Transcranial alternating current stimulation (tACS) is a non-invasive brain stimulation technique that allows the manipulation of intrinsic brain oscillations. Numerous studies have applied tACS in the laboratory to enhance cognitive performance. With this systematic review, we aim to provide an overview of frequency-specific tACS effects on a range of cognitive functions in healthy adults. This may help to transfer stimulation protocols to real-world applications. We conducted a systematic literature search on PubMed and Cochrane databases and considered tACS studies in healthy adults (age > 18 years) that focused on cognitive performance. The search yielded n = 109 studies, of which n = 57 met the inclusion criteria. The results indicate that theta-tACS was beneficial for several cognitive functions, including working memory, executive functions, and declarative memory. Gamma-tACS enhanced performance in both auditory and visual perception but it did not change performance in tasks of executive functions. For attention, the results were less consistent but point to an improvement in performance with alpha- or gamma-tACS. We discuss these findings and point to important considerations that would precede a transfer to real-world applications.

Introduction: Many clinical studies reporting accelerometry data use sum score measures such as percentage of time spent in moderate to vigorous activity which do not provide insight into differences in activity patterns over 24 hours, and thus do not adequately depict circadian activity patterns. Here, we present an improved functional data analysis approach to model activity patterns and circadian rhythms from accelerometer data. As a use case, we demonstrated its application in patients with mild cognitive impairment (MCI) and age-matched healthy older volunteers (HOV). Methods: Data of two studies were pooled for this analysis. Following baseline cognitive assessment participants were provided with accelerometers for seven consecutive days. A function on scalar regression (FoSR) approach was used to analyze 24 hours accelerometer data. Results: Information on 48 HOV (mean age 65 SD 6 years) and 18 patients with MCI (mean age 70, SD 8 years) were available for this analysis. MCI patients displayed slightly lower activity in the morning hours (minimum relative activity at 6:05 am: -41.3%, 95% CI -64.7 to -2.5%, p = 0.031) and in the evening (minimum relative activity at 21:40 am: -48.4%, 95% CI -68.5 to 15.4%, p = 0.001) as compared to HOV after adjusting for age and sex. Discussion: Using a novel approach of FoSR, we found timeframes with lower activity levels in MCI patients compared to HOV which were not evident if sum scores of amount of activity were used, possibly indicating that changes in circadian rhythmicity in neurodegenerative disease are detectable using easy-to-administer accelerometry. Clinical trials: Effects of Brain Stimulation During Nocturnal Sleep on Memory Consolidation in Patients With Mild Cognitive Impairments, ClinicalTrial.gov identifier: NCT01782391. Effects of Brain Stimulation During a Daytime Nap on Memory Consolidation in Patients With Mild Cognitive Impairment, ClinicalTrial.gov identifier: NCT01782365.

Theta oscillations support memory formation, but their exact contribution to the communication between prefrontal cortex (PFC) and the hippocampus is unknown. We tested the functional relevance of theta oscillations as a communication link between both areas for memory formation using transcranial alternating current stimulation (tACS). Healthy, young participants learned two lists of Dutch-German word pairs and retrieved them immediately and with a 30-min delay. In the encoding group (N = 30), tACS was applied during the encoding of list 1. List 2 was used to test stimulation aftereffects. In the retrieval group (N = 23), we stimulated during the delayed recall. In both groups, we applied tACS bilaterally at prefrontal and tempo-parietal sites, using either individualized theta frequency or 15 Hz (as control), according to a within-subject design. Stimulation with theta-tACS did not alter overall learning performance. An exploratory analysis revealed that immediate recall improved when word-pairs were learned after theta-tACS (list 2). Applying theta-tACS during retrieval had detrimental effects on memory. No changes in the power of the respective frequency bands were observed. Our results do not support the notion that impacting the communication between PFC and the hippocampus during a task by bilateral tACS improves memory. However, we do find evidence that direct stimulation had a trend for negatively interfering effects during immediate and delayed recall. Hints for beneficial effects on memory only occurred with aftereffects of the stimulation. Future studies need to further examine the effects during and after stimulation on memory formation.

