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Objective Altered activity within reward-related neural regions, including the ventral striatum (VS) and medial prefrontal cortex (mPFC), is associated with concurrent problematic substance use. The aims of the present study were (a) to identify patterns of reward-related neural activity that prospectively predicted changes in alcohol use 2 years after magnetic resonance imaging in a sample of adolescents, and (b) to examine whether these patterns differed by sex. We also tested whether depression symptoms or impulsivity mediated associations between neural activity and future alcohol use. Method Participants were 262 adolescents (129 male and 133 female) of Mexican origin who completed the Monetary Incentive Delay task during a functional magnetic resonance imaging scan at age 16. Participants reported on their alcohol use at ages 16 and 18. Results Results indicated that different patterns of reward-related neural activity predicted future increases in alcohol use for male and female adolescents. In boys, higher VS activity during reward anticipation and average ventral mPFC activity during reward feedback predicted increases in alcohol use from age 16 to 18 years; in girls, higher dorsal mPFC activity and blunted VS activity during reward anticipation predicted increases in alcohol use from age 16 to 18 years. Depression symptoms or impulsivity did not mediate these associations. Conclusion The results suggest that different pathways of risk may lead to problematic alcohol use for adolescent boys and girls. These sex differences in neural risk pathways have important implications for prevention and intervention approaches targeting Mexican-origin youth.

BACKGROUND: Early adolescent onset of substance use is a robust predictor of future substance use disorders. We examined the relation between age of substance use initiation and resting state functional connectivity (RSFC) of the core reward processing (nucleus accumbens; NAcc) to cognitive control (prefrontal cortex; PFC) brain networks. METHOD: Adolescents in a longitudinal study of Mexican-origin youth reported their substance use annually from ages 10 to 16 years. At age 16, 69 adolescents participated in a resting state functional magnetic resonance imaging scan. Seed-based correlational analyses were conducted using regions of interest in bilateral NAcc. RESULTS: The earlier that adolescents initiated substance use, the stronger the connectivity between bilateral NAcc and right dorsolateral PFC, right dorsomedial PFC, right pre-supplementary motor area, right inferior parietal lobule, and left medial temporal gyrus. DISCUSSION: The regions that demonstrated significant positive linear relationships between the number of adolescent years using substances and connectivity with NAcc are nodes in the right frontoparietal network, which is central to cognitive control. The coupling of reward and cognitive control networks may be a mechanism through which earlier onset of substance use is related to brain function over time, a trajectory that may be implicated in subsequent substance use disorders. Language: en

We identify a novel contextual variable that alters the evaluation of delayed rewards in healthy participants and those diagnosed with attention deficit/hyperactivity disorder (ADHD). When intertemporal choices are constructed of monetary outcomes with rounded values (e.g., $25.00), discount rates are greater than when the rewards have nonzero decimal values (e.g., $25.12). This finding is well explained within a dual system framework for temporal discounting in which preferences are constructed from separate affective and deliberative processes. Specifically, we find that round dollar values produce greater positive affect than do nonzero decimal values. This suggests that relative involvement of affective processes may underlie our observed difference in intertemporal preferences. Furthermore, we demonstrate that intertemporal choices with rounded values recruit greater brain responses in the nucleus accumbens to a degree that correlates with the size of the behavioral effect across participants. Our demonstration that a simple contextual manipulation can alter self-control in ADHD has implications for treatment of individuals with disorders of impulsivity. Overall, the decimal effect highlights mechanisms by which the properties of a reward bias perceived value and consequent preferences.

