Computer-assisted training of executive functions in adult patients with non-progressive acquired brain damage - a pilot study on efficacy of a new therapeutic application.

Executive dysfunction is most often caused by post-traumatic or post-stroke damage to the prefrontal regions of the brain. The aim of this study was to compare the efficacy of two computer-assisted therapy programs for executive dysfunctions in patients with acquired brain injury. Patients were trained using either a newly developed application ExeSystem (designed to help improve the ability to manage and control one's own behavior by performing tasks imitating natural, everyday situations) or a combination of two commercial applications RehaCom and CogniPlus. Data collected after a three-week period of therapy conducted in two 15-person groups of participants indicated comparable efficacy of both therapy programs in improving quality of daily functioning, executive attention, as well as planning and problem-solving but not memory. The improvement in social competence (p = .028) was the only advantage of therapy with the ExeSystem. Therapeutic interactions using computer programs were shown to be positively evaluated by patients (p < .01). This study confirmed at least equal efficacy of computer-based executive function therapy using ExeSystem compared to RehaCom and CogniPlus. However, despite the implementation of a more ecological and comprehensive approach to the content of a new application, the benefits of this approach were limited.

Clinical significance of self-descriptive apathy assessment in patients with neurological form of Wilson's disease.

BACKGROUND AND AIM: Apathy is one of the neuropsychiatric symptoms of Wilson's disease (WD) which typically affects the brain's fronto-basal circuits. Lack of agreed diagnostic criteria and common use of self-description assessment tools lead to underestimation of this clinical phenomenon. The aim of this study was to investigate whether subjective and informant-based clinical features of apathy in patients with WD enable clinicians to make a valid diagnosis. METHODS: Multiple aspects of goal-oriented behavior were assessed in 30 patients with the neurological form of WD and 30 age-matched healthy participants using two questionnaires, the Lille Apathy Rating Scale (LARS) and the Dysexecutive Questionnaire (DEX). Both included a self-descriptive and a caregiver/proxy version. Cognitive functioning was estimated with the use of Addenbrooke's Cognitive Examination-Revised. RESULTS: Patients obtained significantly worse scores on all clinical scales when more objective measures were considered. Features of apathy and executive dysfunction were revealed in patients' caregiver versions of LARS and DEX, which may indicate poor self-awareness of patients with WD. Roughly 30% of participants were likely to present with clinically meaningful symptoms, independent of cognitive dysfunction. CONCLUSIONS: Methods relying on self-description appear inferior to informant-based scales when diagnosing apathy. More objective criteria and measurement tools are needed to better understand this clinical syndrome.

Neuronavigated 1 Hz rTMS of the left angular gyrus combined with visuospatial therapy in post-stroke neglect.

BACKGROUND: Visuospatial neglect (VSN) may be caused by an inter-hemispheric imbalance of neural activity after brain injury. Repetitive transcranial magnetic stimulation (rTMS) allows rebalancing restoration to a certain degree, relieving neglect symptoms. OBJECTIVE: This study investigates the therapeutic effect of 1 Hz rTMS applied over the left angular gyrus combined with visual scanning training in patients with left VSN in the subacute stroke phase. METHODS: Twenty-eight patients with VSN were randomly assigned to either experimental (fifteen sessions of rTMS consisted of 1800 magnetic pulses delivered to the left angular gyrus with a neuronavigation control), or control group (fifteen sessions of sham stimulation), followed by visual scanning training. VSN severity was assessed both before and after treatment with a 3-month follow up employing the Behavioural Inattention Test and functional measures. RESULTS: No statistically significant differences were detected in outcome measures between the rTMS and sham groups after completion of 3-week therapy and at 3-month follow up. The magnitude of stimulation effects was not associated either with lesion volume, its location, or baseline motor threshold. CONCLUSIONS: Our study did not confirm efficacy of 1 Hz rTMS over the angular gyrus as an adjuvant method to visual scanning training in patients with VSN in the subacute stroke.

Comprehensive cognitive training improves attention and memory in patients with severe or moderate traumatic brain injury.

