Higher substance use is associated with low executive control neural activity and higher inflammation.

Individuals with substance use problems show lower executive control and alterations in prefrontal brain systems supporting emotion regulation and impulse control. A separate literature suggests that heightened inflammation also increases risk for substance use, in part, through targeting brain systems involved in executive control. Research on neural and inflammatory signaling in substance use, however, has occurred in parallel. Drawing on recent neuroimmune network models, we used fMRI to examine the relationships between executive control-related brain activity (as elicited by an n-back working memory task), peripheral inflammation, as quantified by inflammatory cytokines and C-reactive protein (CRP), and substance use for the past month in 93 participants [mean age = 24.4 (SD = 0.6)]. We operationalized low executive control as a neural inefficiency during the n-back task to achieve normative performance, as reflected in higher working memory-related brain activity and lower activity in the default mode network (DMN). Consistent with prediction, individuals with low executive control and high inflammation reported more substance use over the past month, controlling for behavioral performance on the n-back, sex, time between assessments, body-mass-index (BMI), and personal socioeconomic status (SES) (interaction between inflammation and working memory-related brain activity, b = 0.210, p = 0.005; interaction between inflammation and DMN, b = -0.219, p < 0.001). Findings suggest that low executive control and high inflammation may be associated with higher substance use. This has implications for understanding psychological, neural, and immunological risk for substance use problems and the development of interventions to target each of these components.

Neuroanatomical foundations of delayed reward discounting decision making II: Evaluation of sulcal morphology and fractal dimensionality.

Delayed reward discounting (DRD) is a form of decision-making reflecting valuation of smaller immediate rewards versus larger delayed rewards, and high DRD has been linked to several health behaviors, including substance use disorders, attention-deficit/hyperactivity disorder, and obesity. Elucidating the underlying neuroanatomical factors may offer important insights into the etiology of these conditions. We used structural MRI scans of 1038 Human Connectome Project participants (Mage = 28.86, 54.7% female) to explore two novel measures of neuroanatomy related to DRD: 1) sulcal morphology (SM; depth and width) and 2) fractal dimensionality (FD), or cortical morphometric complexity, of parcellated cortical and subcortical regions. To ascertain unique contributions to DRD preferences, indicators that displayed significant partial correlations with DRD after family-wise error correction were entered into iterative mixed-effect models guided by the association magnitude. When considering only SM indicators, the depth of the right inferior and width of the left central sulci were uniquely associated with DRD preferences. When considering only FD indicators, the FD of the left middle temporal gyrus, right lateral orbitofrontal cortex, and left lateral occipital and entorhinal cortices uniquely contributed DRD. When considering SM and FD indicators simultaneously, the right inferior frontal sulcus depth and left central sulcus width; and the FD of the left middle temporal gyrus, lateral occipital cortex and entorhinal cortex were uniquely associated with DRD. These results implicate SM and FD as features of the brain that underlie variation in the DRD decision-making phenotype and as promising candidates for understanding DRD as a biobehavioral disease process.

Delayed Reward Discounting as a Prognostic Factor for Smoking Cessation Treatment Outcome: A Systematic Review.

INTRODUCTION: While large proportions of smokers attempt to quit, rates of relapse remain high and identification of valid prognostic markers is of high priority. Delayed reward discounting (DRD) is a behavioral economic index of impulsivity that has been associated with smoking cessation, albeit inconsistently. This systematic review sought to synthesize the empirical findings on DRD as a predictor of smoking cessation treatment outcome, to critically appraise the quality of the literature, and to propose directions for future research. AIMS AND METHODS: A total of 734 articles were identified, yielding k = 14 studies that met the eligibility criteria. The Quality in Prognosis Studies (QUIPS) tool was used to assess methodological quality of the included studies. RESULTS: Individual study methods were highly heterogeneous, including substantial variation in research design, DRD task, clinical subpopulation, and treatment format. The predominant finding was that steeper DRD (higher impulsivity) was associated with significantly worse smoking cessation outcomes (10/14 studies). Negative results tended to be in pregnant and adolescent subpopulations. The QUIPS results suggested low risk of bias across studies; 11/14 studies were rated as low risk of bias for 5/6 QUIPS domains. CONCLUSIONS: This review revealed consistent low-bias evidence for impulsive DRD as a negative prognostic predictor of smoking cessation treatment outcome in adults. However, methodological heterogeneity was high, precluding meta-analysis and formal tests of small study bias. The prospects of targeting impulsive DRD as a potentially modifiable risk factor or providing targeted treatment for smokers exhibiting high levels of discounting are discussed. IMPLICATIONS: These findings indicate consistent evidence for DRD as a negative prognostic factor for smoking cessation outcome in adults. As such, DRD may be a useful as a novel treatment target or for identifying high-risk populations requiring more intensive treatment.

