Virtual delivery of improvisational movement and social engagement interventions in the IMOVE trial during the COVID-19 pandemic.

Background: IMOVE evaluated the contributions of movement and social engagement to quality of life, brain network connectivity, and motor and social-emotional functioning in people with early-stage Alzheimer's disease participating with a caregiver. In response to COVID-19 restrictions, a pilot study was conducted to assess integrity of key elements of the intervention and feasibility of virtual intervention delivery. Methods: Participants in the parent study were randomized to one of 4 study conditions (Movement Group [MG], Movement Alone [MA], Social Group [SG], or Usual Care [UC; control]). To test virtual adaptations of each condition, groups of three participant-caregiver dyads (6 individuals) who had completed the parent trial participated in virtual adaptation classes. We adopted an engineering-inspired, rapid refinement model to optimize virtual interventions on the dimensions of social connectedness, fun, and physical exertion. After completing one iteration, participants gave feedback and adjustments were made to the intervention. This process was repeated until no further adjustments were needed. Results: The MA arm easily transitioned to virtual format. The virtual MG intervention required the most iterations, with participants reporting needs for additional technology support, higher level of physical exertion, and stronger social connection. The virtual SG intervention reported good social connection, but needed additional technology instruction and measures to promote equal participation. Conclusions: Our pilot study results underscore the feasibility of delivering remote social and/or dance interventions for older adults and provide a useful road map for other research teams interested in increasing their reach by adapting in-person group behavioral interventions for remote delivery.

IMOVE: Protocol for a randomized, controlled 2x2 factorial trial of improvisational movement and social engagement interventions in older adults with early Alzheimer's disease.

Background: In addition to cognitive impairment, people with Alzheimer's disease (PWAD) experience neuropsychiatric symptoms (e.g., apathy, depression), altered gait, and poor balance that further diminish their quality of life (QoL). Here, we describe a unique, randomized, controlled trial to test the hypothesis that both movement and social engagement aspects of a group dance intervention alter the connectivity of key brain networks involved in motor and social-emotional functioning and lead to improved QoL in PWAD. Methods: IMOVE (NCT03333837) was a single-center, randomized, controlled 2x2 factorial trial that assigned PWAD/caregiver dyads to one of 4 study conditions (Movement Group, Movement Alone, Social Group, or Usual Care control). The Movement Group participated in twice-weekly group improvisational dance (IMPROVment® Method) classes for 12 weeks. The Movement Alone intervention captured the same dance movement and auditory stimuli as the group class without social interaction, and the Social Group used improvisational party games to recapitulate the fun and playfulness of the Movement Group without the movement. The primary outcome was change in QoL among PWAD. Key secondary outcomes were functional brain network measures assessed using graph-theory analysis of resting-state functional magnetic resonance imaging scans, as well as neuropsychiatric symptoms, gait, and balance. Results: A total of 111 dyads were randomized; 89 completed the study, despite interruption and modification of the protocol due to COVID-19 restrictions (see companion paper by Fanning et al.). The data are being analyzed and will be submitted for publication in 2023.

Effects of an Allostatic Closed-Loop Neurotechnology (HIRREM) on Brain Functional Connectivity Laterality in Military-Related Traumatic Stress.

BACKGROUND AND PURPOSE: Brain asymmetries are reported in posttraumatic stress disorder, but many aspects of laterality and traumatic stress remain underexplored. This study explores lateralization changes in resting state brain network functional connectivity in a cohort with symptoms of military-related traumatic stress, associated with use of a closed-loop neurotechnology, HIRREM. METHODS: Eighteen participants (17 males, mean age 41 years [SD = 7]) received 19.5 (1.1) HIRREM sessions over 12 days. Whole brain resting magnetic resonance imaging was done pre- and post-HIRREM. Laterality of functional connectivity was assessed on a whole brain basis, and in six predefined networks or regions. Laterality of connectivity within networks or regions was assessed separately from laterality of connections between networks or regions. RESULTS: Before HIRREM, significant laterality effects of connection type (ipsilateral for either side, or contralateral in either direction) were observed for the whole brain, within networks or regions, and between networks or regions. Post-HIRREM, there were significant changes for within-network or within-region analysis in the motor network, and changes for between-network or between-region analyses for the salience network and the motor cortex. CONCLUSIONS: Among military service members and Veterans with symptoms of traumatic stress, asymmetries of network and brain region connectivity patterns were identified prior to usage of HIRREM. A variety of changes in lateralized patterns of brain connectivity were identified postintervention. These laterality findings may inform future studies of brain connectivity in traumatic stress disorders, with potential to point to mechanisms of action for successful intervention.

