In the last two decades, repetitive transcranial magnetic stimulation (rTMS) has been studied as a therapeutic tool in several neuropsychiatric disorders, primarily for the treatment of major depression (MD) where it has shown a consistent and reproducible therapeutic effect (Feinsod et al.1998; George et al.1997, 1999; Pascual-Leone et al.1996). Previous studies have demonstrated that left high-frequency (⩾5 Hz) (George et al.2000) and right low-frequency (⩽1 Hz) (Klein et al.1999) rTMS to the prefrontal cortex (PFC) is effective in the treatment of MD. The antidepressant effects of rTMS might be related to its capacity to modulate neuronal plasticity which has been suggested to be altered in depression (Castren, 2005; Normann et al.2007). Results of our previous work (Chistyakov et al.2005a) demonstrated that a positive rTMS treatment response is associated with enhancement of left hemisphere excitability. Furthermore, similar changes in cortical excitability following electroconvulsive therapy (ECT) and pharmacological treatment are correlated with clinical improvement in MD (Chistyakov et al.2005b). The mechanisms of such excitability shifts are unclear, but might be related to long-term potentiation (LTP) and long-term depression (LTD), as shown in animal studies (Hess & Donoghue, 1996). Human studies with rTMS have demonstrated changes in plasticity and cortical function extending beyond the immediate stimulation period. In general, high-frequency rTMS transiently facilitates cortical responses (Pascual-Leone et al.1994) while low-frequency rTMS inhibits cortical excitability (Chen et al.1997). However, these effects have typically been short lasting (10–20 min), of moderate size and variable. Furthermore, the magnitude of the therapeutic effect of rTMS is modest with a small to moderate effect size. This calls for the design of more effective rTMS paradigms that will achieve a more robust antidepressant effect.
Theta-burst electrical stimulation (TBS) has long been known as a highly effective method to induce LTP and LTD in animals. Recently, Huang & Rothwell (2004) and Huang et al. (2005) reported safe application of TBS without noticeable adverse effects in humans, using rTMS techniques. Three magnetic pulses with an inter-stimulus interval of 20 ms (50 Hz) were applied repeatedly every 200 ms representing the theta rhythm of 5 Hz. This stimulation method produced more robust and enduring changes in cortical excitability (Huang et al.2007, 2008, 2009; Ishikawa et al.2007; Katayama & Rothwell, 2007). The application of this paradigm to humans allows induction of long-lasting excitatory and inhibitory changes in cortical excitability, simply by varying the stimulus sequence. When applied continuously for 40 s over the motor cortex, referred as continuous theta-burst stimulation (cTBS), theta-burst rTMS causes a suppression of motor-evoked potentials lasting up to several hours. In contrast, the interruption of this sequence every 2 s for 8 s results in a long-lasting facilitation and this stimulation paradigm was termed intermittent TBS (iTBS) (Huang et al.2005). These changes were shown to be consistent and robust across subjects. Thus theta-burst TMS seems to offer an advantage to some of the shortcomings of conventional rTMS and might be more effective than currently used rTMS treatments.
The aim of the present study was 2-fold: (1) to evaluate the safety and tolerability of TBS of different type, intensity and duration; (2) to assess preliminarily therapeutic efficacy of TBS in patients with MD.
Materials and methods
A total of 33 patients were recruited from the population of MD patients hospitalized for treatment of their depression. All provided written informed consent to participate in the study, which was approved by Rambam Medical Center Ethics Committee. Patients aged 20–75 yr were included in the trial if they met DSM-IV criteria for MD and were capable of providing informed consent and cooperate sufficiently in the clinical and neurophysiological assessment. Exclusion criteria were: (1) suicidal risk, (2) evidence of a disease that might affect central and peripheral nerve conduction, (3) seizure disorder, (4) history of head trauma in the last year, (5) systemic uncontrolled disease, (6) implanted electronic devices (e.g. pacemaker, cochlear implant, deep brain stimulator) or metallic implants and (7) drug or alcohol abuse in the last 6 months.
