Repetitive transcranial magnetic stimulation as a treatment for Alzheimer's disease: A randomized placebo-controlled double-blind clinical trial.

We report results of a large multisite double-blind randomized trial investigating the short and long-term efficacy of repetitive transcranial magnetic stimulation (rTMS) applied to patients with Alzheimer's disease (AD) at mild to moderate stages, in doses of either 2 or 4 weeks of treatment (5 days/week), whilst compared with 4 weeks of sham rTMS. Randomization to treatment group was stratified based on age and severity. The objectives of this study were to: 1) investigate the efficacy of active rTMS versus sham, 2) investigate the effect of dose of treatment (2 or 4 weeks), and 3) investigate the length of benefits from treatment. The rTMS pulses (20 â€‹Hz, 30 pulses/train, 25 trains, 10-s intertrain interval) were applied serially to the left and right dorsolateral prefrontal cortex using neuro-navigation. We compared the primary outcome measure's (ADAS-Cog) score changes from pre- to post-treatment, with assessments at baseline and 4 more times up to 6 months post-treatment. Data of 135 patients were analyzed. The mean total ADAS-Cog score at baseline did not differ between the active and sham treatment groups, nor across the three study sites. The overall results show significant cognitive improvement after treatment up to two months post-treatment with either sham or active coils. The results show both short and long-term benefits of active rTMS treatment but also show similar benefits for sham coil treatment of mild/moderate AD. We discuss this finding in the context of the existing literature on rTMS therapy for AD, as well as evidence of the sham coil's potential to induce a low-level current in the brain. TRIAL REGISTRATION: https://clinicaltrials.gov/ct2/show/NCT02908815.

How accurate are coordinate systems being used for transcranial magnetic stimulation?

When applying transcranial magnetic stimulation (TMS) to the brain, it is desired to be as precise as possible to reach a target area in the brain. For that, neuronavigational system using individuals' MRI scans were developed to guide TMS pulses delivery. All neuronavigational systems need coordinates of the target area to guide the TMS coil. Talairach coordinate system, which uses the Talairach-Tournoux atlas, is the most common system used with TMS pulses. In this study we investigated how an average Talairach coordinate from 50 healthy individuals is close to the actual location of the hand area of the primary motor cortex to investigate if that elicit a motor response in the hand; thus, investigating the fitness and accuracy of the Talairach coordinate system. We performed this experiment on six individuals (ages 61-82). When applying TMS single pulses to hand area with the given Talairach coordinate system adjusted with the MRI of each participant, three participants had involuntary twitch and three participants had no consistent physical response, as corroborated by electromyography of the abductor pollicis brevis and first dorsal interosseous muscles at the resting motor threshold intensity. Subsequently, by trial-and-error, the hand area was successfully stimulated on those three non-responder participants. The largest deviation from the Talairach coordinates was found to be 19.5 mm, measured on the surface of the cranium, between the true hand area and the mean Talairach coordinate. This finding implies that using generalized coordinates might be misleading when choosing the optimal location for brain stimulation.

Does Resting Motor Threshold correlate with severity of Alzheimer's disease?

Conflicting results have emerged from studies examining the potential of resting motor threshold (RMT) as a neurophysiological marker for Alzheimer's disease (AD) diagnosis and progression. In this study, we estimated the strength of the association between RMT measurements and severity of cognitive impairment in a relatively large sample (N=128) of clinical trial participants with mild (Clinical Dementia Rating - CDR=1) to moderate (CDR=2) AD. RMT for each participant was determined by applying single-pulse transcranial magnetic stimulation repeated at varying intensities over left and right sides of the primary motor cortex. RMT is the minimum intensity that evoked a visible contralateral involuntary finger twitch and RMT asymmetry is the absolute difference between the left and right RMT measurements. Cognitive impairment was measured with the Montreal Cognitive Assessment (MoCA) and the Alzheimer Disease Assessment Scale - Cognitive (ADAS-Cog) scores. Although the left and right RMT was lower in CDR 2 than in CDR 1 participants, neither RMT nor RMT asymmetry correlated significantly with cognitive test scores. In conclusion, our study in a large sample size does not support the idea that RMT is a sensitive marker of cognitive decline/severity in AD. Clinical Relevance- This study provides evidence that RMT may not be useful for AD progression monitoring.

The effect of transcranial alternating current stimulation (tACS) on cognitive function in older adults with dementia.

Recent studies have shown a positive effect of transcranial alternating current stimulation (tACS), a noninvasive brain stimulation technique, on cognitive function of healthy individuals [1]. However, investigation into the effects of tACS on individuals with dementia or mild cognitive impairment (MCI) is lacking. In this pilot study, we investigated the hypothesis that following a regular schedule of challenging brain exercises combined with simultaneous tACS application would improve the working memory and cognitive function of older adults with memory impairments. Further, we explored whether pairing brain exercises with tACS would result in longer-lasting positive effects on cognitive function than brain exercises alone. A total of 17 older adults (12 males, 5 females, 70 ± 7 years), each with a diagnosis of mild to moderate dementia were enrolled in the study. All participants completed brain exercises in the lab on the following schedule: two 30-minute sessions per day, 5 days/week for 4 weeks consecutively. Eleven of the participants received brain exercises paired with tACS application at 40Hz. We evaluated cognitive function of the participants at baseline, post-intervention and 1-month followup using the Wechsler Memory Scale (WMS-IV) as an independent assessment of our brain exercises. Both the non-tACS and tACS groups significantly improved their WMS scores from baseline to post-intervention assessments. Comparison of the post-intervention and 1-month follow-up assessments indicated that the tACS group maintained their improvement significantly better than the non-tACS group.