Subjective memory complaints are associated with decreased cortical thickness in Veterans with histories of mild traumatic brain injury.

Objective: Memory problems are frequently endorsed in Veterans following mild traumatic brain injury (mTBI), but subjective complaints are poorly associated with objective memory performance. Few studies have examined associations between subjective memory complaints and brain morphometry. We investigated whether self-reported memory problems were associated with objective memory performance and cortical thickness in Veterans with a history of mTBI. Methods: 40 Veterans with a history of remote mTBI and 29 Veterans with no history of TBI completed the Prospective-Retrospective Memory Questionnaire (PRMQ), PTSD Checklist (PCL), California Verbal Learning Test-2nd edition (CVLT-II), and 3 T T1 structural magnetic resonance imaging. Cortical thickness was estimated in 14 a priori frontal and temporal regions. Multiple regressions adjusting for age and PCL scores examined associations between PRMQ, CVLT-II scores, and cortical thickness within each Veteran group. Results: Greater subjective memory complaints on the PRMQ were associated with lower cortical thickness in the right middle temporal gyrus (ß = 0.64, q = .004), right inferior temporal gyrus (ß = 0.56, q = .014), right rostral middle frontal gyrus (ß = 0.45, q = .046), and right rostral anterior cingulate gyrus (ß = 0.58, q = .014) in the mTBI group but not the control group (q's > .05). These associations remained significant after adjusting for CVLT-II learning. CVLT-II performance was not associated with PRMQ score or cortical thickness in either group. Conclusions: Subjective memory complaints were associated with lower cortical thickness in right frontal and temporal regions, but not with objective memory performance, in Veterans with histories of mTBI. Subjective complaints post-mTBI may indicate underlying brain morphometry independently of objective cognitive testing.

An Examination of Racial/Ethnic Differences on the Neurobehavioral Symptom Inventory Among Veterans Completing the Comprehensive Traumatic Brain Injury Evaluation: A Veterans Affairs Million Veteran Program Study.

OBJECTIVE: The purpose of this study was to explore racial/ethnic differences in neurobehavioral symptom reporting and symptom validity testing among military veterans with a history of traumatic brain injury (TBI). METHOD: Participants of this observational cross-sectional study (N = 9,646) were post-deployed Iraq-/Afghanistan-era veterans enrolled in the VA's Million Veteran Program with a clinician-confirmed history of TBI on the Comprehensive TBI Evaluation (CTBIE). Racial/ethnic groups included White, Black, Hispanic, Asian, Multiracial, Another Race, American Indian or Alaska Native, and Native Hawaiian or Other Pacific Islander. Dependent variables included neurobehavioral symptom domains and symptom validity assessed via the Neurobehavioral Symptom Inventory (NSI) and Validity-10, respectively. RESULTS: Chi-square analyses showed significant racial/ethnic group differences for vestibular, somatic/sensory, and affective symptoms as well as for all Validity-10 cutoff scores examined (≥33, ≥27, ≥26, >22, ≥22, ≥13, and ≥7). Follow-up analyses compared all racial/ethnic groups to one another, adjusting for sociodemographic- and injury-related characteristics. These analyses revealed that the affective symptom domain and the Validity-10 cutoff of ≥13 revealed the greatest number of racial/ethnic differences. CONCLUSIONS: Results showed significant racial/ethnic group differences on neurobehavioral symptom domains and symptom validity testing among veterans who completed the CTBIE. An enhanced understanding of how symptoms vary by race/ethnicity is vital so that clinical care can be appropriately tailored to the unique needs of all veterans. Results highlight the importance of establishing measurement invariance of the NSI across race/ethnicity and underscore the need for ongoing research to determine the most appropriate Validity-10 cutoff score(s) to use across racially/ethnically diverse veterans.

Research Letter: PTSD Symptom Severity and Multiple Traumatic Brain Injuries Are Associated With Elevated Memory Complaints in Veterans With Histories of Mild TBI.