Recent cannabis use is associated with smaller hippocampus volume: High-resolution segmentation of structural subfields in a large non-clinical sample.

There is mixed evidence that individuals who use cannabis have reduced hippocampal and amygdalar gray matter volume, potentially because of small sample sizes and imprecise morphological characterization. New automated segmentation procedures have improved the measurement of these structures and allow better examination of their subfields, which have been linked to distinct aspects of memory and emotion. The current study applies this new segmentation procedure to the Human Connectome Project Young Adult dataset (N = 1080) to investigate associations of cannabis use with gray matter volume in the hippocampus and amygdala. Results revealed significant bilateral inverse associations of hippocampal volume with recent cannabis use (THC+ urine drug screen; P < .005). Hippocampal subfield analyses indicated these associations were primarily driven by the head of the hippocampus, the first section of the cornu amonis (CA1), the subicular complex, and the molecular layer of the hippocampus. No associations were detected for age of cannabis initiation, the frequency of cannabis use across the lifespan, or the lifetime presence of cannabis use disorder. In one of the largest studies to date, these results support the hypothesis that recent cannabis use is linked to reduced hippocampal volume, but that this effect may dissipate following prolonged abstinence. Furthermore, these results clarify the specific subfields which may be most associated with recent cannabis use.

The Protective Effects of Supportive Parenting on the Relationship Between Adolescent Poverty and Resting-State Functional Brain Connectivity During Adulthood.

Children growing up in poverty are vulnerable to negative changes in the developing brain; however, these outcomes vary widely. We tested the hypothesis that receipt of supportive parenting would offset the association between living in poverty during adolescence and the connectivity of neural networks that support cognition and emotion regulation during young adulthood. In a sample of African American youths (N = 119) living in the rural South, poverty status and receipt of supportive parenting were assessed when youths were 11 to 13 and 16 to 18 years old. At age 25, resting-state functional connectivity of the central-executive and emotion-regulation neural networks was assessed using functional MRI. The results revealed that more years spent living in poverty presaged less connectivity in both neural networks among young adults who received low levels of supportive parenting but not among those who received high levels of such parenting.

Cannabis involvement and neuropsychological performance: findings from the Human Connectome Project

Background: There is evidence that heavy cannabis use is associated with decrements in cognitive performance, but findings are mixed and studies are often limited by small sample sizes and narrow adjustment for potential confounding variables. In a comparatively large sample, the current study examined associations between multiple indicators of cannabis use in relation to performance on a variety of neuropsychological tasks. Methods: Participants were 1121 adults (54% female) enrolled in the Human Connectome Project. Cannabis involvement comprised recent cannabis use (positive tetrahydrocannabinol screen), total number of lifetime uses, cannabis use disorder and age at first use. The neuropsychological battery comprised performance in episodic memory, fluid intelligence, attention, working memory, executive function, impulsive decision-making, processing speed and psychomotor dexterity. Covariates were age, sex, income, family structure and alcohol and tobacco use. Results: Positive urinary tetrahydrocannabinol status was associated with worse performance in episodic memory and processing speed, and positive cannabis use disorder status was associated with lower fluid intelligence (all p < 0.005). No other significant associations were present. Limitations: The sample was limited to young adults aged 22­36 years. The measures of cannabis involvement were relatively coarse. Conclusion: Beyond an array of potential confounders, recent cannabis use was associated with deficits in memory and psychomotor performance, and cannabis use disorder was associated with lower overall cognitive functioning in a large normative sample of adults. The findings pertaining to recent use have particular relevance for occupational settings.

