A Safety and Tolerability Study – Cognitive Effects in Healthy Volunteers

Shalvata Medical Health Center, Hod-Hasharon, Israel

1 January, 2006

A second safety study was conducted in Shalvata Mental-Health Center, Hod HaSharon, Israel in 2005 (Zangen et al., 2006).

The study assessed any possible health risks, as well as cognitive and emotional transient effects of the novel design of BrainsWay® Deep TMS H-Coils.

Comparing treatments conducted with H1-coil, H2-coil, Standard figure-8 coil (Quadstim; manufactured by MagStim) and Sham coil. The treatment groups (H1-coil TMS, H2-coil TMS, figure-8 coil TMS & sham TMS) did not differ in age, years of education and sex.

35 healthy subjects completed the entire experimental course with three dropouts occurring after the first visit (1Hz stimulation) for non research related reasons.

All subjects participated in three treatment sessions, one session per day on days 1, 3 and 5. The treatments were at different TMS frequencies.

On day 1, 1Hz stimulation,

On day 3, 10 Hz stimulation

On day 5, 20 Hz stimulation.

Safety measures, specific cognitive tests and emotional scales were conducted 30 minutes before and 45 to 60 minutes and 90 to 120 minutes after the rTMS session. Subjects were also monitored for any possible change in hearing threshold.  Audiograms were obtained before and at the end of treatment phase on day 6-8.

Analysis of short clinical assessments protocols and additional safety measurements revealed that the TMS stimulations were well tolerated by the subjects with no major side-effects (compared with figure-8 and sham coil stimulations) such as accidental seizure induction, local pain of the scalp, transient headache and dizziness, transient hypotension, visual disturbances, weakness, parenthesis, instability, vertigo, tinnitus, or other bodily sensations. In addition, the clinical inspection of the scalp area, conducted immediately after each stimulation session, showed no skin lesions. Auditory thresholds measured by audiograms (conducted pre and post TMS treatments) indicated no transient auditory threshold shifts, indicating no hearing loss of the subjects. Similarly, there were also no significant changes in physical measures, such as hemodynamic measures (blood pressure and heart rate), perceived headache or changes in headache intensity (measured by the Visual Analog Scale (VAS)) or general neurological measures (e.g., time to walk 5m forward, backward, etc.).

This safety study analyzed relative transient cognitive effects, using the CANTAB battery computerized neuropsychological test battery and  using tests of spatial-motor performance, attention, memory and executive functions (MOT, RTI, SRM, PRM, SSP & SWM). Several subjects showed improvements in cognitive performance with each treatment visit, as well as after each stimulation (compared to their performance pre stimulation). These changes are most likely related to learning experience. Overall the changes were not different for the four treatment groups and no evidence was found for possible deterioration in cognitive performance due to the TMS treatments.

Since the deep TMS coils were conceived for their possible antidepressant effects, special emphasize was put on monitoring emotional effects of the coils. These emotional effects were evaluated using the Positive and Negative Affect Schedule (PANAS), a 20-item self-report measure monitoring changes in the affective state of the subjects (Watson, Clark, & Tellegen, 1988). The PANAS includes two factors; positive and negative affect factor (PA/NA), as well as a visual-analog scale for self-reported mood state. The study results demonstrated an increase in subjects’ positive emotions, with H2-coil subjects showing higher positive emotions during the stimulation sessions, and H1-coil showing increased positive emotions 24-36 hours after last stimulation. At the same time, there is no evidence for lasting changes in negative affect or feelings of dissociation (although the stimulation may lead to transient feelings of dissociation, with no differential effect