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Objective Irritability is a common characteristic in ADHD. We examined whether dysfunction in neural connections supporting threat and reward processing was related to irritability in adolescents and young adults with ADHD. Method We used resting-state fMRI to assess connectivity of amygdala and nucleus accumbens seeds in those with ADHD ( n = 34) and an age- and gender-matched typically-developing comparison group ( n = 34). Results In those with ADHD, irritability was associated with atypical functional connectivity of both seed regions. Amygdala seeds showed greater connectivity with right inferior frontal gyrus and caudate/putamen, and less connectivity with precuneus. Nucleus accumbens seeds showed altered connectivity with middle temporal gyrus and precuneus. Conclusion The irritability-ADHD presentation is associated with atypical functional connectivity of reward and threat processing regions with cognitive control and emotion processing regions. These patterns provide novel evidence for irritability-associated neural underpinnings in adolescents and young adults with ADHD. The findings suggest cognitive and behavioral treatments that address response to reward, including omission of an expected reward and irritability, may be beneficial for ADHD.

Human immunodeficiency virus (HIV) affects millions of people globally. The associated stigma remains a challenge for individuals living with HIV and children and adolescents face the additional challenge of withstanding the peer, pubertal and identity challenges associated with growing up. The current systematic review aimed to define and explore the major stigma-related challenges of children and adolescents from their own perspectives. A secondary aim was to identify any challenges distinct to childhood and adolescence. Studies included individuals aged 3 to 18 years who were aware of their status. Fifteen studies met inclusion criteria. Narrative synthesis was conducted on the included studies. Five analytic themes emerged describing major stigma-related challenges: disclosure-related anxiety, medication adherence, feelings of abnormality, mental health issues and social exclusion. Disclosure-related anxiety and feelings of abnormality appeared to be largely confined to the experience of children and adolescents. Many of the themes centred around peer influence, highlighting the need to belong in youth. Results suggest that youth require tailored interventions targeting their age-specific challenges.

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.

Highlights • Working memory (WM). • Load versus Complexity. • ADHD. • FMRI. • Working Memory Striatum and Cerebellum., Working memory (WM) deficits are key in attention deficit hyperactivity disorder (ADHD). Nevertheless, WM is not universally impaired in ADHD. Additionally, the neural basis for WM deficits in ADHD has not been conclusively established, with regions including the prefrontal cortex, cerebellum, and caudate being implicated. These contradictions may be related to conceptualizations of WM capacity, such as load (amount of information) versus operational-complexity (maintenance-recall or manipulation). For instance, relative to neurotypical (NT) individuals, complex WM operations could be impaired in ADHD, while simpler operations are spared. Alternatively, all operations may be impaired at higher loads. Here, we compared the impact of these two components of WM capacity: load and operational-complexity, between ADHD and NT, behaviorally and neurally. We hypothesized that the impact of WM load would be greater in ADHD, and the neural activation would be altered. Participants (age-range 12–23 years; 50 ADHD (18 females); 82 NT (41 females)) recalled three or four objects (load) in forward or backward order (operational-complexity) during functional magnetic resonance imaging scanning. The effects of diagnosis and task were compared on performance and neural engagement. Behaviorally, we found significant interactions between diagnosis and load, and between diagnosis, load, and complexity. Neurally, we found an interaction between diagnosis and load in the right striatum, and between diagnosis and complexity in the right cerebellum and left occipital gyrus. The ADHD group displayed hypo-activation compared to NT group during higher load and greater complexity. This informs mechanisms of functional problems related to WM in adolescents and young adults with ADHD (e.g., academic performance) and remedial interventions (e.g., WM-training).

Objectives Significant genetic variability of metabolism confounds reliable clinical use of methadone because physicians have no way of identifying individual patient metabolism. The methadone/metabolite ratio (MMR), the numerical ratio of serum methadone to its inactive metabolite ethylidine-dimethyl-diphenypyrrolidine (EDDP), represents the net expression of the genes controlling metabolism. The MMR has been adapted to four established pharmacogenetic metabolic categories: ultra-rapid (URM), extensive (EM, normal), intermediate (IM), and ultra-slow (USM). Methods This study reports on the analysis of 1700 paired peak and trough serum samples for methadone and EDDP. The MMR data were stratified by metabolic category. The reliability of these categories and the relationship of the MMR to 2 other laboratory assessments, a peak/trough ratio (PTR) and a methadone half-life, was tested. Additionally, peak and trough serum levels were analyzed by MMR category. Results Each category of MMR identified significantly different mean serum levels (peak and trough), peak/trough ratios, and half-lives. When serum levels were analyzed, evidence of subtherapeutic serum levels were found, predominantly in the URM and EM categories. Seventeen percent of peak serum levels were greater than 1000 ng (a level indicating potential toxicity) with a range up to 2384 ng, predominantly in the IM and USM categories. Conclusions The MMR measures an individual's phenotype for methadone metabolism. The data suggested underdosing in the URM category, as well as evidence of excessive dosing in IM and USM categories. The MMR provides a guide to safe and effective dosing, an alternative to the pharmacokinetically 'blind' dosing algorithms currently in use.

