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Most substance use begins in adolescence. Both childhood trauma and associated post-traumatic stress disorder (PTSD) increase risk for early substance use, which is associated with greater eventual severity of substance use disorders (SUDs). When co-occurring, PTSD and SUD can reinforce and exacerbate each other, necessitating integrated treatment approaches. To systematically review existing literature on interventions for prevention or treatment of SUDs among adolescents (aged 10–24) with a history of trauma, with or without PTSD, we searched databases (PubMed, PsycInfo, CINAHL, Cochrane CENTRAL) using search terms related to substance use, trauma, adolescents, and interventions. Searches identified 8134 unique articles, 68 of which prompted full-text screening. Authors extracted data, applied the Effective Public Health Practice Project Quality Assessment Tool to evaluate the evidence, and synthesized findings. Thirty three articles met eligibility criteria, including 13 RCTs. Twenty studies (10 RCTs) evaluated interventions for substance use and co-occurring problems among youth with a history of trauma, predominantly via individual therapy based on cognitive-behavioral principles, although group therapy, case management, and other approaches have also been studied. Interventions with exposure-based components were infrequent but had robust results and minimal adverse outcomes. Thirteen studies examined differential response of youth with a history of trauma to standard SUD treatments, compared to youth without a history of trauma, with mixed findings. Youth with a history of trauma face elevated risk of SUDs and may respond differently to SUD treatments. Several promising interventions have been recently developed. [ABSTRACT FROM AUTHOR]

Emerging research on psychological adjustment during the COVID-19 outbreak has suggested that young people may be particularly vulnerable to increases in negative affect during the pandemic. However, the association between alcohol use in youth and change in negative affect during this unprecedented time is not clear. Using an online survey, this study obtained scores on negative affect (before and during the COVID-19 pandemic), pandemic-related stress, change in drinking frequency, and traits including resilience, impulsivity and anhedonia, from a sample of drinkers and non-drinkers, up to the age of 21. Young drinkers experienced a greater increase in negative affect during the pandemic compared to non-drinkers, and this differential rise in negative affect was mediated by the pandemic-related stress of social isolation. Young drinkers also experienced a decrease in alcohol use during the pandemic, but this was not associated with a change in negative affect. Interestingly, young drinkers with greater resilience and lower anhedonia reported less increase in negative affect during the COVID-19 pandemic. Taken together, these results show that the greater increase in negative affect that young drinkers experienced during the COVID-19 pandemic, compared to their non-drinking counterparts, was mediated by pandemic-related social isolation. Moreover, greater resilience and lower anhedonia may have served as protective factors for mitigating the social isolation-induced worsening of negative affect in young drinkers during the pandemic. These findings may inform future studies investigating potential indicators of maladaptive affective responses to public health crises in vulnerable adolescent populations. [ABSTRACT FROM AUTHOR]

Objective: Methylphenidate has prominent effects in the dopamine-rich striatum that are absent for the selective norepinephrine transporter inhibitor atomoxetine. This study tested whether baseline striatal activation would predict differential response to the two medications in youth with attention-deficit/hyperactivity disorder (ADHD).Method: A total of 36 youth with ADHD performed a Go/No-Go test during functional magnetic resonance imaging at baseline and were treated with methylphenidate and atomoxetine using a randomized cross-over design. Whole-brain task-related activation was regressed on clinical response.Results: Task-related activation in right caudate nucleus was predicted by an interaction of clinical responses to methylphenidate and atomoxetine (F1,30 = 17.00; p < .001). Elevated caudate activation was associated with robust improvement for methylphenidate and little improvement for atomoxetine. The rate of robust response was higher for methylphenidate than for atomoxetine in youth with high (94.4% vs. 38.8%; p = .003; number needed to treat = 2, 95% CI = 1.31-3.73) but not low (33.3% vs. 50.0%; p = .375) caudate activation. Furthermore, response to atomoxetine predicted motor cortex activation (F1,30 = 14.99; p < .001).Conclusion: Enhanced caudate activation for response inhibition may be a candidate biomarker of superior response to methylphenidate over atomoxetine in youth with ADHD, purportedly reflecting the dopaminergic effects of methylphenidate but not atomoxetine in the striatum, whereas motor cortex activation may predict response to atomoxetine. These data do not yet translate directly to the clinical setting, but the approach is potentially important for informing future research and illustrates that it may be possible to predict differential treatment response using a biomarker-driven approach.Clinical Trial Registration Information: Stimulant Versus Nonstimulant Medication for Attention Deficit Hyperactivity Disorder in Children; https://clinicaltrials.gov/; NCT00183391. [ABSTRACT FROM AUTHOR]