OBJECTIVE: The evaluation of memory complaints in mild traumatic brain injury (mTBI) remains an important clinical consideration, especially in the context of comorbid psychiatric symptoms such as posttraumatic stress disorder (PTSD). We compared subjective memory complaints in veterans with and without a history of mTBI, examined ratings between those with single versus multiple mTBIs, and investigated associations between memory complaints and PTSD symptom severity. METHODS: 117 outpatient veterans (mTBI: n = 79 [single mTBI: n = 22, multiple mTBI: n = 57], military controls [MCs]: n = 38) completed a TBI history assessment, the Prospective-Retrospective Memory Questionnaire (PRMQ), and the PTSD Checklist-Military Version (PCL-M). RESULTS: Hierarchical multiple regression showed that greater PCL-M scores significantly predicted elevated PRMQ-Total scores, accounting for 38% of the variance explained (P < .001). mTBI status predicted an additional 5% of variance in memory complaints (P < .01). The multiple-mTBI group endorsed more memory complaints than either MCs (P < .01) or the single-mTBI group (P < .05), who did not differ from MCs (P > .50). CONCLUSIONS: Comorbid PTSD symptoms are an important factor when considering memory complaints in veterans with a reported history of mTBI. However, independent of comorbid PTSD symptoms, mTBI status-particularly in the context of repetitive neurotrauma-uniquely contributes to memory complaints. Findings suggest that veterans with a history of multiple mTBIs may be a particularly vulnerable group in need of specialized interventions and/or psychoeducation.

Predictors of cognitive and physical fatigue in post-acute mild-moderate traumatic brain injury.

Post-traumatic fatigue (PTF) is a common, disabling, and often chronic symptom following traumatic brain injury (TBI). Yet, the impact of chronic cognitive and physical fatigue and their associations with psychiatric, sleep, cognitive, and psychosocial sequelae in mild-moderate TBI remain poorly understood. Sixty Veterans with a history of mild-moderate TBI and 40 Veteran controls (VC) were administered the Modified Fatigue Impact Scale, a validated measure of TBI-related cognitive and physical fatigue as well as measures of neuropsychiatric, psychosocial, sleep, and objective cognitive functioning. Compared to VC, TBI Veterans endorsed significantly greater levels of cognitive and physical fatigue. In TBI, psychiatric symptoms, sleep disturbance, and post-traumatic amnesia (PTA) were associated with both cognitive and physical fatigue, while loss of consciousness (LOC) and poor attention/processing speed were related to elevations in cognitive fatigue only. In regression analyses, anxiety, sleep disturbance, and LOC significantly predicted cognitive fatigue, while only post-traumatic stress symptoms and PTA contributed to physical fatigue. Cognitive and physical fatigue are problematic symptoms following mild-moderate TBI that are differentially associated with specific injury and psychiatric sequelae. Findings provide potential symptom targets for interventions aimed at ameliorating fatigue, and further underscore the importance of assessing and treating fatigue as a multi-dimensional symptom following TBI.

Cognitive fatigue is associated with reduced anterior internal capsule integrity in veterans with history of mild to moderate traumatic brain injury.

No known studies have directly examined white matter microstructural correlates of cognitive fatigue post-TBI in a Veteran sample. We therefore investigated the relationship between cognitive fatigue and white matter integrity in Veterans with history of mild to moderate TBI (mmTBI). 59 Veterans (TBI = 34, Veteran Controls [VCs] = 25]) with and without history of mmTBI underwent structural 3T DTI scans and completed questionnaires related to cognitive fatigue and psychiatric symptoms. Tractography was employed on six regions of interest, including the anterior and posterior limbs of the internal capsule; genu; body and splenium of the corpus callosum; and cingulum bundle. Group analyses revealed that those with history of mmTBI displayed significantly greater levels of cognitive fatigue relative to those with no history of head injury (p = .02). Within the mmTBI group, independent of psychiatric symptoms, decreased white matter microstructural integrity of the left anterior internal capsule was associated with greater levels of cognitive fatigue (p = .01). Results show that the subjective experience of cognitive fatigue following neurotrauma may be linked to the disruption of striato-thalamo-cortical tracts that are important in mediating arousal and higher-order cognitive processes. These findings build upon those from existing functional neuroimaging studies in those with history of TBI, providing further evidence for the neural basis of cognitive fatigue in head injured adults.

Problem alcohol use in veterans with mild traumatic brain injury: Associations with cognitive performance and psychiatric symptoms.