Delay discounting (DD) is the phenomenon of individuals discounting future rewards as a function of time. It has been studied extensively in chronic schizophrenia (SZ) and the results of these studies have been variable. Comorbidity in chronic samples could be one reason for the mixed findings and studies in first-episode (FE) samples are surprisingly lacking. Bipolar disorder (BP) which shares some genetic and symptom features with SZ could serve as an interesting comparison group for DD but has been underexplored. Here we present the first study that combines FE SZ, FE BP with psychotic features, as well as healthy controls and study DD with two versions of the task. We found that SZ showed steeper discounting than HC and BP on the well-validated Kirby DD task. SZ showed no difference than HC on a separate DD task with smaller rewards presented with decimal places and shorter delays. As a preliminary finding, DD was found to be positively related to positive symptoms in FE SZ, while no relationship was found between negative symptoms and DD. In addition, we found comparable DD in BP compared to HC. Ultimately, our data may help elucidate the psychopathology in SZ and BP during intertemporal decision making.

Objectives Pregnancy profoundly alters drug metabolism, accelerating clearance and confounding medication management, primarily through induction of CYP450 enzymes. Methadone is a CYP450 substrate with altered pharmacokinetics during pregnancy. We report on the use of serum methadone/metabolite ratios (MMRs) to monitor changes in methadone metabolism through the perinatal period and to objectively guide methadone dosing. Previous research found average MMRs in nonpregnant populations of between 11.3 and 12.7. Methods Serum methadone and its major metabolite 2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine concentrations were analyzed in 67 samples from 23 pregnant patients treated for opioid use disorder, and their calculated ratio was used to document changes in methadone clearance across trimesters and postpartum. Lower ratios indicate increased clearance. Results The average MMR during pregnancy was 6.1. Ratios declined significantly from trimester 1 to trimester 3 (P = 0.007), and then rose significantly from trimester 3 to postpartum (P = 0.001). The per cent of ratios that were 4 or less, indicating ultrarapid metabolism, increased from 8% to 30% to 38% across trimesters, and decreased to 5% postpartum. Forty-four per cent of individual patients had at least 1 prepartum ratio of 4 or less. Conclusions This study documents significant metabolic changes occurring perinatally, which indicate the need for both changes in methadone dose and dose frequency to maintain maternal/fetal stability, and also dose reductions as hypermetabolism reverses postpartum. MMRs provide an objective tool to more efficiently improve the safety and efficacy of methadone dosing perinatally.

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

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.

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.

Objective: This study compared affect recognition abilities between adults with and without ADHD. Method: The sample consisted of 51 participants (34 men, 17 women) divided into 3 groups: ADHD-combined type (ADHD-C; n = 17), ADHD-predominantly inattentive type (ADHD-I; n = 16), and controls ( n = 18). The mean age was 34 years. Affect recognition abilities were assessed by the Diagnostic Analysis of Nonverbal Accuracy (DANVA). Results: ANOVA showed that the ADHD-I group made more fearful emotion errors relative to the control group. Inattentive symptoms were positively correlated, whereas hyperactive-impulsive symptoms were negatively correlated with affect recognition errors. Conclusion: These results suggested that affect recognition abilities may be impaired in adults with ADHD and that affect recognition abilities are more adversely affected by inattentive than hyperactive-impulsive symptoms.

This article reviews evidence for the presence of a compensatory, alternative, neural system and its possible link to associated processing strategies in children and adults with attention deficit hyperactivity disorder (ADHD). The article presents findings on a region by region basis that suggests ADHD should be characterized not only by neural hypo-activity, as it is commonly thought but neural hyperactivity as well, in regions of the brain that may relate to compensatory brain and behavioral functioning. In this context studies from the functional neuroimaging literature are reviewed. We hypothesize that impaired prefrontal (PFC) and anterior cingulate (ACC) cortex function in ADHD reduces the ability to optimally recruit subsidiary brain regions and strategies to perform cognitive tasks. The authors conclude that healthy individuals can recruit brain regions using visual, spatial or verbal rehearsal for tasks as needed. In contrast, individuals with ADHD may be less able to engage higher order executive systems to flexibly recruit brain regions to match given task demands. This may result in greater reliance on neuroanatomy that is associated with visual, spatial, and motoric processing rather than verbal strategies. The authors speculate that this impaired flexibility in recruiting brain regions and associated strategies limits adaptation to new cognitive demands as they present and may require more effortful processing.

