Combined Cognitive Training and Vortioxetine Mitigates Age-Related Declines in Functional Brain Network Integrity.

OBJECTIVE: Age-related cognitive decline is common and potentially modifiable with cognitive training. Combining cognitive training with pro-cognitive medication offers an opportunity to modify brain networks to mitigate age-related cognitive decline. We tested the hypothesis that the efficacy of cognitive training could be amplified by combining it with vortioxetine, a pro-cognitive and pro-neuroplastic multimodal antidepressant. METHODS: We evaluated the effects of 6 months of computerized cognitive training plus vortioxetine (versus placebo) on resting state functional connectivity in older adults (age 65+) with age-related cognitive decline. We first evaluated the association of functional connectivity with age and cognitive performance (N = 66). Then we compared the effects of vortioxetine plus cognitive training versus placebo plus cognitive training on connectivity changes over the training period (n = 20). RESULTS: At baseline, greater age was significantly associated with lower within-network strength and network segregation, and poorer cognitive function. Cognitive training plus vortioxetine over 6 months positively impacted the relationship between age to mean network segregation. These effects were not observed in the placebo group. In contrast, vortioxetine did not modify the relationship of age to change in mean within-network strength. Exploratory analyses identified the cingulo-opercular network as the network most affected by cognitive training plus vortioxetine. CONCLUSION: This preliminary study provides evidence that combining cognitive training with pro-cognitive medication may modulate the effects of aging on functional brain networks. Results indicate that for older adults experiencing age-related cognitive decline, vortioxetine has a potentially beneficial effect on the correspondence between aging and functional brain network segregation. These results await replication in a larger sample.

Aging and task design shape the relationship between response time variability and emotional response inhibition.

Intra-individual variability (IIV) refers to within-person variability in behavioural task responses. Several factors can influence IIV, including aging and cognitive demands. The present study investigated effects of aging on IIV of response times during executive functioning tasks. Known age-related differences in cognitive control and emotion processing motivated evaluating how varying the design of emotional response inhibition tasks would influence IIV in older and younger adults. We also tested whether IIV predicted inhibitory control across task designs and age groups. Older and younger adults (N = 237) completed one of three versions of a stop-signal task, which all displayed happy, fearful, or neutral faces in Stop trials. An independent group of older and younger adults (N = 80) completed a go/no-go task also employing happy, fearful and neutral faces. Results showed older adults had more consistent responses (lower IIV) than younger adults in the stop-signal task, but not the go/no-go task. Lower IIV predicted more efficient emotional response inhibition for fear faces in the stop-signal task, but only when attention to emotion was task-relevant. Collectively, this study clarifies effects of aging and task design on IIV and illustrates how task design impacts the relationship between IIV and emotional response inhibition in younger and older adults.

Positive information facilitates response inhibition in older adults only when emotion is task-relevant.

Emotional information is integral to everyday life and impacts a variety of cognitive abilities including response inhibition, a critical skill for maintaining appropriate and flexible behaviour. However, reported effects of emotion on response inhibition are inconsistent in younger adults, and very limited in older adults. Effects of aging are especially relevant because emotion regulation improves with aging despite declining inhibitory control over neutral information. Across three studies, we assessed the impact of emotional facial expressions on response inhibition in younger and older adults while manipulating attention to task stimuli. Emotional faces (versus neutral faces) altered response inhibition only when task instructions required explicit attention to emotional attributes of the faces. When directly comparing fear faces to happy faces, both age groups had better response inhibition to happy faces. Age further influenced differences across conditions, in that happy faces enhanced response inhibition relative to neutral faces in older adults but not younger adults. Thus, emotional response inhibition for task-relevant (but not task-irrelevant) positive information is enhanced in late life compared to early adulthood. The present work extends the nascent literature on emotional response inhibition in aging, and proffers a framework to reconcile the mixed literature on this topic in younger adults.

Disentangling cognition and emotion in older adults: the role of cognitive control and mental health in emotional conflict adaptation.

