Contributions of loneliness to cognitive impairment and dementia in older adults are independent of other risk factors and Alzheimer's pathology: a narrative review.

Loneliness significantly contributes to cognitive impairment and dementia in older adults. Loneliness is a distressing feeling resulting from a perceived lack of social connection (i.e., a discrepancy between desired and actual social relationships), while social isolation is a related term that can be defined by number and type of social relationships. Importantly, loneliness is distinct from social isolation in that it is associated with a distressing self-perception. The primary focus of this narrative review is the impact of chronic loneliness on cognitive impairment and dementia among older adults. Loneliness has a significant association with many factors that are related to worse cognition, and therefore we include discussion on health, mental health, as well as the physiological effects of loneliness, neuropathology, and potential treatments. Loneliness has been shown to be related to development of dementia with a hazard ratio (HR) risk comparable to having a single APOE4 gene. The relationship of dementia to loneliness appears to be at least partially independent of other known dementia risk factors that are possibly associated with loneliness, such as depression, educational status, social isolation, and physical activity. Episodic memory is not consistently impacted by loneliness, which would be more typically impaired if the mild cognitive impairment (MCI) or dementia was due to Alzheimer's disease (AD) pathology. In addition, the several longitudinal studies that included neuropathology showed no evidence for a relationship between loneliness and AD neuropathology. Loneliness may decrease resilience, or produce greater cognitive change associated with the same level of AD neuropathology. Intervention strategies to decrease loneliness in older adults have been developed but need to consider key treatment targets beyond social isolation. Loneliness needs to be assessed in all studies of cognitive decline in elders, since it significantly contributes to the variance of cognitive function. It will be useful to better define the underlying mechanism of loneliness effects on cognition to determine if it is similar to other psychological factors related to excessive stress reactivity, such as neuroticism or even depression, which are also associated with cognitive decline. It is important from a health perspective to develop better strategies to decrease loneliness in older adults.

Patterns of Respiration Rate Reactivity in Response to a Cognitive Stressor Associate With Self-Reported Mental Health Outcomes.

Many studies have examined physiological responses to acute stress in healthy and clinical populations. Some have documented exaggerated physiological stress reactivity in response to acute stress, while others have reported blunted physiological stress reactivity. Although the literature is conflicted, the relationship between abnormal physiological stress reactivity and negative outcomes is well-established. However, past research has neglected a critical aspect of physiological stress response - respiration - and it is unclear whether differences in respiration rate responses to acute stress are related to health outcomes. This secondary cross-sectional analysis explored differences in outcomes between three subgroups: blunted, moderate, and exaggerated respiration rate reactivity to an acute stress task. In a sample of at least mildly-stressed older adults (n = 55), we found that perceived stress (b = -7.63; p = .004) and depression (b = -9.13; p = .007) were significantly lower in the moderate reactivity group compared to the high reactivity group, and that self-reported mindfulness (b = 10.96; p = .008) was significantly lower in the moderate reactivity group as compared to the low reactivity group. Across outcomes, participants in the moderate range of physiological reactivity showed less negative and more positive psychological attributes and better health outcomes, while the blunted subgroup demonstrated more negative and less positive psychological attributes and worse health outcomes overall, when compared to the exaggerated and moderate groups. This study extends the literature by adding respiration to markers of acute physiological stress reactivity and demonstrating the effects of blunted respiration reactivity on negative psychological attributes and health outcomes.

Methodology and preliminary data on feasibility of a neurofeedback protocol to improve visual attention to letters in mild Alzheimer's disease.

