Children of alcoholics (COAs) are at elevated risk to develop alcohol and other substance use disorders. The neurobiological underpinnings of this heightened vulnerability are presently not well understood. This study investigated whether, in humans, COAs have different functioning of the mesolimbic reward circuitry beyond prior substance use confounds, and examined potential group differences in neural response in relation to alcohol use and behavioral risk. We studied twenty 18 to 22 year-old COAs and 20 controls, developmentally well-characterized for substance use and selected to match on sex, age, IQ, lifetime substance use and associated problems, and precursive (age 12–14) externalizing behavioral risk. None met criteria for DSM-IV diagnosis. Neural responses to anticipation of reward and loss were assessed using functional magnetic resonance imaging during a monetary incentive delay task. Overall, COAs showed reduced ventral striatum activation during anticipation of monetary reward and loss compared to controls. However, further analysis revealed that blunted nucleus accumbens (NAcc) response was only observed in COAs who have not demonstrated any problem drinking behavior. In addition, uniquely in COAs, NAcc activation was positively correlated with precursive externalizing risk, as well as current and lifetime alcohol consumption. These findings suggest a multilevel developmental process whereby lower precursive behavioral risk appears protective of later problem alcohol use in COAs, which is further associated with a blunted NAcc response to incentive anticipation, potentially reflecting a resilience mechanism. Moreover, the results suggest a close association between motivational responses, alcohol consumption, and behavioral risk, may underlie addiction vulnerability in COAs.

Background Parental alcoholism substantially raises risk for offspring alcoholism, an effect thought to be mediated by a dysregulation in impulse control. Adult alcoholics have alterations in the frontostriatal system involved in regulating impulsive responses. However, it remains controversial whether these alterations reflect pre-existing traits predisposing to problem alcohol use, or are secondary to alcohol involvement. Methods Sixty-one 16 to 22 year olds were tested using a go/no-go task during functional MRI. Forty-one had at least one parent with a diagnosis of alcohol use disorder (AUD; FH+) and 20 had no parent with AUD (FH−). Two FH+ subgroups were created to disentangle alcohol involvement from preexisting risk: the FH+ control (n=20) group had low alcohol problems, differing from the FH− group only by family history. The FH+ problem group (n=21) had high alcohol problems. Results The ventral caudate deactivated during successful inhibition in the FH− but not the FH+ groups, regardless of problem alcohol involvement. Regression analyses showed that ventral caudate deactivation was related to fewer externalizing problems as well as family history. Orbital and left medial prefrontal regions were deactivated in both the FH− and FH+ control groups but not the FH+ problem group. Activation in these regions was associated with alcohol and other drug use. Conclusions These findings suggest a preexisting abnormality in ventral striatal function in youth at risk for AUD, which may lead to inappropriate motivational responding; and suggest that with alcohol use, the prefrontal “control” mechanism loses efficiency, further dysregulating the frontostriatal motivational circuitry.

These results are consistent with dissociable patterns of neural activation underlying risk and resiliency in COAs. We propose that the pattern observed in the resilient COAs represents an active emotional monitoring function, which may be a protective factor in this group. On the other hand, the vulnerable group displayed a pattern consistent with active suppression of affective responses, perhaps resulting in the inability to engage adaptively with emotional stimuli.

BACKGROUND Differences in fronto-striatal connectivity in problem substance users have suggested reduced influence of cognitive regions on reward-salience regions. Youth with a family history of alcoholism (FH+) have disrupted ventral striatal processing compared with controls with no familial risk (FH−). As sensation-seeking represents an additional vulnerability factor, we hypothesized that functional connectivity during reward anticipation would differ by family history, and would mediate the relationship between sensation-seeking and drinking in high-risk subjects. METHODS Seventy 18–22 year olds (49 FH+/21 FH−) performed a monetary incentive delay task during functional magnetic resonance imaging. Group connectivity differences for incentive (reward/loss) vs. neutral conditions were evaluated with psychophysiological interaction (PPI) analysis, seeded in nucleus accumbens (NAcc). Indirect effects of sensation-seeking on drinking volume through accumbens connectivity were tested. RESULTS NAcc connectivity with paracentral lobule/precuneus and sensorimotor areas was decreased for FH− versus increased for FH+ during incentive anticipation. In FH+, task-related functional coupling between left NAcc and supplementary sensorimotor area (SSMA) and right precuneus correlated positively with sensation-seeking and drinking volume and mediated their relationship. In FH−, left NAcc-SSMA connectivity correlated negatively with sensation-seeking but was not related to drinking. CONCLUSIONS These results suggest preexisting differences in accumbens reward-related functional connectivity in high-risk subjects. NAcc coupling with SSMA, involved in attention and motor networks, and precuneus, a default mode structure, appear to mediate sensation-seeking’s effect on drinking in those most at-risk. Differences in accumbens connectivity with attention/motor/default networks, rather than control systems, may influence the reward system’s role in vulnerability for substance abuse.

Background The biomarker model of Alzheimer’s disease (AD) hypothesizes a dynamic sequence of amyloidosis, neurodegeneration, and cognitive decline, as an individual progresses from preclinical AD to dementia. Despite supportive evidence from cross-sectional studies, verification with long-term within-individual data is needed. Methods Autosomal dominant AD (ADAD) mutation carriers, aged 21 years or older (no cognitive restrictions), were recruited from across the United States via referral by colleagues or ADAD families themselves. Sixteen individuals with mutations in PSEN1, PSEN2 or APP, aged 28 to 56, were assessed longitudinally every one to two years, between March 23, 2003 and August 1, 2014. Participants completed two to eight assessments (total=83), over a period of two to eleven years. We measured global amyloid-beta load with Pittsburgh Compound-B PET, posterior cortical metabolism with [18F]fluorodeoxyglucose PET, hippocampal volume (age-, and gender-corrected) with T1 MRI, verbal memory with 10-item delayed word recall, and general cognition with Mini Mental State Exam. We estimated overall biomarker trajectories across estimated years from symptom onset (EYO) using linear mixed models, and compared ADAD estimates to cross-sectional data from cognitively normal, older controls selected to be negative for amyloidosis, hypometabolism, and hippocampal atrophy. In seven individuals with the longest follow-up (seven/eight assessments spanning six to eleven years), we further examined the within-individual progression of amyloidosis, metabolism, hippocampal volume, and cognition, to identify progressive within-individual change in these markers (increase/decrease of greater than two Z-scores standardized to controls). Findings Significant differences in ADAD compared to controls (p<0·01) were detected in the following order: increased amyloidosis (−7.5 EYO), decreased metabolism (0 EYO), decreased hippocampal volume and verbal memory (+7.5 EYO), decreased general cognition (+10 EYO). Within-individual examination of AD markers found three individuals demonstrating active amyloidosis, without progressive neurodegeneration or cognitive decline. Two amyloid-positive individuals showed neither active amyloidosis, nor progressive neurodegeneration or cognitive decline. The two remaining amyloid-positive individuals showed progressive neurodegeneration and cognitive decline, without further progressive amyloidosis. Interpretation Our results strongly support amyloidosis as the earliest progressive component of the biomarker model in ADAD. Our within-individual examination further suggests three sequential phases across ADAD development: 1) active amyloidosis, 2) stable amyloid-positive and, 3) progressive neurodegeneration and cognitive decline, indicating that amyloid-beta accumulation is largely complete before progressive neurodegeneration and cognitive decline in our ADAD cohort, supporting efforts to target early amyloid-beta deposition as a means of secondary prevention in this population.

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