OBJECTIVE: Recent research suggests cognition has a bidirectional relationship with emotional processing in older adults, yet the relationship is still poorly understood. We aimed to examine a potential relationship between late-life cognitive function, mental health symptoms, and emotional conflict adaptation. We hypothesized that worse cognitive control abilities would be associated with poorer emotional conflict adaptation. We further hypothesized that a higher severity of mental health symptoms would be associated with poorer emotional conflict adaptation. METHODS: Participants included 83 cognitively normal community-dwelling older adults who completed a targeted mental health and cognitive battery, and emotion and gender conflict-adaptation tasks. RESULTS: Consistent with our hypothesis, poorer performance on components of cognitive control, specifically attention and working memory, was associated with poorer emotional conflict adaptation. This association with attention and working memory was not observed in the non-affective-based gender conflict adaptation task. Mental health symptoms did not predict emotional conflict adaptation, nor did performance on other cognitive measures. CONCLUSION: Our findings suggest that emotion conflict adaptation is disrupted in older individuals who have poorer attention and working memory. Components of cognitive control may therefore be an important potential source of inter-individual differences in late-life emotion regulation and cognitive affective deficits. Copyright © 2016 John Wiley & Sons, Ltd.

Connectivity underlying emotion conflict regulation in older adults with 5-HTTLPR short allele: a preliminary investigation.

OBJECTIVE: The serotonin transporter polymorphism short (s) allele is associated with heightened emotional reactivity and reduced emotion regulation, which increases vulnerability to depression and anxiety disorders. We investigated behavioral and neural markers of emotion regulation in community-dwelling older adults, contrasting s allele carriers and long allele homozygotes. METHODS: Participants (N = 26) completed a face-word emotion conflict task during functional magnetic resonance imaging, in which facilitated regulation of emotion conflict was observed on face-word incongruent trials following another incongruent trial (i.e., emotional conflict adaptation). RESULTS: There were no differences between genetic groups in behavioral task performance or neural activation in postincongruent versus postcongruent trials. By contrast, connectivity between dorsal anterior cingulate cortex (ACC) and pregenual ACC, regions previously implicated in emotion conflict regulation, was impaired in s carriers for emotional conflict adaptation. CONCLUSION: This is the first demonstration of an association between serotonin transporter polymorphism and functional connectivity in older adults. Poor dorsal ACC-pregenual ACC connectivity in s carriers may be one route by which these individuals experience greater difficulty in implementing effective emotional regulation, which may contribute to their vulnerability for affective disorders.

The effect of divided attention on emotion-induced memory narrowing.

Individuals are more likely to remember emotional than neutral information, but this benefit does not always extend to the surrounding background information. This memory narrowing is theorised to be linked to the availability of attentional resources at encoding. In contrast to the predictions of this theoretical account, altering participants' attentional resources at encoding by dividing attention did not affect emotion-induced memory narrowing. Attention was divided using three separate manipulations: a digit ordering task (Experiment 1), an arithmetic task (Experiment 2) and an auditory discrimination task (Experiment 3). Across all three experiments, divided attention decreased memory across the board but did not affect the degree of memory narrowing. These findings suggest that theories to explain memory narrowing must be expanded to include other potential mechanisms beyond the limitations of attentional resources.

Memory for the 2008 presidential election in healthy ageing and mild cognitive impairment.

The present study examined memory accuracy and confidence for personal and public event details of the 2008 presidential election in healthy older adults and those with mild cognitive impairment (MCI). Participants completed phone interviews within a week after the election and after a 10-month delay. MCI patients and healthy older adults had comparable emotional reactions to learning the outcome of the election, with most people finding it to be a positive experience. After the delay period, details about the election were better remembered by all participants than a less emotionally arousing comparison event. However, MCI patients had more difficulty than healthy older adults correctly recalling details of public information about the election, although often the MCI patients could recognise the correct details. This is the first study to show that MCI patients' memory can benefit from emotionally arousing positive events, complementing the literature demonstrating similar effects for negative events.

Cerebrospinal fluid Aß42 moderates the relationship between brain functional network dynamics and cognitive intraindividual variability.

As Alzheimer's disease (AD) pathology accumulates, resting-state functional connectivity (rs-fc) within and between brain networks decreases, and fluctuations in cognitive performance known as intraindividual variability (IIV) increase. Here, we assessed the relationship between IIV and anticorrelations in rs-fc between the default mode network (DMN)-dorsal attention network (DAN) in cognitively normal older adults and symptomatic AD participants. We also evaluated the relationship between cerebrospinal fluid (CSF) biomarkers of AD (amyloid-beta [Aß42] and tau) and IIV-anticorrelation in rs-fc. We observed that cognitive IIV and anticorrelations between DMN × DAN were higher in individuals with AD compared with cognitively normal participants. As DMN × DAN relationship became more positive, cognitive IIV increased, indicating that stronger anticorrelations between networks support more consistent cognitive performance. Moderation analyses indicated that continuous CSF Aß42, but not CSF total tau, moderated the relationship between cognitive IIV and DMN × DAN, collectively demonstrating that greater amyloid burden and alterations in functional network dynamics are associated with cognitive changes seen in AD. These findings are valuable, as they suggest that amyloid affects cognitive functioning during the early stages of AD.