INTRODUCTION: Given that little is known about the associations between alcohol use, cognition, and psychiatric symptoms among veterans with a history of mild traumatic brain injury (mTBI), we aimed to (a) characterize how they differ from veteran controls on a measure of problem drinking; (b) investigate whether problem drinking is associated with demographic or mTBI characteristics; and (c) examine the associations between alcohol use, mTBI history, psychiatric functioning, and cognition. METHOD: We assessed 59 veterans (n = 32 with mTBI history; n = 27 military controls) for problem alcohol use (Alcohol Use Disorders Identification Test: AUDIT), psychiatric symptoms, and neuropsychological functioning. RESULTS: Compared to controls, veterans with mTBI history were more likely to score above the AUDIT cutoff score of 8 (p = .016), suggesting a higher rate of problem drinking. Participants with mTBI history also showed elevated psychiatric symptoms (ps < .001) and lower cognitive scores (ps < .05 to < .001). Veterans with higher AUDIT scores were younger (p = .05) and had less education (p < .01) and more psychiatric symptoms (ps < .01), but mTBI characteristics did not differ. After controlling for combat and mTBI history (R(2) = .04, ns) and posttraumatic stress disorder (PTSD) symptoms (ΔR(2) = .08, p = .05), we found that higher AUDIT scores were associated with poorer attention/processing speed, F(9, 37) = 2.55, p = .022; ΔR(2) = .26, p = .03. CONCLUSIONS: This preliminary study suggested that veterans with mTBI history may be at increased risk for problem drinking. Problem alcohol use was primarily associated with more severe PTSD symptoms and poorer attention/processing speed, though not with combat or mTBI characteristics per se. Importantly, findings emphasize the importance of assessing for and treating problematic alcohol use and comorbid psychiatric symptoms among veterans, including those with a history of neurotrauma.

Neuropsychiatric Predictors of Post-Injury Headache After Mild-Moderate Traumatic Brain Injury in Veterans.

OBJECTIVES: To determine differences in neuropsychiatric complaints between Veterans with mild to moderate traumatic brain injury (TBI), with and without headache, compared with Veteran controls, and to identify neuropsychiatric predictors of headache severity. BACKGROUND: Mild to moderate TBI is a common occurrence in Veterans, and is frequently associated with complaints of headache. Neuropsychiatric complaints are also common among individuals who have sustained head injury, although the relationship between these factors and headache after injury is unclear. Research is needed to comprehensively determine differences between individuals with mild to moderate traumatic brain injury who differ with respect to headache, and which injury, psychological, or sleep and fatigue factors predict headache severity. METHODS: A cross-sectional study compared 85 Veterans in three groups (positive for TBI and headache, positive for TBI without significant headache, and a control group) on a set of injury characteristics and neuropsychiatric variables. Correlates of headache severity were examined, and a regression model was used to identify significant independent predictors of headache severity. RESULTS: Individuals with mild to moderate TBI and headache endorsed significantly greater neuropsychiatric symptoms than participants in the other groups (η(p)2 = .23-.36) Neuropsychiatric complaints, as well as presence of posttraumatic amnesia, were correlated with headache in the subsample with TBI (rs = .44-.57). When entering all predictors into a regression model, only fatigue represented a significant independent predictor of headache severity (ß = .59, R2 = .35). CONCLUSIONS: Rather than being a global risk factor, mild to moderate TBI was associated with poorer mental health outcomes, particularly for those who endorse headache. Findings underscore the possibility that Veterans with history of TBI who present with complaints of headache may represent a particularly vulnerable subgroup. Additionally, our findings suggest that clinical outcomes may be improved in those with neurotrauma by incorporating a focus on fatigue in treatment.

The Relationship Between Postconcussive Symptoms and Quality of Life in Veterans With Mild to Moderate Traumatic Brain Injury.

OBJECTIVE: To assess the relationship between postconcussive symptoms and quality of life (QOL) in Veterans with mild to moderate traumatic brain injury (TBI). METHODS: Sixty-one Operation Enduring Freedom/Operation Iraqi Freedom/Persian Gulf War Veterans with a history of mild or moderate TBI, more than 6 months postinjury, and 21 demographically matched Veteran controls were administered self-report measures of QOL (World Health Organization Quality of Life-BREF) and postconcussive symptom severity (Neurobehavioral Symptom Inventory). RESULTS: Perceived QOL was significantly worse in Veterans with mild-moderate TBI than in controls. In the TBI group, QOL was predominantly associated with affective symptoms, and moderate to strong correlations with fatigue and depression were evident across all QOL areas. Multivariate analyses revealed depression and fatigue to be the best predictors of Psychological, Social, and Environmental QOL, whereas sleep difficulty best predicted Physical QOL in mild-moderate TBI. CONCLUSION: Veterans with post-acute mild-moderate TBI evidence worse QOL than demographically matched Veteran controls. Affective symptoms, and specifically those of fatigue, depression, and sleep difficulty, appear to be the most relevant postconcussive symptoms predicting QOL in this population. These findings underscore the importance of examining specific symptoms as they relate to post-acute TBI QOL and provide guidance for treatment and intervention studies.

