Feasibility of a Telehealth Compensatory Cognitive Training Program for Older Adults with Mild Cognitive Impairment.

OBJECTIVES: Older adults experiencing mild cognitive impairment (MCI) may benefit from compensatory cognitive training (CCT). This study investigated the feasibility of telehealth CCT among older adults with MCI. METHODS: Adults age 55+ with MCI (n = 28) and a care partner (n = 18) participated in telehealth CCT. Participants rated sessions' technological interference on an adapted 0-100 session rating scale (higher scores=less interference). Clinicians provided ratings and qualitative feedback on types of interference experienced. Feasibility was assessed by enrollment and completion rates, and through ratings and feedback. RESULTS: 6% of contacts declined participation due to telehealth delivery. 24 of 28 participants completed the program, with no dropouts due to telehealth. Participants (M = 81.32, SD = 25.61) and clinicians (M = 76.24, SD = 33.37) rated technological interference as infrequent. Clinicians indicated most interference did not impact sessions, though 4% required rescheduling due to interference. CONCLUSIONS: Telehealth delivery was not a barrier to recruitment, enrollment, or completion of CCT. Technological problems were mostly minor. Telehealth CCT could support access to and intervention among older adults with MCI. CLINICAL IMPLICATIONS: Telehealth CCT for older adults with MCI was feasible, with mild issues not impacting session completion. Clinicians should be prepared to offer support as technological issues arise, or have dedicated technological support services.

Cannabis Use and Resting State Functional Connectivity in the Aging Brain.

Several lines of evidence suggest that older adults (aged 65+) sharply increased their cannabis use over the last decade, highlighting a need to understand the effects of cannabis in this age group. Pre-clinical models suggest that cannabinoids affect the brain and cognition in an age-dependent fashion, having generally beneficial effects on older animals and deleterious effects on younger ones. However, there is little research on how cannabis affects the brains of older adults or how older adults differ from younger adults who use cannabis. Resting state functional connectivity (rsFC) measures provide sensitive metrics of age-related cognitive decline. Here we compared rsFC in older adults who are either regular users of cannabis or non-users. We found stronger connectivity between sources in the hippocampus and parahippocampal cortex, and targets in the anterior lobes of the cerebellum in older adult cannabis users relative to non-users. A similar pattern of strengthened connectivity between hippocampal and cerebellar structures was also present in 25-35 year old non-users in comparison to 60-88 year old non-users. These findings suggest that future studies should examine both the potential risks of cannabinoids, as well as a potential benefits, on cognition and brain health for older adults.

Long-Term Recreational Cannabis Use Is Associated With Lower Executive Function and Processing Speed in a Pilot Sample of Older Adults.

More older adults are using cannabis for recreational and/or medical purposes, but most studies examining cognitive function and cannabis use do not include older adults. The current small pilot study sought to compare cognitive function and emotional functioning among adults age 60 and older who were regular, primarily recreational cannabis users (n = 28) and nonusers (n = 10). A bimodal distribution was observed among cannabis users such that they had either initiated regular use more recently ("short-term" users; ≤7 years, n = 13) or earlier in life ("long-term" users; ≥19 years, n = 15). Nonusers, short-term, and long-term users were not different in depression, anxiety, or emotion regulation, or alcohol use. Nonusers scored significantly higher than long-term users in executive function. Short-term users scored significantly higher than long-term users in executive function, processing speed, and general cognition. Additionally, greater recent cannabis use frequency was negatively associated with working memory. The current findings suggest that short-term recreational cannabis use does not result in differences in cognitive performance compared to nonusers, which may indicate that short-term use is relatively benign in older adults. However, longer duration of use is associated with poorer processing speed and executive functioning, and more recent cannabis use is associated with poorer working memory, which may impact older adults' overall cognitive functioning.

Recent tobacco use has widespread associations with adolescent white matter microstructure.