Impact of individual differences upon emotion-induced memory trade-offs.

After seeing a scene containing an emotional component (e.g., a snake in a forest) people often demonstrate a "trade-off" in memory, where memory for the emotional component (e.g., the snake) is good, but memory for the nonemotional elements (e.g., the forest) is poor. The result is an incomplete memory retaining central emotional information at the expense of neutral background information. Though almost everyone demonstrates the trade-off, there may be individual differences in the magnitude of the effect. We investigated whether differences in the strength of the trade-off would correlate with anxiety levels, working memory capacity, and executive functioning abilities. Sixty-four participants studied scenes comprised of a negative or neutral item placed on a neutral background, and memory was later tested for items and backgrounds separately. The magnitude of the trade-off correlated positively with anxiety and negatively with visuospatial working memory and executive function. These results suggest that greater anxiety, poor visuospatial working memory, and poor executive function may inhibit formation of complete mental representations of these complex emotional scenes.

Augmenting Computerized Cognitive Training With Vortioxetine for Age-Related Cognitive Decline: A Randomized Controlled Trial.

OBJECTIVE: Age-related cognitive decline, the deterioration in functions such as memory and executive function, is faced by most older adults and affects function and quality of life. No approved treatments exist for age-related cognitive decline. Computerized cognitive training has been shown to provide consistent albeit modest improvements in cognitive function as measured by neuropsychological testing. Vortioxetine, an antidepressant medication, has putative procognitive and proneuroplastic properties and therefore may be able to augment cognitive training. In this placebo-controlled study, the authors tested the cognitive benefits of vortioxetine added to cognitive training for adults age 65 or older with age-related cognitive decline. METHODS: After a 2-week lead-in period of cognitive training, 100 participants were randomly assigned to receive either vortioxetine or placebo in addition to cognitive training for 26 weeks. The primary outcome measure was global cognitive performance, assessed by the NIH Toolbox Cognition Battery Fluid Cognition Composite. The secondary outcome measure was functional cognition, assessed by the UCSD Performance-Based Skills Assessment. All participants received motivational messaging and support from study staff to maximize adherence to the training. RESULTS: Participants who received vortioxetine with cognitive training showed a greater increase in global cognitive performance compared with those who received placebo with cognitive training. This separation was significant at week 12 but not at other assessment time points. Both groups showed improvement in the secondary outcome measure of functional cognition, with no significant difference between groups. CONCLUSIONS: Vortioxetine may be beneficial for age-related cognitive decline when combined with cognitive training. These findings provide new treatment directions for combating cognitive decline in older adults.

Effects of emotional valence and arousal upon memory trade-offs with aging.

Attention can be attracted faster by emotional relative to neutral information, and memory also can be strengthened for that emotional information. However, within visual scenes, often there is an advantage in memory for central emotional portions at the expense of memory for peripheral background information, called an emotion-induced memory trade-off. The authors examined how aging impacts the trade-off by manipulating valence (positive, negative) and arousal (low, high) of a central emotional item within a neutral background scene and testing memory for item and background components separately. They also assessed memory after 2 study-test delay intervals, to investigate age differences in the trade-off over time. Results revealed similar patterns of performance between groups after a short study-test delay, with both age groups showing robust memory trade-offs. After a longer delay, young and older adults showed enhanced memory for emotional items but at a cost to memory for background information only for young adults in negative arousing scenes. These results emphasize that attention and consolidation stage processes interact to shape how emotional memory is constructed in young and older adults.

Response bias for picture recognition in patients with Alzheimer disease.

OBJECTIVE: To investigate whether changing recognition stimuli from words to pictures would alter response bias in patients with Alzheimer disease (AD). BACKGROUND: Response bias is an important aspect of memory performance in patients with AD, as they show an abnormally liberal response bias compared with healthy older adults. We have previously found that despite changes in discrimination produced by varying the study and test list length, response bias remained remarkably stable in both patients with AD and older adult controls. METHODS: Patients with mild AD and healthy older adults underwent two separate study-test sessions of pictures and words. For both pictures and words, increasing study-test list lengths were used to determine whether bias changed as a factor of discrimination or task difficulty. RESULTS: Consistent with apriori hypotheses, healthy older adults showed increased discrimination and shifted to a more liberal response bias for pictures compared with words. In contrast, despite their higher level of discrimination for pictures, patients with AD showed a similar response bias for both pictures and words. Bias was consistent across varying study-test lengths for both groups. CONCLUSIONS: These results suggest that response bias is a relatively invariant factor of an individual with AD that remains liberal regardless of discrimination or stimulus type.

