer follow-up are needed to define the indications, efficacy, and durability of the unilateral approach. For now, the case offers a carefully documented proof of principle that in epilepsy surgery, as in so much of neuroscience, matching the intervention to the individual patient’s network may matter more than following the standard template.

Subject of Research: Unilateral deep brain stimulation of the anterior thalamic nucleus for drug-resistant focal epilepsy

Article Title: Case Report: Successful treatment of drug-resistant epilepsy with unilateral deep brain stimulation of the anterior nucleus of the thalamus

Article References: Sasaki, R., Yamada, K., Tamura, K., Kinoshita, M., Park, Y.-S., Sadikot, A. F., & Nakagawa, I. (2026). Case Report: Successful treatment of drug-resistant epilepsy with unilateral deep brain stimulation of the anterior nucleus of the thalamus. Frontiers in Neuroscience, 20, Article 1978183. https://doi.org/10.3389/fnins.2026.1978183

Image Credits: AI Generated

DOI: 10.3389/fnins.2026.1978183

Keywords: deep brain stimulation, drug-resistant epilepsy, anterior nucleus of the thalamus, neuromodulation, focal epilepsy, case report, electroencephalography, vagus nerve stimulation, thalamus, epilepsy surgery, responsive neurostimulation, neuroscience

The findings, published in the journal Dystonia on 19 October 2026, come from a retrospective review of patients treated at Emory University Hospital in Atlanta between 2008 and 2025. The cohort comprised nine men and nine women, with nine diagnosed with tardive dystonia, two with tardive dyskinesia, and seven with both conditions. The mean age at onset of tardive symptoms was 42.0 years, and patients had endured their movement disorders for an average of 9.0 years before surgery, with some suffering for as long as 28 years. Sixteen patients carried psychiatric diagnoses, and fifteen had been exposed to dopamine receptor blocking agents for psychiatric indications, while three received the causative drugs for other conditions, including promethazine in one patient and metoclopramide in two.

Tardive syndromes remain common despite the widespread adoption of second-generation antipsychotics. One of the largest meta-analyses reported an average prevalence of tardive dyskinesia of 25.3 percent among patients receiving dopamine receptor blocking agents, with first-generation antipsychotics associated with a prevalence of 30.0 percent compared with 20.7 percent for second-generation agents. The reported prevalence of tardive dystonia varies widely, ranging from 0.5 to 21.6 percent. Tardive dystonia is characterized by sustained or intermittent involuntary posturing and torsional muscle contractions, most commonly involving the craniocervical region, although the trunk and limbs may also be affected. Tardive dyskinesia, by contrast, produces stereotyped, repetitive involuntary movements, most often affecting the oro-bucco-lingual region. Both conditions can cause social distress and, in severe cases, significant physical disability.

Current pharmacological options remain limited. In 2017, two vesicular monoamine transporter 2 inhibitors were approved by the U.S. Food and Drug Administration for the treatment of tardive dyskinesia and remain the only FDA-approved agents for this indication. Nevertheless, treatment of tardive dystonia and tardive dyskinesia remains challenging because of incomplete response, medication intolerance, limited access, and cost. Other treatments such as anticholinergics for tardive dystonia, amantadine, benzodiazepines, and botulinum toxin injections are often tried with limited effect. Because tardive dystonia and tardive dyskinesia commonly co-occur, anticholinergics must be used with caution, as this medication class can worsen dyskinesia. These therapeutic challenges have fueled growing interest in surgical interventions, particularly deep brain stimulation.

Deep brain stimulation involves implanting electrodes into specific brain regions and delivering electrical pulses to modulate abnormal neural activity. For tardive syndromes, the globus pallidus internus is the most commonly targeted region, similar to idiopathic dystonia, although a few reports have also described efficacy with stimulation of the subthalamic nucleus. Currently, DBS is considered a Level C recommendation for the treatment of tardive dystonia and tardive dyskinesia. Available studies are largely small retrospective case series reporting improvements in disease-specific rating scales ranging from 30 to 100 percent, with most studies reporting improvements greater than 60 percent. The only randomized, sham-controlled DBS trial in tardive dystonia and dyskinesia demonstrated a reduction in hyperkinetic movements but did not reach statistical significance, possibly because of limited statistical power and the relatively short follow-up duration of three to six months.

In the new study, seventeen patients underwent bilateral GPi DBS surgery and one patient received unilateral right-sided stimulation. Quadripolar DBS electrodes were implanted using microelectrode recordings or intraoperative MRI guidance, and the implanted systems included commercially available devices from Medtronic, Boston Scientific, and Abbott. Postoperative programming was initiated approximately four weeks after surgery, with stimulation settings adjusted over subsequent sessions as part of routine clinical care. Each patient underwent pre-operative psychiatric clearance prior to surgery. Clinical outcomes were assessed preoperatively and at approximately one-year, three-year, and five-year follow-up visits using the Burke-Fahn-Marsden Dystonia Rating Scale for patients with tardive dystonia, the Toronto Western Spasmodic Torticollis Rating Scale for those with prominent cervical dystonia, and the Abnormal Involuntary Movement Scale for patients with tardive dyskinesia.

The results were striking. The mean preoperative BFMDRS motor score was 27.5, and it dropped to 9.1 at short-term follow-up, 5.0 at mid-term follow-up, and 4.1 at long-term follow-up, with all reductions reaching statistical significance at Bonferroni-adjusted p values below 0.001. The corresponding mean percentage improvements were 64.1 percent, 83.8 percent, and 88.0 percent, respectively. Three patients achieved complete resolution of motor symptoms, corresponding to 100 percent improvement, and this response was maintained through their last follow-up visits. Axial dystonia, including neck and trunk involvement, improved significantly at all follow-up time points, with the mean axial subscore falling from 12.3 preoperatively to 1.6 at long-term follow-up. Extremity dystonia also improved significantly at mid-term and long-term follow-up, with the mean extremity subscore decreasing from 9.1 to 0.3. Speech, swallowing, and orofacial dystonia subscores showed numerical improvement without reaching statistical significance, a pattern the authors attribute to limited statistical power rather than absence of clinical benefit.

Among the subset of patients with available TWSTRS scores, the mean score decreased from 50.3 preoperatively to 21.7 at long-term follow-up, with the most apparent improvements observed in the severity and disability subscores. Among the nine patients with tardive dyskinesia, four had available AIMS scores, which decreased from 15.8 preoperatively to 5.0 at mid-term follow-up, with the most apparent improvement seen in the orofacial and global judgement subscores. The authors note that the small number of patients with available preoperative and postoperative AIMS data limits interpretation and precludes definitive conclusions regarding DBS effectiveness for tardive dyskinesia in this cohort, although the observed downward trend is consistent with prior studies reporting improvement in tardive dyskinesia after GPi DBS.