Background: Brain-computer interface (BCI) systems are controlled by users through neurophysiological input for a variety of applications, including communication, environmental control, and motor rehabilitation. Although individuals with severe speech and physical impairment are the primary users of this technology, BCIs have emerged as a potential tool for broader populations, including delivering cognitive training/interventions with neurofeedback (NFB). Methods: This paper describes the development and preliminary testing of a protocol for use of a BCI system with NFB as an intervention for people with mild Alzheimer's disease (AD). The intervention focused on training visual attention and language skills, as AD is often associated with functional impairments in both. This funded pilot study called for enrolling five participants with mild AD in a six-week BCI EEG-based NFB intervention that followed a four-to-seven-week baseline phase. While two participants completed the study, the remaining three participants could not complete the intervention phase because of COVID-19 restrictions. Results: Preliminary pilot results suggested: (1) participants with mild AD were able to participate in a study with multiple assessments per week and complete all outcome measures, (2) most outcome measures were reliable during the baseline phase, and (3) all participants with mild AD learned to operate a BCI spelling system with training. Conclusions: Although preliminary results demonstrate practical feasibility to deliver NFB intervention using a BCI to adults with AD, completion of the protocol in its entirety with more participants is needed to further assess whether implementing NFB-based cognitive intervention is justified by functional treatment outcomes. Trial registration: This study was registered with ClinicalTrials.gov (NCT03790774).

Target-Related Alpha Attenuation in a Brain-Computer Interface Rapid Serial Visual Presentation Calibration.

This study evaluated the feasibility of using occipitoparietal alpha activity to drive target/non-target classification in a brain-computer interface (BCI) for communication. EEG data were collected from 12 participants who completed BCI Rapid Serial Visual Presentation (RSVP) calibrations at two different presentation rates: 1 and 4 Hz. Attention-related changes in posterior alpha activity were compared to two event-related potentials (ERPs): N200 and P300. Machine learning approaches evaluated target/non-target classification accuracy using alpha activity. Results indicated significant alpha attenuation following target letters at both 1 and 4 Hz presentation rates, though this effect was significantly reduced in the 4 Hz condition. Target-related alpha attenuation was not correlated with coincident N200 or P300 target effects. Classification using posterior alpha activity was above chance and benefitted from individualized tuning procedures. These findings suggest that target-related posterior alpha attenuation is detectable in a BCI RSVP calibration and that this signal could be leveraged in machine learning algorithms used for RSVP or comparable attention-based BCI paradigms.

Respiration rate during a stress task moderates neuroticism and perceived stress in older adults.

BACKGROUND: Research suggests that respiration rate is related to psychological factors such as neuroticism and perceived stress in addition to physiological factors. However, it is unclear how respiration rate during a laboratory stress task relates to the relationship between neuroticism and perceived stress. PARTICIPANTS AND PROCEDURE: This cross-sectional secondary analysis examined respiration rate during a stress task in moderating the relationship between neuroticism and perceived stress in a sample of generally healthy older adults (n = 64). Respiration data were collected during an auditory oddball paradigm and the Portland Arithmetic Stress Task (PAST), a laboratory-based cognitive stressor. RESULTS: The results indicated that respiration rate during the PAST significantly moderated the relationship between neuroticism and perceived stress (p = .031), such that participants who exhibited a very low (-1.78 SD) respiration rate showed a non-significant relationship between neuroticism and perceived stress, whereas participants with average (mean; p < .001) and elevated respiration rates (+1 SD; p < .001) exhibited a significant positive relationship between neuroticism and perceived stress. CONCLUSIONS: These findings add to a body of literature suggesting that stress reactivity is an important link between personality factors and negative outcomes. However, this is the first study to our knowledge to examine the role of physiological stress reactivity in buffering this relationship. The results suggest that individuals higher in neuroticism may attenuate the relationship between stress vulnerability and perceived stress through decreased physiological stress reactivity, particularly by exhibiting slow breathing during a stressor.

Blood pressure variability and night-time dipping assessed by 24-hour ambulatory monitoring: Cross-sectional association with cardiac structure in adolescents.