Impairments in cognitive control are a defining feature of schizophrenia. Aspects of cognitive control include proactive control-the maintenance of task rules or goals to bias attention and maintain preparedness-and reactive control-the engagement of attention in reaction to changing cognitive demands. Proactive control is thought to be particularly impaired in schizophrenia. We sought to examine proactive and reactive control in schizophrenia, as measured by reaction time (RT) variability, and especially long RTs, which are thought to represent lapses in proactive control, during the Stroop paradigm. Furthermore, we sought to examine the neural underpinnings of lapses in proactive control and the subsequent engagement of reactive control in those with schizophrenia, as compared to healthy controls, using fMRI. We found that patients with schizophrenia displayed greater RT variability and more extremely long RTs than controls suggesting that proactive control was weaker in the schizophrenia than in the control group. All of the subjects engaged regions of the cognitive control network during long RTs, consistent with an engagement of reactive control following a failure in proactive control on these trials. The schizophrenia group, however, displayed significantly diminished activity in these regions relative to controls. Our results suggest increased failures in proactive control, but also impaired reactive control, in schizophrenia as compared to healthy subjects.

A challenge facing clinical neuroscientists is how best to synthesize diverse and sometimes inconsistent evidence for neuropsychological deficits and brain system dysfunction found in psychiatric disorders into models that guide etiological and treatment research. Multiple-pathway models suggest that psychiatric symptoms might arise from pathophysiology in different neural systems. This study tested dual-pathway model predictions for attention-deficit/hyperactivity disorder (ADHD) that reward and executive function cognitive deficits should be related to abnormalities in corresponding functionally specialized neural systems.Behavioral inhibition and preference for immediate rewards were assessed in N = 251 adolescent boys and girls ages 12 to 18 diagnosed with DSM-IV combined-subtype ADHD or non-ADHD control subjects. Following taxometric analyses of test performance, the resulting subgroups were compared on a functional magnetic resonance imaging monetary incentive delay task probing reward anticipation and go/no-go task of motor response inhibition.Three ADHD subgroups were identified consistent with different proposed pathways-ADHD with executive function/motor inhibition deficits, ADHD with both executive and reward deficits, and ADHD with relatively normal test performance. Each cognitive domain mapped to different ADHD brain dysfunction features as expected. However, no brain abnormalities were found common to all ADHD subgroups despite the fact they had nearly identical ADHD-related clinical characteristics.The results suggest that combined-subtype ADHD is a collection of discrete disorders for which a comparable behavioral end point arises through different neurobiological pathways. The findings raise caution about applying common cause, single-deficit conceptual models to individual ADHD patients and should prompt researchers to consider biologically defined, multifactorial etiological models for other psychiatric diagnoses.

The goal of this study was to extend our previous findings of abnormal prefrontal function in methamphetamine (MA) abusers and controls and to link the imaging data to behavioral, demographic and drug use variables. We used a fast event-related functional magnetic resonance imaging (fMRI) design to examine trial-to-trial reaction time (RT) adjustments in 30 MA abusers and 30 controls. A variant of the Stroop task was employed to measure influence of response conflict on RT, including the level of trial-to-trial RT adjustments seen after conflict trials. Compared to control subjects, MA abusers exhibited reduced RT adjustments and reduced activation in the prefrontal cortex (PFC) after conflict trials. RT adjustment correlated negatively with PFC brain activity in the MA group, while a trend for a positive correlation was observed in controls. No correlations were observed between task performance or brain activity and age, education or drug use variables. These data support our previous findings that the ability to adapt a behavioral response based on prior experience is compromised in MA abusers. Interestingly, these impairments do not appear to be linked to drug use patterns or to educational levels.

Functional Magnetic Resonance Imaging (fMRI) represents a powerful tool with which to examine brain functioning and development in typically developing pediatric groups as well as children and adolescents with clinical disorders. However, fMRI data can be highly susceptible to misinterpretation due to the effects of excessive levels of noise, often related to head motion. Imaging children, especially with developmental disorders, requires extra considerations related to hyperactivity, anxiety and the ability to perform and maintain attention to the fMRI paradigm. We discuss a number of methods that can be employed to minimize noise, in particular movement-related noise. To this end we focus on strategies prior to, during and following the data acquisition phase employed primarily within our own laboratory. We discuss the impact of factors such as experimental design, screening of potential participants and pre-scan training on head motion in our adolescents with developmental disorders and typical development. We make some suggestions that may minimize noise during data acquisition itself and finally we briefly discuss some current processing techniques that may help to identify and remove noise in the data. Many advances have been made in the field of pediatric imaging, particularly with regard to research involving children with developmental disorders. Mindfulness of issues such as those discussed here will ensure continued progress and greater consistency across studies.