Heavy alcohol use, marijuana use, and concomitant use by adolescents are associated with unique and shared cognitive decrements.

To assess recovery of cognitive effects, we investigated neuropsychological performance after 1 month of monitored abstinence in teens with histories of heavy episodic drinking, protracted marijuana use, or concomitant use of alcohol and marijuana. Adolescents (ages 16-18 years) with histories of heavy episodic drinking (HED; n=24), marijuana use (MJ; n=20), both heavy alcohol and marijuana use (HED+MJ; n=29), and socio-demographically similar control teens (CON; n=55) completed a neuropsychological battery following 4 weeks of monitored abstinence. Groups were similar on 5th grade standardized test scores, suggesting comparable academic functioning before onset of substance use. Relative to CON, HED showed poorer cognitive flexibility (p=.006), verbal recall (p=.024), semantic clustering (p=.011), and reading skills (p=.018). MJ performed worse than CON on inhibition task accuracy (p=.015), cued verbal memory (p=.031), and psychomotor speed (p=.027). Similar to HED youth, HED+MJ showed differences relative to CON on cognitive flexibility (p=.024) and verbal recall (p=.049). As with MJ teens, HED+MJ showed poorer task accuracy (p=.020). Unique to the HED+MJ group was poorer working memory (p=.012) relative to CON. For all substance using participants, worse performance across domains correlated with more lifetime use of alcohol and of marijuana, more withdrawal symptoms from alcohol, and earlier age of onset of marijuana use (ps<.05). Heavy alcohol use, marijuana use, and concomitant use of both substances during adolescence appear to be associated with decrements in cognitive functioning, and each substance (or combination of substances) may be linked to poorer performance in specific cognitive domains.

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.

Changes in emotional reactivity and distress tolerance among heavy drinking adolescents during sustained abstinence.

BACKGROUND: Negative affect and low distress tolerance have been associated with increased likelihood of alcohol consumption and relapse. This study utilized the Paced Auditory Serial Attention Test - Computerized Version (PASAT-C) to examine affective reactivity, cognitive performance, and distress tolerance during early abstinence among heavy drinking adolescents. METHODS: Participants, ages 16 to 18 (50% female), were 23 heavy episodic drinking youth (HED) and 23 demographically matched, nondrinking teens (CON). Both groups were drawn from the same schools and assessed at 3 time points: HED was first studied within 10 days (M = 4.26, SD = 4.4) of heavy episodic drinking and then at two 2-week intervals over 4 subsequent weeks of abstinence from alcohol and drugs. CON were studied at the same 2-week intervals. RESULTS: From the findings, it was observed that HED responded with greater emotional response to the PASAT-C (i.e., greater increases in frustration and irritability and greater decreases in happiness) at the initial assessment, but their affective responses diminished with sustained abstinence. CON and HED task performance did not differ at the initial assessment or across time. HED showed faster task discontinuation times to the PASAT-C at the first assessment, and both groups reduced task persistence across testings. Among HED, greater lifetime and recent alcohol consumption, alcohol-induced blackouts, and withdrawal symptoms were associated with increases in negative affect with PASAT-C exposure. Earlier age of onset of alcohol use was linked to poorer performance. CONCLUSIONS: Heavy episodic drinking adolescents demonstrated heightened emotional reactivity and poorer distress tolerance to a cognitively challenging task during early abstinence. The combination of elevated negative affect and low distress tolerance may place adolescents at a heightened risk of escalations in or return to alcohol involvement.

Adolescent heavy episodic drinking: neurocognitive functioning during early abstinence.