Traumatic brain injury (TBI) leads to cognitive disorders, the most frequently affected functions being attention and memory. The present study aimed to investigate the effects of a cognitive rehabilitation program, consisting of individual and group interventions, on attention and memory in patients with TBI. Fifteen patients-in the postacute phase of recovery from moderate-to-severe TBI and subsequent cognitive disorders-were enrolled on a three-week waiting list and then underwent a three-week cognitive rehabilitation program. The patients were assessed using a set of five neuropsychological attention and memory tests. The patients and their caregivers were questioned to assess subjective changes in the everyday functioning of the former. The introduction of cognitive training was associated with improvement in one memory test and in two measures of attention. Mean effect size across all tests was higher over the period with treatment compared to the period without (d = 0.36 vs. 0.03). Both patients and caregivers reported significant improvements in everyday functioning (p < .05). There were no further improvements at the four-month follow-up assessment. A comprehensive program of cognitive rehabilitation may improve attention and memory, as well as everyday cognitive functioning, in patients with severe or moderate TBI.

Alternating Hemiplegia of Childhood in Two Adult Patients with a Mild Syndrome.

We describe the cognitive-behavioral functioning of two adult patients with a mild form of alternating hemiplegia of childhood (AHC). AHC is a rare, chronic neurodevelopmental syndrome manifesting in infancy or early childhood, with recurrent hemiplegic or hemidystonic attacks, various nonepileptic paroxysmal events, and cognitive-behavioral impairments, including mental delay of varying degrees. We conducted neurologic and neuroimaging examinations, as well as a neuropsychological assessment, of two men (22 and 30 years old) with mutations in the ATP1A3 gene (p.Leu757Pro and p.Val332Glu) who were experiencing typical AHC transient episodes of alternating weakness or paralysis in order to investigate causes of their poor social functioning. During neurologic examinations of both patients, which were performed between attacks, we observed involuntary movements such as chorea and upper-limb tremor. One patient also had dysarthria. Magnetic resonance imaging revealed no parenchymal brain lesions or atrophy in either patient. Neuropsychological examinations demonstrated near-normal (patient 1) or normal (patient 2) global cognitive functioning, with some isolated executive functioning deficits. Both patients had emotional and social dysfunction as well as difficulties adapting to normal adult life. Although the clinical presentation of AHC is usually dramatic, some patients have mild forms of the syndrome (eg, no significant intellectual disability). However, motor and movement disorders, as well as coexisting emotional-affective abnormalities, may affect these patients' ability to adapt to independent life.

Effects of group versus individual therapy for patients with memory disorder after an acquired brain injury: A randomized, controlled study.

INTRODUCTION: This randomized, controlled, single-blind study compared the efficacy of group versus individual memory rehabilitation therapy for patients with acquired brain injury (ABI). Subjects (N = 65) were assigned to individual (IT), group (GT), or no (NT) therapy during the three-week rehabilitation program. A neuropsychological assessment was conducted before treatment, immediately after completing treatment, and 4 months after completing treatment. Three levels of functioning were assessed: participation, disability, and impairment. The primary outcome measure was the Rivermead Behavioural Memory Test (RBMT). The results of the cognitive measures in the three groups at subsequent assessments were compared, and the effect sizes were calculated to investigate the magnitude of improvement. RESULTS: There were no significant changes in self-reported patient memory problems for the participation-level measures. However, relatives of participants in the GT group reported a decreased frequency of memory failures (p = .026). According to the ability-level measure (RBMT), both therapeutic groups had similar significant improvements (p < .001), and the effect sizes were large in both groups. Although the NT group also improved (p = .015), the effect size was small. The differences between the three groups were not significant according to analysis of variance (ANOVA). However, after therapy was completed, only the GT group continued to improve (p = .013). For the impairment-level measures, the IT group showed significant improvement post treatment in three out of four measures (p < .05). This group had medium effect sizes, while the other groups showed a small or marginal effect. CONCLUSIONS: Cognitive rehabilitation - either in a group or individually - led to equally enhanced memory functioning in ABI patients, but the effects were not significantly different from those for patients in the NT group. GT and IT had specific effects on different levels of functioning.

Cognitive and psychiatric symptoms in Wilson disease.

Wilson disease - can present with such a variety of psychiatric and cognitive symptoms that it has been named the "great masquerader." Symptoms may include cognitive deficits, impairment of executive function, mood disturbance or psychosis. These impairments may occur in different stages of the disease and with varying intensity in individual patients. This chapter reviews the literature and authors' clinical experiences of the assessment, mechanism, and prevalence of cognitive and psychiatric pathology occurring in Wilson disease. Evidence of pharmacologic and nonpharmacologic treatments is also discussed.