Associations Between Drinking and Cortical Thickness in Younger Adult Drinkers: Findings From the Human Connectome Project.

BACKGROUND: Previous neuroimaging studies examining relations between alcohol misuse and cortical thickness have revealed that increased drinking quantity and alcohol-related problems are associated with thinner cortex. Although conflicting regional effects are often observed, associations are generally localized to frontal regions (e.g., dorsolateral prefrontal cortex [DLPFC], inferior frontal gyrus [IFG], and anterior cingulate cortex). Inconsistent findings may be attributed to methodological differences, modest sample sizes, and limited consideration of sex differences. METHODS: This study examined neuroanatomical correlates of drinking quantity and heavy episodic drinking in a large sample of younger adults (N = 706; Mage  = 28.8; 51% female) using magnetic resonance imaging data from the Human Connectome Project. Exploratory analyses examined neuroanatomical correlates of executive function (flanker task) and working memory (list sorting). RESULTS: Hierarchical linear regression models (controlling for age, sex, education, income, smoking, drug use, twin status, and intracranial volume) revealed significant inverse associations between drinks in past week and frequency of heavy drinking and cortical thickness in a majority of regions examined. The largest effect sizes were found for frontal regions (DLPFC, IFG, and the precentral gyrus). Follow-up regression models revealed that the left DLPFC was uniquely associated with both drinking variables. Sex differences were also observed, with significant effects largely specific to men. CONCLUSIONS: This study adds to the understanding of brain correlates of alcohol use in a large, gender-balanced sample of younger adults. Although the cross-sectional methodology precludes causal inferences, these findings provide a foundation for rigorous hypothesis testing in future longitudinal investigations.

A Family Focused Intervention Influences Hippocampal-Prefrontal Connectivity Through Gains in Self-Regulation.

The stressors associated with poverty increase the risks for externalizing psychopathology; however, specific patterns of neurobiology and higher self-regulation may buffer against these effects. This study leveraged a randomized control trial, aimed at increasing self-regulation at ~11 years of age. As adults, these same individuals completed functional MRI scanning (Mage  = 24.88 years; intervention n = 44; control n = 49). Functional connectivity between the hippocampus and ventromedial prefrontal cortex was examined in relation to the intervention, gains in self-regulation, and present-day externalizing symptoms. Increased connectivity between these brain areas was noted in the intervention group compared to controls. Furthermore, individual gains in self-regulation, instilled by the intervention, statistically explained this brain difference. These results begin to connect neurobiological and psychosocial markers of risk and resiliency.

Distinct functional and structural neural underpinnings of working memory.

Working memory (WM), the short-term abstraction and manipulation of information, is an essential neurocognitive process in daily functioning. Few studies have concurrently examined the functional and structural neural correlates of WM and the current study did so to characterize both overlapping and unique associations. Participants were a large sample of adults from the Human Connectome Project (N = 1064; 54% female) who completed an in-scanner visual N-back WM task. The results indicate a clear dissociation between BOLD activation during the WM task and brain structure in relation to performance. In particular, while activation in the middle frontal gyrus was positively associated with WM performance, cortical thickness in this region was inversely associated with performance. Additional unique associations with WM were BOLD activation in superior parietal lobule, cingulate, and fusiform gyrus and gray matter volume in the orbitofrontal cortex and cuneus. Across findings, substantially larger effects were observed for functional associations relative to structural associations. These results provide further evidence implicating frontoparietal subunits of the brain in WM. Moreover, these findings reveal the distinct, and in some cases opposing, roles of brain structure and neural activation in WM, highlighting the lack of homology between structure and function in relation to cognition.

