Transient Aphasia Induced by Intermittent Theta Burst Stimulation

To the editor

Theta burst stimulation (TBS) is a novel form of transcranial magnetic stimulation that rapidly alters synaptic plasticity (1). During TBS, short bursts of high-frequency (typically 50 Hz) stimulation are repeated at 5 Hz (200 ms interval). When TBS is delivered in trains separated by rest periods (intermittent; iTBS) it has shown long-term potentiation-like effects on cortical neurons. In the last several years, numerous reports have indicated that repeated applications of iTBS have efficacy to reduce symptoms of major depressive disorder (2). Moreover, there is early evidence that it can improve PTSD symptoms (3) and clinical outcomes for up to one year (4). The majority of clinical data supporting therapeutic applications of iTBS come from studies that targeted the dorsolateral prefrontal cortex (DLPFC), and the promise of this approach has prompted various groups to investigate its use to other cortical targets and therapeutic indications as proposed in (5). During methods development for a project evaluating the use of iTBS to modulate cognitive control in obsessive-compulsive disorder, we tested an 1800 pulse iTBS protocol over the left inferior frontal gyrus (IFG) using international 10/20 coordinate F7 for coil placement in a research volunteer.

Case report

A 40-year-old right-handed unmedicated white male with no known medical or psychiatric history received a single application of iTBS with the coil placed over the F7 coordinate to target underlying IFG. F7 was chosen as a convenient way to target the IFG without MRI-guided neuronavigation. The stimulation protocol was 80% of active motor threshold for 45% stimulator output, total 1800 pulses over 9.5 minutes (50 Hz triplets delivered at 5 Hz), delivered using a Magstim Super Rapid 2+1 system using an 70mm air film cooled-coil (Magstim, Whitland, U.K.). The session was well tolerated, with mild treatment site discomfort. After the session, the volunteer noticed that his speech was fluent and grammatically intact, but initiation was significantly effortful. Manual language production (typing words) was also effortful. Comprehension was intact, and no other neurological deficits were observed. Because of the unexpected nature of the event, further testing was not performed. The effects lasted approximately 45 minutes, after which time the symptoms resolved completely.

This type of language disruption, particularly expressive (i.e. Broca’s) aphasia, has long been demonstrated after injury (e.g. left middle cerebral artery stroke) to the IFG. The transient disruptive (virtual lesion) effect we observed was likely due to the close proximity of the stimulation site with Broca’s area (6). This is shown in Figure 1, which represents a SimNIBS simulation (v3.1; 7) of TMS applied to F7. One interpretation of this effect was that our 1800-pulse iTBS protocol resulted in an inhibitory effect on regional brain activity. Previous studies have used conventional 1 Hz rTMS to produce virtual lesions in this area (e.g., 9), presumably through inhibitory effects. Gamboa and colleagues (8) demonstrated that while a standard 600-pulse iTBS had a facilitatory effect on motor cortex excitability, application of a prolonged iTBS protocol with 1200 pulses produced the opposite, inhibiting the amplitude of subsequent motor evoked potentials. A similar reversal of anticipated after-effects was observed when a continuous theta burst (cTBS) protocol length was doubled. Of note, iTBS (600-pulses administered daily for ten days) delivery to Broca’s area (stimulation target defined by fMRI) has been shown to promote plasticity and improve post-stroke aphasia (10), presumably through an excitatory mechanism. Therefore, it is possible the acute inhibitory effect we observed on speech was due to the prolonged iTBS protocol we used. Since formal testing was not performed, we are unable to quantify the deficits above the subject self-report, and it is possible that other deficits occurred.

Figure 1. Electrical Field Simulation of Transcranial Magnetic Stimulation over F7.

E-field simulation using SimNIBS (7) indicates electrical field induction zone when targeting iTBS to EEG coordinate F7/left IFG, using a 70mm Magstim coil. The dashed line indicates approximate location of Broca’s area; simulation indicates significant induced electrical field within and immediately adjacent to Broca’s area.

This report underscores the need for exploration of iTBS parameter space and associated neurophysiological effects, limitations of 10/20 EEG coordinates for stimulating specific cortical targets, and the importance of awareness of adjacent brain regions and their functions when delivering TMS. Furthermore, observed behavioral effects of longer iTBS protocols might not follow the anticipated direction of excitatory or inhibitory effects seen with shorter protocols.