Short- and Long-term Central Action of Botulinum Neurotoxin Treatment in Laryngeal Dystonia

Abstract

Background and objectives: Laryngeal dystonia (LD) is isolated task-specific focal dystonia selectively impairing speech production. The first choice of LD treatment is botulinum neurotoxin (BoNT) injections into the affected laryngeal muscles. However, whether BoNT has a lasting therapeutic effect on disorder pathophysiology is unknown. We investigated short-term and long-term effects of BoNT treatment on brain function in patients with LD.

Methods: A total of 161 participants were included in the functional MRI study. Statistical analyses examined central BoNT effects in patients with LD who were stratified based on the effectiveness and duration of treatment.

Results: Patients with LD who were treated and benefited from BoNT injections had reduced activity in the left precuneus compared with BoNT-naive and treatment nonbenefiting patients. In addition, BoNT-treated patients with adductor LD had decreased activity in the right thalamus, whereas BoNT-treated abductor patients with LD had reduced activity in the left inferior frontal cortex. No statistically significant differences in brain activity were found between patients with shorter (1-5 years) and longer (13-28 years) treatment durations. However, patients with intermediate treatment duration of 6-12 years showed reduced activity in the right cerebellum compared with patients with both shorter and longer treatment durations and reduced activity in the right prefrontal cortex compared with patients with shorter treatment duration.

Discussion: Our findings suggest that the left precuneus is the site of short-term BoNT central action in patients with LD, whereas the prefrontal-cerebellar axis is engaged in the BoNT response in patients with intermediate treatment duration of 6-12 years. Involvement of these structures points to indirect action of BoNT treatment on the dystonic sensorimotor network through modulation of motor sequence planning and coordination.

Figure 1. Graphical Review of the Current Literature Examining BoNT Central Effects in LD and Other Forms of Focal Dystonia

A review of 19 neuroimaging studies investigating the effects of BoNT treatment on brain function reveals the timeline of their treatment cycle at which patients were assessed in each study (see eTable 1, links.lww.com/WNL/C151). Most of the studies recruited patients around the peak efficacy of BoNT injections at 1–1.5 months posttreatment; the short-and long-term effects have not yet been investigated. The bars show the total number of studies per BoNT modulatory effect on brain activity. Studies involving patients with LD are shown with striped color bars; studies involving other forms of focal dystonia (blepharospasm, orofacial dystonia, cervical dystonia, hand dystonia) are shown in solid color bars. BoNT = botulinum neurotoxin; LD = laryngeal dystonia.

Figure 2. Overview of Patient Stratification Depicts (A) Primary Experimental Groups and (B) Secondary Experimental Groups Used for Statistical Comparisons

ABLD = abductor LD; ADLD = adductor LD; BoNT = botulinum neurotoxin; LD = laryngeal dystonia.

Figure 3. Short-Term and Long-Term Central Effects of BoNT Treatment in Patients With LD

(A) Statistically significant differences in brain activity during speech production are shown between (a) an aggregate group of patients with LD and HCs (FWE-corrected p ≤ 0.05 with minimum voxelwise threshold p ≤ 0.00001 and cluster size ≥343 mm³), (b) BoNT-naive and BoNT-treated patients with LD (FWE-corrected p ≤ 0.05 with minimum voxelwise threshold p ≤ 0.01 and cluster size ≥1,715 mm³), (c) patients with LD with and without benefits from BoNT treatment (whole-brain voxelwise-corrected p ≤ 0.01 with a minimum cluster size of ≥858 mm³), and (d) long-term effects of BoNT treatment in patients receiving injections between 1 and 28 years (whole-brain voxelwise-corrected p ≤ 0.01 with a minimum cluster size of ≥858 mm³). (B) In phenotypically stratified groups, statistically significant differences in brain activity during speech production are shown between (a) BoNT-naive patients with ADLD and patients with ABLD, (b) BoNT-treated patients with ADLD and patients with ABLD, (c) BoNT-naive and treated patients with ADLD, and (d) BoNT-naive and treated patients with ABLD. Statistical significance is set at whole-brain voxelwise-corrected p ≤ 0.01 with minimum cluster size ≥858 mm³. Brain slices are shown in the AFNI standard Talairach-Tournoux space. Color bars represent the t scores. ABLD = abductor type LD; ADLD = adductor type LD; BoNT = botulinum neurotoxin; FWE = family-wise error; LD = laryngeal dystonia.

Figure 4. Relationships Between LD Clinical Features and Brain Functional Alterations

(A) Scatter plots show statistically significant correlations between regional mean percent BOLD signal change and (a) disorder duration in patients with LD, (b) duration and age at disorder onset in BoNT-naive patients with LD, (c) symptom severity in BoNT-naive patients with LD, and (d) symptom severity in BoNT-treated patients with LD with 13–28 years of treatment duration. (B) Scatter plots depict statistically significant correlations between regional mean percent BOLD signal change and (a) disorder duration in BoNT-naive patients with ADLD and BoNT-treated ABLD, (b) age at disorder onset in BoNT-treated patients with ADLD, (c) symptom severity in BoNT-treated patients with ADLD, and (d) symptom severity in BoNT-naive patients with ABLD and BoNT-treated patients with ABLD. Statistical significance is set at whole-brain voxelwise-corrected p ≤ 0.05 with minimum cluster size ≥214 mm³ and R_s ≥ ±0.40. ABLD = abductor type LD; ADLD = adductor type LD; BFMDRS = Burke-Fahn-Marsden Dystonia Rating Scale; BoNT = botulinum neurotoxin; LD = laryngeal dystonia.