Neural correlates of tobacco cue reactivity predict duration to lapse and continuous abstinence in smoking cessation treatment.

It has been hypothesized that neural reactivity to drug cues in certain limbic/paralimbic regions of the brain is an indicator of addiction severity and a marker for likelihood of success in treatment. To address this question, in the current study, 32 participants (44 percent female) completed a functional magnetic resonance imaging cigarette cue exposure paradigm 2 hours after smoking, and then enrolled in a 9-week smoking cessation treatment program. Neural activation to smoking cues was measured in five a priori defined limbic/paralimbic regions previously implicated with cue reactivity across substances. These included regions of the ventral striatum, anterior cingulate cortex and amygdala. Cox proportional hazard modeling was conducted to predict the number of days to first smoking lapse by using neural activation in these regions. Greater neural activation during pre-treatment exposure to smoking cues in the right ventral striatum, the left amygdala, and the anterior cingulate was associated with longer periods of abstinence following cessation. A similar pattern was present for continuous abstinence for the full duration of treatment. While baseline levels of nicotine dependence were strongly associated with treatment outcome, activation in the right ventral striatum predicted duration of abstinence beyond level of nicotine dependence. These results suggest that pre-treatment reactivity to smoking cues in areas associated with cue reactivity may be associated with successfully maintaining abstinence during treatment. This is consistent with models that propose that as addiction becomes more severe, motivational processing shifts from regions that subserve reward salience and learning to regions responsible motor behavior and habit learning.

Neuroanatomical foundations of delayed reward discounting decision making.

Resolving tradeoffs between smaller immediate rewards and larger delayed rewards is ubiquitous in daily life and steep discounting of future rewards is associated with several psychiatric conditions. This form of decision-making is referred to as delayed reward discounting (DRD) and the features of brain structure associated with DRD are not well understood. The current study characterized the relationship between gray matter volume (GMV) and DRD in a sample of 1038 healthy adults (54.7% female) using cortical parcellation, subcortical segmentation, and voxelwise cortical surface-based group analyses. The results indicate that steeper DRD was significantly associated with lower total cortical GMV, but not subcortical GMV. In parcellation analyses, less GMV in 20 discrete cortical regions was associated with steeper DRD. Of these regions, only GMV in the middle temporal gyrus (MTG) and entorhinal cortex (EC) were uniquely associated with DRD. Voxelwise surface-based analyses corroborated these findings, again revealing significant associations between steeper DRD and less GMV in the MTG and EC. To inform the roles of MTG and EC in DRD, connectivity analysis of resting state data (N = 1003) using seed regions from the structural findings was conducted. This revealed that spontaneous activity in the MTG and EC was correlated with activation in the ventromedial prefrontal cortex, posterior cingulate cortex, and inferior parietal lobule, regions associated with the default mode network, which involves prospection, self-reflective thinking and mental simulation. Furthermore, meta-analytic co-activation analysis using Neurosynth revealed a similar pattern across 11,406 task-fMRI studies. Collectively, these findings provide robust evidence that morphometric characteristics of the temporal lobe are associated with DRD preferences and suggest it may be because of their role in mental activities in common with default mode activity.

Gender Differences in Cognitive Test Performance in Adults With Heart Failure.

BACKGROUND: Cognitive deficits are found in up to 73% of persons with heart failure (HF) and are associated with increased mortality and other poor clinical outcomes. It is known that women have better memory test performance than men do in healthy samples, but gender differences in cognitive performance in the context of HF are not well understood and may have important clinical implications. OBJECTIVE: The objective of this study was to examine possible gender differences in cognitive function in a sample of individuals with HF (98.9% New York Heart Association class II and III). METHODS: A total of 183 adults with HF (116 men and 67 women) completed a neuropsychological test battery as part of a larger project. Measures were chosen to assess functioning in attention/executive function and memory. RESULTS: After controlling for demographic and medical factors, multivariate analysis of covariance revealed that men and women differed on memory test performance (λ = 0.90, F4, 169 = 4.76, P = .001). Post hoc comparisons revealed that women performed better on California Verbal Learning Test Learning, Short Recall, and Delayed Recall. No differences emerged on tests of attention/executive function (λ = 0.97, F5, 168 = 0.96, P = .44). CONCLUSIONS: In this sample of persons with HF, men exhibited poorer performance on memory measures than women did. Future studies are needed to determine the underlying mechanisms for this pattern and its possible influence on daily function.