Emotional Response Inhibition Is Greater in Older Than Younger Adults.

Emotional information rapidly captures our attention and also often invokes automatic response tendencies, whereby positive information motivates approach, while negative information encourages avoidance. However, many circumstances require the need to override or inhibit these automatic responses. Control over responses to emotional information remains largely intact in late life, in spite of age-related declines in cognitive control and inhibition of responses to non-emotional information. The goal of this behavioral study was to understand how the aging process influences emotional response inhibition for positive and negative information in older adults. We examined emotional response inhibition in 36 healthy older adults (ages 60-89) and 44 younger adults (ages 18-22) using an emotional Go/No-Go task presenting happy (positive), fearful (negative), and neutral faces. In both younger and older adults, happy faces produced more approach-related behavior (i.e., fewer misses), while fearful faces produced more avoidance-related behavior, in keeping with theories of approach/avoidance-motivated responses. Calculation of speed/accuracy trade-offs between response times and false alarm rates revealed that younger and older adults both favored speed at the expense of accuracy, most robustly within blocks with fearful faces. However, there was no indication that the strength of the speed/accuracy trade-off differed between younger and older adults. The key finding was that although younger adults were faster to respond to all types of faces, older adults had greater emotional response inhibition (i.e., fewer false alarms). Moreover, younger adults were particularly prone to false alarms for happy faces. This is the first study to directly test effects of aging on emotional response inhibition. Complementing previous literature in the domains of attention and memory, these results provide new evidence that in the domain of response inhibition older adults may more effectively employ emotion regulatory ability, albeit on a slower time course, compared to younger adults. Older adults' enhanced adaptive emotion regulation strategies may facilitate resistance to emotional distraction. The present study extends the literature of emotional response inhibition in younger adulthood into late life, and in doing so further elucidates how cognitive aging interacts with affective control processes.

Aging memory for pictures: using high-density event-related potentials to understand the effect of aging on the picture superiority effect.

High-density event-related potentials (ERPs) were used to understand the effect of aging on the neural correlates of the picture superiority effect. Pictures and words were systematically varied at study and test while ERPs were recorded at retrieval. Here, the results of the word-word and picture-picture study-test conditions are presented. Behavioral results showed that older adults demonstrated the picture superiority effect to a greater extent than younger adults. The ERP data helped to explain these findings. The early frontal effect, parietal effect, and late frontal effect were all indistinguishable between older and younger adults for pictures. In contrast, for words, the early frontal and parietal effects were significantly diminished for the older adults compared to the younger adults. These two old/new effects have been linked to familiarity and recollection, respectively, and the authors speculate that these processes are impaired for word-based memory in the course of healthy aging. The findings of this study suggest that pictures allow older adults to compensate for their impaired memorial processes, and may allow these memorial components to function more effectively in older adults.

Effects of distinctive encoding on source-based false recognition: further examination of recall-to-reject processes in aging and Alzheimer disease.

OBJECTIVE: To examine the use of distinctive materials at encoding on recall-to-reject monitoring processes in aging and Alzheimer disease (AD). BACKGROUND: AD patients, and to a lesser extent older adults, have shown an impaired ability to use recollection-based monitoring processes (eg, recall-to-reject) to avoid various types of false memories, such as source-based false recognition. METHOD: Younger adults, healthy older adults, and AD patients engaged in an incidental learning task, in which critical category exemplars were either accompanied by a distinctive picture or were presented as only words. Later, participants studied a series of categorized lists in which several typical exemplars were omitted and were then given a source memory test. RESULTS: Both older and younger adults made more accurate source attributions after picture encoding compared with word-only encoding, whereas AD patients did not exhibit this distinctiveness effect. CONCLUSIONS: These results extend those of previous studies showing that monitoring in older adults can be enhanced with distinctive encoding, and suggest that such monitoring processes in AD patients many be insensitive to distinctiveness.

Emotional Contrast and Psychological Function Impact Response Inhibition to Threatening Faces.

Poor inhibitory control over negative emotional information has been identified as a possible contributor to affective disorders, but the distinct effects of emotional contrast and fearful versus angry faces on response inhibition remain unknown. In the present study, young adults completed an emotional go/no-go task involving happy, neutral, and either fearful or angry faces. Results did not reveal differences in accuracy or speed between angry and fearful face conditions. However, responses were slower and indicated poorer inhibition in blocks where threatening faces were paired with happy, versus neutral, faces. Results may reflect cognitive load of emotional valence contrast, such that higher contrast blocks (containing threatening with happy faces) produced more conflict and required more processing than lower contrast blocks (threatening with neutral faces). Preliminary findings also revealed higher anxiety and depression symptoms corresponded with slower responses and worse accuracy, consistent with patterns of adverse impacts of anxiety and depression on response inhibition to threatening faces, even at subclinical levels of symptomatology.

