Time of Day Effects on Inhibitory Functioning: Cognitive and Neural Evidence of Sundowning in Amnestic Mild Cognitive Impairment.

BACKGROUND: Amnestic mild cognitive impairment (aMCI), a prodromal phase of Alzheimer's disease (AD), is characterized by episodic memory dysfunction, but inhibitory deficits have also been commonly reported. Time of day (TOD) effects have been confirmed in 1) healthy aging on cognitive processes such as inhibitory control, and 2) on behavior in AD (termed the sundowning effect), but no such research has addressed aMCI. OBJECTIVE: The present study examined the impact of TOD on the behavioral and electrophysiological correlates of inhibition in 54 individuals with aMCI and 52 healthy controls (HCs), all of morning chronotype. METHODS: Participants were randomly assigned to complete two inhibition tasks (Go-NoGo and Flanker) during their optimal (morning) or non-optimal (evening) TOD, while electroencephalography was recorded. RESULTS: Both tasks elicited changes in N2 and P3 event-related potential (ERP) components, which commonly index inhibitory functioning. Analyses showed that the Go-NoGo difference in P3 amplitude was reduced in individuals with aMCI relative to HCs. Compared to HCs, the Flanker difference in P3 amplitude was also reduced and coincided with more errors in the aMCI group. Notably, these behavioral and ERP differences were exaggerated in the non-optimal TOD relative to the optimal TOD. CONCLUSION: Findings confirm the presence of inhibition deficits in aMCI and provide novel evidence of sundowning effects on inhibitory control in aMCI. Results reinforce the need to consider the influences of TOD in clinical assessments involving individuals with aMCI.

The Effects of Aging and Time of Day on Inhibitory Control: An Event-Related Potential Study.

Time of day (TOD) influences on executive functions have been widely reported, with greater efficiency demonstrated at optimal relative to non-optimal TOD according to one's chronotype (i.e., synchrony effect). Older adults (OAs) show declines in inhibitory control and are more sensitive to the effects of circadian variation on executive functioning. To date, no studies have investigated the effects of TOD and aging on executive functioning using electrophysiological measures. The present study investigated the effects of aging and TOD on the neural correlates of inhibitory processing (N2 and P3) using event-related potentials (ERPs). Go-NoGo and Flanker tasks were administered to 52 OAs of morning chronotype and 51 younger adults (YAs) of afternoon-to-evening chronotype who were randomly assigned to morning or afternoon test sessions, with the optimal TOD for OAs in the morning and for YAs in the afternoon/evening. While behavioral results demonstrated no TOD effects, ERPs indicated synchrony effects. Both YAs and OAs showed greater modulation of Go-NoGo N2 and greater P3 amplitude during the non-optimal than optimal TOD, consistent with the synchrony effect. For the Flanker task, age differences in P3 amplitude were only apparent during the non-optimal TOD. These results suggest that processes associated with inhibitory control are differentially affected by TOD and aging, with age-related reductions in inhibitory efficiency during off-peak test times on measures of interference control. These findings highlight the sensitivity of ERPs to detect TOD effects in the absence of behavioral differences, confirm more pronounced TOD effects in OAs relative to YAs on ERP measures of interference control, and reinforce the need to assess and control for circadian typology in research studies.

Default Mode Network and Neural Phase Synchronization in Healthy Aging: A Resting State EEG Study.

Aging is associated with altered brain connectivity within the default mode network (DMN). Although research using functional magnetic resonance imaging has quantified age-related alterations in functional connectivity within this network during resting state, it is less clear how this may be reflected in electrophysiological measures, and how this relates to cognitive performance in older adults. The aim of this study was to quantify age differences in phase synchrony of the DMN during resting state, with particular focus on connectivity between the anterior node (i.e., medial prefrontal cortex, or mPFC) and other associated regions in this network. Electroencephalography was recorded from 55 younger adults (18-30 years, 28 females) and 34 older adults (64-88 years, 16 females) in two resting state conditions (eyes-open and -closed). Source-level functional connectivity was quantified using phase-locking value (PLV) with a spatial filter of six sources of interest, and were subjected to data-driven permutation testing between groups from 1 to 50 Hz. Older adults also completed tests of memory, language, executive functioning, and processing speed. Findings indicated decreased connectivity in the alpha2 range for older than younger adults between the mPFC and other DMN regions including the left angular gyrus and bilateral lateral temporal cortices, the latter of which were associated with lower performance in semantic fluency and executive functioning in older adults. Furthermore, greater PLV in theta and beta bands between the mPFC and posterior cingulate regions were found in older than younger adults. These results suggest age-related changes in DMN functional connectivity are non-uniform and frequency-dependent, and may reflect poorer performance in cognitive domains thought to decline with aging.

