Gamma neuromodulation improves episodic memory and its associated network in amnestic mild cognitive impairment: a pilot study.

Amnestic mild cognitive impairment (aMCI) is a predementia stage of Alzheimer's disease associated with dysfunctional episodic memory and limited treatment options. We aimed to characterize feasibility, clinical, and biomarker effects of noninvasive neurostimulation for aMCI. 13 individuals with aMCI received eight 60-minute sessions of 40-Hz (gamma) transcranial alternating current stimulation (tACS) targeting regions related to episodic memory processing. Feasibility, episodic memory, and plasma Alzheimer's disease biomarkers were assessed. Neuroplastic changes were characterized by resting-state functional connectivity (RSFC) and neuronal excitatory/inhibitory balance. Gamma tACS was feasible and aMCI participants demonstrated improvement in multiple metrics of episodic memory, but no changes in biomarkers. Improvements in episodic memory were most pronounced in participants who had the highest modeled tACS-induced electric fields and exhibited the greatest changes in RSFC. Increased RSFC was also associated with greater hippocampal excitability and higher baseline white matter integrity. This study highlights initial feasibility and the potential of gamma tACS to rescue episodic memory in an aMCI population by modulating connectivity and excitability within an episodic memory network.

Enhancing cognitive control in amnestic mild cognitive impairment via at-home non-invasive neuromodulation in a randomized trial.

Individuals with multi-domain amnestic mild cognitive impairment (md-aMCI) have an elevated risk of dementia and need interventions that may retain or remediate cognitive function. In a feasibility pilot study, 30 older adults aged 60-80 years with md-aMCI were randomized to 8 sessions of transcranial alternating current stimulation (tACS) with simultaneous cognitive control training (CCT). The intervention took place within the participant's home without direct researcher assistance. Half of the participants received prefrontal theta tACS during CCT and the other half received control tACS. We observed high tolerability and adherence for at-home tACS + CCT. Within 1-week, only those who received theta tACS exhibited improved attentional abilities. Neuromodulation is feasible for in-home settings, which can be conducted by the patient, thereby enabling treatment in difficult to reach populations. TACS with CCT may facilitate cognitive control abilities in md-aMCI, but research in a larger population is needed to validate efficacy.

Structural and functional network mechanisms of rescuing cognitive control in aging.

Age-related declines in cognitive control, an ability critical in most daily tasks, threaten individual independence. We previously showed in both older and younger adults that transcranial alternating current stimulation (tACS) can improve cognitive control, with effects observed across neural regions distant from the stimulated site and frequencies outside the stimulated range. Here, we assess network-level changes in neural activity that extend beyond the stimulated site and evaluate anatomical pathways that subserve these effects. We investigated the potential to rescue cognitive control in aging using prefrontal (F3-F4) theta (6 Hz) or control (1 Hz) tACS while older adults engaged in a cognitive control video game intervention on three consecutive days. Functional connectivity was assessed with EEG by measuring daily changes in frontal-posterior phase-locking values (PLV) from the tACS-free baseline. Structural connectivity was measured using MRI diffusion tractography data collected at baseline. Theta tACS improved multitasking performance, and individual gains reflected a dissociation in daily PLV changes, where theta tACS strengthened PLV and control tACS reduced PLV. Strengthened alpha-beta PLV in the theta tACS group correlated positively with inferior longitudinal fasciculus and corpus callosum body integrity, and further explained multitasking gains. These results demonstrate that theta tACS can improve cognitive control in aging by strengthening functional connectivity, particularly in higher frequency bands. However, the extent of functional connectivity gains is limited by the integrity of structural white matter tracts. Given that advanced age is associated with decreased white matter integrity, results suggest that the deployment of tACS as a therapeutic is best prior to advanced age.

Research outside the laboratory: Longitudinal at-home neurostimulation.

