Against that backdrop, a clinical trial led by Honey and colleagues attracted significant attention when it reported the first prospective evaluation of deep brain stimulation of the ventral intermediate nucleus of the thalamus, or Vim-DBS, as a treatment for laryngeal dystonia. The phase I study enrolled six patients with laryngeal dystonia and co-occurring voice tremor in a randomized, double-blind, cross-over design. One group received three months of active stimulation followed by three months without it, while the other group followed the reverse sequence. Outcomes were measured with the Voice-Related Quality of Life questionnaire, the Voice Handicap Index, and the Unified Spasmodic Dysphonia Rating Scale. Now, a multidisciplinary team of specialists in neurology, neurosurgery, otolaryngology, and speech science has published a pointed commentary in the journal Dystonia arguing that the trial’s conclusions deserve far more caution than they have received.

The commentary, authored by Lena C. O’Flynn, Giovanni Battistella, Kristina Simonyan, and colleagues from institutions including Harvard Medical School, University Hospital Cologne, Tokyo Women’s Medical University, and University College London, identifies fundamental flaws in the trial’s methodology. Although the study was designed as a double-blind investigation, the authors report that all six patients became aware of the blinded sequence during the study, effectively rendering the blinding unsuccessful. Moreover, patients appear to have been retrospectively asked to guess which group they had been assigned to, a procedure not defined in the study’s clinical protocol. Because the cross-over design also lacked a wash-out period between the stimulation-on and stimulation-off conditions, the effects of each condition were likely contaminated by carryover from the other. Taken together, these failures effectively reclassified the trial as an open-label study, yet the outcomes were discussed as if patients had participated in a rigorously blinded cross-over design.

The stakes of such design failures are considerable. Invasive interventions such as deep brain stimulation are associated with placebo effects exceeding 50 percent, substantially stronger than those seen with non-invasive treatments, according to prior systematic reviews of surgical placebo controls. When blinding collapses, the door opens wide for expectation effects to masquerade as therapeutic benefit. The commentary’s authors emphasize that adherence to the pre-registered clinical trial protocol is imperative, particularly when the intervention involves brain surgery and the patient population is one that is often desperate for new options.

Beyond the blinding problems, the commentary takes issue with the outcome measures themselves. The Voice-Related Quality of Life and Voice Handicap Index are patient-reported instruments that capture the impact of voice problems on wellbeing, but they do not differentiate between disorder-specific symptoms. A well-known clinical observation holds that quality of life and laryngeal dystonia severity do not necessarily correlate: patients with mild symptoms may experience greater quality-of-life burden than those with severe symptoms. The overall severity component of the Unified Spasmodic Dysphonia Rating Scale, meanwhile, is a compound score blending laryngeal dystonia-specific features such as roughness, breathiness, and strain with voice tremor measurements, without offering differential diagnostics. Because these tools lack specificity, the commentary argues, they may inaccurately assess symptom severity, and more specialized assessments of dystonia-characteristic voice breaks, harshness, strain, breathiness, and tremor have been recommended instead.

The statistical picture is equally troubling. The trial’s authors stated that every patient reported improvement in quality of life and voice quality, yet the reported p-values of 0.07 and 0.06 did not reach conventional thresholds for statistical significance, and one of the six patients experienced no symptom improvement at all. The commentary notes that this statement contradicts the actual outcome of the trial and represents an over-generalization of the findings. Furthermore, the published report deviated from the pre-registered protocol: the planned analysis of variance with Bonferroni-corrected pairwise comparisons was not carried out as specified, and the enrolled cohort included a patient outside the study’s eligible age range. The findings, in short, showed no statistically significant improvement of laryngeal dystonia voice symptoms following thalamic stimulation, a result consistent with previous reports that also failed to demonstrate significant therapeutic effects of Vim-DBS in this disorder.

A crucial confound, according to the commentary, is the presence of voice tremor. All six patients in the trial had voice tremor, and some also had essential tremor, yet the study did not separately address the effects of thalamic stimulation on tremor symptoms. This matters enormously because Vim-DBS has an established track record for tremor disorders: it has been the standard of care for medication-refractory essential tremor since receiving approval from the United States Food and Drug Administration in 1997, and the same research group has previously shown that both bilateral and unilateral thalamic stimulation significantly reduce voice tremor symptoms, findings since replicated by other teams. In light of the absence of differential classification between dystonic and tremulous voice symptoms, the commentary suggests that any reported changes in the trial may have been driven more by reductions in voice tremor than by improvements in laryngeal dystonia itself.