Reaction Time Intraindividual Variability Reveals Inhibitory Deficits in Single- and Multiple-Domain Amnestic Mild Cognitive Impairment.

OBJECTIVES: Amnestic mild cognitive impairment (aMCI), a prodromal stage of Alzheimer's disease and other dementias, is characterized by episodic memory impairment. Recent evidence has shown inhibitory control deficits in aMCI, but the extent of these deficits across inhibitory domains (i.e., response inhibition and interference control) and aMCI subtypes (i.e., single vs multiple domain) remains unclear. Few studies have included reaction time intraindividual variability (RT IIV) in these efforts. The aim of this study was to compare response inhibition and interference control between aMCI subtypes using measures of accuracy, mean RT, and RT IIV. METHODS: We report data from 34 individuals with single-domain aMCI (sdaMCI, 66-86 years), 20 individuals with multiple-domain aMCI (mdaMCI, 68-88 years), and 52 healthy controls (HC, 64-88 years) who completed tasks of response inhibition (Go-NoGo) and interference control (Flanker). Group differences in accuracy, mean RT, and RT IIV were examined for both tasks. RESULTS: Individuals with mdaMCI had higher RT IIV than the other groups on both tasks. In RT IIV, we observed an interference control deficit in mdaMCI and sdaMCI relative to healthy controls, a finding not observed through accuracy or mean RT. DISCUSSION: RT IIV may detect subtle differences in inhibition deficits between aMCI subtypes that may not be evident with conventional behavioral measures. Findings support the supplementary use of RT IIV when assessing early executive function deficits.

Aging Enhances Neural Activity in Auditory, Visual, and Somatosensory Cortices: The Common Cause Revisited.

In humans, age-related declines in vision, hearing, and touch coincide with changes in amplitude and latency of sensory-evoked potentials. These age-related differences in neural activity may be related to a common deterioration of supra-modal brain areas (e.g., PFC) that mediate activity in sensory cortices or reflect specific sensorineural impairments that may differ between sensory modalities. To distinguish between these two possibilities, we measured neuroelectric brain activity while 37 young adults (18-30 years, 18 males) and 35 older adults (60-88 years, 20 males) were presented with a rapid randomized sequence of lateralized auditory, visual, and somatosensory stimuli. Within each sensory domain, we compared amplitudes and latencies of sensory-evoked responses, source activity, and functional connectivity (via phase-locking value) between groups. We found that older adults' early sensory-evoked responses were greater in amplitude than those of young adults in all three modalities, which coincided with enhanced source activity in auditory, visual, and somatosensory cortices. Older adults also showed stronger neural synchrony than young adults between superior prefrontal and sensory cortices; and in older adults, the degree of phase synchrony was positively correlated with the magnitude of source activity in sensory areas. Critically, older adults who showed enhanced neural activity in one sensory domain also showed enhanced activity in other modalities. Together, these findings support the common cause hypothesis of aging and highlight the role of prefrontal regions in exerting top-down control over sensory cortices.SIGNIFICANCE STATEMENT A prominent theory of aging posits that age-related declines in sensory processing across domains are related to a single common neurobiological mechanism. However, the neural evidence supporting this common cause hypothesis has remained elusive. Our study revealed robust age-related changes in three sensory domains across a range of neural metrics. Importantly, older adults who showed increased neural activity within one sensory domain also showed enhanced neural activity in the other two sensory modalities. No such relation among activity in sensory cortices was observed in young adults. Age-related increases in neural activity in sensory cortices coincided with enhanced neural synchrony between the PFC and sensory cortices, underlining the importance of the PFC in regulating sensory processing.