The present study investigated the rate and pattern of neuropsychological recovery in heavy episodic drinking teens during the initial days to weeks of abstinence from alcohol. Adolescents (ages, 16-18 years) with histories of heavy episodic drinking (HED; N = 39) and socio-demographically similar control teens (CON; N = 26) were recruited from San Diego area schools. HED and CON were comparable on 5th grade standardized math and language arts test performance to ensure similar functioning before onset of substance use. Participants were administered three neuropsychological test batteries with 2-week intervals during a 4-week monitored abstinence period. HED teens performed worse overall than CON on tests of prospective memory (p = .005), cognitive switching (p = .039), inhibition task accuracy (p = .001), verbal memory (p's < .045), visuospatial construction (p's < .043), and language and achievement (p's < .008). The statistically significant group × time interaction for block design demonstrated normalization within the 4 weeks of abstinence for the HED (p = .009). This study identified cognitive performance deficits associated with heavy episodic drinking in adolescence during early abstinence and with sustained 4-week abstention. These findings suggest alcohol-related influences on several underlying brain systems that may predate the onset of alcohol abuse or dependence or take longer than 4 weeks to recover.

White matter integrity in veterans with mild traumatic brain injury: associations with executive function and loss of consciousness.

OBJECTIVE: We investigated using diffusion tensor imaging (DTI) and the association between white matter integrity and executive function (EF) performance in postacute mild traumatic brain injury (mTBI). In addition, we examined whether injury severity, as measured by loss of consciousness (LOC) versus alterations in consciousness (AOC), is related to white matter microstructural alterations and neuropsychological outcome. PARTICIPANTS: Thirty Iraq and Afghanistan War era veterans with a history of mTBI and 15 healthy veteran control participants. RESULTS: There were no significant overall group differences between control and mTBI participants on DTI measures. However, a subgroup of mTBI participants with EF decrements (n = 13) demonstrated significantly decreased fractional anisotropy of prefrontal white matter, corpus callosum, and cingulum bundle structures compared with mTBI participants without EF decrements (n = 17) and control participants. Participants having mTBI with LOC were more likely to evidence reduced EF performances and disrupted ventral prefrontal white matter integrity when compared with either mTBI participants without LOC or control participants. CONCLUSIONS: Findings suggest that altered white matter integrity contributes to reduced EF in subgroups of veterans with a history of mTBI and that LOC may be a risk factor for reduced EF as well as associated changes to ventral prefrontal white matter.

Impact of Adolescent Alcohol and Drug Use on Neuropsychological Functioning in Young Adulthood: 10-Year Outcomes.

BACKGROUND: Alcohol and other substance use disorders (AUD/SUD) are common among youth and often continue into adulthood; therefore, the neurocognitive effects of substance use are of great concern. Because neuromaturation continues into young adulthood, youth with AUD/SUD may be at risk for lasting cognitive decrements. This study prospectively examines neuropsychological functioning over 10 years as a function of AUD/SUD history and outcomes. METHODS: The 51 participants consisted of 18 youth with persisting AUD/SUD, 19 youth with remitted AUD/SUD, and 14 community youth with no AUD/SUD history followed over 10 years (ages 16 to 27 on average) with neuropsychological testing and substance use interviews on 8 occasions. Neuropsychological performance from baseline to 10-year follow-up was compared between the three groups. RESULTS: Despite scoring higher than controls at intake, both AUD/SUD groups showed a relative decline in visuospatial construction at 10-year follow-up (p=.001). Regressions showed that alcohol use (ß=-.33, p < .01) and drug withdrawal symptoms (ß=-.31, p<.05) over follow-up were predictive of year 10 visuospatial function. Alcohol use also predicted verbal learning and memory (ß=-.28, p<.05), while stimulant use predicted visual learning and memory function (ß=-.33, p=.01). More recent substance use was associated with poorer executive function (ß=.28, p<.05). DISCUSSION: These findings confirm prior studies suggesting that heavy, chronic alcohol and other substance use persisting from adolescence to young adulthood may produce cognitive disadvantages, primarily in visuospatial and memory abilities. Youth who chronically consume heavy quantities of alcohol and/or experience drug withdrawal symptoms may be particularly at risk for cognitive deterioration by young adulthood.

Changes in neuropsychological functioning over 10 years following adolescent substance abuse treatment.