IMPORTANCE: Given the prevalence of alcohol, cannabis, and tobacco use during adolescence, it is important to explore the relative relationship of these three substances with brain structure. OBJECTIVE: To determine associations between recent alcohol, cannabis, and tobacco use and white and gray matter in a large sample of adolescents. DESIGN, SETTING, AND PARTICIPANTS: MRI data were collected in N = 200 adolescents ages 14-18 (M = 15.82 years; 67% male; 61% Hispanic/Latino). On average, during the past month, participants reported consuming 2.05 drinks per 1.01 drinking day, 0.64 g per 6.98 cannabis use days, and 2.49 cigarettes per 12.32 smoking days. MAIN OUTCOMES AND MEASURES: General linear models were utilized to examine past 30-day average quantities of alcohol, cannabis, and tobacco use, age, sex, and sex by substance interactions in skeletonized white matter (fractional anisotropy and axial, radial, and mean diffusivity) and voxel-based morphometry of gray matter (volume/density). RESULTS: Tobacco use was negatively associated with white matter integrity (radial and mean diffusivity) with peak effects in inferior and superior longitudinal fasciculi. Cannabis use was negatively associated with white matter integrity (axial diffusivity) in a small cluster in the left superior longitudinal fasciculus. No associations were observed between recent alcohol use and white or gray matter overall, but interactions showed significant negative associations between alcohol use and white matter in females. CONCLUSIONS AND RELEVANCE: It is important to note that recent tobacco use, particularly given the popularity of e-tobacco/vaping in this age group, had widespread associations with brain structure in this sample of adolescents.

Preliminary results from a pilot study examining brain structure in older adult cannabis users and nonusers.

Exploring associations among cannabis use, brain structure, and cognitive function in older adults offers an opportunity to observe potential harm or benefit of cannabis. This pilot study assessed structural magnetic resonance imaging in older adults who were either current cannabis users (n = 28; mean age 69.8 years, 36% female) or nonusers (n = 28; mean age 66.8 years, 61% female). Recruitment targeted users who reported at least weekly use for at least the last year, although users had 23.55 years of regular cannabis use on average (SD=19.89, range 1.5-50 years). Groups were not significantly different in terms of sex, years of education, alcohol use, or anxiety symptoms, but were significantly different in age and depression symptoms. Users and nonusers did not differ in terms of total gray or white matter volumes controlling for age and depression symptoms, but users showed greater regional volume of left putamen, lingual cortex, and rostral middle frontal cortex. No significant differences between groups were observed in performance on a brief computerized cognitive battery. These results suggest that cannabis use likely does not have a widespread impact on overall cortical volume while controlling for age.

DRD2 promoter methylation and measures of alcohol reward: functional activation of reward circuits and clinical severity.

Studies have identified strong associations between D2 receptor binding potential and neural responses to rewarding stimuli and substance use. Thus, D2 receptor perturbations are central to theoretical models of the pathophysiology of substance dependence, and epigenetic changes may represent one of the fundamental molecular mechanisms impacting the effects of alcohol exposure on the brain. We hypothesized that epigenetic alterations in the promoter region of the dopamine D2 receptor (DRD2) gene would be associated with cue-elicited activation of neural reward regions, as well as severity of alcohol use behavior. The current study leveraged functional neuroimaging (fMRI) during an alcohol reward paradigm (n = 383) to test associations among DRD2 promoter methylation in peripheral tissue, signal change in the striatum during the presentation of alcohol cues, and severity of alcohol use disorder (AUD). Controlling for age, DRD2 promoter methylation was positively associated with responses to alcohol cues in the right accumbens (partial r = 0.144, P = 0.005), left putamen (partial r = 0.133, P = 0.009), right putamen (partial r = 0.106, P = 0.039), left caudate (partial r = 0.117, P = 0.022), and right caudate (partial r = 0.133, P = 0.009), suggesting that DRD2 methylation was positively associated with robust activation in the striatum in response to reward cues. DRD2 methylation was also positively associated with clinical metrics of AUD severity. Specifically, controlling for age, DRD2 methylation was associated with Alcohol Use Disorders Identification Test total (partial r = 0.140, P = 0.002); Impaired Control Scale total (partial r = 0.097, P = 0.044) and Alcohol Dependence Scale total (partial r = 0.152, P = 0.001). Thus, DRD2 methylation may be a critical mechanism linking D2 receptors with functional striatal brain changes and clinical severity among alcohol users.