Background: Accumulating evidence suggests that sleep disordered breathing (SDB) is under-recognized in youth and adults with ADHD. SDB may contribute to exacerbating pre-existing ADHD symptoms and may play a role in the development of cognitive deficits that may mimic ADHD symptoms., Method: We conducted a focused review of publications on cross-prevalence, overlapping clinical and neurobiological characteristics and possible mechanisms linking SDB and ADHD., Results: Exiting studies suggest that co-occurrence of SDB and ADHD is as high as 50%, with frequent overlap of clinical symptoms such as distractibility and inattention. Mechanisms linking these conditions may include hypoxia during sleep, sleep fragmentation and activation of inflammation, all of which may affect brain structure and physiology to produce disturbances in attention., Conclusions: The relationship between SDB and ADHD symptoms appear well-supported and suggests that more research is needed to better optimize procedures for SDB assessment in youth being evaluated and/or treated for ADHD., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: Iliyan Ivanov – no conflicts. Ben Miraglia – no conflicts. Dana Prodanova – no conflicts. Jeffrey Newcorn – in the last three years J.H.N. was a consultant/advisory board member for Adlon Therapeutics, Cingulate Therapeutics, Corium, Hippo T&C, Ironshore, Lumos, Medice, MindTension, Myriad, NLS, OnDosis, Otsuka, Rhodes, Shire/Takeda, Signant and Supernus; he received research support from Adlon, Otsuka, Shire, Supernus; honoraria for disease state lectures from Otsuka and Shire, and served as a consultant for the US National Football League.

Background: Research examining the potential effects of stimulant exposure in childhood on subsequent development of substance use disorder (SUD) have focused on differences in the brain reward system as a function of risk., Methods: 18 drug naïve children ages 7 to 12 years (11 High Risk [ADHD + ODD/CD]; 7 Low Risk [ADHD only]), underwent fMRI scans before and after treatment with mixed amphetamine salts, extended release (MAS-XR). We examined correlations between clinical ratings and fMRI activation at baseline and following treatment as a function of risk status., Results: High Risk children had higher activation than Low Risk children at baseline during both the Reward and Surprising Non-Reward conditions. Treatment produced strong differential effects on brain activation pertinent to group and reward outcome., Conclusions: Findings support the hypothesized role of reward mechanisms in SUD risk, and suggest that stimulant treatment may have differential effects on reward processing in relation to SUD risk., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: Iliyan Ivanov—no conflicts, Beth Krone—in the last 3 years was a consultant for Signant Health, Mind Tension, Hippo T&C, and Maxis Health, Kurt Schulz—no conflicts, Riaz Shaik—no conflicts, Muhammad Parvaz—no conflicts, Jeffrey Newcorn—in the last three years J.H.N. was a consultant/advisory board member for Adlon Therapeutics, Cingulate Therapeutics, Corium, Hippo T&C, Ironshore, Lumos, Medice, MindTension, Myriad, NLS, OnDosis, Otsuka, Rhodes, Shire/Takeda, Signant and Supernus; he received research support from Adlon, Otsuka, Shire, Supernus; honoraria for disease state lectures from Otsuka and Shire, and served as a consultant for the US National Football League.