Previously, Anderson, Ramo, Cummins, and Brown (2010) described six distinct patterns of alcohol and other drug (AOD) use during the decade following adolescents' treatment for alcohol and other substance use disorders (A/SUD). This time period represents a phase of significant neurodevelopment, and the influence of substance use on the brain is a concern. In the present study, we examined patterns of neuropsychological function over these 10 years in relation to the AOD trajectories identified for youth as they transition into their twenties. Participants were part of a longitudinal research project following adolescents with and without A/SUD who received neuropsychological examinations at baseline and up to 7 times thereafter spanning 10 years (N = 213; 46% female at baseline). Neuropsychological trajectories were significantly related to substance involvement patterns over time on measures of verbal learning and memory (ps = .011 to <.0001), visuospatial memory (p = .0002), and verbal attention/working memory (p = .020), with heavier use patterns generally followed by poorer cognition. Heavy use of alcohol alone was independently associated with poorer verbal memory over time. Furthermore, substance withdrawal symptoms during each follow-up time point were related to poorer verbal learning and memory scores (ps < .05), whereas substance abuse/dependence diagnostic criteria were not related to neuropsychological performance levels. These findings suggest that AOD use during adolescence and young adulthood may primarily influence performance that relies on later maturing brain structures, although further research is needed. Higher levels of AOD withdrawal symptoms may signify greater neuropsychological impairment, reflecting potential neurotoxic effects of AOD use.

Longitudinal study of cognition among adolescent marijuana users over three weeks of abstinence.

BACKGROUND: Cognitive deficits that persist up to a month have been detected among adult marijuana users, but decrements and their pattern of recovery are less known in adolescent users. Previously, we reported cognitive deficits among adolescent marijuana users after one month of abstinence (Medina, Hanson, Schweinsburg, Cohen-Zion, Nagel, & Tapert, 2007). In this longitudinal study, we characterized neurocognitive changes among marijuana-using adolescents across the first three weeks of abstinence. METHOD: Participants were adolescent marijuana users with limited alcohol and other drug use (n=19) and demographically similar non-using controls (n=21) ages 15-19. Participants completed a brief neuropsychological battery on three occasions, after 3days, 2weeks, and 3weeks of stopping substance use. Abstinence was ascertained by decreasing tetrahydrocannabinol metabolite values on serial urine drug screens. Verbal learning, verbal working memory, attention and vigilance, and time estimation were evaluated. RESULTS: Marijuana users demonstrated poorer verbal learning (p<.01), verbal working memory (p<.05), and attention accuracy (p<.01) compared to controls. Improvements in users were seen on word list learning after 2weeks of abstinence and on verbal working memory after 3weeks. While attention processing speed was similar between groups, attention accuracy remained deficient in users throughout the 3-week abstinence period. CONCLUSIONS: This preliminary study detected poorer verbal learning and verbal working memory among adolescent marijuana users that improved during three weeks of abstinence, while attention deficits persisted. These results implicate possible hippocampal, subcortical, and prefrontal cortex abnormalities.

Hippocampal volumes in adolescents with and without a family history of alcoholism.

BACKGROUND AND OBJECTIVES: The hippocampus may be vulnerable to the effects of heavy alcohol use during adolescence, which is a time of continued neurodevelopment. However, differences in hippocampal volume may be due to risk factors such as a family history (FH) of alcoholism. We examined hippocampal volumes in youth with and without a FH of alcoholism prior to the initiation of alcohol use. METHODS: Participants were demographically matched adolescents (aged 12-14) with positive (n = 15; FHP) and negative (n = 15; FHN) FH of alcoholism. Each group consisted of 10 males and 5 females with minimal previous substance use. Manual hippocampal tracings were completed on high-resolution magnetic resonance images by reliable raters, and intracranial volumes were controlled in analyses. RESULTS: FH groups did not differ on memory or hippocampal volumes, but group x gender interactions (p < .05) indicated that FHP males had larger left hippocampi than FHN males. Females showed greater left versus right hippocampal asymmetry, while males showed larger right versus left asymmetry. For all adolescents, larger right hippocampal volumes predicted poorer delayed visual memory (p < .01). CONCLUSION AND SIGNIFICANCE: Alcoholism risk factors, such as family history of alcoholism, may differentially influence adolescent hippocampal development for boys as compared to girls. Results suggest that FH does not account for prior findings of reduced left hippocampal volumes in heavy drinking youth. Findings are preliminary, but suggest that future studies examining the effects of alcohol use on the adolescent brain should consider the influence of FH, especially among boys.

Neurocognitive impairments in MDMA and other drug users: MDMA alone may not be a cognitive risk factor.