The goal of the present study was to examine distributed attentional functions in long-term but currently abstinent methamphetamine (MA) abusers using a task that measures attentional alertness, orienting, and conflict resolution.Thirty currently abstinent MA abusers (1 month-5 years) and 22 healthy non-substance using adults were administered a multimodal version of the Attentional Network Task (ANT-I). In this task subjects identified the direction of a centrally presented arrow using a key press. Analyses examined the interaction between alerting tones, location cueing and congruency between the target arrows and flanking distractor stimuli.All participants were faster when an auditory tone preceded the trial onset (p0.001), on trials in which a valid cue preceded the location of the target arrow (p0.001), and on congruent trials (i.e., when all display arrows faced in the same direction) (p0.001). Of primary interest was the finding that MA abusers were more influenced by the conflict between the peripheral arrows and the central target arrow (p=0.009). There were also correlations between length of drug sobriety and executive function as well as between drug-induced psychiatric symptoms and alertness.These results suggest that chronic MA abusers display cognitive deficits that may reflect a specific vulnerability to distraction on a task of executive function. These findings are consistent with other studies that have reported deficits in anterior attentional systems and top-down cognitive control.

PUBLISHED, Three previous studies using the GO/NOGO task were examined to characterize the pattern of functional activation seen during error-related processing. The large sample size (n = 44) also allowed investigation of the influence of individual differences in age, sex, self-reported absentmindedness and reaction speed on the level of activation. Errors were seen to activate a network of regions including the anterior cingulate cortex (ACC), pre-supplementary motor area (pre-SMA), bilateral insula, thalamus and right inferior parietal lobule. Split-half comparisons performed for each of the individual difference variables indicated greater ACC and pre-SMA activation for older subjects while slower responders showed greater activation in the parietal, lateral PFC, insula and ACC regions. Whereas males and females demonstrated equivalent levels of activation in both the ACC and insula, self-reported absentmindedness related to reduced activation in these regions. Our review of the current imaging literature on error-related activation indicates that, despite the use of a variety of other cognitive paradigms, the network of regions identified here is consistent with these previous studies, suggesting that these regions are critical to a `general? error-related response. Furthermore, this response is, in part, influenced by individual differences in both demographic characteristics and behavioural performance.

This study investigated the dynamics of cognitive control instability in methamphetamine (MA) abuse, as well its relationship to substance-induced psychiatric symptoms and drug use patterns.We used an ex-Gaussian reaction time (RT) distribution to examine intraindividual variability (IIV) and excessively long RTs (tau) in an individual's RT on a Stroop task in 30 currently drug-abstinent (3 months to 2 years) MA abusers compared with 27 nonsubstance-abusing control subjects. All subjects underwent functional magnetic resonance imaging while performing the Stroop task, which allowed us to measure the relationship between IIV and tau to functional brain activity.Elevated IIV in the MA compared with the control group did not reach significance; however, when the MA group was divided into those subjects who had experienced MA-induced psychosis (MAP+) (n = 19) and those who had not (n = 11), the MAP+ group had higher average IIV compared with the other groups (p.03). In addition, although control subjects displayed a relationship between IIV and conflict-related brain activity in bilateral prefrontal cortex such that increased IIV was associated with increased activity, the MAP+ group displayed this relationship in right prefrontal cortex only, perhaps reflecting elevated vigilance in the MAP+ group. Greater IIV did not correlate with severity of use or months MA abstinent. No group differences emerged in tau values.These results suggest increased cognitive instability in those MA-dependent subjects who had experienced MA-induced psychosis.