All patients received at least one medication trial as outpatients and were hospitalized due to lack of response or deterioration of their clinical condition. Patients were invited to participate in the study soon after their admission and were maintained on their previous medications throughout the course of TBS treatment. Out of 33 patients, 12 were receiving antidepressants, mostly SSRIs or SNRIs, and 20 were on a combination of antidepressants and mood stabilizers. One patient received only mood stabilizers.
Initially, 13 patients were randomized to receive one of the two treatment conditions: (1) iTBS (hereafter iTBS1200) to the left dorsolateral prefrontal cortex (DLPFC) (n=7); (2) continuous TBS (hereafter cTBS1200) to the right DLPFC (n=6). The intensity of stimulation was 90% of the active motor threshold (aMT). Each treatment session consisted of 600 stimuli repeated twice daily (1200 stimuli per day) for 10 consecutive work days. This protocol was termed ‘short TBS’. As evident from these 13 patients, right-sided cTBS appeared to have a more prominent antidepressant action. Thus, right-sided stimulation was further amended in six patients who received 900 stimuli per session at 100% aMT intensity applied twice daily (a total of 1800 stimuli per day, hereafter cTBS1800), and in 14 additional patients who received 1800 stimuli per session delivered in two consecutive trains of 900 stimuli each separated by a 30-min interval and repeated twice daily (a total of 3600 stimuli per day, hereafter cTBS3600). These protocols were termed ‘amended TBS’.
TBS was applied through a 70-mm figure-of-eight coil (peak magnetic field 2.2 T) connected to a Magstim Super Rapid2 (Magstim Company Ltd, UK) magnetic stimulator with four booster modules as well as an integrated two-channel EMG amplifier and system acquisition software. The system enables recording of motor-evoked potentials for threshold determination as well as programming of different modes of stimulation including TBS protocols. The coil was placed tangentially to the scalp with the handle pointed backwards, 5 cm anterior to the site optimal for producing the motor response in the contralateral abductor pollicis brevis (APB) muscle. As originally described by Huang et al. (2005), TBS consisted of triple-pulse 50-Hz bursts given at a rate of 5 Hz (i.e. 200 ms between each burst). For iTBS, a 2-s TBS train was repeated every 10 s. cTBS was applied as a single uninterrupted TBS train. As previously mentioned, the stimulus intensity was 90% aMT in patients who received 1200 stimuli per day (short TBS protocol) and 100% aMT in patients who received 1800 and 3600 stimuli per day (amended TBS protocol). However, due to limitations of the stimulator the maximal TBS intensity which could be applied in the amended TBS protocol was 51% of the maximal stimulator output. For this reason, in seven patients (two who received cTBS1800 and five who received cTBS3600) whose aMT was higher than 51% of the maximal stimulator output, the actual stimulus intensity was 92.3±2.5% aMT.
Patients were seated in an armchair and earplugs were used during the treatment session.
Assessment of motor thresholds
The resting motor threshold (rMT) was defined as the lowest stimulus intensity capable of eliciting in the relaxed APB muscle at least five motor responses with amplitude of at least 50 µV in a series of 10 consecutive trials of single-pulse TMS. aMT was measured during a voluntary isometric contraction of the contralateral APB with the force level of about 20% of maximal EMG. It was defined as the minimum stimulus intensity required to produce motor responses >100 µV in five consecutive single-pulse TMS trials.
Severity of depression was assessed by the HAMD and the Clinical Global Impression (CGI) scale. Ratings were performed by a trained psychiatrist at baseline and weekly thereafter. Marked clinical improvement was defined as a reduction of ⩾50% in HAMD.
The effects of TBS on depression scores were analysed using repeated-measures ANOVA with group (iTBS1200, cTBS1200, cTBS1800, cTBS3600) as the between-subject factor, and time (baseline, after 1 wk, after 2 wk) as the inter-subject term. Between-group comparisons of the frequencies of categorical variables were carried out by the χ2 test. The results were considered significant if p<0.05.