The researchers also mapped the locations of the active electrode contacts at the last follow-up visits, finding coordinates of 20.6 mm lateral, 2.5 mm anterior, and 1.1 mm inferior relative to the mid-commissural point. These locations were consistent with the GPi target region used for dystonia and aligned with previously reported GPi stimulation sites in tardive syndromes. The mean stimulation parameters at the same timepoint were 3.8 mA amplitude, 95.1 μs pulse width, and 119.4 Hz frequency, generally consistent with commonly used GPi DBS settings for dystonia. Over time, stimulation parameters were adjusted as clinically indicated, whereas electrode configuration remained unchanged from short-term to last follow-up in all but one patient. The mean changes in amplitude, pulse width, and frequency between time intervals were modest, and no persistent stimulation-related adverse effects were reported.

Safety findings were encouraging. One patient developed skin erosion and infection at the burr hole site, which resolved without DBS lead explantation. Otherwise, no persistent stimulation-related adverse effects were reported, and no patient had exacerbations of underlying psychiatric disorders based on chart review. This low complication rate supports the overall safety of GPi DBS in appropriately selected patients with medically refractory tardive syndromes. The authors suggest that given the robust and sustained improvement and low surgical complication rate observed in this cohort, earlier consideration of DBS may be reasonable in selected patients with severe, disabling, and treatment-refractory tardive syndromes. The mean duration of tardive symptoms before surgery was nine years, with a range of three to twenty-eight years, and the authors argue that earlier surgical intervention may facilitate timely symptomatic relief and durable long-term benefit.

The study has limitations. The retrospective design limited the uniformity of clinical assessments, and outcome assessments were not blinded, which may have introduced observer bias. Follow-up data were incomplete, particularly at later time points, which may have affected estimates of long-term treatment effect. Different rating scales were used depending on clinical phenotype, and not all patients had all outcome measures available. The small number of patients with available TWSTRS and AIMS data limited statistical power for subgroup analyses. Despite these constraints, the study adds to the growing evidence supporting GPi DBS as a safe and effective treatment for medically refractory tardive dystonia with sustained long-term benefit, and suggests potential benefit for tardive dyskinesia. Larger, multicenter prospective studies with standardized outcome measures and long-term follow-up are needed to further define the efficacy, durability, and optimal stimulation parameters of DBS for tardive syndromes.

The pattern of continued improvement from short-term to long-term follow-up may reflect the delayed and cumulative therapeutic response to GPi stimulation previously described in dystonia. This temporal profile suggests that clinically meaningful improvement can be sustained for several years after implantation, and that the greatest gains may accrue gradually as the nervous system adapts to the modulation of pallidal output. For patients who have exhausted medication options and endured years of involuntary movements, the findings offer a compelling case that pallidal deep brain stimulation can provide durable, life-changing relief from one of the most challenging complications of psychiatric drug therapy.

Subject of Research: The long-term efficacy of globus pallidus deep brain stimulation in tardive dystonia and dyskinesia

Article Title: The long-term efficacy of globus pallidus deep brain stimulation in tardive dystonia and dyskinesia

Article References: Je, G., Miocinovic, S., Huang, V., Aia, P. G., Tripathi, R., Buetefisch, C. M., Esper, C. D., Higginbotham, L. A., Triche, S., Factor, S. A., & Radmard, S. (2026). The long-term efficacy of globus pallidus deep brain stimulation in tardive dystonia and dyskinesia. Dystonia, 5, Article 17246. https://doi.org/10.3389/dyst.2026.17246

Image Credits: AI Generated

DOI: 10.3389/dyst.2026.17246

Keywords: deep brain stimulation, tardive dystonia, tardive dyskinesia, globus pallidus internus, GPi DBS, movement disorders, dystonia, antipsychotics, neurology, neurosurgery, long-term, efficacy

The study, published in the open-access journal iScience, combined deep transcranial magnetic stimulation, or DTMS, with intermittent theta burst stimulation, an excitatory patterned protocol known as iTBS. Unlike conventional TMS, which uses a figure-of-eight coil to focus stimulation on a small patch of superficial cortex, DTMS employs specialized H-coils whose magnetic fields spread across broader cortical and subcortical territory. The H7 coil used in the trial engages the bilateral prefrontal cortex and the anterior cingulate cortex simultaneously, two regions that anchor executive control and conflict monitoring. Pairing this wide-field engagement with iTBS, which mimics endogenous theta-gamma coupling and efficiently induces synaptic plasticity in under four minutes, offered the researchers a way to modulate an entire distributed network rather than an isolated hotspot.

Nineteen right-handed healthy adults, seven men and twelve women with a mean age of about twenty-five, completed the randomized crossover trial. Each participant received both active stimulation and a sham condition in separate sessions separated by a two-week washout, with the order counterbalanced and assignments concealed in sealed envelopes. Before and after each intervention, the researchers recorded cortical hemodynamics with a portable functional near-infrared spectroscopy, or fNIRS, device. The sensor packed twenty-four light sources and sixteen detectors into fifty-two channels covering fourteen regions of interest, from the dorsolateral prefrontal cortex through primary and secondary motor areas to somatosensory and parietal language regions. Resting-state signals were captured over eight minutes, followed by a three-minute dual-task test in which participants walked at a comfortable pace, turned to avoid obstacles, and answered oral serial subtraction questions posed by the experimenters.

The behavioral result was striking. In a mixed-effects model controlling for baseline performance, the increase in the number of completed calculations was significantly greater after active DTMS than after sham stimulation, with a treatment effect of F(1,17) = 12.546 and p = 0.003. Participants who averaged roughly forty-eight calculations before stimulation completed about fifty-nine afterward, a jump of nearly eleven problems in three minutes. No significant period or sequence effects emerged, ruling out simple practice or ordering artifacts. Accuracy, already above ninety percent at baseline, did not differ significantly between conditions, though a trend favored active stimulation. The authors argue that a ceiling effect on correctness limited sensitivity, and that the gain in throughput therefore reflects improved processing efficiency rather than a speed-accuracy trade-off.

The neurovascular data told a complementary story. During the dual-task condition, mean oxygenated hemoglobin, or HbO, concentration rose significantly more after DTMS than after sham in the right secondary motor cortex, which encompasses the premotor and supplementary motor areas, and in the left somatosensory association cortex, with p values of 0.022 and 0.033 respectively. Deoxygenated hemoglobin fell significantly in the right secondary motor cortex, consistent with elevated neural activation. Whole-brain waveforms showed overall greater cortical activation following active stimulation, while resting-state activation did not differ between conditions. The authors interpret this task-specific pattern through the lens of state-dependent plasticity, the principle articulated by Silvanto and Pascual-Leone that neuromodulatory effects require specific brain states, such as task activation, to be expressed. The synaptic changes induced by iTBS may lie dormant until the network is recruited by actual cognitive-motor demand.

Correlation analyses added mechanistic texture. Changes in calculation quantity were positively correlated with HbO changes in the left secondary motor cortex and negatively correlated with activation in the right Wernicke area, the parietal region corresponding to the right supramarginal gyrus. Accuracy improvements rose with bilateral secondary motor cortex activation but declined with greater activation in the right primary motor cortex and right Wernicke area. Under the neural efficiency hypothesis, efficient networks activate critical regions precisely while suppressing interfering ones. The serial subtraction task is language-dependent and left-lateralized, so fluent performance plausibly demands focused allocation to the left language-motor circuit while suppressing right-hemisphere vigilance and error monitoring signals that would otherwise divert attention.