The use of noninvasive transcranial electrical stimulation (tES) has rapidly increased over the past two decades. Yet, tES continues to be largely implemented in laboratory and rehabilitation settings, thereby limiting accessibility to the broader population. We have previously demonstrated that transcranial alternating current stimulation (tACS) in the theta (4-7 Hz) band improves cognitive control, such as multitasking, in younger adults following a single tACS session, as well as in older adults following three tACS sessions. Here, the goal was to extend our in-lab results by (1) assessing the feasibility for at-home tACS and (2) evaluating whether five tACS sessions may yield continuing improvements in multitasking ability in young adults. Participants (aged 18 - 34 years) received bilateral prefrontal tACS while engaged in an adaptive multitasking training over five consecutive days in their home settings. Participants were randomly assigned to receive either 20-minutes of theta or delta tACS during daily multitasking training. Prior to and on the day immediately following five days of tACS, we assessed performance on single task, multitask, and sustained attention ability with analyses of variance statistics. 92.1% of participants were able to self-administer tACS at home without researcher assistance. However, we observed that both theta and delta tACS groups exhibited improvements in both single and multitask performance. Compared to previously collected data, five days of theta tACS was comparable to one day of theta tACS. However, theta tACS has continued benefits in older, but not younger adults as evidenced by previous research. Both groups similarly improved in sustained attention. These results demonstrate that laboratory paradigms utilizing neurostimulation can be effectively deployed in a home environment without direct support from research personnel. Moreover, these results suggest that while theta tACS may facilitate multitasking improvements over one session, multiple sessions of theta tACS results in diminishing returns in young adults. Additional research will be required to confirm if delta activity plays an important role in multitasking ability.

Individual predictors and electrophysiological signatures of working memory enhancement in aging.

A primary goal of translational neuroscience is to identify the neural mechanisms of age-related cognitive decline and develop protocols to maximally improve cognition. Here, we demonstrate how interventions that apply noninvasive neurostimulation to older adults improve working memory (WM). We found that one session of sham-controlled transcranial direct current stimulation (tDCS) selectively improved WM in older adults with more education, extending earlier work and underscoring the importance of identifying individual predictors of tDCS responsivity. Improvements in WM were associated with two distinct electrophysiological signatures. First, a broad enhancement of theta network synchrony tracked improvements in behavioral accuracy, with tDCS effects moderated by education level. Further analysis revealed that accuracy dynamics reflected an anterior-posterior network distribution regardless of cathode placement. Second, specific enhancements of theta-gamma phase-amplitude coupling (PAC) reflecting tDCS current flow tracked improvements in reaction time (RT). RT dynamics further explained inter-individual variability in WM improvement independent of education. These findings illuminate theta network synchrony and theta-gamma PAC as distinct but complementary mechanisms supporting WM in aging. Both mechanisms are amenable to intervention, the effectiveness of which can be predicted by individual demographic factors.

Individual differences in neuroanatomy and neurophysiology predict effects of transcranial alternating current stimulation.

BACKGROUND: Noninvasive transcranial electrical stimulation (tES) research has been plagued with inconsistent effects. Recent work has suggested neuroanatomical and neurophysiological variability may alter tES efficacy. However, direct evidence is limited. OBJECTIVE: We have previously replicated effects of transcranial alternating current stimulation (tACS) on improving multitasking ability in young adults. Here, we attempt to assess whether these stimulation parameters have comparable effects in older adults (aged 60-80 years), which is a population known to have greater variability in neuroanatomy and neurophysiology. It is hypothesized that this variability in neuroanatomy and neurophysiology will be predictive of tACS efficacy. METHODS: We conducted a pre-registered study where tACS was applied above the prefrontal cortex (between electrodes F3-F4) while participants were engaged in multitasking. Participants were randomized to receive either 6-Hz (theta) tACS for 26.67 min daily for three days (80 min total; Long Exposure Theta group), 6-Hz tACS for 5.33 min daily (16-min total; Short Exposure Theta group), or 1-Hz tACS for 26.67 min (80 min total; Control group). To account for neuroanatomy, magnetic resonance imaging data was used to form individualized models of the tACS-induced electric field (EF) within the brain. To account for neurophysiology, electroencephalography data was used to identify individual peak theta frequency. RESULTS: Results indicated that only in the Long Theta group, performance change was correlated with modeled EF and peak theta frequency. Together, modeled EF and peak theta frequency accounted for 54%-65% of the variance in tACS-related performance improvements, which sustained for a month. CONCLUSION: These results demonstrate the importance of individual differences in neuroanatomy and neurophysiology in tACS research and help account for inconsistent effects across studies.

