An Investigation of Affective Personality Traits in Alzheimer's Disease: SEEKING as a Possible Predictor for Early-Stage Alzheimer's Dementia.

OBJECTIVE: The aim of the current study was to investigate affective personality traits in Alzheimer's disease, a neurodegenerative condition mainly characterized by episodic memory impairment. METHOD: The sample included 69 participants from 3 diagnostic categories. Twenty-five participants were diagnosed with subjective cognitive impairment (SCI), 26 participants were diagnosed with mild cognitive impairment of the amnestic type (aMCI), and the remaining 18 participants were diagnosed with early-stage Alzheimer's dementia (ADD). Diagnostic labels were given as a result of detailed neurological, neuropsychological, and neuroradiological assessment. Affective personality traits were assessed via Affective Neuroscience Personality Scales (ANPS). RESULTS: The only significant intergroup difference was obtained for the SEEKING subscale of ANPS. Here, ADD group scored significantly lower compared to the SCI group. The results of logistic regression analysis also indicated that SEEKING score successfully predicted early-stage ADD diagnosis. CONCLUSION: The results suggest that a specific personality constellation characterized by reduced investment in the outside world might be associated with Alzheimer's disease, either as a risk factor or a byproduct of the neurodegenerative process initiated by AD pathology.

Does transcranial direct current stimulation enhance cognitive performance in Parkinson's disease mild cognitive impairment? An event-related potentials and neuropsychological assessment study.

BACKGROUND: Parkinson's disease-mild cognitive impairment (PD-MCI) is garnering attention as a key interventional period for cognitive impairment. Currently, there are no approved treatments for PD-MCI and encouraging results of transcranial direct current stimulation (tDCS) combined with other interventions have been proposed, though the efficacy and neural mechanisms of tDCS alone have not been studied in PD-MCI yet. OBJECTIVES: The present double-blind, randomized, sham-controlled study assessed the effects of tDCS over the dorsolateral prefrontal cortex on cognitive functions via neuropsychological and electrophysiological evaluations in individuals with PD-MCI for the first time. METHOD: Twenty-six individuals with PD-MCI were administered 10 sessions of active (n = 13) or sham (n = 13) prefrontal tDCS twice a day, for 5 days. Changes were tested through a comprehensive neuropsychological battery and event-related potential recordings, which were performed before, immediately, and 1 month after the administrations. RESULTS: Neuropsychological assessment showed an improvement in delayed recall and executive functions in the active group. N1 amplitudes in response to targets in the oddball test-likely indexing attention and discriminability and NoGo N2 amplitudes in the continuous performance test-likely indexing cognitive control and conflict monitoring increased in the active group. Active stimulation elicited higher benefits 1 month after the administrations. CONCLUSION: The present findings substantiate the efficacy of tDCS on cognitive control and episodic memory, along with the neural underpinnings of cognitive control, highlighting its potential for therapeutic utility in PD-MCI. TRIAL REGISTRATION: NCT 04,171,804. Date of registration: 21/11/2019.

Effects of transcranial magnetic stimulation on neurobiological changes in Alzheimer's disease (Review).

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by cognitive decline and brain neuronal loss. A pioneering field of research in AD is brain stimulation via electromagnetic fields (EMFs), which may produce clinical benefits. Noninvasive brain stimulation techniques, such as transcranial magnetic stimulation (TMS), have been developed to treat neurological and psychiatric disorders. The purpose of the present review is to identify neurobiological changes, including inflammatory, neurodegenerative, apoptotic, neuroprotective and genetic changes, which are associated with repetitive TMS (rTMS) treatment in patients with AD. Furthermore, it aims to evaluate the effect of TMS treatment in patients with AD and to identify the associated mechanisms. The present review highlights the changes in inflammatory and apoptotic mechanisms, mitochondrial enzymatic activities, and modulation of gene expression (microRNA expression profiles) associated with rTMS or sham procedures. At the molecular level, it has been suggested that EMFs generated by TMS may affect the cell redox status and amyloidogenic processes. TMS may also modulate gene expression by acting on both transcriptional and post­transcriptional regulatory mechanisms. TMS may increase brain cortical excitability, induce specific potentiation phenomena, and promote synaptic plasticity and recovery of impaired functions; thus, it may re­establish cognitive performance in patients with AD.

Neuronavigated rTMS inhibition of right pars triangularis anterior in stuttering: Differential effects on reading and speaking.

