Predicting response time variability from task and resting-state functional connectivity in the aging brain.

Aging is associated with declines in a host of cognitive functions, including attentional control, inhibitory control, episodic memory, processing speed, and executive functioning. Theoretical models attribute the age-related decline in cognitive functioning to deficits in goal maintenance and attentional inhibition. Despite these well-documented declines in executive control resources, older adults endorse fewer episodes of mind-wandering when assessed using task-embedded thought probes. Furthermore, previous work on the neural basis of mind-wandering has mostly focused on young adults with studies predominantly focusing on the activity and connectivity of a select few canonical networks. However, whole-brain functional networks associated with mind-wandering in aging have not yet been characterized. In this study, using response time variability-the trial-to-trial fluctuations in behavioral responses-as an indirect marker of mind-wandering or an "out-of-the-zone" attentional state representing suboptimal behavioral performance, we show that brain-based predictive models of response time variability can be derived from whole-brain task functional connectivity. In contrast, models derived from resting-state functional connectivity alone did not predict individual response time variability. Finally, we show that despite successful within-sample prediction of response time variability, our models did not generalize to predict response time variability in independent cohorts of older adults with resting-state connectivity. Overall, our findings provide evidence for the utility of task-based functional connectivity in predicting individual response time variability in aging. Future research is needed to derive more robust and generalizable models.

Protocol for a randomized controlled trial of mindfulness-based stress reduction to improve attentional control in older adults (HealthyAgers trial).

BACKGROUND: Mindfulness meditation is a form of mind-body intervention that has increasing scientific support for its ability to reduce age-related declines in cognitive functioning, improve affective health, and strengthen the neural circuitry supporting improved cognitive and affective health. However, the majority of existent studies have been pilot investigations with small sample sizes, limited follow-up data, and a lack of attention to expectancy effects. Here, we present the study design of a Phase I/II, efficacy trial-HealthyAgers trial-that examines the benefits of a manualized mindfulness-based stress reduction program in improving attentional control and reducing mind-wandering in older adults. METHODS: One hundred fifty older adults (ages 65-85 years) will be randomized into one of two groups: an eight-week mindfulness program or an eight-week, placebo-controlled, lifestyle education program. Behavioral and neuroimaging assessments are conducted before and after the training. Participants are then invited to booster sessions once every three months for a period of 12 months with post-intervention follow-up assessments conducted at 6-months and 12-months. The primary outcomes for the study are behavioral measures of attentional control and mind-wandering. Additional, secondary outcomes include network strength in an a priori defined neuromarker of attentional control, fluid and everyday cognition, emotion regulation strategy use, and markers of inflammation. DISCUSSION: This study will establish the efficacy of a group-based, low-cost mind-body intervention for the inter-related facets of attentional control and mind-wandering in older adults. Strengths of this study include a well-designed, placebo-controlled comparison group, use of web/mobile application to track study adherence, and longitudinal follow-up. TRIAL REGISTRATION: Clinicaltrials.gov (# NCT03626532 ). Registered August 4, 2018.

Stimulation of Dorsolateral Prefrontal Cortex Enhances Adaptive Cognitive Control: A High-Definition Transcranial Direct Current Stimulation Study.

Conflict adaptation is a hallmark effect of adaptive cognitive control and refers to the adjustment of control to the level of previously experienced conflict. Conflict monitoring theory assumes that the dorsolateral prefrontal cortex (DLPFC) is causally involved in this adjustment. However, to date, evidence in humans is predominantly correlational, and heterogeneous with respect to the lateralization of control in the DLPFC. We used high-definition transcranial direct current stimulation (HD-tDCS), which allows for more focal current delivery than conventional tDCS, to clarify the causal involvement of the DLPFC in conflict adaptation. Specifically, we investigated the regional specificity and lateralization of potential beneficial stimulation effects on conflict adaptation during a visual flanker task. One hundred twenty healthy participants were assigned to four HD-tDCS conditions: left or right DLPFC or left or right primary motor cortex (M1). Each group underwent both active and sham HD-tDCS in crossover, double-blind designs. We obtained a sizeable conflict adaptation effect (measured as the modulation of the flanker effect as a function of previous response conflict) in all groups and conditions. However, this effect was larger under active HD-tDCS than under sham stimulation in both DLPFC groups. In contrast, active stimulation had no effect on conflict adaptation in the M1 groups. In sum, the present results indicate that the DLPFC plays a causal role in adaptive cognitive control, but that the involvement of DLPFC in control is not restricted to the left or right hemisphere. Moreover, our study confirms the potential of HD-tDCS to modulate cognition in a regionally specific manner. SIGNIFICANCE STATEMENT: Conflict adaptation is a hallmark effect of adaptive cognitive control. While animal studies have suggested causal involvement of the DLPFC in this phenomenon, such evidence is currently lacking in humans. The present study used high-definition transcranial direct current stimulation (HD-tDCS) to demonstrate that the DLPFC is causally involved in conflict adaptation in humans. Our study confirms a central claim of conflict monitoring theory, which up to now has predominantly relied on correlational studies. Our results further indicate an equal involvement of the left and right DLPFC in adaptive control, whereas stimulation of a control region-the primary motor cortex-had no effect on adaptive control. The study thus confirms the potential of HD-tDCS to modulate cognition in a regionally specific manner.

Using connectome-based models of working memory to predict emotion regulation in older adults.