Perhaps the most intriguing finding concerns the secondary motor cortex as a relay station. After DTMS, interhemispheric activation correlations between the left and right dorsolateral prefrontal cortex, secondary motor cortex, and somatosensory association cortex were particularly strong, suggesting that excitatory stimulation may reduce interhemispheric inhibition and shift homologous regions from alternating suppression toward synchronous excitation. Left prefrontal and posterior parietal activation rose in parallel, and left secondary motor cortex hemodynamics increased alongside both. The authors propose that DTMS under the iTBS protocol strengthens the frontoparietal network, with the secondary motor cortex functioning as a transitional hub that transforms abstract cognitive commands from the prefrontal cortex and concrete sensory information from the parietal cortex into coordinated motor output. This bridging role is especially prominent in the left hemisphere, where the language and motor systems converge.

Exploratory functional connectivity analyses revealed several DTMS-induced changes, including enhanced connectivity between the left Broca area and right prefrontal, primary motor, and secondary motor regions during the dual task, but none survived false discovery rate correction, so the authors treat these as preliminary observations rather than definitive evidence of network reorganization. Baseline comparisons did show, after correction, that dual-task functional connectivity was significantly lower than resting-state connectivity, a pattern consistent with the neural efficiency hypothesis but also with alternative explanations such as task-dependent network segregation. Additional hemodynamic features indicated that cortical HbO response speed accelerated significantly in the bilateral prefrontal cortex and right Broca area after stimulation, and HbR response speed increased in several regions, with integral values mirroring mean concentration changes and confirming task-related activation levels.

The study has clear limits that the authors acknowledge candidly. There were no separate single-task walking or single-task calculation conditions and no quantitative gait measures, so the hemodynamic responses reflect combined cognitive and motor processes rather than isolated mechanisms. fNIRS captures cortical signals only, so the findings cannot directly establish whether DTMS modulates subcortical functional connectivity, even though prior work shows the H7 coil reaches the anterior cingulate. Blinding was procedural rather than formally verified, and the modest sample size of nineteen demands replication. Long-term effects of repeated deep stimulation on deep brain tissue, including glial responses and chronic inflammation, remain unexplored and warrant longitudinal multimodal imaging studies.

Even so, the trial offers a compelling proof of concept that a single session of wide-field excitatory neuromodulation can expand the computational capacity available for walking-and-thinking behavior in healthy brains, without degrading correctness. Because dual-task impairment tracks fall risk, reduced mobility, and cognitive decline in aging and neurological disorders, establishing a baseline framework in healthy adults is a prerequisite for translational work. If the state-dependent plasticity principle holds in older or clinical populations, future protocols might time stimulation to coincide with task engagement, individualize coil positioning, and combine larger cohorts with multimodal neuroimaging to determine whether the frontoparietal-secondary motor relay can be reliably strengthened. For now, the image of a brain that computes faster on its feet after a few minutes of patterned magnetic pulses is a vivid demonstration of how far noninvasive network modulation has traveled from the single-hotspot era.

Subject of Research: Neuroscience

Article Title: Deep TMS modulates neurovascular responses and enhances dual-task computation in healthy adults

Article References: Zeng, B., Wang, W., Ding, Z., Wang, C., Li, C., Yuan, R., Zhou, B., & Zhu, Y. (2026). Deep TMS modulates neurovascular responses and enhances dual-task computation in healthy adults. iScience, 29(11), Article 117586. https://doi.org/10.1016/j.isci.2026.117586

Image Credits: AI Generated

DOI: 10.1016/j.isci.2026.117586

Keywords: deep TMS, dual-task, fNIRS, neuromodulation, frontoparietal network, motor cortex, cognitive-motor integration, Deep, modulates, neurovascular, responses, enhances

The review is notable for its scope and its candor. Sugar and Pirio Richardson searched PubMed, Embase, Web of Science, and Cochrane databases for studies published between 2019 and 2025 that described non-motor symptoms in dystonia and changes after treatment. From 408 records identified after removal of duplicates, 89 met the criteria for full-text review, and ultimately 22 reports plus 10 additional studies found through reference screening were included. The authors stratified the evidence by treatment type, including deep brain stimulation, ablative surgery, botulinum toxin injection, and non-invasive therapies such as physical therapy and psychotherapy, and by dystonia body distribution, distinguishing generalized from focal and segmental forms. The picture that emerges is one of a field still in its infancy, where non-motor outcomes are almost always secondary endpoints, scales are heterogeneous, and meta-analysis is precluded by the sheer variety of assessment tools used across studies.

The neuroimaging literature offers a unifying explanation for why dystonia patients suffer so much beyond their movements. Dystonia is increasingly understood as a network disorder, and resting-state functional imaging studies have documented abnormal activity in brain structures involved in both motor and non-motor networks. The cerebellum, which modulates input related to sensorimotor, salience, and default mode networks, has been implicated across non-motor symptoms including pain perception, depression, and anxiety. In cervical dystonia, social phobia is common and appears to arise from a sense of body deformation and anticipation of negative perception by others, a self-conscious hypervigilance in public spaces that is out of proportion to motor severity and leads to self-stigmatization, isolation, and depression. This perception is thought to reflect erroneous assignment of salience to unimportant stimuli, involving salience network structures like the amygdala and cerebellar structures that interact with the salience network. The severity of the neuropsychiatric burden is stark: 32.3 percent of patients with isolated dystonia report a history of suicidal behavior, a rate significantly higher than that of the general population.

Sleep and wake symptoms are equally prevalent and equally neglected. Fatigue and excessive daytime sleepiness significantly impact quality of life in dystonia patients, influencing their perceptions of the disease and their satisfaction with treatment. Compared to healthy controls, patients with dystonia exhibit reduced daytime activity as measured by both self-report and accelerometry data. Sleep disturbances are present in up to 70 percent of patients with cervical dystonia, and across various dystonia subtypes patients experience higher rates of insomnia, poorer sleep quality, reduced sleep duration, and lower sleep efficiency. Dysregulation of circadian rhythm networks, particularly cerebellar hyperactivity, has been proposed as a potential contributing factor to these sleep-wake disturbances. In Meige syndrome, a segmental form of dystonia affecting the face and neck, sleep disorders were observed in 23 percent of participants in one study, typically developing three to fifteen years before the onset of motor symptoms, highlighting sleep dysfunction as a primary non-motor feature of the disorder rather than a consequence of it.

Pain, perhaps the most tangible of the non-motor symptoms, has the most consistent treatment response. In cervical dystonia, pain arises from complex mechanisms including increased muscle contraction affecting muscle spindles and their associated pain receptors, alterations in peripheral sensitivity due to neuropeptide activity, abnormal processing of pain pathways, and impaired inhibitory signalling. Patients with blepharospasm frequently experience eye pain and photophobia. Across four studies involving 141 patients with cervical dystonia, botulinum toxin consistently relieved pain as measured by the McGill Pain Questionnaire, the Toronto Western Spasmodic Torticollis Rating Scale pain subscale, and the Pain Numeric Rating Scale. In a large case series of 408 patients with oromandibular dystonia treated with botulinum toxin injections, significant improvements were found in pain, sleep, mood, and psychosocial functioning as assessed by the Oromandibular Dystonia Questionnaire-25, with idiopathic patients demonstrating greater improvements than those with tardive dystonia. However, pain may recur between injection cycles, and its persistence is associated with lower patient satisfaction with treatment.