Background: ADHD is often described as a disorder of altered reward sensitivity, yet few studies have examined the extent to which: (i) treatments for ADHD impact reward-related mechanisms; and (ii) changes in the reward system are associated with clinical improvement. This study addresses these issues - examining the extent to which clinical improvement following lisdexamfetamine (LDX) treatment is associated with changes in brain reward system activation., Methods: Twenty adults (M = 11, 55%, F = 9, 45%), ages 19-52 (M = 33.9, SD = 10.0) with ADHD participated in a randomized cross-over study with lisdexamfetamine (LDX) and placebo (PB). Changes in brain activation were assessed during functional magnetic resonance (fMRI) scans: after receiving 3-5 weeks of treatment with LDX and 3-5 weeks of no drug/PB. fMRI contrasts were derived from the passive-avoidance (PA) learning task, which assessed reward-related learning using computational variables. We analyzed the following conditions: the Choice-Phase, modulated by the expected value (EV; i.e., object-choose and object-reject), and the Feedback-Phase, modulated by the prediction error (PE; i.e., reward and punish). Clinical symptom severity was assessed via interview with the ADHD-Rating Scale (ADHD-RS-IV). To address the primary objective, we performed group-level mass-univariate regression analyses between LDX and PB of percent change of the ADHD-RS total scores and the four contrast images under the Choice- and Feedback-conditions. Significance was set at a whole-brain voxel-wise threshold of p < 0.05 with family-wise error (FWE) correction and an extent (cluster) threshold of 50 contiguous voxels., Results: Improvement in ADHD symptoms with LDX was accompanied by significantly increased activation in a series of brain regions previously implicated in reinforcement processing in the choice and feedback conditions (e.g., left caudate and putamen, right orbitofrontal cortex, left middle frontal, superior frontal, and precentral gyri)., Conclusions: These findings, while preliminary, are the first to show that ADHD symptom improvement with stimulant treatment is associated with increased responsiveness of brain systems engaged in reward processing. Results support the hypothesis that LDX treatment may restore balance to dysfunction (e.g., hypoactivation) within the brain reward circuitry in adults with ADHD. Trial RegistrationClinicaltrials.gov Identifier: NCT01924429., Competing Interests: Declaration of competing interest The authors declare the following competing interests: Jeffrey Newcorn – in the last 3 years J.H.N. was a consultant/advisory board member for Adlon Therapeutics, Cingulate Therapeutics, Corium, Hippo T&C, Ironshore, Lumos, Lundbeck, Medice, Mind Tension, Myriad, NLS, OnDosis, Otsuka, Rhodes, Shire/Takeda, and Supernus; he received research support from Adlon, Otsuka, Shire, Supernus; honoraria for disease state lectures from Otsuka and Shire, and served as a consultant for the US National Football League; Iliyan Ivanov – no conflcits, Beth Krone – in the last 3 years was a consultant for Hippo T&C; Xioabo Li – no conflicts; Stephanie Duhoux – no conflict; Stuart White – no conflict; Kurt Schulz – no conflicts; AC Bedard-no conflicts; Juan Pedraza - Lenard Adler – in the last 3 years Dr Adler has received grant/research support from Shire/Takeda Pharmaceuticals, Otsuka; has served as a consultant to Bracket/Signant, Shire/Takeda Pharmaceuticals, Otsuka Pharmaceuticals, SUNY, the National Football League, and Major League Baseball; and has received royalty payments (as inventor) since 2004 from NYU for license of adult ADHD scales and training materials; James Blair – no conflicts., (Copyright © 2023. Published by Elsevier Ltd.)

In this study, we present the synthesis of five novel compounds by combining flurbiprofen with various substituted 2-phenethylamines. The synthesized derivatives underwent comprehensive characterization using techniques such as 1 H- and 13 C-NMR spectroscopy, UV-Vis spectroscopy, and high-resolution mass spectrometry (HRMS). Detailed HRMS analysis was performed for each of these newly created molecules. The biological activities of these compounds were assessed through in vitro experiments to evaluate their potential as anti-inflammatory and antioxidant agents. Furthermore, the lipophilicity of these derivatives was determined, both theoretically using the c Log P method and experimentally through partition coefficient (R M ) measurements. To gain insights into their binding affinity, we conducted an in silico analysis of the compounds' interactions with human serum albumin (HSA) using molecular docking studies. Our findings reveal that all of the newly synthesized compounds exhibit significant anti-inflammatory and antioxidant activities, with results statistically comparable to the reference compounds. Molecular docking studies further explain the observed in vitro results, shedding light on the molecular mechanisms behind their biological activities. Using in silico method, toxicity was calculated, resulting in LD 50 values. Depending on the administration route, the novel flurbiprofen derivatives show lower toxicity compared to the standard flurbiprofen.

Herein, we report the obtaining of new hybrid molecules of amphetamine with different profens (amfens). The obtained amfens are characterized by their melting points, UV, 1 H-, 13 C-NMR, and HRMS spectra. A complete and detailed mass spectral analysis of the newly obtained derivatives of amphetamine with ibuprofen, flurbiprofen, ketoprofen, naproxen, and carprofen was performed. In vitro inhibition of albumin denaturation of each new compound was assessed, and they showed significant activity. The IC 50 values of the obtained amphetamine-profen derivatives ranged from 92.81 to 159.87 µg/mL. This indicates that the new hybrids inherit the anti-inflammatory properties of profens. Using in silico method, the toxicity was also calculated. The obtained results are given in LD 50 values. Depending on the route of administration, the amfens are less toxic compared to the standard amphetamine.