Greater blood pressure (BP) is associated with greater left ventricular mass indexed to height2.7 (LVMi2.7) in adolescents. This study examined whether greater BP variability and reduced night-time dipping are associated with cardiac remodeling in a general population of adolescents. A cross-sectional analysis was undertaken in 587 UK adolescents (mean age 17.7 years; 43.1% male). BP was measured in a research clinic and using 24-hour ambulatory monitoring. We examined associations (for both systolic and diastolic BP) of: 1) clinic and 24-hour mean BP; 2) measures of 24-hour BP variability: standard deviation weighted for day/night (SDdn), variability independent of the mean (VIM) and average real variability (ARV); and 3) night-time dipping with cardiac structures. Cardiac structures were assessed by echocardiography: 1) LVMi2.7; 2) relative wall thickness (RWT); 3) left atrial diameter indexed to height (LADi) and 4) left ventricular internal diameter in diastole (LVIDD). Higher systolic BP was associated with greater LVMi2.7. Systolic and diastolic BP were associated with greater RWT. Associations were inconsistent for LADi and LVIDD. There was evidence for associations between both greater SDdn and ARV and higher RWT (per 1 SD higher diastolic ARV, mean difference in RWT was 0.13 SDs, 95% CI 0.045 to 0.21); these associations with RWT remained after adjustment for mean BP. There was no consistent evidence of associations between night-time dipping and cardiac structure. Measurement of BP variability, even in adolescents with blood pressure in the physiologic range, might benefit risk of cardiovascular remodeling assessment.

The effects of an internet-based mindfulness meditation intervention on electrophysiological markers of attention.

Evidence suggests that mindfulness meditation training has the potential to train aspects of attention. However, the neurophysiological mechanisms underpinning the attentional benefits from mindfulness remain unclear. This randomized controlled trial examined changes in electrophysiological markers of attention before and after completion of a 6-week internet-based mindfulness intervention. EEG and ERP data were collected from 64 generally healthy, mildly stressed older adults. Participants were randomized to an internet-based mindfulness-based stress reduction course (IMMI), an internet-based health and wellness education course, or a waitlist control condition. Attentional N2 and P3 evoked potentials were derived from active and passive auditory oddball paradigms. Participants in the IMMI group showed significantly greater differences in P3 peak-trough amplitude between the active and passive oddball paradigms at endpoint relative to controls. There were no significant relationships between the intervention and N2 potentials. Our data demonstrate a measurable increase in attentional control when discriminating or directing attention away from auditory stimuli for older adult participants who received mindfulness training. These findings lend support to the use of the P3 as a neurophysiological measure of meditation engagement and intervention efficacy.

Perceived stress mediates the relationship between mindfulness and negative affect variability: A randomized controlled trial among middle-aged to older adults.

Despite the interest in mindfulness over the past 20 years, studies have only recently begun to examine mindfulness in older adults. The primary aim of this study was to evaluate pretreatment to post-treatment change in negative affect variability (NAV) following a mindfulness training among 134 mildly stressed, middle-aged to older adults. The secondary aim was to assess if the effects of mindfulness training on NAV would be partially explained by pretreatment to post-treatment reductions in perceived stress, a trend that would be congruent with several stress models. In this randomized control trial, participants were assigned to either a 6-week mindfulness meditation training programme or to a wait list control. Ecological momentary assessment, a data capturing technique that queries about present moment experiences in real time, captured NAV. Mixed-model ANOVAs and a path analysis were conducted. Participants in the mindfulness meditation training significantly reduced NAV when compared with wait list control participants. Further, there was a significant indirect group effect on reductions in NAV through change in perceived stress. Few studies have tested mechanisms of action, which connect changes that occur during mindfulness training with psychological outcomes in older adults. Understanding the mechanisms by which mindfulness enhances well-being may optimize interventions.

Negative Affect Influences Electrophysiological Markers of Visual Working Memory in Mildly Stressed Older Adults.

Negative affect (NA) has been related to lower working memory performance across all ages, including in older adults where it has been suggested as a marker for later cognitive impairments. However, NA-related decreases in working memory performance have not been shown in a full range of working memory paradigms or fully explored in the context of electrophysiological measures of working memory. We examined the impact of NA and related markers on an electroencephalography (EEG) marker of visual working memory (VWM) capacity, referred to as the contralateral delay activity (CDA). This study analyzed data collected from 48 cognitively intact, mildly stressed older adults (50-74 years old) who completed a VWM change-detection task to elicit the CDA, as well as self-rated measures of affect, stress, neuroticism and depression. Regression analyses revealed significant CDA amplitude effects with NA across task conditions. These results indicate a reduction in a physiological measure of VWM capacity in high-NA participants. These results are of interest as NA has been associated with a greater risk for worse cognitive function, detrimental health outcomes and reduced quality of life in older adults. This research adds to our understanding of how NA impacts older adults and gives a potential biomarker for successful intervention outcomes.