Reduced Gray Matter Volume Is Associated With Poorer Instrumental Activities of Daily Living Performance in Heart Failure.

BACKGROUND: Heart failure patients require assistance with instrumental activities of daily living in part because of the high rates of cognitive impairment in this population. Structural brain insult (eg, reduced gray matter volume) is theorized to underlie cognitive dysfunction in heart failure, although no study has examined the association among gray matter, cognition, and instrumental activities of daily living in heart failure. OBJECTIVES: The aim of this study was to investigate the associations among gray matter volume, cognitive function, and functional ability in heart failure. METHODS: A total of 81 heart failure patients completed a cognitive test battery and the Lawton-Brody self-report questionnaire to assess instrumental activities of daily living. Participants underwent magnetic resonance imaging to quantify total gray matter and subcortical gray matter volume. RESULTS: Impairments in instrumental activities of daily living were common in this sample of HF patients. Regression analyses controlling for demographic and medical confounders showed that smaller total gray matter volume predicted decreased scores on the instrumental activities of daily living composite, with specific associations noted for medication management and independence in driving. Interaction analyses showed that reduced total gray matter volume interacted with worse attention/executive function and memory to negatively impact instrumental activities of daily living. CONCLUSIONS: Smaller gray matter volume is associated with greater impairment in instrumental activities of daily living in persons with heart failure, possibly via cognitive dysfunction. Prospective studies are needed to clarify the utility of clinical correlates of gray matter volume (eg, cognitive dysfunction) in identifying heart failure patients at risk for functional decline and determine whether interventions that target improved brain and cognitive function can preserve functional independence in this high-risk population.

Decreases in daily physical activity predict acute decline in attention and executive function in heart failure.

BACKGROUND: Reduced physical activity (PA) may be one factor that contributes to cognitive decline and dementia in heart failure (HF). Yet, the longitudinal relationship between PA and cognition in HF is poorly understood owing to limitations of past work, including single-time assessments of PA. This is the first study to examine changes in objectively measured PA and cognition over time in HF. METHODS AND RESULTS: At baseline and 12 weeks, 57 HF patients completed psychosocial self-report measures and a neuropsychological battery and wore an accelerometer for 7 days. At baseline, HF patients spent an average of 597.83 (SD 75.91) minutes per day sedentary. Steps per day declined from baseline to the 12-week follow-up; there was also a trend for declines in moderate-vigorous PA. Regression analyses controlling for sex, HF severity, and depressive symptoms showed that decreases in light (P = .08) and moderate-vigorous (P = .04) daily PA emerged as strong predictors of declines in attention/executive function over the 12-week period, but not of memory or language. CONCLUSIONS: Reductions in daily PA predicted acute decline in attention/executive function in HF, but not of memory or language. Modifications to daily PA may attenuate cognitive decline, and prospective studies are needed to test this possibility.

Daily Physical Activity Is Associated with Subcortical Brain Volume and Cognition in Heart Failure.

Cognitive impairment in heart failure (HF) is believed to in part stem from structural brain alterations, including shrinkage of subcortical regions. Fortunately, neurocognitive dysfunction in HF can be mitigated by physical activity (PA), though mechanisms for this phenomenon are unclear. PA is protective against age-related cognitive decline that may involve improved structural integrity to brain regions sensitive to aging (e.g., subcortical structures). Yet, no study has examined the benefits of PA on the brain in HF and we sought to do so and clarify related cognitive implications. Fifty older adults with HF completed a neuropsychological battery and wore an accelerometer for 7 days. All participants underwent brain MRI. This study targeted subcortical brain volume given subcortical alterations are often observed in HF and the sensitivity of PA to subcortical structures in other patient populations. Participants averaged 4348.49 (SD=2092.08) steps per day and greater daily steps predicted better attention/executive function, episodic memory, and language abilities, p's<.05. Medical and demographically adjusted regression analyses revealed higher daily steps per day predicted greater subcortical volume, with specific effects for the thalamus and ventral diencephalon, p's<.05. Greater subcortical volume was associated with better attention/executive function, p<.05. Higher daily PA was associated with increased subcortical brain volume and better cognition in older adults with HF. Longitudinal work is needed to clarify whether daily PA can attenuate brain atrophy in HF to reduce accelerated cognitive decline in this population.