The surgical evidence is far more mixed. Deep brain stimulation of the globus pallidus internus, the subthalamic nucleus, and the ventral intermediate nucleus of the thalamus has been investigated over the past five years in thirteen publications, including one randomized controlled trial, six case series, five prospective non-controlled studies, and one prospective crossover double-blind study. In a randomized double-blind crossover trial of six patients with laryngeal dystonia, thalamic deep brain stimulation improved mood as assessed with the Beck Depression Inventory, while cognition as measured by the Montreal Cognitive Assessment was not impacted. In a study of 37 patients with cervical dystonia, pallidal deep brain stimulation significantly improved pain as measured after five years of stimulation, but did not find an impact on mood as measured by the Hospital Anxiety and Depression Scale despite significant motor improvement. In direct comparisons of subthalamic versus pallidal stimulation in 71 patients with isolated dystonia, both targets produced equivalent long-term benefits for mood and pain, though the subthalamic group experienced improvements in motor and mood symptoms within one month while similar benefits in the pallidal group were not observed until six months. Neither target had an impact on cognitive function as assessed by the Mini Mental Status Exam and the Montreal Cognitive Assessment.

Ablative therapies, including radiofrequency and focused ultrasound ablation of the pallidothalamic tracts, show promise in targeting both motor and non-motor symptoms including mood and pain, but come with inherent risks. In 2022, a group reported on 35 patients with cervical dystonia who underwent unilateral radiofrequency ablation of Forel’s Field H1, finding that pain scores improved by 40 percent as measured by the Toronto Western Spasmodic Torticollis Rating Scale pain subscale, but with a high incidence of adverse events in 50 percent of patients. Expanding upon this work, the same group reported on ten patients with cervical dystonia in 2024 who underwent focused ultrasound pallidothalamic tractotomy, demonstrating modest improvement at six months in depression, anxiety, and apathy as assessed by the Beck Depression Inventory, the Beck Anxiety Inventory, and the Apathy Evaluating Scale. Adverse events included prolonged loss of hand dexterity in 30 percent of participants, thought to be related to associated hypotonia. Both studies were limited by short-term follow-up ranging from six to eighteen months, leaving the important question of long-term benefits to future study.

Botulinum toxin, the mainstay of focal dystonia treatment, consistently improved mood and pain across multiple dystonia populations, though the mood benefit appears transient. Over the past five years, six studies examined the impact of botulinum toxin injection on mood symptoms in cervical dystonia. Four studies found improvements in mood at the peak of botulinum toxin effect, four to six weeks post-injection, in a combined total of 121 patients, measured using various scales including the Beck Anxiety Inventory, the Beck Depression Inventory, the Hamilton Anxiety and Depression Rating Scales, the State-Trait Anxiety Inventory, and the Toronto Western Spasmodic Torticollis Rating Scale psych subscale. In contrast, two studies with follow-up intervals ranging from three months to two years reported no sustained impact on mood symptoms in a combined 105 patients. These findings suggest that botulinum toxin has an immediate impact on mood symptoms but may not produce sustained modifications. Notably, changes in non-motor symptoms including mood, pain, and sleep did not correlate with changes in motor severity, supporting non-motor symptoms as primary features of cervical dystonia independent of motor symptom severity and suggesting a direct effect of botulinum toxin on these symptoms.

Non-invasive therapies, including physical therapy, psychotherapy, and behavioral interventions, produced mixed results but offer important insights into the patient experience. In one randomized controlled trial, 40 patients with cervical dystonia received specialized physical therapy while 32 patients followed a standard physical therapy protocol, and both groups showed significant improvements in pain and mood as measured by the Toronto Western Spasmodic Torticollis Rating Scale pain scale, the Pain Numeric Rating Scale, the Beck Anxiety Inventory, and the Beck Depression Inventory, though no between-group differences were observed at twelve-month follow-up. Another negative crossover randomized controlled trial involving 17 patients with cervical dystonia compared botulinum toxin treatment alone, botulinum toxin with kinesiotaping, and botulinum toxin with sham taping, finding no differences between groups in non-motor symptoms as measured by the Dystonia Non-Motor Symptoms Questionnaire, the Hospital Anxiety and Depression Scale, and the Pittsburgh Sleep Quality Index. An internet-based cognitive behavioral therapy program compared to routine care in a small randomized controlled study of 20 patients with cervical dystonia over a six-month period showed trends toward improved anxiety and depression scores, and participants reported that the treatment was beneficial, but no significant differences were observed between the two groups. A survey of 118 participants with cervical dystonia found that illness perception and coping strategies accounted for 59 percent of the variance in anxiety and 61 percent of the variance in depression and health-related quality of life, highlighting the importance of these psychological factors in adjustment to the disease.

The authors of the review are careful to acknowledge the limitations of the evidence base. The review protocol was not published and was expanded after the initial PubMed review to include the other databases, introducing the possibility of reporting bias. Within the primary studies, common biases included performance bias given the lack of a control arm in most reports, and outcome reporting bias, especially as non-motor symptoms were mostly secondary outcomes and non-significant findings were less likely to be included for publication. The overall quality of the studies reviewed was limited by small sample sizes and the absence of control groups. Meta-analysis of the reviewed data is precluded by the heterogeneous use of scales in non-motor symptom assessment, a well-documented challenge in dystonia research. Several validated scales have been developed for distinct dystonia subgroups, but these generally focus on motor symptoms, limiting their capacity to comprehensively assess non-motor outcomes. Progress has been made in the past five years, including the development of a digital patient-centered outcome tool to measure non-motor symptoms in cervical dystonia, the Pain Scale for Adult-Onset Idiopathic Dystonia and its validation in cervical dystonia, the Dystonia Pain Classification System, and the Oromandibular Dystonia Rating Scale, which includes non-motor domains.

Perhaps the most provocative finding of the review is the emerging evidence that dystonia patients can be phenotyped into distinct subgroups based on non-motor symptom severity rather than motor symptom severity. Recent studies have identified two phenotypes within the cervical dystonia population: one motor-predominant, with fewer non-motor symptoms, lower disability, and better quality of life, and another non-motor-predominant, with higher rates of depression, anxiety, sleep dysfunction, cognitive complaints, and pain. These subgroups did not differ in sex, motor severity, duration of dystonia, or the presence of tremor or alleviating maneuvers, though a potential age difference was noted, with the non-motor-predominant group being older. Regarding sex differences, other research has shown that women with blepharospasm have a higher frequency of non-motor symptoms and are more likely to have multiple comorbid non-motor symptoms, and women with cervical dystonia report worse health-related quality of life compared to men. The impact of sex on dystonia and non-motor symptoms warrants further investigation, especially given the increased penetrance of cervical dystonia in women, who are affected at least twice as often as men.