Seemingly distinct cognitive tasks often activate similar anatomical networks. For example, the right fronto-parietal cortex is active across a wide variety of paradigms suggesting that these regions may subserve a general cognitive function. We utilized fMRI and a GO/NOGO task consisting of two conditions, one with intermittent unpredictive “cues-to-attend” and the other without any “cues-to-attend,” in order to investigate areas involved in inhibition of a prepotent response and top-down attentional control. Sixteen subjects (5 male, ages ranging from 20 to 30 years) responded to an alternating sequence of the letters X and Y and withheld responding when the alternating sequence was broken (e.g., when X followed an X). Cues were rare stimulus font-color changes, which were linked to a simple instruction to attend to the task at hand. We hypothesized that inhibitions and cues, despite requiring quite different responses from subjects, might engage similar top-down attentional control processes and would thus share a common network of anatomical substrates. Although inhibitions and cues activated a number of distinct brain regions, a similar network of right dorsolateral prefrontal and inferior parietal regions was active for both. These results suggest that this network, commonly activated for response inhibition, may subserve a more general cognitive control process involved in allocating top-down attentional resources.

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.

Increase in the number of opioid-dependent pregnant women delivering babies at risk for neonatal abstinence syndrome prompted a US Government Accountability Office report documenting deficits in research and provider knowledge about care of the maternal/fetal unit and the neonate. There are 3 general sources of dependence: untreated opioid use disorder, pain management, and medication-assisted treatment with methadone or buprenorphine. A survey of methadone patients' experiences when telling a physician of their pregnancy and opioid dependence demonstrated physician confusion about proper care, frequent negative interactions with the mother, and failures to provide appropriate referral. Patients in pain management were discharged without referral when the physician was told of the pregnancy. Methadone and buprenorphine were frequently seen negatively because they "caused" neonatal abstinence syndrome. Most mothers surveyed had to find opioid treatment on their own. How dependence is managed medically is a critical determinant of the level of stress on both mother and fetus, and therefore another determinant of neonatal health. The effects of both opioid withdrawal stress and maternal emotional stress on neonatal and developmental outcomes are reviewed. Currently, there have been efforts to criminalize maternal opioid dependence and to encourage or coerce pregnant women to undergo withdrawal. This practice poses both acute risks of fetal hypoxia and long-term risks of adverse epigenetic programming related to catecholamine and corticosteroid surges during withdrawal. Contemporary studies of the effects of withdrawal stress on the developing fetal brain are urgently needed to elucidate and quantify the risks of such practices. At birth, inconsistencies in the hospital management of neonates at risk for neonatal abstinence syndrome have been observed. Neglect of the critical role of maternal comforting in neonatal abstinence syndrome management is an iatrogenic and preventable cause of poor outcomes and long hospitalizations. Rooming-in allows for continuous care of the baby and maternal/neonatal attachment, often unwittingly disrupted by the neonatal intensive care unit environment. Recommendations are made for further research into physician/patient interactions and into optimal dosing of methadone and buprenorphine to minimize maternal/fetal withdrawal.

BackgroundA neurobiological-based classification of attention-deficit/hyperactivity disorder (ADHD) subtypes has thus far remained elusive. The aim of this study was to use oscillatory changes in the electroencephalogram (EEG) related to informative cue processing, motor preparation, and top-down control to investigate neurophysiological differences between typically developing (TD) adolescents, and those diagnosed with predominantly inattentive (IA) or combined (CB) (associated with symptoms of inattention as well as impulsivity/hyperactivity) subtypes of ADHD.MethodsThe EEG was recorded from 57 rigorously screened adolescents (12 to 17 years of age; 23 TD, 17 IA, and 17 CB), while they performed a cued flanker task. We examined the oscillatory changes in theta (3-5 Hz), alpha (8-12 Hz), and beta (22-25 Hz) EEG bands after cues that informed participants with which hand they would subsequently be required to respond.ResultsRelative to TD adolescents, the IA group showed significantly less postcue alpha suppression, suggesting diminished processing of the cue in the visual cortex, whereas the CB group showed significantly less beta suppression at the electrode contralateral to the cued response hand, suggesting poor motor planning. Finally, both ADHD subtypes showed weak functional connectivity between frontal theta and posterior alpha, suggesting common top-down control impairment.ConclusionsWe found both distinct and common task-related neurophysiological impairments in ADHD subtypes. Our results suggest that task-induced changes in EEG oscillations provide an objective measure, which in conjunction with other sources of information might help distinguish between ADHD subtypes and therefore aid in diagnoses and evaluation of treatment.

