Accelerated theta burst stimulation in a case of therapy-resistant depression developed after left anterior temporal lobectomy

Here we present a case of a female patient in her early forties, who was diagnosed with post-traumatic hemorrhagic contusion of the basal ganglia due to an accident 30 years ago. Since, she experiences grand mal seizures. Due to the severity of the convulsions and the medically refractory epileptic state, a left anterior temporal lobectomy (ATL) was performed some five years ago. See also Fig. 1. Although this procedure successfully reduced the occurrence of the epileptic seizures to zero, she developed severe depressive symptoms. Individual counselling and psychopharmacotherapy brought no improvement. In consultation with the treating psychiatrist and neurosurgeon, a treatment with accelerated rTMS was proposed.

It was decided to start with stimulation contralateral to the lobectomy site, at the level of the right dorsolateral prefrontal cortex (DLPFC). For safety reasons, in analogy of the low frequency protocols for depression over the right DLPFC, we first opted for ‘inhibitory’ cTBS using a Magstim Rapid2 Plus1 magnetic stimulator (Magstim Company Limited, Minneapolis,USA). Neuroanatomical images of the patient’s brain were used to localize both right and left DLPFC (i.e. center parts of the midprefrontal gyrus [Brodmann9/46]), with neuronavigation (Brainsight™, Rogue Research, Inc). To reduce the number of stimulation days, we applied accelerated TBS, a relatively new rTMS protocol where the total number of stimulations remain the same compared to the standard once-daily stimulation paradigms, but results in a shorter treatment period (only in a few days instead of several weeks) []. In our case, the patient received 20 cTBS sessions over a period of four days, at five sessions per day. The sessions were separated by 15-min stimulation-free intervals. As documented in Huang et al. [], for one cTBS session, the following parameters were used: frequency 50Hz, burst fre-quency 5Hz, 600 pulses in total, given in one cycle including 200 30 burst of 3 pulses. The stimulation intensity was set at 80% of the resting motor threshold. Depression severity was evaluated by the 17-item Hamilton Depression Rating Scale (HDRS). During the treatment, the intake of antiepileptics (lamotrigine 100 mg twice daily and carbamazepine retard 400 + 200 mg daily) was continued and the intake of antidepressants was stopped. She was antidepressant-free two weeks before cTBS treatment. Unfortunately, this accelerated (a)cTBS paradigm showed a negligible clinical efficacy (HDRS score from 29 to 27), indicating that acTBS of the right DLPFC did not adequately reduced depressive symptoms.

Therefore, we decided - despite the increased risk of epileptic seizures - to apply the more excitatory accelerated (a)iTBS paradigm delivered on the left DLPFC (this zone lies more cranial and more anterior of the resection area). For one iTBS session the frequency was set at 50Hz, burst frequency 5Hz, and 600 pulses in total a spread over 20 cycles in which each cycle includes 10 burst of 3 pulses each, with a train duration of 2 seconds and an inter-train interval of 6 seconds, as described in Ref. []. The stimulation intensity was set at 100%. The patient received 20 iTBS sessions over four consecutive days, i.e. five sessions per day (also with 15 minutes intersession pause). No medical treatment changes were applied. After completion of the iTBS sessions clinical response was obtained (HDRS score back from 29 to 14), which can be considered as clinical response. Based on the Reliable Change Index (RCI), this change on the HDRS score was −4.4, which is also statistically significant []. Furthermore, the VAS, which was presented to the patient weekly, indicated no significant side effects before and during the acTBS or aiTBS sessions. The patient only reported localized scalp sensitivity, headache and fatigue at the beginning of the stimulation sessions. These adverse reactions were temporary in nature and remedied by pain medication and it was therefore concluded that the treatment was generally well tolerated. Importantly, epileptic seizures did not occur during either stimulation protocol, indicating that these treatments in such patients are potentially safe. Notwithstanding, after this treatment protocol was completed and the patient was referred to her treating physician again, a final clinical evaluation 14 days after the last stimulation 57 session she showed again signs of clinical depression (HDRS = 22), indicating a rather short clinical beneficial effect of aiTBS.

To summarize, temporal lobe seizures are the most common type of epilepsy in adults. Approximately 30% of the patients do not respond well to pharmacotherapy and therefore may qualify for ATL, an effective treatment of refractory epileptic seizures []. The prevalence of de novo depression following surgery is estimated to be 4–18% []. Unfortunately, treatment with antidepressants is limited in the case of refractory epilepsy when clinically depressed, because it cannot be excluded that these drugs can lead to the development of spontaneous and recurring seizures in previously normal brain regions (epileptogenesis) []. Furthermore, some of the antiepileptic drugs that act through modulation of gamma-aminobutyric acidergic neurotransmission could cause a worsening of the psychiatric symptoms [].

With a precautionary note that it only concerned one patient, and we cannot extrapolate our accelerated TBS findings to regular rTMS treatment protocols for depression, our observations indicate that in ATL patients with medically refractory depression these accelerated iTBS and cTBS protocols could have a safe treatment profile. Yet, only aiTBS treatment resulted in clinical response, however short-lived (only 14 days). These results have some consistency with a previous study that also found that left DLPFC stimulation, but not right, was effective in alleviating depressive symptoms caused by structural abnormalities []. Despite these similar conclusions we cannot rule out the possibility that the clinical response is (in part) due to the higher number of stimulation sessions, the higher applied intensity, and not the frequency and/or site of TBS. It is therefore entirely possible that a reversed order of stimulation, i.e. iTBS of the left DLPFC followed by cTBS of the right DLPFC, could produce a similar result, also with the classical daily stimulation sessions. The fast relapse in depression also confirms that (accelerated) rTMS is an acute treatment application and that after care is mandatory. Reaching clinical response but not remission, additional aiTBS treatment sessions could have been necessary. This would have been not only be required to prevent early relapse, but in some patients receiving accelerated protocols the trajectory of response will vary between fast and slower responders []. Additional controlled studies are required to confirm the rapid antidepressant effect of TBS in patients who underwent anterior temporal lobectomy, and further research is needed how to prolong and maintain the clinical response.

• Chris Baeken, Department of Psychiatry and Medical Psychology, University Hospital Ghent and department of Psychiatry, University Hospital Brussels, Belgium.
• Sara De Witte, Department of Psychiatry and Medical Psychology, University Hospital Ghent, Belgium.
• Hannelore Tandt, Department of Psychiatry and Medical Psychology, University Hospital Ghent, Belgium.
• Jeroen Vervaet, Department of Psychiatry and Medical Psychology, University Hospital Ghent, Belgium.
• Gilbert MD Lemmens, Department of Psychiatry and Medical Psychology, University Hospital Ghent, Belgium.