Neuropsychological characteristics of encephalopathy in Susac's Syndrome - Case report.

Susac's Syndrome (SS) is a rare, autoimmune angiopathy characterized by hearing loss, retinal artery occlusions and encephalopathy, which is usually expressed in multifocal neurological signs and symptoms, confusion state and cognitive impairment. There have been few descriptions of neuropsychological assessment of SS. We present a case study of 29-year-old woman who developed full SS. During the post-acute stage of disease, she was admitted to neurorehabilitation ward to improve her cognitive-behavioral and motor functioning. The initial assessment revealed attention, memory and executive dysfunctions, as well as behavioral changes including impulsivity, affective dysregulation and reduced self-awareness of disease deficits. After five weeks recovery process supported by rehabilitation program, improvement was observed, although some cognitive-behavioral deficits were still present in the follow-up assessment.

Adding transcutaneous electrical nerve stimulation to visual scanning training does not enhance treatment effect on hemispatial neglect: a randomized, controlled, double-blind study.

BACKGROUND: Left-sided transcutaneous electrical nerve stimulation (TENS) increases right hemispheric activity, which may improve the rehabilitative outcome of hemispatial neglect. OBJECTIVE: To examine the behavioral effect of electrical stimulation of the nerve afferents of the left hand during early neuropsychological rehabilitation of post-stroke patients with hemispatial neglect. METHODS: This randomized, controlled, double-blind study included 29 patients (enrolled in the experimental or control group) with left hemispatial neglect after right hemispheric stroke. For 3 weeks, patients received 15 therapeutic sessions involving TENS (active or sham) with a mesh glove applied on the entire left hand during the first 30 minutes of a 45-minute conventional visual scanning training (VST). Signs of hemispatial neglect were assessed using a psychometric test before and after treatment. RESULTS: Univariate analysis of covariance revealed that differences between the control and experimental groups were not significant after treatment (F(1, 22) = 0.294, P = 0.593) when adjusted for pre-treatment scores and time since stroke onset. This suggested that electrical stimulation failed to mitigate the severity of hemispatial neglect symptoms. CONCLUSION: Our study did not provide evidence of the effectiveness of TENS when added to VST during early rehabilitation for patients with post-stroke hemispatial neglect. Other techniques (applied alone or together) should be sought to improve recovery in this population.

Encephalopathy in Wilson disease: copper toxicity or liver failure?

Hepatic encephalopathy (HE) is a complex syndrome of neurological and psychiatric signs and symptoms that is caused by portosystemic venous shunting with or without liver disease irrespective of its etiology. The most common presentation of Wilson disease (WD) is liver disease and is frequently associated with a wide spectrum of neurological and psychiatric symptoms. The genetic defect in WD leads to copper accumulation in the liver and later in other organs including the brain. In a patient presenting with Wilsonian cirrhosis neuropsychiatric symptoms may be caused either by the metabolic consequences of liver failure or by copper toxicity. Thus, in clinical practice a precise diagnosis is a great challenge. Contrary to HE in neurological WD consciousness, is very rarely disturbed and pyramidal signs, myoclonus dominate. Asterixis and many other clinical symptoms may be present in both disease conditions and are quite similar. However details of neurological assessment as well as additional examinations could help in differential diagnosis.

Visual disorders, the prosopometamorphopsia and prosopagnosia type in the early days after the onset of brain hemorrhagic stroke--a case report.

Presented case report illustrates symptoms of prosopometamorphopsia (PM) and prosopagnosia, observed in the early days after the onset of a hemorrhagic stroke resulting from a complication of endovascular treatment of intracranial aneurysms and the use of anticoagulation therapy. PM is a visual disorder in which faces are perceived as distorted. The female patient described in the present study reported that faces she looked at seemed younger or older than in reality or as if they were dirty, swollen, or with a grimace. She also experienced symptoms of prosopagnosia, which is difficulty of recognizing familiar faces of people (e.g., of her husband and daughter). In the interview 6 months after the first examination, the patient reported spontaneous withdrawal of the visual disturbances.

Diverse attention deficits in patients with neurologically symptomatic and asymptomatic Wilson's disease.