Predictors of Improvements in Mental Health From Mindfulness Meditation in Stressed Older Adults.

Context • The benefits of a mindfulness meditation (MM) intervention are most often evidenced by improvements in self-rated stress and mental health. Given the physiological complexity of the psychological stress system, it is likely that some people benefit significantly, whereas others do not. Clinicians and researchers could benefit from further exploration to determine which baseline factors can predict clinically significant improvements from MM. Objectives • The study intended to determine (1) whether the baseline measures for participants who significantly benefitted from MM training were different from the baseline measures of participants who did not, and (2) whether a classification analysis using a decision-tree, machine-learning approach could be useful in predicting which individuals would be most likely to improve. Design • The research team performed a secondary analysis of a previously completed randomized, controlled clinical trial. Setting • The study occurred at the Oregon Health & Science University (Portland, OR, USA) and in participants' homes. Participants • Participants were 134 stressed, generally healthy adults from the metropolitan area of Portland, Oregon, who were 50 to 85 y old. Intervention • Participants were randomly assigned either to a 6-wk MM intervention group or to a waitlist control group, who received the same MM intervention after the waitlist period. Outcome Measures • Outcome measures were assessed at baseline and at 2-mo follow-up intervals. A responder was defined as someone who demonstrated a moderate, clinically significant improvement on the mental health component (MHC) of the short-form health-related quality of life (SF-36) (ie, a change ≥4). The MHC had demonstrated the greatest effect size in the primary analysis of the previously mentioned randomized, controlled clinical trial. Potential predictors were demographic information and baseline measures related to stress and affect. Univariate statistical analyses were performed to compare the values of predictors in the responder and nonresponder groups. In addition, predictors were chosen for a classification analysis using a decision tree approach. Results • Of the 134 original participants, 121 completed the MM intervention. As defined previously, 61 were responders and 60 were nonresponders. Analyses of the baseline measures demonstrated significant differences between the 2 groups in several measures: (1) the positive and negative affect schedule negative subscale (PANAS-neg), (2) the SF-36-MHC, and (3) the SF-36 energy/fatigue, with clinically worse scores being associated with greater likelihood of being a responder. Disappointingly, the decision-tree analyses were unable to achieve a classification rate of better than 65%. Conclusions • The differences in predictor variables between responders and nonresponders to an MM intervention suggested that those with worse mental health at baseline were more likely to improve. Decision-tree analysis was unable to usefully predict who would respond to the intervention.

EEG Frequency Changes Prior to Making Errors in an Easy Stroop Task.

Background: Mind-wandering is a form of off-task attention that has been associated with negative affect and rumination. The goal of this study was to assess potential electroencephalographic markers of task-unrelated thought, or mind-wandering state, as related to error rates during a specialized cognitive task. We used EEG to record frontal frequency band activity while participants completed a Stroop task that was modified to induce boredom, task-unrelated thought, and therefore mind-wandering. Methods: A convenience sample of 27 older adults (50-80 years) completed a computerized Stroop matching task. Half of the Stroop trials were congruent (word/color match), and the other half were incongruent (mismatched). Behavioral data and EEG recordings were assessed. EEG analysis focused on the 1-s epochs prior to stimulus presentation in order to compare trials followed by correct versus incorrect responses. Results: Participants made errors on 9% of incongruent trials. There were no errors on congruent trials. There was a decrease in alpha and theta band activity during the epochs followed by error responses. Conclusion: Although replication of these results is necessary, these findings suggest that potential mind-wandering, as evidenced by errors, can be characterized by a decrease in alpha and theta activity compared to on-task, accurate performance periods.

Do psychosocial predictors affect the following days' cortisol awakening response? Expanding the temporal frame with which to explore morning cortisol.