The theories of overlapping motor and non-motor network dysfunction suggest that motor treatments could potentially influence non-motor symptoms, and while this hypothesis is plausible and offers practical benefits, evidence supporting a sustained and clinically significant non-motor response to motor treatments remains inconclusive. The findings of this systematic review do not clarify whether the non-motor symptoms of dystonia are primary features of the disease or secondary to motor symptoms, and it remains likely that both factors contribute to the patient experience. Similar to Parkinson’s disease, a tailored approach addressing each patient’s specific combination of non-motor features, with symptom-specific interventions, may be necessary for optimal management. The authors conclude that better detection and treatment of non-motor symptoms in dystonia are needed to wholly treat patients with this disorder, and that future research must focus on high-quality studies with non-motor improvement as a primary outcome, standardized rating scales across studies, and refined phenotyping of dystonia subgroups to facilitate meta-analyses and improve the reproducibility of treatment outcomes.

Subject of Research: Neuroscience

Article Title: Treating non-motor symptoms in dystonia: a systematic review

Article References: Sugar, D., & Pirio Richardson, S. (2025). Treating non-motor symptoms in dystonia: a systematic review. Dystonia, 4, Article 14545. https://doi.org/10.3389/dyst.2025.14545

Image Credits: AI Generated

DOI: 10.3389/dyst.2025.14545

Keywords: dystonia, non-motor symptoms, botulinum toxin, deep brain stimulation, systematic review, neurology, pain, quality of life, Treating, non-motor, symptoms, systematic

The study, published in July 2025 in the journal Dystonia, is, according to its authors, the first report of advanced programming and lead revision surgery in GPi deep brain stimulation for DYT-11. That gap in the literature is itself telling. Because the condition is rare and because most published patients respond quickly to simple monopolar settings, clinicians have had almost no guidance for what to do when stimulation falls short. The meta-analytic literature on myoclonus dystonia is dominated by single-patient reports — the median number of patients per study in one analysis was just one — which makes the field especially vulnerable to publication bias toward success stories. The Florida team’s retrospective chart review of three patients offers a rare look at the troubleshooting playbook that usually stays inside the clinic.

The first patient, a 27-year-old woman with a family history of DYT-11 and a confirmed SGCE variant, had developed generalized myoclonus and cervical dystonia in early childhood and received bilateral GPi leads at age eighteen. Years later she arrived at the Fixel Institute with near-constant jerks and dystonic pain despite functioning hardware. Imaging-based lead localization showed her electrodes sat reasonably within the posteromedial GPi, but monopolar testing revealed narrow therapeutic windows: the currents needed to help her symptoms quickly triggered side effects, likely from current spreading into the adjacent internal capsule. Thirteen months of systematic programming — sweeping amplitudes, pulse widths, and frequencies, and trying bipolar configurations — failed to deliver satisfactory control of both her myoclonus and her dystonia.

The surgical team then did something that had never been documented for this disease: they replaced her leads. Three months after bilateral revision surgery with newer-generation electrodes, a single programming session resolved her dystonia-related pain and tension completely and significantly reduced her spontaneous myoclonus. The new leads were positioned lateral and ventral to the originals, which allowed the team to tolerate higher, more effective settings. The numbers are striking. On the Burke-Fahn-Marsden scale, her dystonia score in the stimulation-on state fell from 21 before revision to 1 at seven months, settling at 3 by thirteen months. What had been a near-failure of neuromodulation became, after a few millimeters of repositioning, a near-complete response.

The second case illustrates a different failure mode. A 30-year-old woman diagnosed in childhood had benefited rapidly from her original GPi implants, but her condition deteriorated precipitously and her device was explanted over concern for a hardware infection. When new leads were reimplanted, the benefit never fully returned. At the Florida center, testing showed low thresholds for side effects, and lead localization revealed that the replacement electrodes sat dorsal on the right and anteromedial on the left relative to the originals — subtly but meaningfully off target. Her programming had grown baroque, relying on interleaving, a technique that cycles two independent stimulation settings through the same lead, without perceived benefit. After a multidisciplinary evaluation, the team revised the leads again. Post-revision, she tolerated higher currents on simple monopolar settings; one year later she had no residual dystonia, and at 23 months her benefit was sustained with a United Dystonia Rating Scale score of 13, down from 25 before revision.

The third patient required no surgery at all, only persistence at the programming console. A 75-year-old woman with a decades-long history of tremor, dystonia, and myoclonus, diagnosed late in life through genetic testing, underwent staged bilateral GPi implantation. In the operating room, stimulation at her most ventral contact actually worsened her myoclonus — an early warning that standard settings would not suffice. Simple configurations and pulse width adjustments failed, and raising amplitude brought benefit only at the cost of capsular side effects. The breakthrough came through increasingly complex configurations: double monopolar settings improved her myoclonus, and a three-contact bipolar arrangement unlocked further amplitude tuning. Six months after her second lead was placed, her Toronto Western Spasmodic Torticollis Rating Scale score had fallen from 38 to 14; at twelve months it was 7, and at 33 months she reported no residual disability.

Beyond the clinical narratives, the study contributes something more novel: brain recordings from inside the patients’ own stimulators. All three were implanted with sensing-enabled pulse generators that capture local field potentials, or LFPs — the summed electrical chatter of neurons near the electrode contacts. The team extracted 30-second resting recordings, computed power spectra using Welch’s method, and normalized the features with the FOOOF technique, which separates periodic oscillations from the background aperiodic signal. Across the group, effective stimulation and optimization were accompanied by statistically significant reductions in both low beta power, spanning roughly 12 to 20 hertz, and high beta power, from 20 to 30 hertz, with p-values of 0.02 and below 0.001 respectively. In each patient, broadband beta activity that had been prominent before revision or optimization diminished once the therapy was working.

That observation matters because beta oscillations in the pallidum are an emerging, if contested, biomarker in the dystonia field. In Parkinson’s disease, excessive beta activity in the motor circuitry is a well-established target of stimulation, and some programmers have begun using beta suppression as feedback for tuning settings. In dystonia, the picture is murkier: some studies link low-frequency pallidal oscillations to involuntary muscle activity, while others argue that beta power is not elevated in heterogeneous dystonia populations — one small study even used dystonia patients as the control group for studying beta bursts in Parkinson’s disease, on the assumption they would show no elevation. The Florida team suggests that beta activity may play an underrecognized role in genetic dystonia specifically, but they are careful to flag the caveat that their cohort numbers three patients and requires confirmation in larger samples. Prior LFP work in myoclonus dystonia has been limited to a single artifact-reduction paper involving three patients, none with confirmatory genetic data.

The practical lessons the authors draw are as valuable as the electrophysiology. Their troubleshooting algorithm starts with a monopolar review; if side effect thresholds are uniformly below 3 milliamperes at a 90-microsecond pulse width and 130 hertz, they suspect the lead cannot deliver enough energy to treat dystonia, and they escalate methodically — amplitude first, then pulse width, then frequency, then bipolar and directional configurations, reserving interleaving and cycling for patients who initially respond and then lose benefit. They also emphasize a phenomenological pitfall: myoclonus tends to respond faster and more completely than dystonia, so clinicians may mistake adequate myoclonus control for overall success and accept suboptimal dystonia improvement. Setting expectations — that dystonia relief may take months — is framed as central to patient satisfaction.