OBJECTIVE: Cognitive deficits in patients with Wilson's disease (WD) have been reported in several studies, but there was no detailed analysis of the various components of attention, one of the most significant factors of the executive system. Our study determined the pattern of deficits in attention subsystems in WD patients, including selective attention, divided attention, attention switching, and sustained attention. METHOD: We examined 67 WD patients using the Test of Everyday Attention (TEA)-33 participants with neurological symptoms and 34 who were neurologically asymptomatic, but most with mild hepatic dysfunctions. The results were compared with 43 matched healthy controls. RESULTS: The group of WD patients with neurological symptoms performed significantly worse (p < .05) in all components of attention: sustained attention, selective attention, divided attention, and attentional switching. WD patients without neurological symptoms exhibited significantly lower results in one component-sustained attention (p < .05). None of the TEA subtests scores were associated significantly with Unified Wilson's Disease Rating Scale scores, which may reflect that the cognitive and neurological consequences of WD are relatively independent. CONCLUSIONS: We found a deficiency in all components of attention in neurological WD patients. The most frequently disturbed function was attention switching. Relatively milder deficits concerned divided, selective, and sustained attention. These are all abilities creating the core of the executive system and are regulated by subcortical prefrontal circuits, which are usually dysfunctional in WD patients. In neurologically asymptomatic patients, an isolated deficit of sustained attention occurs; this may be a sign of mild hepatic encephalopathy.

Pure alexia after damage to the right fusiform gyrus in a right-handed male.

Pure alexia refers to a rare acquired reading disorder commonly associated with damage to the posterior part of the left medial occipito-temporal (fusiform) gyrus, which is known as the visual word-form area (VWFA) and thought to be the neural basis for visual processing of letters and words. Right-sided lesions very rarely lead to pure alexia in right-handed individuals. We report a case of a 33-year-old right-handed man with isolated pure alexia resulting from a hemorrhagic lesion to the right fusiform gyrus. A limited recovery of reading skills was observed within six weeks post onset. During this period, the patient spontaneously developed a letter-by-letter reading strategy. Functional magnetic resonance imaging revealed right-hemisphere dominance for language as well as bilateral reading-related activity in the fusiform gyri. Our case indicates that pure alexia may arise as a consequence of damage to the right fusiform gyrus even in right-handed patients (who still may have right hemisphere dominance for language and reading skills), and may lead to a severe reading disorder, as in individuals with left-hemisphere dominance for language.

Neuropsychological and neurological sequelae of out-of-hospital cardiac arrest and the estimated need for neurorehabilitation: a prospective pilot study.

BACKGROUND: Diffuse brain injury is a key component of post-cardiac arrest syndrome reported in 30-80% of survivors of out-of-hospital cardiac arrest (OHCA). It is responsible for a high mortality rate, and is a common cause of cognitive and neurological deficits and disability. Symptom variability and dynamics and the rehabilitation potential remain poorly understood. AIM: To investigate symptom prevalence, type, and severity and the natural course of recovery within 12 months after OHCA, and to estimate neurorehabilitation needs. METHODS: Study participants were selected from OHCA survivors admitted consecutively to a cardiac intensive care unit (CICU) serving 250,000 of Warsaw's inhabitants, according to the following inclusion criteria: first ever nontraumatic, normothermic cardiac arrest, age ≤ 75 years; cardiology ward survival until discharge, and no history of pre-existing brain disease. Patients' cognitive and neurological status and disability were evaluated in the first days after onset and three, six and 12 months later. Neuropsychological assessment focused on attention, memory, executive, linguistic and visuo-spatial abilities. Neurological examination included assessment of cranial nerves, muscle strength and tone, deep tendon reflexes, cerebellar function, sensory function, and gait. The general psychophysical state was classified using the Disability Rating Scale. Patients' neurorehabilitation needs were determined using data collected three months post-OHCA. This data was used to estimate future demands for such resources in Poland. RESULTS: During a 28-month study period, of 69 OHCA patients admitted to the CICU, 29 met the study criteria (33 survived until discharge from cardiology unit; four did not meet further criteria). Severe consciousness disorders were most frequent in the early post-OHCA phase (28%); no unresponsive patients were identified 12 months later. Of responsive patients who were capable of at least minimal co-operation, 100% (early after OHCA) to 57% (12 months after OHCA) had cognitive impairment, usually with neurological symptoms. Memory impairment was the most common and severe problem, followed by executive, attentional, language and visuo-spatial dysfunctions. The prevalence of neurological deficits ranged from 88% (early after OHCA) to 43% (12 months after OHCA). Due to acquired deficits, between 71% (early post-OHCA) and 36% (12 months post-OHCA) of patients were significantly disabled and often dependent. Although dysfunctions tended to improve, over 50% of the patients remained impaired 12 months post-OHCA, and over 30% were significantly disabled. We estimated that about 800 OHCA survivors/year in Poland will develop symptoms requiring neurorehabilitation. CONCLUSIONS: Cognitive and neurological symptoms are common after cardiac arrest brain injury. Establishing specialised neurorehabilitation centres is essential for treating these patients.