The goal of this study was to extend our previous research that reported a significant association between Attention Deficit Hyperactivity Disorder (ADHD)-relevant childhood behaviors and the frequency of methamphetamine (MA)-induced psychotic symptoms in an expanded sample. 190 participants who met DSM-IV criteria for MA dependence were administered the Methamphetamine Experience Questionnaire that assessed MA-induced psychosis. Data related to MA exposure, comorbid drug use, education, familial psychiatric history and assessments of ADHD-relevant childhood behaviors as measured by the Wender Utah Rating Scale (WURS) were collected. Although WURS scores did not differ between 145 MAP+ and 45 MAP- subjects, MAP+ subjects with higher WURS scores were significantly more likely to report more frequent psychosis. Although mean daily MA dosage did not differ between the MAP+ and MAP- subjects, MAP+ subjects who consumed larger doses of MA were significantly more likely to experience frequent psychosis. These data suggest that ADHD-relevant childhood behaviors may interact with MA exposure to reflect a neurobiological vulnerability related to the emergence of frequent MA-induced psychotic symptoms. These results may elucidate factors that contribute to the psychiatric sequelae of MA abuse.

Computerized working memory and executive function training programs designed to target specific impairments in executive functioning are becoming increasingly available, yet how well these programs generalize to improve functional deficits in disorders, such as attention-deficit/hyperactivity disorder (ADHD), beyond the training context is not well-established. The aim of this study was to examine the extent to which working memory (WM) training in children with ADHD would diminish a core dysfunctional behavior associated with the disorder, “off-task” behavior during academic task performance. The effect of computerized WM training (adaptive) was compared to a placebo condition (nonadaptive) in a randomized, double-blind, placebo-controlled design in 26 children (18 males; age, 7 to 14 years old) diagnosed with ADHD. Participants completed the training in approximately 25 sessions. The Restricted Academic Situations Task (RAST) observational system was used to assess aspects of off-task behavior during the completion of an academic task. Traditional measures of ADHD symptoms (Conners’ Parent Rating Scale) and WM ability (standardized WM tests) were also collected. WM training led to significant reductions in off-task ADHD-associated behavior on the RAST system and improvement on WM tests. There were no significant differences between groups in improvement on parent rating scales. Findings lend insight into the generalizability of the effects of WM training and the relation between deficits in WM and off-task behavioral components of ADHD. These preliminary data suggest WM training may provide a mechanism for indirectly altering academic performance in children with ADHD.

To examine whether overlapping cognitive deficits exist in currently drug-abstinent chronic methamphetamine (MA) abusers and schizophrenia (SZ) patients.Both SZ and chronic MA abuse are associated with frontostriatal disruption as well as deficits in cognitive control, such as selective attention. To identify overlapping cognitive profiles, we compared performance of the 2 groups on the Stroop attention task.Data were analyzed from 69 MA abusers who had been MA-abstinent for differing periods of time and from 23 SZ patients and 38 non-substance-abusing controls.The MA abusers in early abstinence displayed more Stroop interference than the SZ patients (P=0.004), long-term abstinent MA abusers (P=0.009), and controls (P=0.002). In the MA abusers, the magnitude of Stroop interference correlated positively with longer drug use (P=0.01) and negatively with longer drug abstinence (P=0.04). No correlations were found between psychotic symptoms and task performance.On this task of attentional selection, only the MA abusers in early stages of abstinence showed performance deficits compared with controls. More research is needed to further elucidate overlapping patterns between MA abuse and SZ.

Working memory impairments are frequent in Attention Deficit/Hyperactivity Disorder (ADHD) and create problems along numerous functional dimensions. The present study utilized the Visual Serial Addition Task (VSAT) and functional magnetic resonance imaging (fMRI) to explore working memory processes in thirteen typically developing (TD) control and thirteen children with ADHD, Combined type. Analysis of Variance (ANOVA) was used to examine both main effects and interactions. Working memory-specific activity was found in TD children in the bilateral prefrontal cortex. In contrast the within-group map in ADHD did not reveal any working-memory specific regions. Main effects of condition suggested that the right middle frontal gyrus (BA6) and the right precuneus were engaged by both groups during working memory processing. Group differences were driven by significantly greater, non-working memory-specific, activation in the ADHD relative to TD group in the bilateral insula extending into basal ganglia and the medial prefrontal cortex. A region of interest analysis revealed a region in left middle frontal gyrus that was more active during working memory in TD controls. Thus, only the TD group appeared to display working memory-modulated brain activation. In conclusion, children with ADHD demonstrated reduced working memory task specific brain activation in comparison to their peers. These data suggest inefficiency in functional recruitment by individuals with ADHD represented by a poor match between task demands and appropriate levels of brain activity.

