Safety and proof of principle study of cerebellar vermal theta burst stimulation in refractory schizophrenia

Abstract

Background: Early invasive electrical stimulation studies suggested that enhancement of cerebellar vermal activity might prove valuable in symptomatic treatment of refractory neuropsychiatric diseases via modulation of emotion and affect. This proof of principle study aimed to test this hypothesis using noninvasive brain stimulation, and to explore the safety of this protocol in schizophrenia.

Methods: Eight treatment-refractory patients with schizophrenia underwent ten sessions of intermittent theta burst stimulation (TBS) to the cerebellar vermis using MRI-guided transcranial magnetic stimulation (TMS). Assessments included side effect questionnaires, cardiovascular monitoring, psychiatric evaluations and comprehensive neuropsychological testing before and after TBS and at one-week follow-up.

Results: Overall, TBS was tolerated well with mild side effects primarily comprising neck pain and headache. No serious adverse events occurred. Diastolic blood pressure (BP) showed mild decreases for five minutes post-TBS; no significant changes were detected for systolic BP or pulse. PANSS negative subscale showed significant improvements following TBS and during the follow-up. Calgary Depression Scale and self-report visual analog scales for Happiness and Sadness pointed to significant mood elevation. Neuropsychological testing revealed significantly fewer omissions in working memory and interference conditions of a Continuous Performance Test, a longer spatial span and better delay organization on the Rey-Osterrieth Complex Figure during follow-up. No significant worsening in psychiatric or neuropsychological measures was detected.

Conclusions: Theta burst stimulation of the cerebellar vermis is safe and well-tolerated, while offering the potential to modulate affect, emotion and cognition in schizophrenia. Future randomized, sham-stimulation controlled studies are warranted to support the clinical efficacy of this technique.

FIGURE 1

(A) Location of stimulation in a patient (Talairach coordinates x=0, y=−82, z=−30). Stimulation was performed using frameless stereotaxic system enabling precise targeting in all patients. (B) Vermis warped into the proportional stereotaxic space of Talairach, midsagittal plane (Adapted from Schmahmann et al., 1999).

FIGURE 2

Schematic representation of the experimental design. Clinical safety evaluations comprised psychiatric and neuropsychological assessments at three time points: prior to and following the application of 10 sessions of TBS, and one week later for follow-up purposes. Blood pressure was monitored throughout each TBS session.

FIGURE 3

The graph demonstrates the changes in (A) PANSS and subscales, (B) Calgary Depression Scale, (C) Visual Analogue Scales (Happiness, Sadness and Alertness) and (D) Continuous Performance Test (omissions during memory and interference conditions) for all time points. Significant changes are marked *.