Functional Brain Network Changes Following Use of an Allostatic, Closed-Loop, Acoustic Stimulation Neurotechnology for Military-Related Traumatic Stress.

BACKGROUND AND PURPOSE: Post-traumatic stress disorder is associated with connectivity changes in the default mode, central executive, and salience networks, and other brain regions. This study evaluated changes in network connectivity associated with usage of High-resolution, relational, resonance-based electroencephalic mirroring (HIRREM® ; Brain State Technologies, Scottsdale, AZ), a closed-loop, allostatic, acoustic stimulation neurotechnology, for military-related traumatic stress. METHODS: Eighteen participants (17 males, mean age 41 years [SD = 7], 15 active duty) enrolled in an IRB approved pilot trial for symptoms of military-related traumatic stress. Participants received 19.5 (1.1) HIRREM sessions over 12 days. Symptoms, physiological and functional measures, and whole brain resting MRI were collected before and after HIRREM. Six whole brain functional networks were evaluated using summary variables and community structure of predefined networks. Pre to postintervention change was analyzed using paired-sample statistical tests. RESULTS: Postintervention, there was an overall increase in connectivity of the default mode network (P = .0094). There were decreases of community structure in both the anterior portion of the default mode (medial prefrontal cortex, P = .0097) and in the sensorimotor (P = .005) network. There were no statistically significant changes at the whole brain level, or in the central executive, salience, or other networks analyzed. Participants demonstrated significant improvements in clinical symptoms, as well as autonomic cardiovascular regulation, which have been reported previously. CONCLUSIONS: Use of closed-loop, allostatic, acoustic stimulation neurotechnology (HIRREM) was associated with connectivity changes in the default mode and sensorimotor networks, in directions that may have explained the subjects' clinical improvements.

Graph theory analysis of functional brain networks and mobility disability in older adults.

BACKGROUND: The brain's structural integrity is associated with mobility function in older adults. Changes in function may be evident earlier than changes in structure and may be more directly related to mobility. Therefore, we assessed whether functional brain networks varied with mobility function in older adults. METHODS: Short Physical Performance Battery (SPPB) and resting state functional magnetic resonance imaging were collected on 24 young (mean age = 26.4±5.1) and 48 older (mean age = 72.04±5.1) participants. Older participants were divided into three groups by SPPB score: Low SPPB (score = 7-9), Mid SPPB (score = 10), High SPPB (score = 11-12).Graph theory-based methods were used to characterize and compare brain network organization. RESULTS: Connectivity in the somatomotor cortex distinguished between groups based on SPPB score. The community structure of the somatomotor cortex was significantly less consistent in the Low SPPB group (mean = 0.097±0.05) compared with Young (mean = 0.163±0.09, p = .03) SPPB group. Striking differences were evident in second-order connections between somatomotor cortex and superior temporal gyrus and insula that reached statistical significance. The Low SPPB group (mean = 140.87±109.30) had a significantly higher number of connections than Young (mean = 45.05±33.79, p = .0003) or High (mean = 49.61±35.31, p = .002) SPPB group. CONCLUSIONS: Older adults with poorer mobility function exhibited reduced consistency of somatomotor community structure and a greater number of secondary connections with vestibular and multisensory regions of the brain. Further study is needed to fully interpret these effects, but analysis of functional brain networks adds new insights to the contribution of the brain to mobility.

Drive for consumption, craving, and connectivity in the visual cortex during the imagery of desired food.

There is considerable interest in understanding food cravings given the obesogenic environment of Western Society. In this paper we examine how the imagery of palatable foods affects cravings and functional connectivity in the visual cortex for people who differ on the power of food scale (PFS). Fourteen older, overweight/obese adults came to our laboratory on two different occasions. Both times they ate a controlled breakfast meal and then were restricted from eating for 2.5 h prior to scanning. On 1 day they consumed a BOOST(®) liquid meal after the period of food restriction, whereas on the other day they only consumed water (NO BOOST(®) condition). After these manipulations, they had an fMRI scan in which they were asked to image both neutral objects and their favorite snack foods; they also completed visual analog scales for craving, hunger, and the vividness of the imagery experiences. Irrespective of the BOOST(®) manipulation, we observed marked increases in food cravings when older, overweight/obese adults created images of favorite foods in their minds as opposed to creating an image of neutral objects; however, the increase in food craving following the imagery of desired food was more pronounced among those scoring high than low on the PFS. Furthermore, local efficiency within the visual cortex when imaging desired food was higher for those scoring high as compared to low on the PFS. The active imagery of desired foods seemed to have overpowered the BOOST(®) manipulation when evaluating connectivity in the visual cortex.