PUBLISHED, Top-down control processes are thought to interact with bottom-up stimulus-driven task demands to facilitate the smooth execution of behaviour. Frontal and midline brain areas in humans are believed to subserve these control processes but their distinct roles and the interactions between them remain to be fully elucidated. In this functional magnetic resonance imaging (fMRI) study, we utilized a GO/NO-GO task with cued and uncued inhibitory events to investigate the effect of cue-induced levels of top-down control on NO-GO trial response conflict. We found that, on a within-subjects, trial-for-trial basis, high levels of top-down control, as indexed by left dorsolateral prefrontal activation prior to the NO-GO, resulted in lower levels of activation on the NO-GO trial in the pre-supplementary motor area. These results suggest that prefrontal and midline regions work together to implement cognitive control and reveal that intra-subject variability is reflected in these lateral and midline interactions.

We used fMRI to study the brain processes involved in the executive control of behavior. The Sustained Attention to Response Task (SART), which allows unpredictable and predictable NOGO events to be contrasted, was imaged using a mixed (block and event-related) fMRI design to examine tonic and phasic processes involved in response inhibition, error detection, conflict monitoring and sustained attention. A network of regions, including right ventral prefrontal cortex (PFC), left dorsolateral PFC (DLPFC) and right inferior parietal cortex, was activated for successful unpredictable inhibitions, while rostral anterior cingulate was implicated in error processing and the pre-SMA in conflict monitoring. Furthermore, the pattern of correlations between left dorsolateral PFC, implicated in task-set maintenance, and the pre-SMA were indicative of a tight coupling between prefrontally mediated control and conflict levels monitored more posteriorly. The results reveal that the executive control of behavior can be separated into distinct functions performed by discrete cortical regions.

Attention Deficit/Hyperactivity Disorder (ADHD) is associated with different impairment profiles in the symptom domains of hyperactivity/impulsivity and/or inattention. An additional symptom domain of sluggish cognitive tempo (SCT) has also been proposed. Although there is a degree of correlation between the SCT symptom domain and inattention, it has been proposed as a distinct disorder independent of ADHD. The objective of this study was to examine the neural substrates of cue-related preparatory processes associated with SCT symptoms versus inattentive symptoms in a group of adolescents with ADHD. We also compared cue-related effects in the entire ADHD group compared with a group of typically developing (TD) peers. A modified cued flanker paradigm and fMRI examined brain activity associated with attention preparation and motor response preparation. Between group contrasts between the ADHD and TD group revealed significant hypoactivity in the ADHD group during general attention preparation in the supplementary motor area (SMA) and in the right superior parietal lobe (SPL) during response preparation. In the ADHD group, greater numbers of SCT symptoms were associated with hypoactivity in the left SPL to cues in general whereas greater numbers of inattentive symptoms were associated with greater activity in the SMA to cues that provided no information and less activity in the thalamus during response preparation. Hypoactivity in the SPL with increasing SCT symptoms may be associated with impaired reorienting or shifting of attention. Altered activity in the SMA and thalamus with increasing inattention may be associated with a general problem with response preparation, which may also reflect inefficient processing of the response preparation cue. Our results support a degree of differentiation between SCT and inattentive symptom profiles within adolescents with ADHD., Highlights • We examine cognitive control activity in ADHD SCT versus inattentive symptomatology. • An increase in SCT symptoms was associated with impaired attention orienting. • More inattentive symptoms were associated with impaired response preparation. • SCT activity differed from inattentive activity in adolescents with ADHD.