BACKGROUND: MDMA (3,4-methylenedioxymethamphetamine; "Ecstasy") is an amphetamine derivative with mild hallucinogenic and stimulant qualities. MDMA leads to serotonin (5-hydroxytryptamine; 5-HT) neurotoxicity and has been linked to cognitive impairments. It remains unclear whether these impairments are due to MDMA versus other drug use. METHOD: Neurocognitive functioning was measured in a sample of abstinent polydrug users (n = 52) with a range of MDMA use and healthy nondrug controls (n = 29). Participants completed a comprehensive neuropsychological battery and self-report measures of drug use. RESULTS: Polydrug users performed worse than controls on spatial span and spatial working memory (ps < .05). Among polydrug users, lifetime marijuana use significantly predicted verbal learning and memory performance (p < .01), while MDMA use was not predictive of cognitive impairment. CONCLUSIONS: This study and our previous report (Hanson, Luciana, & Sullwold, 2008) suggest that moderate MDMA use does not lead to persistent impairments above and beyond that associated with generally heavy drug use, but polydrug use may lead to dose-related temporal and frontoparietal dysfunction. Marijuana use may be particularly problematic. Cause-effect relations are unclear.

Prefrontal cortex morphometry in abstinent adolescent marijuana users: subtle gender effects.

Adult human studies suggest frontal dysfunction associated with chronic marijuana (MJ) use, but due to continued neuromaturation, adult studies may not generalize to adolescents. This study characterized prefrontal cortex (PFC) morphometry in chronic MJ-using adolescents following 1 month of monitored abstinence. Data were collected from MJ users (n = 16) and controls (n = 16) aged 16-18. Extensive exclusionary criteria included co-morbid psychiatric and neurologic disorders. Substance use and anatomical measures were collected after 28 days of monitored abstinence. PFC volumes were ascertained from manual tracing by reliable raters on high-resolution magnetic resonance images. After controlling for lifetime alcohol use, gender and intracranial volume, MJ users did not differ from controls in PFC volume. However, marginal group-by-gender interactions were observed (P < 0.09): female MJ users demonstrated comparatively larger PFC volumes while male MJ users had smaller volumes compared with same-gender controls. Further, group status and total PFC volume interacted in predicting executive functioning (P < 0.05). Among MJ users, smaller PFC total volume was associated with better executive functioning while the opposite pattern was seen among the controls. These preliminary results indicate that gender may moderate the relationship between MJ use and PFC morphometry. Given the relationship between larger PFC total volumes and poorer executive functioning among MJ users, female MJ users may be at increased risk for neurocognitive consequences. Future research will measure PFC gray and white matter separately and follow boys and girls over adolescence to examine the influence of MJ use on neurodevelopment.

Reward-related decision-making deficits and elevated impulsivity among MDMA and other drug users.

BACKGROUND: The recreational drug, 3,4-methylenedioxymethamphetamine (MDMA; 'Ecstasy'), is a synthetic amphetamine derivative and a serotonin neurotoxin. MDMA use is associated with cognitive dysfunction and impulsivity, but since polydrug abuse is common among users it is difficult to attribute these problems specifically to MDMA. Moreover, few studies have examined reward-related cognitive processes. Our aim was to examine reward-related decision-making and impulsivity among MDMA users while controlling for polydrug use via appropriate comparison groups. METHODS: We examined decision-making [Iowa Gambling Task, IGT; Bechara, A., Damasio, A.R., Damasio, H., Anderson, S.W., 1994. Insensitivity to future consequences following damage to human prefrontal cortex. Cognition 50, 7-15], self-reported impulsivity (Multidimensional Personality Questionnaire-Brief Form [constraint subscale]; Barratt Impulsiveness Scale; Zuckerman Sensation Seeking Scale), and drug use among 22 abstinent MDMA users, 30 other drug users, and 29 healthy non-drug controls. RESULTS: MDMA and other drug users showed comparable patterns of decision-making and impulsivity. However, both drug groups demonstrated poorer IGT performance and elevated self-reported impulsivity relative to controls. Poorer decision-making was related to heavier drug use in the past year, heavier weekly alcohol use, and meeting lifetime substance use disorder (SUD) criteria for more drug classes. Elevated impulsivity was associated with heavier drug use, heavier weekly alcohol use, more lifetime SUDs, and higher self-reported depression levels. CONCLUSIONS: These findings contradict the idea that MDMA is specifically associated with deficient decision-making. Drug users, in general, may be at risk for decision-making deficits and elevated impulsivity. Such behaviors may represent trait factors that lead to the initiation of drug and alcohol use, and/or they may represent behavior patterns that are exacerbated by extensive use.