Single bouts of aerobic exercise can modulate cortical excitability and executive cognitive function, but less is known about the effect of light-intensity exercise, an intensity of exercise more achievable for certain clinical populations. Fourteen healthy adults (aged 22 to 30) completed the following study procedures twice (≥7 days apart) before and after 30 min of either light aerobic exercise (cycling) or seated rest: neurocognitive battery (multitasking performance, inhibitory control and spatial working memory), paired-pulse TMS measures of cortical excitability. Significant improvements in response times during multitasking performance and increases in intracortical facilitation (ICF) were seen following light aerobic exercise. Light aerobic exercise can modulate cortical excitability and some executive function tasks.Populations with deficits in multitasking ability may benefit from this intervention. K E Y W O R D S cortical excitability, executive function, exercise, neuroplasticity How to cite this article: Morris TP, Fried PJ, Macone J, et al. Light aerobic exercise modulates executive function and cortical excitability. Eur J Neurosci.

Background Alzheimer’s disease (AD) is associated with alterations in cortical perfusion that correlate with cognitive impairment. Recently, neural activity in the gamma band has been identified as a driver of arteriolar vasomotion while, on the other hand, gamma activity induction on preclinical models of AD has been shown to promote protein clearance and cognitive protection. Methods In two open-label studies, we assessed the possibility to modulate cerebral perfusion in 15 mild to moderate AD participants via 40Hz (gamma) transcranial alternating current stimulation (tACS) administered 1 h daily for 2 or 4 weeks, primarily targeting the temporal lobe. Perfusion-sensitive MRI scans were acquired at baseline and right after the intervention, along with electrophysiological recording and cognitive assessments. Results No serious adverse effects were reported by any of the participants. Arterial spin labeling MRI revealed a significant increase in blood perfusion in the bilateral temporal lobes after the tACS treatment. Moreover, perfusion changes displayed a positive correlation with changes in episodic memory and spectral power changes in the gamma band. Conclusions Results suggest 40Hz tACS should be further investigated in larger placebo-controlled trials as a safe, non-invasive countermeasure to increase fast brain oscillatory activity and increase perfusion in critical brain areas in AD patients. Trial registration Studies were registered separately on ClinicalTrials.gov (NCT03290326, registered on September 21, 2017; NCT03412604, registered on January 26, 2018).

Background: Alzheimer’s disease (AD) is characterized by diffuse amyloid-β (Aβ) and phosphorylated Tau (p-Tau) aggregates as well as neuroinflammation. Exogenously-induced 40 Hz gamma oscillations have been showing to reduce Aβ and p-Tau deposition presumably via microglia activation in AD mouse models. Objective: We aimed to translate preclinical data on gamma-induction in AD patients by means of transcranial alternating current stimulation (tACS). Methods: Four participants with mild-to-moderate AD received 1 h of daily 40 Hz (gamma) tACS for 4 weeks (Monday to Friday) targeting the bitemporal lobes (20 h treatment duration). Participant underwent Aβ, p-Tau, and microglia PET imaging with [11C]-PiB, [18F]-FTP, and [11C]-PBR28 respectively, before and after the intervention along with electrophysiological assessment. Results: No adverse events were reported, and an increase in gamma spectral power on EEG was observed after the treatment. [18F]-FTP PET revealed a significant decrease over 2% of p-Tau burden in 3/4 patients following the tACS treatment, primarily involving the temporal lobe regions targeted by tACS and especially mesial regions (e.g., entorhinal cortex). The amount of intracerebral Aβ as measured by [11C]-PiB was not significantly influenced by tACS, whereas 1/4 reported a significant decrease of microglia activation as measured by [11C]-PBR28. Conclusion: tACS seems to represent a safe and feasible option for gamma induction in AD patients, with preliminary evidence of a possible effect on protein clearance partially mimicking what is observed in animal models. Longer interventions and placebo control conditions are needed to fully evaluate the potential for tACS to slow disease progression.

Introduction Frontotemporal dementia (FTD) is a neurodegenerative disorder for which there is no effective pharmacological treatment. Recently, interneuron activity responsible for fast oscillatory brain activity has been found to be impaired in a mouse model of FTD with consequent cognitive and behavioral alterations. In this study, we aim to investigate the safety, tolerability, and efficacy of a novel promising therapeutic intervention for FTD based on 40 Hz transcranial alternating current stimulation (tACS), a form of non‐invasive brain stimulation thought to engage neural activity in a frequency‐specific manner and thus suited to restore altered brain oscillatory patterns. Methods This is a multi‐site, randomized, double‐blind, placebo‐controlled trial on 50 patients with a diagnosis of behavioral variant FTD (bvFTD). Participants will be randomized to undergo either 30 days of 1‐hour daily tACS or Sham (placebo) tACS. The outcomes will be assessed at baseline, right after the intervention and at a 3‐ to 6‐months follow‐up. The primary outcome measures are represented by the safety and feasibility of tACS administration, which will be assessed considering the nature, frequency, and severity of adverse events as well as attrition rate, respectively. To assess secondary outcomes, participants will undergo extensive neuropsychological and behavioral assessments and fluorodeoxyglucose (FDG)–positron emission tomography (PET) scans to evaluate changes in brain metabolism, functional and structural magnetic resonance imaging (MRI), resting and evoked electroencephalography, as well as blood biomarkers to measure changes in neurodegenerative and neuroinflammatory markers. Results The trial started in October 2020 and will end in October 2023. Study protocols have been approved by the local institutional review board (IRB) at each data‐collection site. Discussion This study will evaluate the safety and tolerability of 40 Hz tACS in bvFTD patients and its efficacy on gamma oscillatory activity, cognitive function, and brain glucose hypometabolism.