Modulation of auditory gamma-band responses using transcranial electrical stimulation.

Auditory gamma-band (>30 Hz) activity is a biomarker of cortical excitation/inhibition (E/I) balance in autism, schizophrenia, and bipolar disorder. We provide a comprehensive account of the effects of transcranial alternating current stimulation (tACS) and transcranial direct current stimulation (tDCS) on gamma responses. Forty-five healthy young adults listened to 40-Hz auditory click trains while electroencephalography (EEG) data were collected to measure stimulus-related gamma activity immediately before and after 10 min of 1 mA tACS (40 Hz), tDCS, or sham stimulation to left auditory cortex. tACS, but not tDCS, increased gamma power and phase locking to the auditory stimulus. However, both tACS and tDCS strengthened the gamma phase connectome, and effects persisted beyond the stimulus. Finally, tDCS strengthened the coupling of gamma activity to alpha oscillations after termination of the stimulus. No effects were observed in prestimulus gamma power, the gamma amplitude connectome, or any band-limited alpha measure. Whereas both stimulation techniques synchronize gamma responses between regions, tACS also tunes the magnitude and timing of gamma responses to the stimulus. Results reveal dissociable neurophysiological changes following tACS and tDCS and demonstrate that clinical biomarkers can be altered with noninvasive neurostimulation, especially frequency-tuned tACS.NEW & NOTEWORTHY Gamma frequency-tuned transcranial alternating current stimulation (tACS) adjusts the magnitude and timing of auditory gamma responses, as compared with both sham stimulation and transcranial direct current stimulation (tDCS). However, both tACS and tDCS strengthen the gamma phase connectome, which is disrupted in numerous neurological and psychiatric disorders. These findings reveal dissociable neurophysiological changes following two noninvasive neurostimulation techniques commonly applied in clinical and research settings.

Frontoparietal theta-gamma interactions track working memory enhancement with training and tDCS.

Despite considerable interest in enhancing, preserving, and rehabilitating working memory (WM), efforts to elicit sustained behavioral improvements have been met with limited success. Here, we paired WM training with transcranial direct current stimulation (tDCS) to the frontoparietal network over four days. Active tDCS enhanced WM performance by modulating interactions between frontoparietal theta oscillations and gamma activity, as measured by pre- and post-training high-density electroencephalography (EEG). Increased phase-amplitude coupling (PAC) between the prefrontal stimulation site and temporo-parietal gamma activity explained behavioral improvements, and was most effective when gamma occurred near the prefrontal theta peak. These results demonstrate for the first time that tDCS-linked WM training elicits lasting changes in behavior by optimizing the oscillatory substrates of prefrontal control.

Replacing tDCS with theta tACS provides selective, but not general WM benefits.

Working memory (WM) can be improved after repeated training sessions paired with noninvasive neurostimulation techniques. Previously, we reported that WM training paired with tDCS succeeded behaviorally by enhancing anterior-posterior theta phase coherence and reducing alpha power. Here, in two experiments we tested several theta and alpha frequencies and two transcranial alternating current stimulation (tACS) montages in an effort to shortcut WM training while preserving behavioral gains. In Experiment 1, in separate sessions participants received online tACS at two frequencies derived from the previous study with the respective goal of improving and impairing WM performance. We selected the mean group peak value theta (7 Hz) to benefit WM and alpha (11 Hz) to impair WM. Stimulation (tACS) over right frontoparietal sites (F4-P4) during 3-back WM tasks (object, spatial) produced no behavioral consequences. In Experiment 2 we stimulated at a slower theta frequency (4.5 Hz), which was also significant in our prior study, and tested whether frontoparietal or bifrontal montages would be more effective at improving WM. This experiment revealed selectively improved object WM after right frontoparietal tACS alone. In summary, one session of tACS failed to produce the magnitude or breadth of WM gains observed after 4-10 tDCS-WM training sessions. In short, despite looking for loopholes we found little tACS savings.