For a disease this rare, three carefully documented cases can reshape practice. The series demonstrates that a suboptimal response to deep brain stimulation in DYT-11 is not necessarily the end of the road: lead position, side effect thresholds, and programming complexity all offer levers, and modern sensing devices may eventually guide those adjustments with physiological feedback rather than trial and error. The authors call for future work characterizing the electrophysiology and brain connectomics of DYT-11, and for studies of how lead location relates to biomarkers of response. Until then, their message to clinicians is quietly radical for a field accustomed to easy wins: in myoclonus dystonia, the first setting is often not the best setting, and the tools to fix a struggling stimulator already exist.

Subject of Research: Troubleshooting pallidal deep brain stimulation, including lead revision and advanced programming, in genetically confirmed DYT-11 myoclonus dystonia

Article Title: Challenges in deep brain stimulation for DYT-11: a single center troubleshooting experience

Article References: Remz, M. A., Garg, V., Johnson, K. A., Au, K. L. K., Babajani-Feremi, A., Lavu, V. S., de Hemptinne, C., & Wong, J. K. (2025). Challenges in deep brain stimulation for DYT-11: a single center troubleshooting experience. Dystonia, 4, Article 14485. https://doi.org/10.3389/dyst.2025.14485

Image Credits: AI Generated

DOI: 10.3389/dyst.2025.14485

Keywords: deep brain stimulation, DYT-11, myoclonus dystonia, SGCE gene, globus pallidus, lead revision, local field potentials, beta oscillations, dystonia, neuromodulation, programming, Challenges

Designing clinical trials for dystonia poses formidable methodological challenges because the disorder is both clinically and etiologically heterogeneous. A mechanism-based approach requires deeper understanding of underlying pathophysiology and identification of factors that may impact disease progression, while a phenotypic approach focuses on improving dystonic symptoms by discovering new drugs or building upon existing therapies. Primary outcome measures have been variable, relying mainly on patients’ subjective reports of therapeutic benefit, and objective quantification remains difficult due to the diversity of dystonia presentations. In 2013, the Movement Disorders Society commissioned a task force to review 36 potential rating scales, ultimately recommending seven for craniocervical, laryngeal, and generalized dystonia, including the Toronto Western Spasmodic Torticollis Rating Scale for cervical dystonia, the Jankovic Rating Scale for blepharospasm, the Voice Handicap Index for laryngeal dystonia, and the Fahn-Marsden Dystonia Rating Scale for generalized dystonia. The review’s authors emphasize that development of sensitive and objective clinical outcome measures will be a crucial prerequisite for successful future trials.

On the pharmacological front, the past five years have seen trials targeting the neurotransmitter pathways implicated in dystonia, including dopamine, acetylcholine, and GABA. Levodopa remains the cornerstone treatment for dopa-responsive dystonia, which accounts for about five percent of childhood dystonias, but there are currently no active clinical trials studying dopaminergic therapies. Trihexyphenidyl, an anticholinergic drug introduced in the 1950s, continues to be one of the most effective treatments for generalized dystonia, though side effects like confusion, dry mouth, and drowsiness often limit its use in adults. The Children’s Mercy Hospital in Kansas City is running the TRIKE2 trial, a Phase 1, 16-week, single-arm pilot study evaluating how CYP2D6 and CYP2C19 genotypes influence trihexyphenidyl metabolism in 40 pediatric patients with dystonic cerebral palsy, aiming to inform the feasibility of future pharmacogenomic trials. Meanwhile, the PREDICT-ITB trial at Baylor College of Medicine will enroll 65 children with dystonic cerebral palsy through 2029, following a standardized intrathecal baclofen titration protocol with the Barry-Albright Dystonia Scale as the primary outcome measure at baseline, three, six, and twelve months.

One of the most striking results came from the Massachusetts Eye and Ear Infirmary, which completed recruitment in 2024 for a randomized, placebo-controlled crossover trial of sodium oxybate in spasmodic dysphonia and voice tremor. The trial enrolled 117 participants with laryngeal dystonia, both alcohol-responsive and alcohol-nonresponsive, with and without voice tremor. Results published in 2025 showed that sodium oxybate significantly reduced symptom severity in the alcohol-responsive group, with a mean Visual Analog Scale severity score of 28.0 versus 14.2 for placebo, a difference that reached statistical significance at p = 0.008. No significant benefit was observed in the alcohol-nonresponsive group. Adverse events were mild to moderate, including dizziness in 48 percent, daytime sleepiness in 20 percent, and mild nausea in 14 percent, without serious adverse events. This is the first controlled clinical trial demonstrating sodium oxybate as a therapeutic option for laryngeal dystonia and voice tremor, particularly for alcohol-responsive patients.

VMAT-2 inhibitors, which received FDA approval as valbenazine and deutetrabenazine in 2017 for tardive dystonia and dyskinesia, have been repurposed in recent trials. From 2021 to 2023, the Orthopedic Foundation assessed valbenazine for cervical dystonia in a Phase 4 open-label study of 13 participants who completed 16 weeks of treatment titrated to 80 milligrams per day while maintaining botulinum toxin treatment. Preliminary abstract results reported significant improvements in the TWSTRS at p = 0.01 and in the Visual Analog Scale for pulling at p = 0.02. The University of Pennsylvania recently completed the AUDYT trial, an open-label study of deutetrabenazine in 15 adults with non-dopa-responsive isolated dystonia, titrating the drug from 12 to a maximum of 48 milligrams per day over 12 weeks. Only 40 percent of participants tolerated the maximum dose, and although the median change in the Global Dystonia Rating Scale was zero, the variability was notably wide, suggesting a need for a larger cohort in future trials. Glutamate-targeting drugs have also been explored: perampanel, an AMPA receptor antagonist, showed modest improvements in pain relief and sleep quality in cervical dystonia but was limited by tolerability, while dipraglurant, a negative allosteric modulator of the mGlu5 receptor, was well-tolerated in blepharospasm but provided no meaningful clinical benefit.

Botulinum toxin therapy continues to gain traction as a high-yield area for dystonia research, with five commercially available formulations FDA-approved for first-line treatment of cervical dystonia and only two approved for blepharospasm. The most significant recent advance is daxibotulinumtoxinA, whose molecular size and unique stabilizing excipient peptide enhance binding through electrostatic charge and reduce spread of the toxin, leading to a longer therapeutic duration. In the pivotal ASPEN-1 Phase 3 trial completed in 2020 across 60 international sites, 291 participants with cervical dystonia were randomized to daxibotulinumtoxinA 125 units, 250 units, or placebo. The placebo group had a mean TWSTRS reduction of 4.3 points compared to 12.7 points in the 125-unit group and 10.9 points in the 250-unit group, both highly significant. The duration from injection to loss of 80 percent of peak effect was significantly longer than other botulinum toxin type A formulations, lasting 24 weeks and 20 weeks respectively, with no dose-dependent increases in adverse events. The subsequent ASPEN-OLS open-label extension enrolled 357 patients over 52 weeks, confirming that successive treatments were well-tolerated with dysphagia rates remaining stable or decreasing after repeat dosing.