Neural activation during delay discounting is associated with 6-month change in risky sexual behavior in adolescents.

Background: Identifying cognitive and neural mechanisms of decision making in adolescence can enhance understanding of, and interventions to reduce, risky health behaviors in adolescence. Delay discounting, or the propensity to discount the magnitude of temporally distal rewards, has been associated with diverse health risk behaviors, including risky sex. This cognitive process involves recruitment of reward and cognitive control brain regions, which develop on different trajectories in adolescence and are also implicated in real-world risky decision making. However, no extant research has examined how neural activation during delay discounting is associated with adolescents' risky sexual behavior. Purpose: To determine whether a relationship exists between adolescents' risky sexual behavior and neural activation during delay discounting. Methods: Adolescent participants completed a delay discounting paradigm during functional magnetic resonance imaging (fMRI) scanning, and they reported risky sexual behavior at baseline, 3-, 6-, 9-, and 12-month follow-up time points. Latent growth curve models were employed to determine relationships between brain activation during delay discounting and change in risky sexual behavior over time. Results: Greater activation in brain regions associated with reward and cognitive control (caudate, putamen, nucleus accumbens, anterior cingulate, insula, orbitofrontal cortex, inferior frontal gyrus, dorsolateral prefrontal cortex) during delay discounting was associated with lower mean levels of risky sexual behavior but greater growth over the period from baseline to 6 months. Conclusions: Neural activation during delay discounting is cross-sectionally and prospectively associated with risky sexual behavior in adolescence, highlighting a neural basis of risky decision-making as well as opportunities for early identification and intervention.

Sexual risk-taking and subcortical brain volume in adolescence.

Background: The developmental period of adolescence marks the initiation of new socioemotional and physical behaviors, including sexual intercourse. However, little is known about neurodevelopmental influences on adolescent sexual decision-making. Purpose: We sought to determine how subcortical brain volume correlated with condom use, and whether those associations differed by gender and pubertal development. Methods: We used FreeSurfer to extract subcortical volume among N = 169 sexually experienced youth (mean age 16.07 years; 31.95% female). We conducted multiple linear regressions to examine the relationship between frequency of condom use and subcortical volume, and whether these associations would be moderated by gender and pubertal development. Results: We found that the relationship between brain volume and condom use was better accounted for by pubertal development than by gender, and moderated the association between limbic brain volume and condom use. No significant relationships were observed in reward areas (e.g., nucleus accumbens) or prefrontal cortical control areas. Conclusions: These data highlight the potential relevance of subcortical socioemotional processing structures in adolescents' sexual decision-making.

Neural Correlates of Risky Sex and Response Inhibition in High-Risk Adolescents.

Adolescence is a neurodevelopmental period of heightened sexual risk taking. Neuroimaging can help elucidate crucial neurocognitive mechanisms underlying adolescent sexual risk behavior, yet few empirical studies have investigated this neural link. To address this gap in the literature, we examined the association between neurocognitive function during response inhibition-a known correlate of risk behaviors-and frequency of intercourse without a condom among adolescents. We examined the correlation between condom use and fMRI-based Stroop response in a large ethnically diverse sample of high-risk adolescents (n = 171). Partially replicating previous literature, sexual risk was positively correlated with blood-oxygen-level-dependent (BOLD) activation in the middle frontal gyrus during response inhibition, highlighting the relevance of this region during risky sexual decision making within this age group.

TLR4 Methylation Moderates the Relationship Between Alcohol Use Severity and Gray Matter Loss.