The commentary then points to a more scientifically justified target. Unlike tremor, dystonic symptoms respond most reliably to stimulation of the globus pallidus pars interna, or GPi, and the subthalamic nucleus, particularly in patients with drug-refractory cervical, segmental, and generalized dystonias. Clinical reports of GPi-DBS in laryngeal dystonia patients without voice tremor have shown therapeutic benefit with minimal adverse events. In one detailed study, researchers performed auditory-perceptual evaluations of voice and speech in dystonia patients following bilateral pallidal stimulation and documented significant improvements in overall grade, roughness, and strain at twelve months after surgery, highlighting a delayed but substantial therapeutic impact. Similar long-term improvements have been reported in patients with segmental dystonia and in patients with Meige syndrome. Most tellingly, a recent comparative investigation of GPi-DBS and Vim-DBS in patients with laryngeal dystonia and co-occurring voice tremor found that pallidal stimulation was superior in reducing dystonia-characteristic voice breaks and improving continuous voicing and overall speech intelligibility, whereas thalamic stimulation was most effective at reducing tremor intensity.

The commentary also scrutinizes a follow-up neuroimaging study from the same group, which used diffusion MRI tractography in the same six patients to identify a stimulation sweet spot and define individual biomarkers of DBS response. The researchers arbitrarily categorized individual electrode contacts as effective or ineffective without reporting statistical or numerical thresholds for that classification. The segmentation analysis found that effective contacts targeted thalamic areas linked to the sensorimotor region while ineffective contacts targeted areas connected to the prefrontal region, but these findings did not correlate with laryngeal dystonia symptom improvement, and no statistically significant sweet spot emerged. Nevertheless, the follow-up study concluded that stimulation of thalamic sensorimotor areas is associated with symptom improvement and claimed to have identified a novel biomarker for DBS targeting. The commentary’s authors argue that such claims should be interpreted with caution, as they neither identify the primary pathophysiological factors of laryngeal dystonia nor define the neural correlates of the stimulation response.

The bottom line, the commentary concludes, is that the negative results of this phase I trial do not support advancing to phase II investigations of thalamic deep brain stimulation for laryngeal dystonia. Given the invasiveness of brain surgery and the readiness of most patients with laryngeal dystonia to enroll in new treatments, the authors urge that these findings not be overinterpreted when designing future studies or making clinical neurosurgical decisions. They call for future trials to adhere to Good Clinical Practice guidelines, with strict adherence to predetermined inclusion criteria, a priori hypotheses, and statistical thresholds, along with rigorous power analyses to ensure adequate sample sizes. They also recommend that researchers clearly define the type of speech impairment under study, distinguish co-occurring disorders such as voice tremor, incorporate both objective acoustic measures and patient-reported outcomes, and share voice recordings and precise electrode contact locations and stimulation parameters to enable replication. For a disorder that robs patients of fluent speech, the path forward, the authors insist, must be built on methodological rigor rather than premature optimism.

Subject of Research: Deep brain stimulation targeting for laryngeal dystonia treatment

Article Title: Is thalamic deep brain stimulation the right target to improve laryngeal dystonia symptoms?

Article References: O’Flynn, L. C., Barbe, M. T., Horisawa, S., Barkmeier-Kraemer, J. M., Blitzer, A., Greenlee, J. D. W., Hamzei-Sichani, F., Moretti, P., Nagarajan, S. S., Sharma, N., Rahimpour, S., Rusz, J., Tripoliti, E., Battistella, G., & Simonyan, K. (2025). Is thalamic deep brain stimulation the right target to improve laryngeal dystonia symptoms?. Dystonia, 4, Article 15271. https://doi.org/10.3389/dyst.2025.15271

Image Credits: AI Generated

DOI: 10.3389/dyst.2025.15271

Keywords: laryngeal dystonia, spasmodic dysphonia, deep brain stimulation, ventral intermediate nucleus, globus pallidus interna, voice tremor, clinical trial methodology, botulinum toxin, dystonia, neuromodulation, placebo effect, voice outcomes