Training in rapid auditory processing ameliorates auditory comprehension in aphasic patients: a randomized controlled pilot study.

Experimental studies have often reported close associations between rapid auditory processing and language competency. The present study was aimed at improving auditory comprehension in aphasic patients following specific training in the perception of temporal order (TO) of events. We tested 18 aphasic patients showing both comprehension and TO perception deficits. Auditory comprehension was assessed by the Token Test, phonemic awareness and Voice-Onset-Time Test. The TO perception was assessed using auditory Temporal-Order-Threshold, defined as the shortest interval between two consecutive stimuli, necessary to report correctly their before-after relation. Aphasic patients participated in eight 45-minute sessions of either specific temporal training (TT, n=11) aimed to improve sequencing abilities, or control non-temporal training (NT, n=7) focussed on volume discrimination. The TT yielded improved TO perception; moreover, a transfer of improvement was observed from the time domain to the language domain, which was untrained during the training. The NT did not improve either the TO perception or comprehension in any language test. These results are in agreement with previous literature studies which proved ameliorated language competency following the TT in language-learning-impaired or dyslexic children. Our results indicated for the first time such benefits also in aphasic patients.

Effects of repeated anodal tDCS coupled with cognitive training for patients with severe traumatic brain injury: a pilot randomized controlled trial.

OBJECTIVE: To determine whether cumulative anodal transcranial direct current stimulation (A-tDCS) of the left dorsolateral prefrontal cortex (DLPFC) could enhance rehabilitation of memory and attention in patients with traumatic brain injury (TBI). SETTING: Inpatient and outpatient neurorehabilitation unit. PARTICIPANTS: Twenty-three adult patients, 4- to 92- months post severe TBI. DESIGN: Participants were randomly allocated to 2 groups. The experimental group received A-tDCS (10 minutes; 1 mA; in the DLPFC), followed by rehabilitative cognitive training, daily for 15 days. Controls received A-tDCS for 25 seconds (sham condition) with the same rehabilitation. MAIN MEASURES: Battery of memory and attention tests, which included visual and auditory modalities. Participants were tested twice before beginning rehabilitation (to control for spontaneous recovery), after rehabilitation completion, and 4 months later. RESULTS: Tests scores in both groups were similar at 3 weeks before and immediately before treatment. After treatment, the experimental group exhibited larger effect sizes in 6 of 8 cognitive outcome measures, but they were not significantly different from controls. At follow-up, differences remained insignificant. CONCLUSION: In contrast to previous studies, our study did not provide sufficient evidence to support the efficacy of repeated A-tDCS for enhancing rehabilitation of memory and attention in patients after severe TBI.

Anodal transcranial direct current stimulation in early rehabilitation of patients with post-stroke non-fluent aphasia: a randomized, double-blind, sham-controlled pilot study.

PURPOSE: Recent research in patients with chronic aphasia shows an association between excitatory anodal transcranial direct current stimulation (A-tDCS) of the stroke-affected left hemisphere coupled with speech and language therapy (SLT) and better language performance. The present study aimed to investigate this association during the early post-stroke rehabilitation period, when adaptive changes are most possible on neurophysiological and behavioral levels. METHODS: We randomized 24 patients with non-fluent aphasia to receive 15 consecutive sessions (5 days/week for 3 weeks) of A-tDCS (1 mA, 10 min; n = 14) or sham tDCS (S-tDCS: 1 mA, 25 sec; n = 10) over Broca's area followed by 45-min SLT. Naming ability was assessed before the rehabilitation, after its completion, and three months later. RESULTS: Both groups significantly improved after the therapy. There were no statistically significant between-group differences in the short-term or long-term tDCS effects on naming accuracy and naming time. The A-tDCS group obtained higher effect sizes in naming time, both post-treatment and at the 3-month follow-up, suggesting potential benefits of the stimulation. CONCLUSIONS: The findings provide only weak evidence for A-tDCS-related language gains during early neurorehabilitation of post-stroke aphasia. Further research is needed to explore the effectiveness of this kind of neuromodulation.