Functional neuroimaging studies show an overactivation of speech and language related homologous areas of the right hemisphere in persons who stutter. In this study, we inhibited Broca's homologues using 1 Hz repetitive transcranial magnetic stimulation (rTMS) and assessed its effects on stuttering severity. The investigated cortical areas included pars opercularis (BA44), anterior and posterior pars triangularis (BA45), mouth area on the primary motor cortex (BA4). We collected reading and speaking samples before and after rTMS sessions and calculated the percentage of syllables stuttered. Only right anterior pars triangularis stimulation induced significant changes in speech fluency. Notably, the effects were differential for reading and speaking conditions. Overall, our results provide supportive evidence that right anterior BA45 may be a critical region for stuttering. The observed differential effects following the inhibition of right anterior BA45 merits further study of contributions of this region on different language domains in persons who stutter.

An investigation of affective theory of mind ability and its relation to neuropsychological functions in Alzheimer's disease.

Although cognitive theory of mind (ToM) has been largely studied within neurodegenerative disorders including Alzheimer's disease (AD), studies focusing on affective ToM are relatively limited, yielding inconsistent findings. The current study aimed at investigating affective ToM abilities within different stages of AD (mild AD dementia [ADD], mild cognitive impairment [MCI], and subjective cognitive impairment [SCI]), together with its relationship with neuropsychological functioning. Eighty-one participants were tested with two different ToM tasks (Faux Pas Recognition Test [FPR] and Reading Mind in the Eyes Test [RMET]) and tests of attention, executive functions, episodic memory, and facial recognition. Our results showed two different affective ToM profiles in AD continuum: while ADD group performed poorly on both tasks of ToM, MCI group displayed deteriorated performance on RMET but not on FPR. In addition, ToM performance was significantly related to episodic memory and verbal fluency within the overall sample. These findings suggest that impairment in the decoding process of emotional cues could begin even in the prodromal stage of AD. In contrast, the reasoning process of emotional information, as measured with FPR, could be preserved until the dementia stage. Moreover, the relation of affective ToM with amnestic functions and verbal abilities could provide evidence of a domain-general ToM impairment in AD.

NMDA receptor encephalitis with cancer of unknown primary origin.

PURPOSE: N-methyl-D-aspartate receptor (NMDAR) encephalitis may present as a paraneoplastic syndrome in young women and is often associated with ovarian teratoma. METHODS: We report 2 male cases of NMDAR encephalitis presenting with metastatic cancer of unknown primary origin. RESULTS: Both patients showed cognitive dysfunction as well as other neurological symptoms, slow waves on EEG, and NMDAR antibodies in sera and CSF. Symptoms were effectively treated by pulse steroid and intravenous immunoglobulin treatment. The patients developed metastatic small cell neuroendocrine carcinoma of the parotid gland and inguinal metastatic squamous cell cancer shortly after their neurological episodes. Follow-up PET studies showed small cell lung cancer in the first patient while no primary origin could be found in the second patient. CONLUSIONS: Our cases imply that NMDAR encephalitis may present with metastatic cancers that display slow progression rates and occur after encephalitis attacks.

Long-term effects of contralesional rTMS in severe stroke: safety, cortical excitability, and relationship with transcallosal motor fibers.

BACKGROUND: Contralesional hemispheric repetitive transcranial magnetic stimulation (rTMS) may improve motor function in mild to moderate stroke and effects are considered to be mediated through transcallosal motor fibers. OBJECTIVE: This study aimed to investigate the safety of contralesional rTMS in a selected group of severe chronic stroke patients. METHODS: Ten sessions of 1 Hz rTMS were applied to contralesional primary motor cortex (M1) using neuronavigated stimulation and changes in motor impairment were evaluated before, during and after rTMS applications and at 4-weeks follow-up. Neurophysiological response to stimulation was assessed through cortical excitability evaluations. The relationship between functional and neurophysiological response to rTMS and microstructural integrity of transcallosal motor fibers were searched using diffusion tensor imaging (DTI) based fractional anisotropy (FA). RESULTS: rTMS was well-tolerated with high compliance and no dropouts; no seizures or motor worsening occurred. Transcallosal FA values revealed a positive linear relationship with the mild motor improvement detected after rTMS while higher FA values were observed in subjects with better motor outcome. Cortical excitability showed a significant change in contralesional short-interval intracortical inhibition indicating altered plasticity following rTMS. CONCLUSIONS: Our results suggest that noninvasive neuromodulation of the contralesional hemisphere may present a possibility to assist adaptive neuroplastic changes in severe chronic stroke. Implementation of DTI-derived measures of transcallosal microstructural integrity may allow for individually-tailored interventions to guide processes of interhemispheric neuroplasticity. Further research is warranted to establish the clinical value of these findings in neurorehabilitation settings for subjects with chronic severe stroke.