Memory for the September 11, 2001, terrorist attacks one year later in patients with Alzheimer's disease, patients with mild cognitive impairment, and healthy older adults.

Although there are many opportunities to study memory in patients with Alzheimer's disease (AD) in the laboratory, there are few opportunities to study memory for real world events in these patients. The September 11, 2001 terrorist attacks provided one such opportunity. Patients with AD, patients with mild cognitive impairment (MCI), and healthy older adults were given a telephone questionnaire in the initial weeks after the event, again three to four months later, and finally one year afterwards to evaluate their memory for the September 11, 2001 terrorist attacks. We were particularly interested in using the attacks as an opportunity to examine the decline of episodic memory in patients with AD, patients with MCI, and older adult controls over a period of months. We found that compared to healthy older adults, patients with AD and MCI showed impaired memory at the initial time point, more rapid forgetting from the initial to the three-month time point, and very similar changes in memory from the three-month to the one-year time point. We speculated that these findings were consistent with patients with AD and MCI showing initial impaired encoding and a more rapid rate of forgetting compared with healthy older adults, but that once the memories had been consolidated, their decay rate became similar to that of healthy older adults. Lastly, although memory distortions were common among all groups, they were greatest in the patients with AD.

Episodic memory in Alzheimer's disease: separating response bias from discrimination.

Most studies examining episodic memory in Alzheimer's disease (AD) have focused on patients' impaired ability to remember information, leading to poor discrimination between studied and unstudied items at test. Poor discrimination, however, can also be attributable to an abnormally high rate of false alarms. One cause of a high false alarm rate is an abnormally liberal response bias; that is, responding "old" too liberally to the test items. In the present study, discrimination and response bias were evaluated when participants were given a series of progressively longer study-test lists of unrelated words. As expected, patients with AD showed overall worse discrimination and a more liberal response bias compared with older adult controls. Critically, patients with AD also showed a more liberal response bias than older adults when discrimination was matched between the groups after performance was equated by giving the older adult controls a more difficult test than the patients with AD. This result confirms that the patients' abnormally liberal response bias is not simply attributable to their poor discrimination. Correlation analyses suggest that the patients' liberal response bias is related to the degree of their episodic memory deficit, which may in turn be related to the severity of their disease. Thus, our research suggests that as AD progresses two distinct abnormalities of episodic memory develop: worse discrimination and a more liberal response bias. Possible explanations of this liberal response bias in patients with AD are discussed.

Effects of aging on neural connectivity underlying selective memory for emotional scenes.

Older adults show age-related reductions in memory for neutral items within complex visual scenes, but just like young adults, older adults exhibit a memory advantage for emotional items within scenes compared with the background scene information. The present study examined young and older adults' encoding-stage effective connectivity for selective memory of emotional items versus memory for both the emotional item and its background. In a functional magnetic resonance imaging (fMRI) study, participants viewed scenes containing either positive or negative items within neutral backgrounds. Outside the scanner, participants completed a memory test for items and backgrounds. Irrespective of scene content being emotionally positive or negative, older adults had stronger positive connections among frontal regions and from frontal regions to medial temporal lobe structures than did young adults, especially when items and backgrounds were subsequently remembered. These results suggest there are differences between young and older adults' connectivity accompanying the encoding of emotional scenes. Older adults may require more frontal connectivity to encode all elements of a scene rather than just encoding the emotional item.

How emotion leads to selective memory: neuroimaging evidence.

Often memory for emotionally arousing items is enhanced relative to neutral items within complex visual scenes, but this enhancement can come at the expense of memory for peripheral background information. This 'trade-off' effect has been elicited by a range of stimulus valence and arousal levels, yet the magnitude of the effect has been shown to vary with these factors. Using fMRI, this study investigated the neural mechanisms underlying this selective memory for emotional scenes. Further, we examined how these processes are affected by stimulus dimensions of arousal and valence. The trade-off effect in memory occurred for low to high arousal positive and negative scenes. There was a core emotional memory network associated with the trade-off among all the emotional scene types, however, there were additional regions that were uniquely associated with the trade-off for each individual scene type. These results suggest that there is a common network of regions associated with the emotional memory trade-off effect, but that valence and arousal also independently affect the neural activity underlying the effect.