OBJECTIVE: Alcohol use disorders (AUDs) are associated with decreased gray matter, and neuroinflammation is one mechanism through which alcohol may confer such damage, given that heavy alcohol use may promote neural damage via activation of toll-like receptor 4 (TLR4)-mediated inflammatory signaling cascades. We previously demonstrated that TLR4 is differentially methylated in AUD compared with control subjects, and the present study aims to extend this work by examining whether TLR4 methylation moderates the relationship between alcohol use and gray matter. METHOD: We examined TLR4 methylation and gray matter thickness in a large sample (N = 707; 441 males) of adults (ages 18-56) reporting a range of AUD severity (mean Alcohol Use Disorders Identification Test score = 13.18; SD = 8.02). We used a series of ordinary least squares multiple regression equations to regress gray matter in four bilateral brain regions (precuneus, lateral orbitofrontal, inferior parietal, and superior temporal) on alcohol use, TLR4 methylation, and their interaction, controlling for demographic, psychological, and other substance use variables. RESULTS: After we corrected for multiple tests, a significant Alcohol × TLR4 Methylation interaction emerged in the equations modeling left precuneus and right inferior parietal gray matter. Follow-up analyses examining the nature of these interactions demonstrated a significant negative association between alcohol and precuneus and inferior parietal gray matter in individuals with low TLR4 methylation, but no relationship between alcohol and gray matter in the high methylation group. CONCLUSIONS: These findings suggest that TLR4 methylation may be protective against the damage conferred by alcohol on precuneus and inferior parietal gray matter, thereby implicating TLR4 for further investigation as a possible AUD treatment target.

Structural neuroimaging correlates of alcohol and cannabis use in adolescents and adults.

BACKGROUND AND AIMS: Chronic alcohol use is associated with lower gray matter volume, and we reported recently that alcohol use showed negative associations with widespread gray matter (GM) volume even among young adults. The current study aimed to test the strength of association between (1) alcohol use and GM volume; (2) alcohol use and white matter (WM) integrity; (3) cannabis use and GM volume; and (4) cannabis use and WM integrity among adults and adolescents. DESIGN AND SETTING: General linear models within large pooled cross-sectional samples of adolescents and adults who had participated in studies collecting substance use and neuroimaging data in the southwestern United States. PARTICIPANTS: The current analysis included adults aged 18-55 years (n = 853) and adolescents aged 14-18 years (n = 439) with a range of alcohol and cannabis use. MEASUREMENTS: The dependent variable was GM volume or WM integrity, with key predictors of alcohol use [Alcohol Use Disorders Identification Test (AUDIT) score] and cannabis use (past 30-day use). FINDINGS: Alcohol use showed large clusters of negative associations (ηp2  = 0.028-0.145, P < 0.001) with GM volume among adults and to a lesser extent (one cluster; ηp2  = 0.070, P < 0.05) among adolescents. Large clusters showed significant associations (ηp2  = 0.050-0.124, P < 0.001) of higher alcohol use with poorer WM integrity, whereas adolescents showed no significant associations between alcohol use and WM. No associations were observed between structural measures and past 30-day cannabis use in adults or adolescents. CONCLUSIONS: Alcohol use severity is associated with widespread lower gray matter volume and white matter integrity in adults, and with lower gray matter volume in adolescents.

Negative and interactive effects of sex, aging, and alcohol abuse on gray matter morphometry.

Chronic alcohol use is associated with declines in gray matter (GM) volume, as is the normal aging process. Less apparent, however, is how the interaction between aging and heavy alcohol use affects changes in GM across the lifespan. There is some evidence that women are more vulnerable to the negative effects of alcohol use on GM than men. In the current study, we examined whether localized GM was related to measures of alcohol use disorder (e.g., AUDIT score) in a large sample (N = 436) of participants, ages 18-55 years, with a range of disease severity, using both voxel-based morphometry (VBM) and surface-based morphometry (SBM). We also explored whether GM associations with alcohol use disorder (AUD) severity are moderated by sex and age. Results showed significant negative associations between AUD severity and GM volume throughout temporal, parietal, frontal, and occipital lobes. Women showed more negative effects of alcohol use than men for cortical thickness in left orbitofrontal cortex, but evidence for increased vulnerability based on sex was limited overall. Similarly, a specific age by alcohol use interaction was observed for volume of right insula, but other regional or global interactions were not statistically supported. However, significant negative associations between heavy alcohol use and GM volumes were observed as early as 18-25 years. These findings support that alcohol has deleterious effects on global and regional GM above and beyond age, and, of particular importance, that regional associations emerge in early adulthood. Hum Brain Mapp 37:2276-2292, 2016. © 2016 Wiley Periodicals, Inc.