Frontoparietal tDCS Benefits Visual Working Memory in Older Adults With Low Working Memory Capacity.

Working memory (WM) permits maintenance of information over brief delays and is an essential executive function. Unfortunately, WM is subject to age-related decline. Some evidence supports the use of transcranial direct current stimulation (tDCS) to improve visual WM. A gap in knowledge is an understanding of the mechanism characterizing these tDCS linked effects. To address this gap, we compared the effects of two tDCS montages designed on visual working memory (VWM) performance. The bifrontal montage was designed to stimulate the heightened bilateral frontal activity observed in aging adults. The unilateral frontoparietal montage was designed to stimulate activation patterns observed in young adults. Participants completed three sessions (bilateral frontal, right frontoparietal, sham) of anodal tDCS (20 min, 2 mA). During stimulation, participants performed a visual long-term memory (LTM) control task and a visual WM task. There was no effect of tDCS on the LTM task. Participants receiving right unilateral tDCS showed a WM benefit. This pattern was most robust in older adults with low WM capacity. To address the concern that the key difference between the two tDCS montages could be tDCS over the posterior parietal cortex (PPC), we included new analyses from a previous study applying tDCS targeting the PPC paired with a recognition VWM task. No significant main effects were found. A subsequent experiment in young adults found no significant effect of either tDCS montage on either task. These data indicate that tDCS montage, age and WM capacity should be considered when designing tDCS protocols. We interpret these findings as suggestive that protocols designed to restore more youthful patterns of brain activity are superior to those that compensate for age-related changes.

Task demands, tDCS intensity, and the COMT val158met polymorphism impact tDCS-linked working memory training gains.

Working memory (WM) training paired with transcranial direct current stimulation (tDCS) can improve executive function in older adults. The unclear mechanism of tDCS likely depends on tDCS intensity, and task relevant genetic factors (e.g., for WM: COMT val158met, DAT, BDNF val66met). Higher tDCS intensity does not always lead to greater cognitive gains, and genetic polymorphisms may modulate tDCS-linked WM improvements. To evaluate these factors, 137 healthy older adults provided DNA samples and received Visual and Spatial WM training paired with tDCS (sham, 1, 1.5, 2 mA). After one session of tDCS, significant group differences in WM performance were predicted by COMT val158met status. One month after training, there was a significant interaction of tDCS intensity, COMT genotype, and WM task. Specifically, val/val homozygotes benefited most from 1.5 mA tDCS on Visual WM and from 1 mA tDCS on Spatial WM. For met/met homozygotes, 2 mA resulted in significantly poorer performance compared to 1.5 mA on Spatial WM. While this pattern was observed with relatively small sample sizes, these data indicate that variations in COMT val158met may predict the nature of WM improvement after initial and longitudinal tDCS. This contributes to our understanding of the underlying mechanism by which tDCS affects behaviour.

Frontoparietal neurostimulation modulates working memory training benefits and oscillatory synchronization.

There is considerable interest in maintaining working memory (WM) because it is essential to accomplish most cognitive tasks, and it is correlated with fluid intelligence and ecologically valid measures of daily living. Toward this end, WM training protocols aim to improve WM capacity and extend improvements to unpracticed domains, yet success is limited. One emerging approach is to couple WM training with transcranial direct current stimulation (tDCS). This pairing of WM training with tDCS in longitudinal designs promotes behavioral improvement and evidence of transfer of performance gains to untrained WM tasks. However, the mechanism(s) underlying tDCS-linked training benefits remain unclear. Our goal was to gain purchase on this question by recording high-density EEG before and after a weeklong WM training+tDCS study. Participants completed four sessions of frontoparietal tDCS (active anodal or sham) during which they performed a visuospatial WM change detection task. Participants who received active anodal tDCS demonstrated significant improvement on the WM task, unlike those who received sham stimulation. Importantly, this pattern was mirrored by neural correlates in spectral and phase synchrony analyses of the HD-EEG data. Notably, the behavioral interaction was echoed by interactions in frontal-posterior alpha band power, and theta and low alpha oscillations. These findings indicate that one mechanism by which paired tDCS+WM training operates is to enhance cortical efficiency and connectivity in task-relevant networks.