Targeted memory reactivation (TMR) is an effective technique to enhance sleep-associated memory consolidation. The successful reactivation of memories by external reminder cues is typically accompanied by an event-related increase in theta oscillations, preceding better memory recall after sleep. However, it remains unclear whether the increase in theta oscillations is a causal factor or an epiphenomenon of successful TMR. Here, we used transcranial alternating current stimulation (tACS) to examine the causal role of theta oscillations for TMR during non-rapid eye movement (non-REM) sleep. Thirty-seven healthy participants learned Dutch–German word pairs before sleep. During non-REM sleep, we applied either theta-tACS or control-tACS (23 Hz) in blocks (9 min) in a randomised order, according to a within-subject design. One group of participants received tACS coupled with TMR time-locked two seconds after the reminder cue (time-locked group). Another group received tACS in a continuous manner while TMR cues were presented (continuous group). Contrary to our predictions, we observed no frequency-specific benefit of theta-tACS coupled with TMR during sleep on memory performance, neither for continuous nor time-locked stimulation. In fact, both stimulation protocols blocked the TMR-induced memory benefits during sleep, resulting in no memory enhancement by TMR in both the theta and control conditions. No frequency-specific effect was found on the power analyses of the electroencephalogram. We conclude that tACS might have an unspecific blocking effect on memory benefits typically observed after TMR during non-REM sleep.

Introduction: Current analysis approaches of accelerometry data use sum score measures which do not provide insight in activity patterns over 24 hours, and thus do not adequately depict circadian activity patterns. Here, we used a functional approach to analyze accelerometer data that models activity pattern and circadian rhythm. As a test case, we demonstrated its application in patients with mild cognitive impairment (MCI) and age-matched healthy older volunteers (HOV). Moreover, we assessed the impact of chronotype on distribution of activity data. Methods: Data of two studies were pooled for this analysis. Following baseline cognitive assessment participants were provided with accelerometers for seven consecutive days. A function on scalar regression (FoSR) approach was used to analyze 24 hours accelerometer data. In a second step, analyses were controlled for chronotype using the German version of the morningness-eveningness questionnaire (d-MEQ). Results: Information on 47 HOV (mean age 66 SD 6 years) and 13 patients with MCI (mean age 69, SD 8 years) were available for this analysis. MCI patients displayed slightly higher activity in the morning hours as compared to HOV (maximum relative activity at 7:35 am: 75.6%, 95% CI 2.6 to 200.4%, p = 0.031). After controlling for d-MEQ, disturbed activity patterns were found in MCI of intermediate or evening chronotype, compared to HOV, i.e., MCI presented with higher activities in the morning hours (peak at 8:40 am: 357.6%, 95% CI 92.9 to 985.1, p < 0.001) and early afternoon hours (peak at 1:40 pm: 401.8%, 95% CI 63.9 to 1436.4, p < 0.001). Discussion: Using a novel approach of FoSR, we found timeframes with higher activity levels in MCI patients compared to HOV which were not evident if sum scores of amount of activity were used. In addition, we found that previously described activity patterns as a function of chronotype swere altered in MCI patients, possibly indicating that changes in circadian rhythmicity in neurodegenerative disease are detectable using easy-to-administer accelerometry. Clinical Trials: Effects of Brain Stimulation During Nocturnal Sleep on Memory Consolidation in Patients With Mild Cognitive Impairments, https://clinicaltrials.gov/ct2/show/NCT01782391?term=NCT01782391&rank=1 , ClinicalTrial.gov identifier: NCT01782391 Effects of Brain Stimulation During a Daytime Nap on Memory Consolidation in Patients With Mild Cognitive Impairment, https://clinicaltrials.gov/ct2/show/NCT01782365?term=NCT01782365&rank=1 , ClinicalTrial.gov identifier: NCT01782365