The Cooperative Lifestyle Intervention Program-II (CLIP-II): design and methods.

A complication of cardiovascular disease (CVD) and the metabolic syndrome (MetS) among older adults is loss of mobility. The American Heart Association has identified weight management as a core component of secondary prevention programs for CVD and is an important risk factor for physical disability. The American Society for Nutrition and the Obesity Society have highlighted the need for long-term randomized clinical trials to evaluate the independent and additive effects of diet-induced weight loss (WL) and physical activity in older persons on outcomes such as mobility, muscle function, and obesity related diseases. Here we describe the rationale, design, and methods of a translational study, the Cooperative Lifestyle Intervention Program-II (CLIP-II). CLIP-II will randomize 252 obese, older adults with CVD or MetS to a weight loss only treatment (WL), aerobic exercise training (AT)+WL, or resistance exercise training (RT)+WL for 18 months. The dual primary outcomes are mobility and knee extensor strength. The interventions will be delivered by YMCA community partners with our staff as trainers and advisers. This study will provide the first large scale trial to evaluate the effects of diet-induced WL on mobility in obese, older adults with CVD or MetS as compared to WL combined with two different modes of physical activity (AT and RT). Because uncertainty exists about the best approach for promoting WL in older adults due to concerns with the loss of lean mass, the design also permits a contrast between AT+WL and RT+WL on muscle strength.

Coping with brief periods of food restriction: mindfulness matters.

The obesity epidemic had spawned considerable interest in understanding peoples' responses to palatable food cues that are plentiful in obesogenic environments. In this paper we examine how trait mindfulness of older, obese adults may moderate brain networks that arise from exposure to such cues. Nineteen older, obese adults came to our laboratory on two different occasions. Both times they ate a controlled breakfast meal and then were restricted from eating for 2.5 h. After this brief period of food restriction, they had an fMRI scan in which they were exposed to food cues and then underwent a 5 min recovery period to evaluate brain networks at rest. On one day they consumed a BOOST® liquid meal prior to scanning, whereas on the other day they only consumed water (NO BOOST® condition). We found that adults high in trait mindfulness were able to return to their default mode network (DMN), as indicated by greater global efficiency in the precuneus, during the post-exposure rest period. This effect was stronger for the BOOST® than NO BOOST® treatment condition. Older adults low in trait mindfulness did not exhibit this pattern in the DMN. In fact, the brain networks of those low on the MAAS suggests that they continued to be pre-occupied with the elaboration of food cues even after cue exposure had ended. Further work is needed to examine whether mindfulness-based therapies alter brain networks to food cues and whether these changes are related to eating behavior.

Power of food moderates food craving, perceived control, and brain networks following a short-term post-absorptive state in older adults.

The Power of Food Scale (PFS) is a new measure that assesses the drive to consume highly palatable food in an obesogenic food environment. The data reported in this investigation evaluate whether the PFS moderates state cravings, control beliefs, and brain networks of older, obese adults following either a short-term post-absorptive state, in which participants were only allowed to consume water, or a short-term energy surfeit treatment condition, in which they consumed BOOST®. We found that the short-term post-absorptive condition, in which participants consumed water only, was associated with increases in state cravings for desired food, a reduction in participants' confidence related to the control of eating behavior, and shifts in brain networks that parallel what is observed with other addictive behaviors. Furthermore, individuals who scored high on the PFS were at an increased risk for experiencing these effects. Future research is needed to examine the eating behavior of persons who score high on the PFS and to develop interventions that directly target food cravings.

Acute effect of a high nitrate diet on brain perfusion in older adults.

AIMS: Poor blood flow and hypoxia/ischemia contribute to many disease states and may also be a factor in the decline of physical and cognitive function in aging. Nitrite has been discovered to be a vasodilator that is preferentially harnessed in hypoxia. Thus, both infused and inhaled nitrite are being studied as therapeutic agents for a variety of diseases. In addition, nitrite derived from nitrate in the diet has been shown to decrease blood pressure and improve exercise performance. Thus, dietary nitrate may also be important when increased blood flow in hypoxic or ischemic areas is indicated. These conditions could include age-associated dementia and cognitive decline. The goal of this study was to determine if dietary nitrate would increase cerebral blood flow in older adults. METHODS AND RESULTS: In this investigation we administered a high vs. low nitrate diet to older adults (74.7±6.9 years) and measured cerebral perfusion using arterial spin labeling magnetic resonance imaging. We found that the high nitrate diet did not alter global cerebral perfusion, but did lead to increased regional cerebral perfusion in frontal lobe white matter, especially between the dorsolateral prefrontal cortex and anterior cingulate cortex. CONCLUSION: These results suggest that dietary nitrate may be useful in improving regional brain perfusion in older adults in critical brain areas known to be involved in executive functioning.