Leveraging the test effect to improve maintenance of the gains achieved through cognitive rehabilitation.

OBJECTIVE: An important aspect of the rehabilitation of cognitive and linguistic function subsequent to brain injury is the maintenance of learning beyond the time of initial treatment. Such maintenance is often not satisfactorily achieved. Additional practice, or overtraining, may play a key role in long-term maintenance. In particular, the literature on learning in cognitively intact persons has suggested that it is testing, and not studying, that contributes to maintenance of learning. The present study investigates the hypothesis that continuing to test relearned words in persons with anomia will lead to significantly greater maintenance compared with continuing to study relearned words. METHOD: The current study combines overtraining with the variable of test versus study in examining the effects of overtesting and overstudying on maintenance of word finding in 3 persons with aphasia. First, treatment successfully reestablished the connections between known items and their names. Once the connections were reestablished (i.e., items could be named successfully), each item was placed into 1 of 4 overtraining conditions: test and study, only test, only study, or no longer test or study. Maintenance was probed at 1 month and 4 months following the end of overtraining. RESULTS: The results are consistent with an advantage of testing compared with studying. All 3 participants showed significantly greater maintenance for words that were overtested than for words that were overstudied. This testing benefit persisted at 1 month and 4 months after completion of the treatment. In fact, there was no clear evidence for any benefit of overstudying. CONCLUSIONS: The present study demonstrates that overtesting, but not overstudying, leads to lasting maintenance of language rehabilitation gains in patients with anomia. The implications for the design of other treatment protocols are immense. (PsycINFO Database Record

In vivo genetic dissection of tumor growth and the Warburg effect.

A well-characterized metabolic landmark for aggressive cancers is the reprogramming from oxidative phosphorylation to aerobic glycolysis, referred to as the Warburg effect. Models mimicking this process are often incomplete due to genetic complexities of tumors and cell lines containing unmapped collaborating mutations. In order to establish a system where individual components of oncogenic signals and metabolic pathways can be readily elucidated, we induced a glycolytic tumor in the Drosophila wing imaginal disc by activating the oncogene PDGF/VEGF-receptor (Pvr). This causes activation of multiple oncogenic pathways including Ras, PI3K/Akt, Raf/ERK, Src and JNK. Together this network of genes stabilizes Hifα (Sima) that in turn, transcriptionally up-regulates many genes encoding glycolytic enzymes. Collectively, this network of genes also causes inhibition of pyruvate dehydrogenase (PDH) activity resulting in diminished ox-phos levels. The high ROS produced during this process functions as a feedback signal to consolidate this metabolic reprogramming.

Longitudinal neurostimulation in older adults improves working memory.

An increasing concern affecting a growing aging population is working memory (WM) decline. Consequently, there is great interest in improving or stabilizing WM, which drives expanded use of brain training exercises. Such regimens generally result in temporary WM benefits to the trained tasks but minimal transfer of benefit to untrained tasks. Pairing training with neurostimulation may stabilize or improve WM performance by enhancing plasticity and strengthening WM-related cortical networks. We tested this possibility in healthy older adults. Participants received 10 sessions of sham (control) or active (anodal, 1.5 mA) tDCS to the right prefrontal, parietal, or prefrontal/parietal (alternating) cortices. After ten minutes of sham or active tDCS, participants performed verbal and visual WM training tasks. On the first, tenth, and follow-up sessions, participants performed transfer WM tasks including the spatial 2-back, Stroop, and digit span tasks. The results demonstrated that all groups benefited from WM training, as expected. However, at follow-up 1-month after training ended, only the participants in the active tDCS groups maintained significant improvement. Importantly, this pattern was observed for both trained and transfer tasks. These results demonstrate that tDCS-linked WM training can provide long-term benefits in maintaining cognitive training benefits and extending them to untrained tasks.

The strategy and motivational influences on the beneficial effect of neurostimulation: a tDCS and fNIRS study.