TREM2 mutations implicated in neurodegeneration impair cell surface transport and phagocytosis.

Genetic variants in the triggering receptor expressed on myeloid cells 2 (TREM2) have been linked to Nasu-Hakola disease, Alzheimer's disease (AD), Parkinson's disease, amyotrophic lateral sclerosis, frontotemporal dementia (FTD), and FTD-like syndrome without bone involvement. TREM2 is an innate immune receptor preferentially expressed by microglia and is involved in inflammation and phagocytosis. Whether and how TREM2 missense mutations affect TREM2 function is unclear. We report that missense mutations associated with FTD and FTD-like syndrome reduce TREM2 maturation, abolish shedding by ADAM proteases, and impair the phagocytic activity of TREM2-expressing cells. As a consequence of reduced shedding, TREM2 is virtually absent in the cerebrospinal fluid (CSF) and plasma of a patient with FTD-like syndrome. A decrease in soluble TREM2 was also observed in the CSF of patients with AD and FTD, further suggesting that reduced TREM2 function may contribute to increased risk for two neurodegenerative disorders.

Movement-generated afference paired with transcranial magnetic stimulation: an associative stimulation paradigm.

BACKGROUND: A peripheral nerve stimulus can enhance or suppress the evoked response to transcranial magnetic stimulation (TMS) depending on the latency of the preceding peripheral nerve stimulation (PNS) pulse. Similarly, somatosensory afference from the passively moving limb can transiently alter corticomotor excitability, in a phase-dependent manner. The repeated association of PNS with TMS is known to modulate corticomotor excitability; however, it is unknown whether repeated passive-movement associative stimulation (MAS) has similar effects. METHODS: In a proof-of-principal study, using a cross-over design, seven healthy subjects received in separate sessions: (1) TMS (120% of the resting motor threshold-RMT, optimal site for Flexor Carpi Radialis) with muscle at rest; (2) TMS paired with cyclic passive movement during extension cyclic passive movement (400 pairs, 1 Hz), with the intervention order randomly assigned. Normality was tested using the Kolmogorov-Smirnov test, then compared to pre-intervention baseline using repeated measures ANOVA with a Dunnet multiple comparisons test. RESULTS: MAS led to a progressive and significant decrease in the motor evoked potential (MEP) amplitude over the intervention (R(2) = 0.6665, P < 0.0001), which was not evident with TMS alone (R(2) = 0.0068, P = 0.641). Post-intervention excitability reduction, only present with MAS intervention, remained for 20 min (0-10 min = 68.2 ± 4.9%, P < 0.05; 10-20 min = 73.3 ± 9.7%, P < 0.05). CONCLUSION: The association of somatosensory afference from the moving limb with TMS over primary motor cortex in healthy subjects can be used to modulate corticomotor excitability, and may have therapeutic implications.

Akinetic mutism without a structural prefrontal lesion.

Akinetic mutism is characterized by profound apathy and a lack of verbal and motor output for action, despite preserved alertness. The condition usually follows bilateral damage to the medial frontal subcortical circuits. We report a 59-year-old right-handed woman who was admitted to the neurology ward with sudden-onset akinetic mutism. Her medical history included an ischemic stroke 3 years earlier, with residual anomia and mild agraphia but no motor dysfunction. On this admission, a cranial computed tomography scan disclosed an acute left superior cerebellar infarction embracing the vermis, and a prior left inferior parietal infarct. Electroencephalogram showed bilateral frontal delta-wave activity. Four weeks later, we performed a technetium-99m hexamethylpropyleneamine oxime single-photon emission computed tomography (Tc-HMPAO SPECT) scan to study the patient's frontal lobe function. The SPECT scan revealed the causative bifrontal hypoperfusion, more prominent on the right, while the structurally evident cerebellar infarction was predictably masked by subacute hyperperfusion phenomenon. Contralateral frontal diaschisis is an established sequela of cerebellar infarction. Because this patient also had lesions in the left parietal region, her left prefrontal area was critically deprived of its major reciprocally connected cortical counterparts (right prefrontal and left parietal), and also became dysfunctional. Her resulting bilateral frontal dysfunction is a common cause of akinetic mutism.

