A 63-year-old man was admitted to our hospital with left thalamic hemorrhage. He was in a comatose state when he arrived to the emergency room. His initial Glasgow Coma Scale (GCS) score was 7, but his consciousness level rapidly improved to a GCS score of 14. He had subjective right-sided weakness, but no obvious motor impairment was observed on physical examination. Rehabilitative intervention was conducted focused on locomotion and activities of daily living rather than limb weakness. Computed tomography (CT) revealed a left thalamic hemorrhage with intraventricular hemorrhage (IVH). He received conservative treatment with blood pressure control. Serial follow-up brain CT revealed a newly developed, tiny IVH, but no other hemorrhage. Brain magnetic resonance imaging (MRI) revealed moderate small-vessel disease in the white matter and amyloid angiopathy with diffuse mild cortical atrophy (Figure 1). Although his alertness rapidly improved, he showed fluctuations in consciousness with delirium at night, disorganized thought, inattention, and perceptual disturbances. Antipsychotics were administered, but these symptoms did not improve.
Three weeks after stroke onset, the patient was referred to our rehabilitation department for cognitive rehabilitation. Neurocognitive assessment revealed various behavioral and psychological symptoms. Long-term memory was relatively spared, but short-term memory was markedly reduced. Orientation in space, time, and person was severely impaired. Visual hallucinations of something crawling on the curtains and abrupt changes in emotional status were also observed. The Neuropsychiatric Inventory-Questionnaire (NPI-Q) indicated moderate to severe symptoms, and moderate caregiver distress. His scores on the Korean version of the Mini-Mental Status Exam (K-MMSE); score:, Clinical Dementia Rating (CDR); global score: 3; sum of box score:, and the Korean version of the Montreal Cognitive Assessment (MOCA-K); score: indicated severe neurocognitive impairment (Table 1). We attempted to administer an overall cognitive assessment battery, but this was impossible because of the patient's inattention and perseveration.
A N-methyl-D-aspartate antagonist (NMDA) receptor antagonist (memantine, 10 mg) and anti-depressant (escitalopram 10 mg) were administered to improve his attention and emotional lability, and a small amount of atypical antipsychotics (quetiapine, 12.5 mg) was administered to alleviate his delirium. A neuro-stimulant (methylphenidate) was also administered to improve his attention, but this was stopped because his irritability was aggravated. He received computer-based cognitive-behavioral therapy (CCBT) using CoTras (Netblue Co., Ltd, Korea) software for 3 weeks. However, there was no noticeable change in his cognitive function and neuropsychiatric symptoms. Thus, we decided to apply bilateral rTMS to the DLPFCs, with the consent of the patient and caregiver.
rTMS was performed with a Magstim Super Rapid Stimulator (Magstim Co., United Kingdom) with a 70-mm, figure-eight shape, air cooled coil. The handle was oriented posteriorly, with a 45  angle sagittally. Single-pulse transcranial magnetic stimulation was conducted at the bilateral primary motor cortices to identify the motor hot spot in each hemisphere. The motor-evoked potentials (MEPs) were recorded in the contralateral abductor pollicis brevis, and the motor threshold (MT) was defined as the stimulus intensity required to provoke MEPs of >50 muV in peak-to-peak amplitude, in five of 10 sequential trials. The stimulation target of the DLPFC was defined as 5 cm anterior to the motor hot spot, parallel to the sagittal midline. For low-frequency rTMS, 1-Hz stimulation at 80% MT was applied in three trains of 5-min duration each, with a 1-min inter-train interval, and a total of 900 pulses (a total period of 20 min). For high-frequency rTMS, 10-Hz stimulation at 80% MT was applied in 40 trains of 5-s duration each, with a 25-s inter-train interval, and a total of 2,000 pulses (a total period of 20 min). Low-frequency rTMS was applied to the right DLPFC, followed by high-frequency rTMS to the left DLPFC, with a 5-min pause. CCBT was administered within 30 min after rTMS treatment. A schematic of the treatment protocol is provided in Figure 2. During the rTMS treatment period, the existing medications (memantine, escitalopram, quetiapine) were continuously used.
Bilateral rTMS was applied 53 days after onset of thalamic hemorrhage followed by a total of 10 sessions over 2 weeks. There were no adverse events, such as headaches, seizures, and other neurologic deficits, and there was only mild scalp discomfort during the treatment sessions. Behavioral and psychological symptoms were markedly improved, as assessed by the K-NPIQ (Table 1). Both symptom severity and caregiver distress were improved in all domains, with the exception of delusions, a nocturnal and prandial aberrant activity that was not observed, even before treatment. The MOCA-K score also improved. However, amnestic symptoms were only slightly enhanced. These effects of rTMS persisted for 1 month after treatment.