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.

Attention-deficit hyperactivity disorder (ADHD) is one of the most prevalent childhood psychiatric disorders. Most children with the disorder continue to exhibit significant symptoms as adults as well. Symptoms include inattention, hyperactivity or restlessness, and poor impulse control. ADHD is associated with a strong genetic component via twin, adoption, and family pedigree studies. Molecular genetic study findings, however, suggest genetic heterogeneity underlying similar ADHD phenotypes with support for many genes with only small effects typically contributing to the disorder. Both the dopaminergic and noradrenergic system appear to be altered in ADHD. Structural and functional alterations in frontal and cingulate cortices, basal ganglia, and cerebellar regions are routinely found in ADHD. These altered neurotransmitter systems and neuroanatomical regions subserve cognitive control and reward responsivity functioning – processes that are impaired in ADHD. Current recommendations for evaluating ADHD include the use of interviews and cross-informant and normed rating scales for children and adults with suspected ADHD. Possible comorbid disorders or disorders that may mimic ADHD should also be evaluated. The efficacy of pharmacological treatment for children and adults is well established. Stimulant medications are the recommended first-line psychopharmacological treatment of ADHD; however there are nonstimulant medications that are efficacious in treating ADHD and associated symptoms. School and parent-based behavioral interventions for ADHD can also address ADHD-associated symptoms in children. The benefits of medication or behavioral interventions may not be sustained after active treatment and monitoring of the treatment cease. There is initial support for the application of cognitive-behavioral treatment of ADHD symptoms in adults. Future research should attempt more targeted treatment informed by advances in neuroscience findings.

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.

This chapter reviews selected neuroimaging findings related to long-term amphetamine and methamphetamine (MA) use. An overview of structural and functional (fMRI) MR studies, Diffusion Tensor Imaging (DTI), Magnetic Resonance Spectroscopy (MRS) and Positron Emission Tomography (PET) studies conducted in long-term MA abusers is presented. The focus of this chapter is to present the relevant studies as tools to understand brain changes following drug abstinence and recovery from addiction. The behavioral relevance of these neuroimaging studies is discussed as they relate to clinical symptoms and treatment. Within each imaging section this chapter includes a discussion of the relevant imaging studies as they relate to patterns of drug use (i.e., duration of MA use, cumulative lifetime dose and time MA abstinent) as well as an overview of studies that link the imaging findings to cognitive measures. In our conclusion we discuss some of the future directions of neuroimaging as it relates to the pathophysiology of addiction.

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.

This chapter reviews selected neuroimaging findings related to long-term amphetamine and methamphetamine (MA) use. An overview of structural and functional (fMRI) MR studies, Diffusion Tensor Imaging (DTI), Magnetic Resonance Spectroscopy (MRS) and Positron Emission Tomography (PET) studies conducted in long-term MA abusers is presented. The focus of this chapter is to present the relevant studies as tools to understand brain changes following drug abstinence and recovery from addiction. The behavioral relevance of these neuroimaging studies is discussed as they relate to clinical symptoms and treatment. Within each imaging section this chapter includes a discussion of the relevant imaging studies as they relate to patterns of drug use (i.e., duration of MA use, cumulative lifetime dose and time MA abstinent) as well as an overview of studies that link the imaging findings to cognitive measures. In our conclusion we discuss some of the future directions of neuroimaging as it relates to the pathophysiology of addiction.

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 combined the data of five event-related fMRI studies of response inhibition. The re-analysis (n = 71) revealed response inhibition to be accomplished by a largely right hemisphere network of prefrontal, parietal, subcortical and midline regions, with converging evidence pointing to the particular importance of the right frontal operculum. Functional differences were observed between the sexes with greater activity in females in many of these cortical regions. Despite the relatively narrow age range (18-46), cortical activity, on the whole, tended to increase with age, echoing a pattern of functional recruitment often observed in the elderly. More absent minded subjects showed greater activity in fronto-parietal areas, while speed of Go trial responses produced a varied pattern of activation differences in more posterior and subcortical areas. Although response inhibition produces robust activation in a discrete network of brain regions, these results reveal that individual differences impact on the relative contribution made by the nodes of this network.

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.