Can noninvasive brain stimulation enhance cognition in neuropsychiatric disorders?

Cognitive impairment is a core symptom of many neuropsychiatric diseases and a key contributor to the patient's quality of life. However, an effective therapeutic strategy has yet to be developed. Noninvasive brain stimulation techniques, namely transcranial magnetic stimulation (TMS) and transcranial direct current stimulation (tDCS), are promising techniques that are under investigation for a variety of otherwise treatment-resistant neuropsychiatric diseases. Notably, these tools can induce alterations in neural networks subserving cognitive operations and thus may provide a means for cognitive restoration. The purpose of this article is to review the available evidence concerning cognitive enhancing properties of noninvasive brain stimulation in neuropsychiatry. We specifically focus on major depression, Alzheimer's disease, schizophrenia, autism and attention deficit hyperactivity disorder (ADHD), where cognitive dysfunction is a major symptom and some studies have been completed with promising results. We provide a critical assessment of the available research and suggestions to guide future efforts. This article is part of a Special Issue entitled 'Cognitive Enhancers'.

Crossed aphasia in a dextral patient with logopenic/phonological variant of primary progressive aphasia.

BACKGROUND: Crossed aphasia is a rare phenomenon, with a prevalence of 1% to 2% among all right-handed patients. Two crossed aphasic patients with a nonfluent variant of primary progressive aphasia (PPA) have been reported previously. This report aims to document for the first time the occurrence of crossed logopenic progressive aphasia in a dextral patient. CASE REPORT: A 57-year-old monolingual housewife presented with word-finding difficulties. She was strongly right handed, had no clinical history for brain damage to the left hemisphere, and no left handers in her family history. Her language comprised simple, grammatically correct sentences with a fluctuating speech rate and intermittent word-finding pauses. Rare phonological errors were noted. Sentence repetition tasks showed impairments with grammatically complex sentences. Comprehension was intact as were writing and reading. The language disability remained isolated for 3 years. Cranial magnetic resonance imaging depicted somewhat asymmetrical atrophy of the parietal lobes (R>L), whereas single-photon-emitted computed tomographic imaging demonstrated hypoperfusion in the right parietal cortex, indicating right hemisphere dominance for language. CONCLUSIONS: This case report provides evidence that crossed PPA can present with a logopenic variant in addition to the nonfluent type demonstrated by others. Functional neuroimaging showed unexpected right-sided hypoperfusion in this case with only subtle structural brain asymmetry, implicating a reverse pattern of language dominance.

Noninvasive brain stimulation in traumatic brain injury.

OBJECTIVE: To review novel techniques of noninvasive brain stimulation (NBS), which may have value in assessment and treatment of traumatic brain injury (TBI). METHODS: Review of the following techniques: transcranial magnetic stimulation, transcranial direct current stimulation, low-level laser therapy, and transcranial Doppler sonography. Furthermore, we provide a brief overview of TMS studies to date. MAIN FINDINGS: We describe the rationale for the use of these techniques in TBI, discuss their possible mechanisms of action, and raise a number of considerations relevant to translation of these methods to clinical use. Depending on the stimulation parameters, NBS may enable suppression of the acute glutamatergic hyperexcitability following TBI and/or counter the excessive GABAergic effects in the subacute stage. In the chronic stage, brain stimulation coupled to rehabilitation may enhance behavioral recovery, learning of new skills, and cortical plasticity. Correlative animal models and comprehensive safety trials seem critical to establish the use of these modalities in TBI. CONCLUSIONS: Different forms of NBS techniques harbor the promise of diagnostic and therapeutic utility, particularly to guide processes of cortical reorganization and enable functional restoration in TBI. Future lines of safety research and well-designed clinical trials in TBI are warranted to determine the capability of NBS to promote recovery and minimize disability.

Modulatory effects of theta burst stimulation on cerebellar nonsomatic functions.