An FMRI-compatible Symbol Search task.

Our objective was to determine whether a Symbol Search paradigm developed for functional magnetic resonance imaging (FMRI) is a reliable and valid measure of cognitive processing speed (CPS) in healthy older adults. As all older adults are expected to experience cognitive declines due to aging, and CPS is one of the domains most affected by age, establishing a reliable and valid measure of CPS that can be administered inside an MR scanner may prove invaluable in future clinical and research settings. We evaluated the reliability and construct validity of a newly developed FMRI Symbol Search task by comparing participants' performance in and outside of the scanner and to the widely used and standardized Symbol Search subtest of the Wechsler Adult Intelligence Scale (WAIS). A brief battery of neuropsychological measures was also administered to assess the convergent and discriminant validity of the FMRI Symbol Search task. The FMRI Symbol Search task demonstrated high test-retest reliability when compared to performance on the same task administered out of the scanner (r=.791; p<.001). The criterion validity of the new task was supported, as it exhibited a strong positive correlation with the WAIS Symbol Search (r=.717; p<.001). Predicted convergent and discriminant validity patterns of the FMRI Symbol Search task were also observed. The FMRI Symbol Search task is a reliable and valid measure of CPS in healthy older adults and exhibits expected sensitivity to the effects of age on CPS performance.

The synergistic effects of anxiety and cerebral hypoperfusion on cognitive dysfunction in older adults with cardiovascular disease.

OBJECTIVES: Anxiety is a risk factor for cardiovascular disease (CVD) and is associated with neurocognitive outcomes. The effect of anxiety on brain perfusion in a CVD population has yet to be examined, and no study has investigated the interactive effects of anxiety and cerebral perfusion on cognition. METHODS: A total of 55 older adults with CVD completed the Beck Anxiety Inventory (BAI) and underwent arterial spin labeling to quantify cortical perfusion and thickness. Participants were administered the Mini-Mental State Examination (MMSE) and the Repeatable Battery for the Assessment of Neuropsychological Status. RESULTS: Reduced perfusion predicted poorer cognition and decreased cortical thickness. Higher anxiety score predicted worse memory performance and decreased frontal perfusion. Frontal lobe hypoperfusion combined with increased BAI scores exacerbated poorer MMSE performance. CONCLUSIONS: Higher anxiety may exacerbate the effects of cerebral hypoperfusion on cognitive impairment. Longitudinal studies are needed to confirm our findings and determine whether anxiety treatment improves neurocognitive outcomes in CVD.

Atrial fibrillation exacerbates cognitive dysfunction and cerebral perfusion in heart failure.

BACKGROUND: Heart failure (HF) increases risk for cognitive impairment in part due to the negative effects of cardiac dysfunction on cerebral perfusion. Atrial fibrillation (AF), an independent risk factor for cognitive impairment, often accompanies HF and is associated with lower systemic perfusion. However, no study has examined the associations among AF, cognitive function, and cerebral perfusion in patients with HF. METHODS: A total of 187 HF patients completed neuropsychological testing and underwent transcranial Doppler ultrasonography. Cerebral blood flow velocity of the middle cerebral artery (CBF-V) operationalized cerebral perfusion. A medical chart review ascertained AF. RESULTS: History of AF was found in 32.1% of HF patients. HF patients with AF exhibited worse global cognition, memory, and CBF-V relative to patients without AF. These effects remained after HF severity and other demographic and medical factors were taken into account. Partial correlations controlling for possible confounds showed decreased CBF-V predicted worse cognition in multiple domains in the overall sample (r = 0.13 to 0.15, P < 0.05) and in the subgroup of HF patients with AF (r = 0.26 to r = 0.28, P < 0.05), but not among HF patients without AF. CONCLUSIONS: AF exacerbates cognitive deficits in HF, possibly through its association with decreased cerebral perfusion. Longitudinal studies are needed to determine whether AF accelerates cognitive decline in HF and whether medical (e.g., ablation) and lifestyle interventions (e.g., exercise programs) that target cerebral perfusion improve cognitive outcomes in patients with HF and AF.