Transcranial magnetic stimulation combined with speech and language training in early aphasia rehabilitation: a randomized double-blind controlled pilot study.

BACKGROUND: Functional neuroimaging studies with poststroke aphasia patients have shown increased activation of the unaffected hemisphere, which hypothetically reflects a maladaptive strategy of brain reorganization. OBJECTIVE: We investigated whether repetitive transcranial magnetic stimulation (rTMS) inhibiting the right-hemisphere homologue of Broca's area improves language restitution if combined with speech/language therapy. METHODS: Forty aphasic patients during the subacute phase of ischemic stroke were randomized to a 3-week aphasia rehabilitation protocol in combination with real or sham rTMS. Naming, repetition, and comprehension were assessed using the Boston Diagnostic Aphasia Examination at baseline, immediately after therapy, and 15 weeks after completing treatment. RESULTS: Although language functions improved in both experimental and control groups after 3 weeks, only slight group differences in degree of recovery were revealed between patients receiving rTMS and control participants. Follow-up revealed that severely aphasic rTMS patients demonstrated significantly greater improvement than patients receiving sham stimulation in repetition. CONCLUSIONS: Inhibitory rTMS applied to the right frontal language homologue is not effective for all poststroke aphasia patients, although it might benefit selected patients.

[The value of self-report methods in neuropsychological diagnostics of patients after brain injury]. / Wartosc pomiaru samoopisowego w diagnostyce neuropsychologicznej pacjentów z uszkodzeniem mózgu.

Self-report methods are commonly applied in medicine and psychology. However, their diagnostic value in assessment of patients with acquired brain damage can be limited due to a number of various difficulties encountered by these patients, including cognitive disorders, fatigue, similarity of psychopathological and somatic symptoms, psychological reaction to the disease and limited or lack of insight (anosognosia). In our article we highlight the most important limitations of application of popular frequently used questionnaires in evaluation of brain-injured patients. We also discuss the possible ways of adjusting self-report techniques to requirements of diagnostic process in this clinical population. Proposed modifications refer to, among others, specific construction of diagnostic tools (appropriate content and number of questions, methods of measuring responses), collecting information from relatives, using questionnaires along with more objective measures, and controlling conditions in which the assessment is carried out. Although relying only on self-report methods can be misleading, for an aware clinician it is still an important source of data on patient's subjective opinion and on the way they experience their symptoms.

Association between BDNF-196 G>A and BDNF-270 C>T polymorphisms, BDNF concentration, and rTMS-supported long-term rehabilitation outcome after ischemic stroke.

BACKGROUND: The efficacy of rehabilitation in ischemic stroke patients likely varies because of brain plasticity. One of the main neurotrophins in the central nervous system is brain-derived neurotrophic factor (BDNF). OBJECTIVES: This study aimed to determine allelic and genotypic distribution of BDNF-196 G>A and -270 C>T polymorphisms, and to assess the impact of repetitive transcranial magnetic stimulation (rTMS) on serum BDNF concentrations measured before rehabilitation, after the first 6 h of rehabilitation, and after 3 weeks of rehabilitation. METHODS: Twenty-six patients with hand paresis and 20 with aphasia were randomly assigned to treatment with rTMS or sham stimulation (placebo group). RESULTS: In men with aphasia, after the first 6 h of rTMS-supported rehabilitation, BDNF concentration was lower among rTMS-treated patients than placebo-treated patients. A similar difference was observed in women with aphasia after 3 weeks of rTMS-supported rehabilitation. No significant differences in serum BDNF concentration were observed in patients with different BDNF-196 G>A or -270 C>T genotypes. During the observation period, BDNF concentration did not differ significantly between patients who improved and those who did not. DISCUSSION: One possible explanation for the observed difference between rTMS-stimulated and sham-stimulated patients is the suppression of BDNF production by rTMS in the healthy brain hemisphere.