Inhibitory Control Deficits in Individuals with Amnestic Mild Cognitive Impairment: a Meta-Analysis.

Amnestic mild cognitive impairment (aMCI) is a prodromal stage of Alzheimer's disease that is characterized by impairments in episodic memory. Recent evidence has shown that inhibitory control is also impaired in aMCI. The aim of the present meta-analysis was to quantify inhibitory control ability in individuals with aMCI by examining performance across a range of well-defined inhibition paradigms that tapped into one of three inhibitory control subtypes (i) interference control (e.g., Stroop task), (ii) response inhibition (e.g., Go/Nogo task), or (iii) inhibition of cognitive sets (Wisconsin Card Sort Task). Reference databases (PsychINFO, PubMed, and Web of Science) were searched for studies comparing individuals with aMCI to healthy controls on behavioural measures of inhibition. Across 70 effect sizes involving 2184 adults with aMCI and 3049 controls, overall inhibition deficits of moderate magnitude (g = -0.73) were found among individuals with aMCI. Inhibition deficits were moderate in size regardless of inhibitory control subtype: interference control (g = -0.74), response inhibition (g = -0.71), inhibition of cognitive sets (g = -0.76). Subgroup analyses revealed that Stroop outcome measure (reaction time vs. accuracy) and recruitment source (clinical vs. community) moderated interference control deficits. Together these findings support a generalized inhibition deficit in aMCI, and suggest that inhibition tasks should be included routinely in neuropsychological test batteries to provide a more comprehensive overview of executive dysfunction in aMCI.

Cognitive changes in conjunctive rule-based category learning: An ERP approach.

When learning rule-based categories, sufficient cognitive resources are needed to test hypotheses, maintain the currently active rule in working memory, update rules after feedback, and to select a new rule if necessary. Prior research has demonstrated that conjunctive rules are more complex than unidimensional rules and place greater demands on executive functions like working memory. In our study, event-related potentials (ERPs) were recorded while participants performed a conjunctive rule-based category learning task with trial-by-trial feedback. In line with prior research, correct categorization responses resulted in a larger stimulus-locked late positive complex compared to incorrect responses, possibly indexing the updating of rule information in memory. Incorrect trials elicited a pronounced feedback-locked P300 elicited which suggested a disconnect between perception, and the rule-based strategy. We also examined the differential processing of stimuli that were able to be correctly classified by the suboptimal single-dimensional rule ("easy" stimuli) versus those that could only be correctly classified by the optimal, conjunctive rule ("difficult" stimuli). Among strong learners, a larger, late positive slow wave emerged for difficult compared with easy stimuli, suggesting differential processing of category items even though strong learners performed well on the conjunctive category set. Overall, the findings suggest that ERP combined with computational modelling can be used to better understand the cognitive processes involved in rule-based category learning.

Familiarization may minimize age-related declines in rule-based category learning.

Being able to categorize promotes cognitive economy by reducing the amount of information that an individual needs to remember. This ability is particularly important in older adulthood, when executive functioning abilities are known to decline. Prior research has shown that older adults can learn simple categories quite well but struggle when learning more complex categories which place a demand on executive function resources. The goal of Experiments 1 to 3 was to assess whether familiarizing older adults with complex rule-based or non-rule-based categories prior to beginning a categorization task would minimize age-related categorization deficits. Both rule-based and non-rule-based category learning improved among older adults following pretraining, but the improvements to rule-based learning were more drastic, suggesting that executive functioning plays a heavier role in rule-based category learning. Findings provide a potential solution for improving the category learning abilities of older adults. (PsycINFO Database Record

Category learning in older adulthood: A study of the Shepard, Hovland, and Jenkins (1961) tasks.