Adolescent psychotherapy for addiction medicine: From brain development to neurocognitive treatment mechanisms.

Effectively treating addiction is a challenge among any population, and treatment for adolescents may be particularly challenging in the context of ongoing neurodevelopment, which may alter the brain's initial response to substances as well as its response to treatment. One way to improve treatment outcomes for youth is to use a translational perspective that explicitly connects cognitive and neurodevelopmental fields with the field of behavioral therapies. This integrative approach is a potential first step to inform the correspondence between the neurocognitive and behavioral fields in youth addiction. This chapter seeks to provide context for neurocognitive treatment studies by first discussing recent structural and functional neuroimaging studies showing associations with substance use or behavioral addictions. Several regions of interest are then proposed that appear to also be associated with addiction treatment across multiple studies, namely, the accumbens/striatum, precuneus, insula, anterior cingulate cortex, and dorsolateral prefrontal cortex. This research suggests that reward, self-reflective, and executive control areas might be especially relevant in youth behavioral treatment response, and preliminary evidence suggests that existing treatments may encourage neurocognitive changes in these areas.

Developmental Cognitive Neuroscience of Adolescent Sexual Risk and Alcohol Use.

Human adolescents engage in very high rates of unprotected sex. This behavior has a high potential for unintended, serious, and sustained health consequences including HIV/AIDS. Despite these serious health consequences, we know little about the neural and cognitive factors that influence adolescents' decision-making around sex, and their potential overlap with behaviorally co-occurring risk behaviors, including alcohol use. Thus, in this review, we evaluate the developmental neuroscience of sexual risk and alcohol use for human adolescents with an eye to relevant prevention and intervention implications.

Functional activation during the Stroop is associated with recent alcohol but not marijuana use among high-risk youth.

Despite studies showing the relevance of different decision-making abilities, including response inhibition, to likelihood of using substances during adolescence, few have examined these neural processes among high-risk, substance-using youth. The current study explored associations between alcohol and marijuana use and functional activation differences during Stroop performance among a large sample (N=80) of ethnically-diverse, high-risk youth in an fMRI-based task. In the absence of associations between substance use and task behavioral performance, adolescents with greater alcohol use showed less activation during the more cognitively difficult portion of the task across clusters in bilateral cuneus and precuneus, and right and left superior temporal gyrus. No associations were observed with marijuana use. The current results may suggest neural patterns of deactivation in regions important for cognitive control, such that alcohol use may confer additional risk for future decreased inhibition among these high-risk adolescents. The ability to inhibit prepotent responses has been shown to predict later response to treatment, and early interventions to encourage further development of cognitive control could represent promising options for treatment.

Daily marijuana use is not associated with brain morphometric measures in adolescents or adults.

Recent research has suggested that marijuana use is associated with volumetric and shape differences in subcortical structures, including the nucleus accumbens and amygdala, in a dose-dependent fashion. Replication of such results in well controlled studies is essential to clarify the effects of marijuana. To that end, this retrospective study examined brain morphology in a sample of adult daily marijuana users (n = 29) versus nonusers (n = 29) and a sample of adolescent daily users (n = 50) versus nonusers (n = 50). Groups were matched on a critical confounding variable, alcohol use, to a far greater degree than in previously published studies. We acquired high-resolution MRI scans, and investigated group differences in gray matter using voxel-based morphometry, surface-based morphometry, and shape analysis in structures suggested to be associated with marijuana use, as follows: the nucleus accumbens, amygdala, hippocampus, and cerebellum. No statistically significant differences were found between daily users and nonusers on volume or shape in the regions of interest. Effect sizes suggest that the failure to find differences was not due to a lack of statistical power, but rather was due to the lack of even a modest effect. In sum, the results indicate that, when carefully controlling for alcohol use, gender, age, and other variables, there is no association between marijuana use and standard volumetric or shape measurements of subcortical structures.

Adolescent marijuana users have elevated risk-taking on the balloon analog risk task.