Older adulthood is characterized by enhanced emotional well-being potentially resulting from greater reliance on adaptive emotion regulation strategies. However, not all older adults demonstrate an increase in emotional well-being and instead rely on maladaptive emotion regulation strategies. An important moderator of age-related shifts in strategy preferences is working memory (WM) and its underlying neural circuitry. As such, individual differences in the neural integrity underlying WM may predict older adults' emotion regulation strategy preferences. Our study used whole-brain WM networks-derived from young adults using connectome-based predictive modeling-to predict WM performance and acceptance strategy use in healthy older adults. Older adults (N = 110) completed baseline assessments as part of a randomized controlled trial examining the impact of mind-body interventions on healthy aging. Our results revealed that the WM networks predicted WM accuracy but not acceptance use or difficulties in emotion regulation in older adults. Individual differences in WM performance, but not WM networks, moderated relationships between image intensity and acceptance use. These findings highlight that robust neural markers of WM generalize to an independent sample of healthy older adults but may not generalize beyond cognitive domains to predict emotion-based behaviors.

Modulation of Adaptive Cognitive Control by Prefrontal High-Definition Transcranial Direct Current Stimulation in Older Adults.

OBJECTIVE: Adaptive cognitive control frequently declines in advanced age. Because high-definition transcranial direct current stimulation (HD-tDCS) of the right dorsolateral prefrontal cortex (DLPFC) improved cognitive control in young adults, we investigated if this montage can also improve cognitive control in older individuals. METHOD: In a double-blind, sham HD-tDCS controlled, cross-over design, 36 older participants received right DLPFC HD-tDCS during a visual flanker task. Conflict adaptation (CA) effects on response time (RT) and error rates (ER) assessed adaptive cognitive control. Biophysical modeling assessed the magnitude and distribution of induced current in older adults. RESULTS: Active HD-tDCS enhanced CA in older adults. However, this positive behavioral effect was limited to CA in ER. Similar to results obtained in healthy young adults, current modeling analysis demonstrated focal current delivery to the DLPFC with sufficient magnitude of the induced current to modulate neural function in older adults. DISCUSSION: This study confirms the effectiveness of HD-tDCS to modulate adaptive cognitive control in advanced age.

A Pilot Double-Blind Randomized Controlled Trial of Cognitive Training Combined with Transcranial Direct Current Stimulation for Amnestic Mild Cognitive Impairment.

BACKGROUND: There is currently no effective intervention for improving memory in people at increased risk for dementia. Cognitive training (CT) has been promising, though effects are modest, particularly at follow-up. OBJECTIVE: To investigate whether adjunctive non-invasive brain stimulation (transcranial direct current stimulation, tDCS) could enhance the memory benefits of CT in amnestic mild cognitive impairment (aMCI). METHODS: Participants with aMCI were randomized to receive CT with either Active tDCS (2 mA for 30 min and 0.016 mA for 30 min) or Sham tDCS (0.016 mA for 60 min) for 15 sessions over a period of 5 weeks in a double-blind, sham-controlled, parallel group clinical trial. The primary outcome measure was the California Verbal Learning Task 2nd Edition. RESULTS: 68 participants commenced the intervention. Intention-to-treat (ITT) analysis showed that the CT+Active tDCS group significantly improved at post treatment (p = 0.033), and the CT+Sham tDCS group did not (p = 0.050), but there was no difference between groups. At the 3-month follow-up, both groups showed large-sized memory improvements compared to pre-treatment (CT+Active tDCS: p < 0.01, d = 0.99; CT+Sham tDCS: p < 0.01, d = 0.74), although there was no significant difference between groups. CONCLUSION: This study found that CT+Active tDCS did not produce greater memory improvement compared to CT+Sham tDCS. Large-sized memory improvements occurred in both conditions at follow-up. One possible interpretation, based on recent novel findings, is that low intensity tDCS (used as 'sham') may have contributed biological effects. Further work should use a completely inert tDCS sham condition.

Safety, Tolerability, Blinding Efficacy and Behavioural Effects of a Novel MRI-Compatible, High-Definition tDCS Set-Up.

BACKGROUND: High-definition transcranial direct current stimulation (HD-tDCS) may allow more specific neural modulation than conventional-tDCS. OBJECTIVE: We compared safety, tolerability, blinding efficacy and cognitive effects of a novel HD-tDCS set-up to that of conventional-tDCS and established compatibility with simultaneous functional magnetic resonance imaging (fMRI). METHODS: Two groups of healthy participants completed a visual flanker task either with conventional (N = 30) or HD-tDCS (N = 30) administered to the right dorsolateral prefrontal cortex (1 mA) in a double-blind, sham-tDCS-controlled, cross-over design. HD-tDCS was administered with a one-channel DC-stimulator using a small conductive rubber "centre" electrode and a circular return electrode, mimicking the frequently used 4 × 1 HD-tDCS set-up. Tolerability, adverse effects, impact on performance and blinding efficacy were compared within and between the two montages. In a separate experiment, potential heating and impact on image quality of the novel HD-tDCS set-up were assessed during simultaneous fMRI. RESULTS: Both montages elicited only mild adverse effects and those were less pronounced for the novel HD-tDCS set-up. Participant and investigator blinding was achieved with both montages. Only HD-tDCS resulted in significant modulation of the conflict adaptation effect during the flanker task; however, no differences were found for the direct comparison of the two montages. No significant heating occurred during fMRI and only minor effects on image quality were observed during HD-tDCS. CONCLUSIONS: This study confirmed safety, tolerability and blinding efficacy of a novel, re-usable and MRI-compatible HD-tDCS set-up. It also highlights its potential to exert beneficial effects on behavioural performance. Use of this novel set-up during simultaneous fMRI in future studies will help clarify the neural mechanisms by which this HD-tDCS impacts on behavioural and neural function.