Clinical and functional imaging studies suggest that the cerebellar vermis is involved in the regulation of a range of nonsomatic functions including cardiovascular control, thirst, feeding behavior, and primal emotions. Cerebello-hypothalamic circuits have been postulated to be a potential neuroanatomical substrate underlying this modulation. We tested this putative relationship between the cerebellar vermis and nonsomatic functions by stimulating the cerebellum noninvasively via neuronavigated transcranial magnetic stimulation. In this randomized, counter-balanced, within-subject study, intermittent theta burst stimulation (TBS) was applied on three different days to the vermis and the right and left cerebellar hemispheres of 12 right-handed normal subjects with the aim of modulating activity in the targeted cerebellar structure. TBS-associated changes were investigated via cardiovascular monitoring, a series of emotionally arousing picture stimuli, subjective analog scales for primal emotions, and the Profile of Mood States test. All 36 sessions of cerebellar stimulation were tolerated well without serious adverse events. Cardiovascular monitoring pointed to a mild but significant decrease in heart rate subsequent to vermal stimulation; no changes were detected in systolic or diastolic blood pressure measurements. Subjective ratings detected a significant increase in Thirst and a trend toward increased Appetite following vermal stimulation. These observations are consistent with existing neurophysiological and neuroimaging data indicating a role for the cerebellum in the regulation of visceral responses. In conjunction with the modulatory function of the cerebellum, our results suggest a role for the vermis in somatovisceral integration likely through cerebello-hypothalamic pathways. Further research is warranted to elucidate the potential mechanisms underlying the cerebellar modulation of nonsomatic functions.

Safety and proof of principle study of cerebellar vermal theta burst stimulation in refractory schizophrenia.

BACKGROUND: Early invasive electrical stimulation studies suggested that enhancement of cerebellar vermal activity might prove valuable in symptomatic treatment of refractory neuropsychiatric diseases via modulation of emotion and affect. This proof of principle study aimed to test this hypothesis using noninvasive brain stimulation, and to explore the safety of this protocol in schizophrenia. METHODS: Eight treatment-refractory patients with schizophrenia underwent ten sessions of intermittent theta burst stimulation (TBS) to the cerebellar vermis using MRI-guided transcranial magnetic stimulation (TMS). Assessments included side effect questionnaires, cardiovascular monitoring, psychiatric evaluations and comprehensive neuropsychological testing before and after TBS and at one-week follow-up. RESULTS: Overall, TBS was tolerated well with mild side effects primarily comprising neck pain and headache. No serious adverse events occurred. Diastolic blood pressure (BP) showed mild decreases for five minutes post-TBS; no significant changes were detected for systolic BP or pulse. PANSS negative subscale showed significant improvements following TBS and during the follow-up. Calgary Depression Scale and self-report visual analog scales for Happiness and Sadness pointed to significant mood elevation. Neuropsychological testing revealed significantly fewer omissions in working memory and interference conditions of a Continuous Performance Test, a longer spatial span and better delay organization on the Rey-Osterrieth Complex Figure during follow-up. No significant worsening in psychiatric or neuropsychological measures was detected. CONCLUSIONS: Theta burst stimulation of the cerebellar vermis is safe and well-tolerated, while offering the potential to modulate affect, emotion and cognition in schizophrenia. Future randomized, sham-stimulation controlled studies are warranted to support the clinical efficacy of this technique.

Right cerebral hemiatrophy: neurocognitive and electroclinical features.

The purpose of this study was to retrospectively evaluate the cognitive and electroclinical characteristics of right cerebral hemiatrophy (Dyke-Davidoff-Masson syndrome [DDMS]). Cognitive assessments with a particular emphasis on visuospatial functions, electroclinical features, and neuroimaging characteristics were analyzed for five patients with a clinically and neuroradiologically confirmed diagnosis of right-sided DDMS. Intelligence tests revealed mental retardation in all but one. Neuropsychological assessments demonstrated consistent impairments in tasks that have a spatial component (spatial processing and orientation discrimination), whereas attention, executive functions and verbal memory domains were variably impaired. Electroclinically, the main seizure types were simple partial motor, complex partial, and secondarily generalized seizures. Interictal EEG delineated lower amplitudes and slow background activity in the affected hemisphere. Overall, the cognitive performance of patients with DDMS encompasses a broad spectrum of impairments affecting multiple domains. Our findings support the concept that dorsal visual pathways responsible for spatial processing may be lateralized to the right hemisphere.

Abnormal corticospinal excitability in traumatic diffuse axonal brain injury.