ObjectiveTo investigate the relationship between cortico-motor excitability and cognitive reserve (CR) in cognitively unimpaired older adults (CU) and in older adults with mild cognitive impairment or mild dementia due to Alzheimer’s disease (AD).MethodsData were collected and analyzed from 15 CU and 24 amyloid-positive AD participants aged 50–90 years. A cognitive reserve questionnaire score (CRQ) assessed education, occupation, leisure activities, physical activities, and social engagement. Cortical excitability was quantified as the average amplitude of motor evoked potentials (MEP amplitude) elicited with single-pulse transcranial magnetic stimulation delivered to primary motor cortex. A linear model compared MEP amplitudes between groups. A linear model tested for an effect of CRQ on MEP amplitude across all participants. Finally, separate linear models tested for an effect of CRQ on MEP amplitude within each group. Exploratory analyses tested for effect modification of demographics, cognitive scores, atrophy measures, and CSF measures within each group using nested regression analysis.ResultsThere was no between-group difference in MEP amplitude after accounting for covariates. The primary model showed a significant interaction term of group*CRQ (R2adj = 0.18, p = 0.013), but no main effect of CRQ. Within the CU group, higher CRQ was significantly associated with lower MEP amplitude (R2adj = 0.45, p = 0.004). There was no association in the AD group.ConclusionLower cortico-motor excitability is related to greater CRQ in CU, but not in AD. Lower MEP amplitudes may reflect greater neural efficiency in cognitively unimpaired older adults. The lack of association seen in AD participants may reflect disruption of the protective effects of CR. Future work is needed to better understand the neurophysiologic mechanisms leading to the protective effects of CR in older adults with and without neurodegenerative disorders.

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Background Alzheimer’s disease (AD) is associated with increased cortical excitability, including a risk of seizures and epileptiform discharges. Transcranial magnetic stimulation (TMS) can be used to index cortical excitability non‐invasively, and previous studies have revealed increased TMS excitability measures in AD. However, it is not yet known if TMS shows increased cortical excitability in amyloid‐β positive mild cognitive impairment (Aβ+ MCI), how TMS excitability relates to other AD biomarkers, or the extent to which cortical excitability may predict disease progression. Method TMS was applied to left motor cortex in 18 participants with Aβ+ MCI (aged 70±8.9, 9 females). Resting motor threshold (RMT) was measured as the minimum TMS intensity required to elicit a motor evoked potential on 5/10 trials. The primary analyses tested if RMT differed between Aβ+ MCI participants and a cohort of 36 older healthy controls (OHC; aged 63±9.7, 17 females). Separate linear models in Aβ+ MCI tested the relationship of RMT with hippocampal volume, Aβ burden on [18F]Florbetapir PET, and the Clinical Dementia Rating – Sum of Boxes (CDR‐SB). CDR‐SB was reassessed after 1‐2 years follow‐up, and a CDR‐SB Change Score was calculated to measure cognitive decline. The relationship with RMT and CDR‐SB Change Score was tested using a simple linear regression. Result The primary linear model controlling for age, gender, and scalp‐to‐cortex distance (SCD) showed a between‐group difference in RMT (B=3.62, p=0.023, Figure 1), with Aβ+ MCI showing lower RMT reflecting higher levels of cortical excitability. The covariate of SCD (B=1.92, p<0.001) was also significant. Secondary models with the same covariates showed that lower RMT was related to greater Aβ burden (B=‐0.43, p=0.016), but not hippocampal volume or CDR‐SB. In the subgroup of 10 Aβ+ MCI participants with longitudinal follow‐up, lower RMT predicted of worsening cognition on CDR‐SB Change Score (R=0.74, p=0.015, Figure 2). Conclusion Increased cortical excitability is found in Aβ+ MCI, is related to amyloid burden, and appears to predict greater longitudinal cognitive decline. TMS measures of cortical excitability may be useful as measures of target engagement for future therapies aimed at delaying disease progression in the early symptomatic stages of AD.