Effects of nicotine deprivation and replacement on BOLD-fMRI response to smoking cues as a function of DRD4 VNTR genotype.

INTRODUCTION: Reactivity to smoking cues is an important factor in the motivation to smoke and has been associated with the dopamine receptor 4 variable number tandem repeat (DRD4 exon III VNTR) polymorphism. However, little is known about the associated neural mechanisms. METHODS: Non-treatment-seeking Caucasian smokers completed overnight abstinence and viewed smoking and neutral cues during 2 separate functional magnetic resonance imaging scans while wearing either a nicotine or placebo patch (order randomized) and were genotyped for the DRD4 VNTR. We conducted mixed-effects repeated-measures analyses of variance (within-subject factor: nicotine or placebo patch; between-subject factor: DRD4 long [L: ≥ 1 copy of ≥ 7 repeats] or short [S: 2 copies ≤ 6 repeats] genotype) of 6 a priori regions of interest. RESULTS: Relative to neutral cues, smoking cues elicited greater activity in bilateral ventral striatum and left amygdala during nicotine replacement and deactivation in these regions during nicotine deprivation. A patch × DRD4 interaction was observed in the left amygdala, an area associated with appetitive reinforcement and relapse risk, such that S allele carriers demonstrated greater activation on active patch than on placebo patch. CONCLUSIONS: Brain systems associated with reward salience may become primed and overreactive at nicotine replacement doses intended for the first step of smoking cessation and may become inhibited during nicotine withdrawal in DRD4 S but not in DRD4 L carriers. These findings are consistent with the role of these regions in drug reinforcement and suggest a differential influence of nicotine replacement on amygdala activation in the association of incentive salience with smoking stimuli across DRD4 genotypes.

Reduced cerebral perfusion predicts greater depressive symptoms and cognitive dysfunction at a 1-year follow-up in patients with heart failure.

OBJECTIVE: Cerebral hypoperfusion is common in heart failure (HF) and believed to underlie poor neurocognitive outcomes in this population. Up to 42% of HF patients also exhibit depressive symptomatology that may stem from reduced cerebral blood flow. However, no study has examined this possibility or whether reduced brain perfusion increases risk for future cognitive dysfunction in older adults with HF. METHODS: One hundred HF patients underwent transcranial Doppler ultrasonagraphy to quantify global cerebral blood flow velocity (CBF-V) and were administered a cognitive test battery to assess global cognition, attention/executive function, and memory abilities. All participants then completed the Beck Depression Inventory-II to assess depressive symptomatology. These procedures were performed at baseline and at 12-month follow-up. RESULTS: Repeated measures revealed that CBF-V declined over the 12-month period. Regression analyses showed that reduced baseline CBF-V predicted worse performances in attention/executive function (p < 0.05 for all) and a trend for memory (p = 0.09) in addition to greater depressive symptomatology (p < 0.05) at the 12-month follow-up, even after controlling for baseline factors and medical and demographic variables. CONCLUSIONS: Cerebral perfusion declined over time and was associated with poorer cognitive function and greater depressive symptoms at a 1-year follow-up in HF. Prospective studies with long-term follow-ups that employ neuroimaging are needed to examine whether cognitive dysfunction and depression in HF stem from the adverse effects of cerebral hypoperfusion on the cerebral structure.