Repetitive transcranial magnetic stimulation combined with cognitive training is a safe and effective modality for the treatment of Alzheimer's disease: a randomized, double-blind study.

Cortical excitability can be modulated using repetitive transcranial magnetic stimulation (rTMS). Previously, we showed that rTMS combined with cognitive training (rTMS-COG) has positive results in Alzheimer's disease (AD). The goal of this randomized double-blind, controlled study was to examine the safety and efficacy of rTMS-COG in AD. Fifteen AD patients received 1-h daily rTMS-COG or sham treatment (seven treated, eight placebo), five sessions/week for 6 weeks, followed by biweekly sessions for 3 months. The primary outcome was improvement of the cognitive score. The secondary outcome included improvement in the Clinical Global Impression of Change (CGIC) and Neuropsychiatric Inventory (NPI). There was an improvement in the average ADAS-cog score of 3.76 points after 6 weeks in the treatment group compared to 0.47 in the placebo group and 3.52 points after 4.5 months of treatment, compared to worsening of 0.38 in the placebo (P = 0.04 and P = 0.05, respectively). There was also an improvement in the average CGIC score of 3.57 (after 6 weeks) and 3.67 points (after 4.5 months), compared to 4.25 and 4.29 in the placebo group (mild worsening) (P = 0.05 and P = 0.05, respectively). NPI improved non-significantly. In summary, the NeuroAD system offers a novel, safe and effective therapy for improving cognitive function in AD.

Hypoxemia correlates with attentional dysfunction in patients with obstructive sleep apnea.

PURPOSE: Obstructive sleep apnea is associated with cognitive impairment, but whether hypoxemia or repeated arousals and sleepiness are the underlying mechanism is controversial. Studies using a wide range of attention and executive functions tests in patients with severe sleep apnea are lacking. METHODS: In a prospective cohort study, 40 patients aged 30-70 years, diagnosed with obstructive sleep apnea (apnea-hypopnea index ≥5) were recruited. Patients with known cardiovascular, pulmonary, psychiatric, or neurological disease, and or patients receiving anti-psychotic, sedatives, or stimulant medications were excluded. Patients underwent full overnight polysomnography including continuous oxygen saturation measurements followed by extensive neuropsychological testings in attention and executive function domains. The correlation between sleep apnea severity and patients' performance on the neuropsychological tests was examined. RESULTS: The patients' performance on measures of attention and executive function was significantly worse compared to the average in a normal population. Attention, as reflected by the number of omissions and by the reaction time on the Conners' Continuous Performance Test correlated significantly with the apnea-hypopnea index (r = 0.6, p < 0.001 and r = 0.48, p = 0.003, respectively) and with parameters of hypoxemia, namely the average SpO(2) (r = -0.51, p = 0.002 and r = -0.39, p = 0.02, respectively) and the percent time spent with SpO(2) < 90% (r = 0.57, p < 0.001 and r = 0.39, p = 0.02, respectively), but not with the degree of sleepiness. Executive dysfunction did not correlate with sleep parameters. DISCUSSION: Attention is the predominant cognitive function affected in patients with obstructive sleep apnea and correlates primarily with nocturnal hypoxemia rather than daytime sleepiness or sleep fragmentation. Executive functions, while below average in some patients, do not correlate with polysomnographic parameters.

Beneficial effect of repetitive transcranial magnetic stimulation combined with cognitive training for the treatment of Alzheimer's disease: a proof of concept study.

The current drug treatment for Alzheimer's disease (AD) is only partially and temporary effective. Transcranial magnetic stimulation (TMS) is a non-invasive technique that generates an electric current inducing modulation in cortical excitability. In addition, cognitive training (COG) may improve cognitive functions in AD. Our aim was to treat AD patients combining high-frequency repetitive TMS interlaced with COG (rTMS-COG). Eight patients with probable AD, treated for more than 2 months with cholinesterase inhibitors, were subjected to daily rTMS-COG sessions (5/week) for 6 weeks, followed by maintenance sessions (2/week) for an additional 3 months. Six brain regions, located individually by MRI, were stimulated. COG tasks were developed to fit these regions. Primary objectives were average improvement of Alzheimer Disease Assessment Scale-Cognitive (ADAS-cog) and Clinical Global Impression of Change (CGIC) (after 6 weeks and 4.5 months, compared to baseline). Secondary objectives were average improvement of MMSE, ADAS-ADL, Hamilton Depression Scale (HAMILTON) and Neuropsychiatric Inventory (NPI). One patient abandoned the study after 2 months (severe urinary sepsis). ADAS-cog (average) improved by approximately 4 points after both 6 weeks and 4.5 months of treatment (P < 0.01 and P < 0.05) and CGIC by 1.0 and 1.6 points, respectively. MMSE, ADAS-ADL and HAMILTON improved, but without statistical significance. NPI did not change. No side effects were recorded. In this study, rTMS-COG (provided by Neuronix Ltd., Yokneam, Israel) seems a promising effective and safe modality for AD treatment, possibly as good as cholinesterase inhibitors. A European double blind study is underway.

Quantitative EEG After Brain Stimulation and Cognitive Training in Alzheimer Disease.

PURPOSE: Medications are the currently accepted symptomatic treatment of Alzheimer disease (AD), but their impact on delaying the progression of cognitive deficits and functional impairment is limited. The authors aimed to explore long-term electrophysiological effects of repetitive transcranial magnetic stimulation interlaced with cognitive training on quantitative electroencephalography (EEG) in patients with AD. METHODS: Quantitative EEG was assessed on non-repetitive transcranial magnetic stimulation interlaced with cognitive training treatment days before treatment and after each treatment phase in seven patients with mild AD. RESULTS: After 4.5 months (54 sessions) of treatment, a significant increase of delta activity over the temporal region was found compared with pretreatment values. Nonsignificant increases of the log EEG power were found for alpha band over the frontal and temporal regions, beta band over the frontal region, theta band over the frontal, temporal, and parieto-occipital regions, and delta band over the frontal and parieto-occipital regions. Nonsignificant decreases were found for alpha over the parieto-occipital region, and for beta over the temporal and parieto-occipital regions. A positive correlation was found between log alpha power over the frontal and temporal regions at 6 weeks and Mini-Mental State Examination (MMSE) scores at 6 weeks and 4.5 months, and between log alpha power over the parieto-occipital regions and MMSE scores at 6 weeks. A negative correlation was found between log alpha power over the frontal and temporal regions at 6 weeks and baseline Alzheimer's Disease Assessment Scale-cognitive subscale scores. CONCLUSIONS: Repetitive transcranial magnetic stimulation interlaced with cognitive training has long-term effects on quantitative EEG in patients with mild AD. Further research on the quantitative EEG long-term effects of transcranial magnetic stimulation interlaced with cognitive training is required to confirm the authors' data.