This study aimed to investigate the cortical motor excitability characteristics in diffuse axonal injury (DAI) due to severe traumatic brain injury (TBI). A variety of excitatory and inhibitory transcranial magnetic stimulation (TMS) paradigms were applied to primary motor cortices of 17 patients and 11 healthy controls. The parameters of testing included resting motor threshold (MT), motor evoked potential (MEP) area under the curve, input-output curves, MEP variability, and silent period (SP) duration. The patient group overall revealed a higher MT, smaller MEP areas, and narrower recruitment curves compared to normal controls (p < 0.05). The alterations in excitability were more pronounced with an increase in DAI severity (p < 0.005) and the presence of motor impairment (p < 0.05), while co-existence of focal lesions did not affect the degree of MEP changes. MEP variability was significantly lower in the group with motor impairment only (p < 0.05). The intracortical inhibition, as revealed by SP duration, did not exhibit any significant differences in any of the patient groups. In conclusion, our findings expand the concept that impairment of the excitatory and inhibitory phenomena in the motor cortex does not proceed in parallel and demonstrate distinct patterns of aberrations in TBI. Furthermore, these data suggest that alterations in the corticospinal excitatory mechanisms are determined predominantly by the severity of DAI, and show a significant relationship with clinical motor dysfunction following severe trauma diffusely affecting the motor cortical connections. In severe TBI, motor and functional recovery might be linked to restitution of normal corticospinal mechanisms, indexed by normalization of the cortical excitability parameters.

Safety and behavioral effects of high-frequency repetitive transcranial magnetic stimulation in stroke.

BACKGROUND AND PURPOSE: Electromagnetic brain stimulation might have value to reduce motor deficits after stroke. Safety and behavioral effects of higher frequencies of repetitive transcranial magnetic stimulation (rTMS) require detailed assessment. METHODS: Using an active treatment-only, unblinded, 2-center study design, patients with chronic stroke received 20 minutes of 20 Hz rTMS to the ipsilesional primary motor cortex hand area. Patients were assessed before, during the hour after, and 1 week after rTMS. RESULTS: The 12 patients were 4.7+/-4.9 years poststroke (mean+/-SD) with moderate-severe arm motor deficits. In terms of safety, rTMS was well tolerated and did not cause new symptoms; systolic blood pressure increased from pre- to immediately post-rTMS by 7 mm Hg (P=0.043); and none of the behavioral measures showed a decrement. In terms of behavioral effects, modest improvements were seen, for example, in grip strength, range of motion, and pegboard performance, up to 1 week after rTMS. The strongest predictor of these motor gains was lower patient age. CONCLUSIONS: A single session of high-frequency rTMS to the motor cortex was safe. These results require verification with addition of a placebo group and thus blinded assessments across a wide spectrum of poststroke deficits and with larger doses of 20 Hz rTMS.

An open-label, prospective study of repetitive transcranial magnetic stimulation (rTMS) in the long-term treatment of refractory depression: reproducibility and duration of the antidepressant effect in medication-free patients.

OBJECTIVE: Several studies have assessed the acute antidepressant effects of repetitive transcranial magnetic stimulation (rTMS), and many have revealed positive results. However, the impact of rTMS throughout the long course of major depressive disorder (MDD) and the efficacy of rTMS in the treatment of depressive relapses still remain to be elucidated. METHOD: Sixteen medication-free patients with refractory MDD (diagnosed according to DSM-IV) who initially had clinically significant antidepressant responses to a 10-day course of 10-Hz rTMS were consecutively admitted to the protocol from 1997 to 2001 and were followed for 4 years. The cohort was studied during a total of 64 episodes of depressive relapse. Severity of depression was evaluated with the Hamilton Rating Scale for Depression (HAM-D) and the Beck Depression Inventory (BDI) prior to and after completion of each rTMS treatment course. Clinically significant response was defined as a reduction in HAM-D score of at least 50%. Safety was assessed by serial neurologic examinations and neuropsychological evaluations. RESULTS: Approximately one half of the patients individually sustained a clinically significant response to the repeated courses of rTMS; the mean +/- SD decrease in HAM-D scores was 64.8% +/- 12.6% (p < .0001), and, in BDI scores, 60.4% +/- 20.6% (p < .0001). Despite the lack of adjuvant antidepressant medication, the mean interval between treatment courses was approximately 5 months, and the medication-free period ranged from 26 to 43 months. Transcranial magnetic stimulation was well tolerated, and evaluations regarding the safety of the repeated applications of rTMS revealed no findings of concern. CONCLUSIONS: Repeated rTMS applications have demonstrated a reproducible antidepressant effect in patients with refractory depression who initially showed a clinically significant benefit. The duration of effect varied across patients, but benefits were sustained for a mean of nearly 5 months. Further studies with larger cohorts will be useful in determining the long-term effectiveness of rTMS maintenance therapy.