Much of the extant cortisol awakening response (CAR) literature posits that CAR is an anticipatory response to perceived demands later that same day. However, expanding and switching the temporal order of cortisol and psychosocial influences may motivate more flexible approaches to understanding the dynamic relationship between mind and body, including cumulative strain on the HPA axis. This study was novel because we used two models to explore the effects of one day's emotion regulation and cortisol levels on cortisol and CAR the following day in 100 mildly stressed adults aged 50-81 years old, which contrasts with the more common CAR-anticipatory-response design. In the first model, High negative-affect-variation on day 1 predicted a higher risk of having a flat CAR the next day, relative to the moderate-affect-variation group (RR = 10.10, p < .05). In the second model, higher bedtime cortisol on day 1 was positively associated with waking cortisol (ß = .293, p < .01) and flatter CAR slopes on day 2 (ß = -.422, p < .001). These results show that morning cortisol intercepts and slopes may be associated with previous days' affect variability and levels of bedtime cortisol. These results also suggest that anticipation of demands may extend to the previous day, rather than just the morning of the demand, indicating a broader temporal framework for the study of CAR.

Meditation in Stressed Older Adults: Improvements in self-rated mental health not paralleled by improvements in cognitive function or physiological measures.

To determine if mindfulness meditation (MM) in older adults improves cognition and, secondarily, if MM improves mental health and physiology, 134 at least mildly stressed 50-85 year olds were randomized to a six-week MM intervention or a waitlist control. Outcome measures were assessed at baseline and two months later at Visit 2. The primary outcome measure was an executive function/attentional measure (flanker task). Other outcome measures included additional cognitive assessments, salivary cortisol, respiratory rate, heart rate variability, Positive and Negative Affect Schedule (PANAS), Center for Epidemiologic Studies Depression (CESD), Perceived Stress Scale (PSS), Neuroticism-Extraversion-Openness (NEO) personality traits, and SF-36 health-related quality of life. 128 participants completed the study though Visit 2 assessments. There was no significant change in the primary or other cognitive outcome measures. Even after statistical adjustment for multiple outcomes, self-rated measures related to negative affect and stress were all significantly improved in the MM intervention compared to wait-list group (PANAS-negative, CESD, PSS, and SF-36 health-related quality of life Vitality and Mental Health Component). The SF-36 Mental Health Component score improved more than the minimum clinically important difference. There were also significant changes in personality traits such as Neuroticism. Changes in positive affect were not observed. There were no group differences in salivary cortisol, or heart rate variability. These moderate sized improvements in self-rated measures were not paralleled by improvements in cognitive function or physiological measures. Potential explanations for this discrepancy in stress-related outcomes are discussed to help improve future studies.

A cognitive stressor for event-related potential studies: the Portland arithmetic stress task.

In this experiment, we developed and evaluated the Portland Arithmetic Stress Task (PAST) as a cognitive stressor to evaluate acute and sustained stress reactivity for event-related potential (ERP) studies. The PAST is a titrated arithmetic task adapted from the Montreal Imaging Stress Task (MIST), with added experimental control over presentation parameters, improved and synchronized acoustic feedback and generation of timing markers needed for physiological analyzes of real-time brain activity. Thirty-one older adults (M = 60 years) completed the PAST. EEG was recorded to assess feedback-related negativity (FRN) and the magnitude of the stress response through autonomic nervous system activity and salivary cortisol. Physiological measures other than EEG included heart rate, respiration rate, heart rate variability, blood pressure and salivary cortisol. These measures were collected at several time points throughout the task. Feedback-related negativity evoked-potential responses were elicited and they significantly differed depending on whether positive or negative feedback was received. The PAST also increased systolic blood pressure, heart rate variability and respiration rates compared to a control condition attentional task. These preliminary results suggest that the PAST is an effective cognitive stressor. Successful measurement of the feedback-related negativity suggests that the PAST is conducive to EEG and time-sensitive ERP experiments. Moreover, the physiological findings support the PAST as a potent method for inducing stress in older adult participants. Further research is needed to confirm these results, but the PAST shows promise as a tool for cognitive stress induction for time-locked event-related potential experiments.

Set shifting reaction-time improves following meditation or simple breathcounting in meditators and meditation-naïve participants: Data from naturalistic, ecological momentary-assessment devices.