Other botulinum toxin formulations are being validated in clinical trials even without FDA approval for dystonia. PrabotulinumtoxinA, FDA-approved for glabellar lines, completed a Phase 2 randomized placebo-controlled trial in 57 patients with cervical dystonia, reporting no treatment-related serious adverse events up to 20 weeks, with peak efficacy occurring within two to eight weeks and wearing off starting at 16 weeks. NeubotulinumtoxinA, developed in South Korea as a cost-effective alternative, demonstrated comparable efficacy to abobotulinumtoxinA in a 48-week crossover study of 52 Thai patients with cervical dystonia. LetibotulinumtoxinA showed significant reduction in the Jankovic Rating Scale at four weeks in a 220-participant blepharospasm trial, confirming non-inferiority. Beyond new formulations, trials are optimizing injection parameters: a Phase 4 noninferiority study of 207 patients demonstrated that shorter incobotulinumtoxinA injection intervals of eight weeks were safe and effective for patients with early waning of benefit, while a Western University trial in Canada showed that kinematic-guided onabotulinumtoxinA injection achieved faster symptom reduction than visual assessment alone, with the kinematics group reducing TWSTRS from 39.1 to 27.9 points at six weeks.

Deep brain stimulation, FDA-approved for dystonia in 2003 under a Humanitarian Device Exemption, has seen exciting progress with new targets and innovative programming techniques. A 2024 French multicenter trial published by Cuartero and colleagues implanted dual DBS in 12 patients with medically refractory dystonia, comparing GPi, STN, and thalamic centromedian-parafascicular monotherapy against combined targets. The study confirmed the efficacy and safety of GPi-DBS with 44 percent improvement in dystonia severity at three months, but found no additional benefit from dual-target stimulation or alternative targets alone. In China, the MEIGES trial at Beijing Tiantan Hospital is enrolling 110 patients with idiopathic craniofacial dystonia to investigate whether STN-DBS is noninferior to GPi-DBS, while Qilu Hospital is comparing the two targets in Meige syndrome with 100 patients. Peking University People’s Hospital published results from 98 patients with primary Meige syndrome, showing BFMDRS improvements of 61 to 66 percent at one year and 65 to 71 percent at three years for DBS, compared to 58 percent at one year and 50 percent at three years for pallidotomy. Two active trials at Indiana University and Massachusetts Eye and Ear are exploring DBS for laryngeal dystonia using novel outcome measures including acoustic voice recordings, high-speed videoendoscopy, and intraoperative microelectrode recordings of brain signals during speech production.

Innovative DBS programming is advancing toward personalized therapy. The University of California, San Francisco has enrolled 25 patients, including five with dystonia, in a closed-loop DBS study formulating individualized adaptive algorithms based on specific cortical biomarkers, with each patient undergoing four weeks of open-loop versus four weeks of adaptive mode stimulation. Wuerzburg University Hospital is recruiting 80 participants for a prospective randomized double-blind crossover trial comparing computer-assisted image-based DBS programming against conventional clinician-based programming, aiming to optimize stimulation settings and reduce non-responder rates. Novel brain lesioning techniques are also being tested as alternatives to DBS. The University of Maryland launched a Phase 1 trial in 2024 for MR-guided focused ultrasound pallidotomy in task-specific focal hand dystonia, enrolling 10 patients who failed botulinum toxin and DBS, while the University of the Philippines Manila is investigating focused ultrasound pallidothalamic tractotomy for X-linked dystonia-parkinsonism, now available through expanded access until 2026. The All India Institute of Medical Sciences is planning a cohort study and registry of 250 patients undergoing lesioning procedures for movement disorders, with long-term functional outcomes assessed over a year.

Non-invasive brain stimulation, gene-targeted therapies, and rehabilitative approaches round out the therapeutic landscape. Transcranial magnetic stimulation has shown potential in small cohorts but variability in technique, administration, and response remains a barrier to FDA approval for dystonia. A randomized crossover trial at AIIMS New Delhi targeting the inferior parietal lobule in 16 patients with task-specific focal hand dystonia showed significant improvement in the Writer’s Cramp Rating Scale after real stimulation compared to sham, while Duke University is recruiting for accelerated TMS trials using functional MRI to guide individualized stimulation. Transcranial ultrasound stimulation is emerging as a novel modality, with the University Health Network in Toronto studying low-intensity ultrasound to non-invasively stimulate the basal ganglia. Gene therapy has made rapid advances: in November 2024, the FDA approved the first gene therapy for aromatic L-amino acid decarboxylase deficiency based on positive Phase 1/2 results, with the National Taiwan University Hospital trial showing mean Peabody Developmental Motor Scales-2 scores increasing from 10.4 to 80.5 and cerebrospinal fluid homovanillic acid rising from 6.6 to 30.2 nanomoles per liter in 26 patients. In vitro studies are exploring CRISPR-Cas9 disruption of mutant TorsinA in DYT1 dystonia fibroblasts, showing selective reduction of mutant protein with phenotypic recovery, though no active clinical trials yet test gene-targeted therapy in hereditary dystonia patients. Rehabilitative techniques including vibration therapy, transcutaneous electrical nerve stimulation, osteopathic manipulation, behavioral exercises, and neurofeedback brain-computer interface training are all being explored as adjunctive therapies, with a French TENS trial showing an eight-point TWSTRS reduction from baseline in painful cervical dystonia and the University of Minnesota demonstrating that laryngeal vibrotactile stimulation can improve voice quality within 15 to 20 minutes, though the benefit decays within 30 minutes. The review’s authors conclude that successful therapy development should be based on precise understanding of pathophysiology, validated by sensitive clinical outcome measures in well-designed trials, and supported by correlating changes in biomarkers, with a biology-tailored approach essential as understanding of dystonia subtypes advances.

Subject of Research: Neuroscience

Article Title: A narrative review: clinical trials in therapeutic interventions for dystonia (2020 – 2025)

Article References: Ly, A., Mushtaheed, A., Soliman, M. E., Karp, B., & Cho, H. J. (2025). A narrative review: clinical trials in therapeutic interventions for dystonia (2020 – 2025). Dystonia, 4, Article 14547. https://doi.org/10.3389/dyst.2025.14547

Image Credits: AI Generated

DOI: 10.3389/dyst.2025.14547

Keywords: dystonia, clinical trials, botulinum toxin, deep brain stimulation, gene therapy, movement disorders, neurology, transcranial magnetic stimulation, narrative, review, clinical, trials

The distinction between structural and functional abnormality deserves particular emphasis because it shapes diagnostic expectations. Voxel-based morphometry studies, which quantify gray matter volume across the whole brain, have reported modest volume differences in the sensorimotor cortex, basal ganglia, cerebellum, and thalamus in various dystonia cohorts, but these differences are typically small and inconsistent across samples. Diffusion imaging, which probes the integrity of white matter pathways by measuring the directional diffusion of water molecules, has similarly revealed subtle alterations in tracts connecting the nodes of the motor networks. The very subtlety of these findings reinforces the conclusion that dystonia is primarily a disorder of network dynamics rather than of network architecture. A brain can possess structurally intact connections yet still route information through those connections abnormally, much as a road network can be physically sound while traffic flows along it in a disorganized pattern. Functional imaging modalities capture this dynamic dimension directly, and the convergence of PET, functional MRI, EEG, magnetoencephalography, and functional near-infrared spectroscopy evidence on the same cortico-striato-pallido-thalamocortical and cerebello-thalamocortical loops provides a degree of multimodal consistency that no single modality could achieve alone.