OBJECTIVE: Adolescents who engage in regular marijuana use may have a higher propensity to take unsafe risks despite the possible negative consequences. We compared adolescents with a history of regular marijuana use to non-using teens on a behavioral measure of risk-taking. Given the involvement of the pre-frontal cortex in both risk-taking and executive functioning, we also examined whether risk-taking was associated with measures of executive functioning. METHOD: Fifty-eight demographically similar community youth (ages 17-20; 29% female), including 24 marijuana users and 34 non-using controls, completed the computerized Balloon Analog Risk Task (BART; Lejuez et al., 2002) and measures of substance use and executive function. Primary BART outcome measures included total number of popped balloons and average adjusted pumps (mean pumps excluding popped balloons). RESULTS: Marijuana users had more popped balloons than controls (p<0.05) but did not differ on average adjusted pumps. Using hierarchical multiple regression controlling for age, riskier BART performance (popped balloons) was predictive of past 18-month hard drug use (ß=0.30; p<0.05). Having a higher number of popped balloons was also predictive of past 18-month marijuana use (p<0.05), but age was a stronger predictor than marijuana use. Marijuana users performed worse on one test of executive functioning (psychomotor set-shifting, p<0.05), but this did not correlate with risk-taking. CONCLUSIONS: Our finding of elevated risk-taking among marijuana users is consistent with previous research that substance users may have impaired risk processing. Further, our results suggest that risk-taking is not always associated with executive dysfunction, implying the involvement of distinct neural subsystems.

Exploring the relationship of functional network connectivity to latent trajectories of alcohol use and risky sex.

Alcohol use is a major risk factor associated with unprotected sexual behavior, leading to higher risk of sexually transmitted infections (STI) including the human immunodeficiency virus (HIV). Emerging largely cross-sectional data suggest functional network connectivity strength is associated with problematic alcohol use, and as evidence supports a relationship between risky sexual behaviors and alcohol use, we hypothesized that functional connectivity might be associated with both categories of risk behavior. As part of a sexual risk reduction intervention study, juvenile justice-involved adolescents (N = 239) underwent a baseline functional magnetic resonance imaging scan and completed questionnaires about their alcohol use and risky sexual behavior at 3-month intervals over 12 months of follow up. To test both cross-sectional and longitudinal relationships between alcohol use and sexual risk behaviors, we estimated a parallel process latent growth model that simultaneously modeled the trajectories of alcohol use and sexual risk behavior. Functional connectivity strength was included as an exogenous variable to evaluate its relationship with level of risk and change in risk over time in both behaviors. Associations were found between baseline alcohol use and risky sex, and between longitudinal trajectories of alcohol use and risky sex. Network functional connectivity strength of the dorsal default mode network was associated with initial and longitudinal alcohol use, which may suggest that self-awareness of the effects of alcohol could serve as a useful target to decrease subsequent risky sexual behavior in adolescence.

White matter integrity is associated with alcohol cue reactivity in heavy drinkers.

Neuroimaging studies have shown that white matter damage accompanies excessive alcohol use, but the functional correlates of alcohol-related white matter disruption remain unknown. This study applied tract-based spatial statistics (TBSS) to diffusion tensor imaging (DTI) data from 332 heavy drinkers (mean age = 31.2 ± 9.4; 31% female) to obtain averaged fractional anisotropy (FA) values of 18 white matter tracts. Statistical analyses examined correlations of FA values with blood-oxygenation-level-dependent (BOLD) response to an alcohol taste cue, measured with functional magnetic resonance imaging (fMRI). FA values of nine white matter tracts (anterior corona radiata, body of corpus callosum, cingulate gyrus, external capsule, fornix, inferior frontooccipital fasciculus, posterior corona radiata, retrolenticular limb of internal capsule, and superior longitudinal fasciculus) were significantly, negatively correlated with BOLD activation in medial frontal gyrus, parahippocampal gyrus, fusiform gyrus, cingulum, thalamus, caudate, putamen, insula, and cerebellum. The inverse relation between white matter integrity and functional activation during the alcohol taste cue provides support for the hypothesis that lower white matter integrity in frontoparietal and corticolimbic networks is a factor in loss of control over alcohol consumption.