A comparison is made between the performance of meditators and controls in a letter-number task-switching test. Data were recorded over a five-day period using a previously developed ecological momentary assessment paradigm. Participants consisted of naïve, novice, and experienced meditators, who completed a task-switching reaction time (RT) task before and after 20-min breath-counting sessions. There was a decrease in reaction time over testing days, p < .007, as well as a separate decrease in reaction time pre- to post-meditation, p < .001. RTs decreased each day, as expected, and post-meditation/breath-counting RTs were consistently faster than pre-meditation/breath-counting RTs. These results suggest a meditation effect separate from a learning effect.

Electrophysiological evidence for failures of item individuation in crowded visual displays.

Visual perception is strongly impaired when peripheral targets are surrounded by nearby distractors, a phenomenon known as visual crowding. One common behavioral signature of visual crowding is an increased tendency for observers to mistakenly report the features of nearby distractors instead of the target item. Here, our goal was to distinguish between two possible explanations of such substitution errors. On the one hand, crowding may have its effects after the deployment of attention toward-and individuation of-targets and flankers, such that multiple individuated perceptual representations compete to guide the behavioral response. On the other hand, crowding may prevent the individuation of closely spaced stimuli, thereby reducing the number of apprehended items. We attempted to distinguish these alternatives using the N2pc, an ERP that has been shown to track the deployment of spatial attention and index the number of individuated items within a hemifield. N2pc amplitude increased monotonically with set size in uncrowded displays, but this set size effect was abolished in crowded visual displays. Moreover, these crowding-induced declines in N2pc amplitude predicted individual differences in the rate of substitution errors. Thus, crowding-induced confusions between targets and distractors may be a consequence of failures to individuate target and distractor stimuli during early stages of visual selection.

Visual crowding cannot be wholly explained by feature pooling.

Visual perception is dramatically impaired when a peripheral target is embedded within clutter, a phenomenon known as visual crowding. Despite decades of study, the mechanisms underlying crowding remain a matter of debate. Feature pooling models assert that crowding results from a compulsory pooling (e.g., averaging) of target and distractor features. This view has been extraordinarily influential in recent years, so much so that crowding is typically regarded as synonymous with pooling. However, many demonstrations of feature pooling can also be accommodated by a probabilistic substitution model where observers occasionally report a distractor as the target. Here, we directly compared pooling and substitution using an analytical approach sensitive to both alternatives. In four experiments, we asked observers to report the precise orientation of a target stimulus flanked by two irrelevant distractors. In all cases, the observed data were well described by a quantitative model that assumes probabilistic substitution, and poorly described by a quantitative model that assumes that targets and distractors are averaged. These results challenge the widely held assumption that crowding can be wholly explained by compulsory pooling.

Neural measures reveal a fixed item limit in subitizing.

For centuries, it has been known that humans can rapidly and accurately enumerate small sets of items, a process referred to as subitizing. However, there is still active debate regarding the mechanisms that mediate this ability. For example, some have argued that subitizing reflects the operation of a fixed-capacity individuation mechanism that enables concurrent access to a small number of items. However, others have argued that subitizing reflects the operation of a continuous numerical estimation mechanism whose precision varies with numerosity in a manner consistent with Weber's law. Critically, quantitative models based on either of these predictions can provide a reasonable description of subitizing performance, making it difficult to discriminate between these alternatives solely on the basis of subjects' behavioral performance. Here, we attempted to discriminate between fixed-capacity and continuous estimation models of subitizing using neural measures. In two experiments, we recorded EEGs while subjects performed a demanding subitizing task and examined set-size-dependent changes in a neurophysiological marker of visual selection (the N2pc event-related potential component) evoked by an array of to-be-enumerated items. In both experiments, N2pc amplitudes increased monotonically within the subitizing range before reaching an asymptotic limit at approximately three items. Moreover, inter-participant differences in the location of this asymptote were strongly predictive of behavioral estimates of subitizing span derived from a fixed-capacity model. Thus, neural activity linked with subitizing ability shows evidence of an early and discrete limit in the number of items that can be concurrently apprehended, supporting a fixed-capacity model of this process.