PET studies occupy a distinctive position within this multimodal landscape because they can measure not only metabolic activity but also neurotransmitter systems in vivo. The ability to image dopamine, GABA, and acetylcholine signaling directly connects the network-level abnormalities observed in dystonia with the molecular-level pathophysiology suggested by genetic and pharmacological evidence. Dopamine receptor abnormalities, reduced GABAergic inhibition, and cholinergic dysfunction have each been implicated in dystonia through different lines of investigation, and PET provides the means to observe these systems operating within the living human brain. This molecular-to-network bridge is essential because it prevents the network perspective from becoming purely descriptive. Knowing that a particular loop is dysfunctional is one thing; knowing which neurotransmitter system within that loop is deranged is quite another, and the latter knowledge opens the door to pharmacological interventions that could complement neuromodulation approaches.

The invasive recordings obtained during deep brain stimulation surgery represent a qualitatively different level of measurement precision compared to non-invasive imaging. While functional MRI offers millimeter-scale spatial resolution, its temporal resolution is limited by the hemodynamic response, which unfolds over seconds. EEG and magnetoencephalography offer millisecond temporal resolution but with limited spatial precision. Recordings from DBS electrodes, by contrast, combine high temporal resolution with direct measurement of local field potentials from deep brain structures that are otherwise inaccessible in humans. These recordings have revealed pathological oscillatory activity in the beta and gamma frequency ranges within the basal ganglia and thalamus of dystonia patients, and analyses of stimulus-evoked responses have begun to map effective connectivity, meaning the directed influence of one region on another, within the affected circuits. The concept of effective connectivity is particularly important because it moves beyond correlation. Resting-state functional connectivity can tell us that two regions are co-active, but effective connectivity tells us whether activity in one region drives activity in the other, and in which direction. This directional information is what a network model of pathophysiology ultimately requires.

Non-invasive brain stimulation techniques offer a complementary approach to network interrogation that is fundamentally perturbative rather than observational. Transcranial magnetic stimulation applies brief magnetic pulses that induce electrical currents in the underlying cortex, transiently disrupting or modulating local activity. Transcranial electrical stimulation uses weak currents applied through scalp electrodes to achieve similar effects. Transcranial ultrasound stimulation, a more recent addition to the toolkit, uses focused ultrasound waves to modulate neural activity with potentially greater spatial precision than magnetic or electrical methods. The perturbative logic of these techniques is powerful: if a brain region is a critical node in a dysfunctional network, then transiently disrupting that region should produce measurable changes in network behavior, and those changes can reveal the region’s causal role. Beyond their diagnostic utility, these stimulation methods also carry therapeutic potential. Applications designed to decrease cortical excitation, increase inhibition, and normalize abnormal plasticity have shown promise in small studies, and the ability to combine stimulation with concurrent EEG recording enables closed-loop paradigms in which stimulation parameters are adjusted in real time based on the brain’s response.

The computational modeling platform known as The Virtual Brain represents a significant advance in the effort to integrate multimodal data into a coherent simulation of whole-brain dynamics. Rather than treating each imaging modality as a separate source of findings requiring separate interpretation, The Virtual Brain constructs a personalized model of an individual patient’s brain network using structural connectivity derived from diffusion imaging, then simulates the dynamic behavior that emerges from that architecture. The simulated activity can be compared against the patient’s actual functional imaging data, and discrepancies between simulation and observation can point to specific parameters of network dysfunction. This approach operates at the level of mean-field dynamics, a spatial abstraction that matches the resolution of most human imaging work, and it transforms the network perspective from a descriptive framework into a predictive one. A model that can reproduce a patient’s observed network abnormalities has the potential to predict how those abnormalities will respond to a given intervention, whether that intervention is a particular DBS target, a specific stimulation waveform, or a course of physiotherapy.

Across the clinical spectrum of dystonia, from focal forms affecting a single body region to generalized forms involving multiple body parts, and across the genetic etiologies that underlie many pediatric cases, the network perspective reveals both shared and distinct patterns of dysfunction. The shared patterns suggest common final pathways through which diverse etiologies converge on similar network-level derangements, which is consistent with the observation that symptomatic treatments such as DBS can be effective across multiple dystonia subtypes. The distinct patterns, meanwhile, suggest that phenotypic and genotypic subtypes may require different therapeutic targets or different stimulation parameters. This tension between convergence and divergence is a central theme in the network pathophysiology of dystonia, and resolving it will require the kind of multimodal, integrative approach that the review advocates.

Several understudied dimensions of dystonia network pathophysiology merit attention in future research. Longitudinal and developmental dynamics remain poorly characterized, particularly the question of how the dystonic network evolves over time in individual patients and how it differs between pediatric and adult-onset forms. The relationship between genotype and phenotype, as both axes become better characterized through objective measures, should provide a framework for understanding how specific genetic mutations give rise to specific network topographies. Motor behavior itself provides important constraints on circuit models, since overtrained movement patterns are thought to be a causal factor in many task-specific dystonias, and properly designed physiotherapy interventions should be able to modulate the network toward normalized function. Tremor in dystonia and functional dystonia represent two specific phenotypic aspects that warrant deeper investigation from a network perspective, as both may involve circuit-level mechanisms that overlap with, yet are distinct from, the core dystonic network pathology.

The translation of network insights into precision interventions is already underway. Circuit-guided neuromodulation, in which stimulation targets and parameters are selected based on an individual patient’s network profile, and closed-loop brain stimulation, in which stimulation is delivered only when pathological network states are detected, represent the leading edge of this translation. The convergence of improved imaging, higher-resolution invasive recordings, refined stimulation techniques, and increasingly sophisticated computational models creates the conditions for a genuinely personalized approach to dystonia treatment. Advancing these multimodal and integrative methodologies will be essential to unraveling the complex dynamics underlying dystonia and translating mechanistic insights into interventions that directly target the neural network basis of the disorder.

Subject of Research: Neuroscience

Article Title: Brain network pathophysiology in dystonia

Article References: Peterson, D. A., Kim, M., Chen, R., Eidelberg, D., Gallea, C., Horn, A. G., Lehericy, S., McIntosh, A. R., Perlmutter, J. S., Sadnicka, A., Sanger, T. D., Santarnecchi, E., Starr, P. A., Teller, J. K., Hallett, M., & Simonyan, K. (2026). Brain network pathophysiology in dystonia. Dystonia, 4, Article 15446. https://doi.org/10.3389/dyst.2025.15446

Image Credits: AI Generated

DOI: 10.3389/dyst.2025.15446

Keywords: dystonia, brain networks, deep brain stimulation, neuroimaging, neuromodulation, movement disorders, Brain, network, pathophysiology, scientific research