Working memory (WM) capacity falls along a spectrum with some people demonstrating higher and others lower WM capacity. Efforts to improve WM include applying transcranial direct current stimulation (tDCS), in which small amounts of current modulate the activity of underlying neurons and enhance cognitive function. However, not everyone benefits equally from a given tDCS protocol. Recent findings revealed tDCS-related WM benefits for individuals with higher working memory (WM) capacity. Here, we test two hypotheses regarding those with low WM capacity to see if they too would benefit under more optimal conditions. We tested whether supplying a WM strategy (Experiment 1) or providing greater extrinsic motivation through incentives (Experiment 2) would restore tDCS benefit to the low WM capacity group. We also employed functional near infrared spectroscopy to monitor tDCS-induced changes in neural activity. Experiment 1 demonstrated that supplying a WM strategy improved the high WM capacity participants' accuracy and the amount of oxygenated blood levels following anodal tDCS, but it did not restore tDCS-linked WM benefits to the low WM capacity group. Experiment 2 demonstrated that financial motivation enhanced performance in both low and high WM capacity groups, especially after anodal tDCS. Here, only the low WM capacity participants showed a generalized increase in oxygenated blood flow across both low and high motivation conditions. These results indicate that ensuring that participants' incentives are high may expand cognitive benefits associated with tDCS. This finding is relevant for translational work using tDCS in clinical populations, in which motivation can be a concern.

Enhanced long-term memory encoding after parietal neurostimulation.

Neurostimulation, e.g., transcranial direct current stimulation (tDCS), shows promise as an effective cognitive intervention. In spite of low spatial resolution, limited penetration, and temporary influence, evidence highlights tDCS-linked cognitive benefits in a range of cognitive domains. The left posterior parietal cortex (PPC) is an accessible node in frontoparietal networks engaged during long-term memory (LTM). Here, we tested the hypothesis that tDCS can facilitate LTM by pairing LTM encoding and retrieval with PPC stimulation. Healthy young adults performed a verbal LTM task (California Verbal Learning Task) with four different stimulation parameters. In Experiment 1, we applied tDCS to left PPC during LTM encoding. In Experiment 2, we applied tDCS just prior to retrieval to test the temporal specificity of tDCS during a LTM task. In later experiments, we tested hemispheric specificity by replicating Experiment 1 while stimulating the right PPC. Experiment 1 showed that tDCS applied during LTM encoding improved the pace of list learning and enhanced retrieval after a short delay. Experiment 2 indicated anodal left PPC tDCS only improved LTM when applied during encoding, and not during maintenance. Experiments 3 and 4 confirmed that tDCS effects were hemisphere specific and that no effects were found after right PPC stimulation during encoding. These findings indicate that anodal tDCS to the PPC helps verbal LTM in healthy young adults under certain conditions. First, when it is applied to the left, not the right, PPC and second, when it is applied during encoding.

Hits and misses: leveraging tDCS to advance cognitive research.

The popularity of non-invasive brain stimulation techniques in basic, commercial, and applied settings grew tremendously over the last decade. Here, we focus on one popular neurostimulation method: transcranial direct current stimulation (tDCS). Many assumptions regarding the outcomes of tDCS are based on the results of stimulating motor cortex. For instance, the primary motor cortex is predictably suppressed by cathodal tDCS or made more excitable by anodal tDCS. However, wide-ranging studies testing cognition provide more complex and sometimes paradoxical results that challenge this heuristic. Here, we first summarize successful efforts in applying tDCS to cognitive questions, with a focus on working memory (WM). These recent findings indicate that tDCS can result in cognitive task improvement or impairment regardless of stimulation site or direction of current flow. We then report WM and response inhibition studies that failed to replicate and/or extend previously reported effects. From these opposing outcomes, we present a series of factors to consider that are intended to facilitate future use of tDCS when applied to cognitive questions. In short, common pitfalls include testing too few participants, using insufficiently challenging tasks, using heterogeneous participant populations, and including poorly motivated participants. Furthermore, the poorly understood underlying mechanism for long-lasting tDCS effects make it likely that other important factors predict responses. In conclusion, we argue that although tDCS can be used experimentally to understand brain function its greatest potential may be in applied or translational research.