A cognitive training intervention improves modality-specific attention in a randomized controlled trial of healthy older adults.

Age-related deficits in cognitive and sensory function can result in increased distraction from background sensory stimuli. This randomized controlled trial investigated the effects of a cognitive training intervention aimed at helping healthy older adults suppress irrelevant auditory and visual stimuli. Sixty-six participants received 8 weeks of either the modality-specific attention training program or an educational lecture control program. Participants who completed the intervention program had larger improvements in modality-specific selective attention following training than controls. These improvements also correlated with reductions in bimodal integration during selective attention. Further, the intervention group showed larger improvements than the control group in non-trained domains such as processing speed and dual-task completion, demonstrating the utility of modality-specific attention training for improving cognitive function in healthy older adults.

Reproducibility of graph metrics in FMRI networks.

The reliability of graph metrics calculated in network analysis is essential to the interpretation of complex network organization. These graph metrics are used to deduce the small-world properties in networks. In this study, we investigated the test-retest reliability of graph metrics from functional magnetic resonance imaging data collected for two runs in 45 healthy older adults. Graph metrics were calculated on data for both runs and compared using intraclass correlation coefficient (ICC) statistics and Bland-Altman (BA) plots. ICC scores describe the level of absolute agreement between two measurements and provide a measure of reproducibility. For mean graph metrics, ICC scores were high for clustering coefficient (ICC = 0.86), global efficiency (ICC = 0.83), path length (ICC = 0.79), and local efficiency (ICC = 0.75); the ICC score for degree was found to be low (ICC = 0.29). ICC scores were also used to generate reproducibility maps in brain space to test voxel-wise reproducibility for unsmoothed and smoothed data. Reproducibility was uniform across the brain for global efficiency and path length, but was only high in network hubs for clustering coefficient, local efficiency, and degree. BA plots were used to test the measurement repeatability of all graph metrics. All graph metrics fell within the limits for repeatability. Together, these results suggest that with exception of degree, mean graph metrics are reproducible and suitable for clinical studies. Further exploration is warranted to better understand reproducibility across the brain on a voxel-wise basis.

Discriminative stimulus effects of ethanol in mice lacking the gamma-aminobutyric acid type A receptor delta subunit.

BACKGROUND: Genetically altered mice have been used to examine gene contributions to ethanol phenotypes. Recently, mice with a targeted deletion of the delta subunit of the gamma-aminobutyric acid (GABA)A receptor have been generated. These mice display decreased sensitivity to neuroactive steroids and altered responses to some behavioral effects of ethanol. Given the application of drug discrimination to characterize receptor-mediated stimulus effects of ethanol and given the data showing altered ethanol responses in mice lacking the delta subunit of the GABAA receptor, these mice were characterized in an ethanol-discrimination procedure. It has been shown that neurosteroids will substitute for the discriminative stimulus effects of ethanol, and this study aimed to determine whether the substitution patterns of neuroactive steroids or other GABAA-positive modulators would be altered in these mice. METHODS: Twelve adult delta +/+ and delta-/- mice were trained to discriminate between ethanol 1.5 g/kg and saline in daily 15-min food-reinforced operant sessions. Once the discrimination was trained, substitution tests with ethanol, pentobarbital, midazolam, androsterone, alphaxalone, pregnanolone, morphine, zolpidem, and MK-801 were conducted. RESULTS: Both delta+/+ and delta-/- mice acquired ethanol discrimination in a similar number of days. Ethanol, midazolam, alphaxalone, pregnanolone, and MK-801 fully substituted (>80%) for ethanol in both delta+/+ and delta-/- mice. Pentobarbital fully substituted for ethanol in delta-/- mice but only partially substituted (74%) for ethanol in delta+/+ mice. Androsterone, zolpidem, and morphine did not substitute for ethanol in either delta+/+ or delta-/- mice. There were no significant differences in the response rate-suppressing effects of any of the compounds between delta+/+ and delta-/- mice. CONCLUSIONS: The training dose of ethanol resulted in substitution of five GABAA receptor ligands, indicating a robust GABAA mediation of ethanol's discriminative stimulus effects. Deletion of the delta subunit of the GABAA receptor does not alter the acquisition of an ethanol/saline discrimination or the substitution patterns of GABAA-positive modulators. Therefore, the delta subunit is not necessary in the mediation of ethanol-like effects of any of the GABAA ligands tested, including sensitivity to ethanol, barbiturate, benzodiazepine, and neurosteroid discriminative stimulus effects.