Shepard, Hovland, and Jenkins (1961) examined the categorization abilities of younger adults using tasks involving single-dimensional rule learning, disjunctive rule learning, and family resemblance learning. The current study examined category learning in older adults using this well-known category set. Older adults, like younger adults, found category tasks with a single relevant dimension the easiest to learn. In contrast to younger adults, older adults found complex disjunctive rule-based categories harder to learn than family resemblance based categories. Disjunctive rule-based category learning appeared to be the most difficult for older adults to learn because this category set placed the heaviest demands on working memory, which is known to be a cognitive function that declines with normal aging. The authors discuss why complex rule-based category learning is considered more difficult for older adults to learn relative to younger adults, drawing parallels to developmental research.

Ego depletion interferes with rule-defined category learning but not non-rule-defined category learning.

Considerable research on category learning has suggested that many cognitive and environmental factors can have a differential effect on the learning of rule-defined (RD) categories as opposed to the learning of non-rule-defined (NRD) categories. Prior research has also suggested that ego depletion can temporarily reduce the capacity for executive functioning and cognitive flexibility. The present study examined whether temporarily reducing participants' executive functioning via a resource depletion manipulation would differentially impact RD and NRD category learning. Participants were either asked to write a story with no restrictions (the control condition), or without using two common letters (the ego depletion condition). Participants were then asked to learn either a set of RD categories or a set of NRD categories. Resource depleted participants performed more poorly than controls on the RD task, but did not differ from controls on the NRD task, suggesting that self regulatory resources are required for successful RD category learning. These results lend support to multiple systems theories and clarify the role of self-regulatory resources within this theory.

Learning categories via rules and similarity: comparing adults and children.

Two experiments explored the different strategies used by children and adults when learning new perceptual categories. Participants were asked to learn a set of categories for which both a single-feature rule and overall similarity would allow for perfect performance. Other rules allowed for suboptimal performance. Transfer stimuli (Experiments 1 and 2) and single features (Experiment 2) were presented after training to help determine how the categories were learned. In both experiments, we found that adults made significantly more optimal rule-based responses to the test stimuli than children. Children showed a variety of categorization styles, with a few relying on the optimal rules, many relying on suboptimal single-feature rules, and only a few relying on overall family resemblance. We interpret these results within a multiple systems framework, and we argue that children show the pattern they do because they lack the necessary cognitive resources to fully engage in hypothesis testing, rule selection, and verbally mediated category learning.

Rule-based category learning in children: the role of age and executive functioning.

Rule-based category learning was examined in 4-11 year-olds and adults. Participants were asked to learn a set of novel perceptual categories in a classification learning task. Categorization performance improved with age, with younger children showing the strongest rule-based deficit relative to older children and adults. Model-based analyses provided insight regarding the type of strategy being used to solve the categorization task, demonstrating that the use of the task appropriate strategy increased with age. When children and adults who identified the correct categorization rule were compared, the performance deficit was no longer evident. Executive functions were also measured. While both working memory and inhibitory control were related to rule-based categorization and improved with age, working memory specifically was found to marginally mediate the age-related improvements in categorization. When analyses focused only on the sample of children, results showed that working memory ability and inhibitory control were associated with categorization performance and strategy use. The current findings track changes in categorization performance across childhood, demonstrating at which points performance begins to mature and resemble that of adults. Additionally, findings highlight the potential role that working memory and inhibitory control may play in rule-based category learning.

Better mood and better performance. Learning rule-described categories is enhanced by positive mood.

Theories of mood and its effect on cognitive processing suggest that positive mood may allow for increased cognitive flexibility. This increased flexibility is associated with the prefrontal cortex and the anterior cingulate cortex, both of which play crucial roles in hypothesis testing and rule selection. Thus, cognitive tasks that rely on behaviors such as hypothesis testing and rule selection may benefit from positive mood, whereas tasks that do not rely on such behaviors should not be affected by positive mood. We explored this idea within a category-learning framework. Positive, neutral, and negative moods were induced in our subjects, and they learned either a rule-described or a non-rule-described category set. Subjects in the positive-mood condition performed better than subjects in the neutral- or negative-mood conditions in classifying stimuli from rule-described categories. Positive mood also affected the strategy of subjects who classified stimuli from non-rule-described categories.