Background: Widely used psychotropic medications for obsessive-compulsive disorder (OCD) may change the volumes of subcortical brain structures, and differently in children vs. adults. We measured subcortical volumes cross-sectionally in patients finely stratified for age taking various common classes of OCD drugs., Methods: The ENIGMA-OCD consortium sample (1081 medicated/1159 unmedicated OCD patients and 2057 healthy controls aged 6-65) was divided into six successive 6-10-year age-groups. Individual structural MRIs were parcellated automatically using FreeSurfer into 8 regions-of-interest (ROIs). ROI volumes were compared between unmedicated and medicated patients and controls, and between patients taking serotonin reuptake inhibitors (SRIs), tricyclics (TCs), antipsychotics (APs), or benzodiazepines (BZs) and unmedicated patients., Results: Compared to unmedicated patients, volumes of accumbens, caudate, and/or putamen were lower in children aged 6-13 and adults aged 50-65 with OCD taking SRIs (Cohen's d = -0.24 to -0.74). Volumes of putamen, pallidum (d = 0.18-0.40), and ventricles (d = 0.31-0.66) were greater in patients aged 20-29 receiving APs. Hippocampal volumes were smaller in patients aged 20 and older taking TCs and/or BZs (d = -0.27 to -1.31)., Conclusions: Results suggest that TCs and BZs could potentially aggravate hippocampal atrophy of normal aging in older adults with OCD, whereas SRIs may reduce striatal volumes in young children and older adults. Similar to patients with psychotic disorders, OCD patients aged 20-29 may experience subcortical nuclear and ventricular hypertrophy in relation to APs. Although cross-sectional, present results suggest that commonly prescribed agents exert macroscopic effects on subcortical nuclei of unknown relation to therapeutic response., Competing Interests: Conflict of Interest Dr. Arnold reported holding the Alberta Innovates Translational Health Chair in Child and Youth Mental Health outside the submitted work. Prof. Mataix-Cols receives royalties for contributing articles to UpToDate, Wolters Kluwer Health and fees from Elsevier for editorial tasks (all unrelated to the submitted work). Dr. Narayanaswamy reported Government of India grants DST INSPIRE faculty grant IFA12-LSBM-26 and BT/06/IYBA/2012 outside the submitted work. Dr. Reddy reported Government of India grants SR/S0/HS/0016/2011 and BT/PR13334/Med/30/259/2009 outside the submitted work. Dr. Venkatasubramanian reported Wellcome-DBT India Alliance grant 500236/Z/11/Z outside the submitted work. Dr. Simpson reported Biohaven Research support for a clinical trial and royalties from UpToDate, Inc. and Cambridge University Press outside the submitted work. Dr. Soreni reported support from Lundbeck-IIT outside the submitted work. Dr. Walitza has received in the last 3 years royalties from Thieme Hogrefe, Kohlhammer, Springer, Beltz; Her work was supported in the last 3 years by the Swiss National Science Foundation (SNF), diff. EU FP7s, HSM Hochspezialisierte Medizin of the Kanton Zurich, Switzerland, Bfarm Germany, ZInEP, Hartmann Müller Stiftung, Olga Mayenfisch, Gertrud Thalmann Fonds (all unrelated to the submitted work). Dr. Thompson has received a research grant from Biogen, Inc., unrelated to the topic of this paper., (Copyright © 2022. Published by Elsevier B.V.)

Evidence of sensitization following stimulants administration in humans is just emerging, which prevents reaching more definitive conclusions in favor or against a purported protective role of stimulant treatments for ADHD for the development of substance use disorders. Existing evidence from both animal and human research suggest that stimulants produce neurophysiological changes in the brain reward system, some of which could be persistent. This could be relevant in choosing optimal treatments for young patients with ADHD who have additional clinical risk factors for substance abuse (e.g. conduct disorder (CD) and/or familial addictions). Here we stipulate that, while the majority of youth with ADHD greatly benefit from treatments with stimulants, there might be a subpopulation of individuals whose neurobiological profiles may confer risk for heightened vulnerability to the effects of stimulants on the responsiveness of the brain reward system. We propose that focused human research is needed to elucidate the unknown effects of prolonged stimulant exposure on the neurophysiology of the brain reward system in young patients with ADHD., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

While pharmacological treatments for psychiatric disorders have offered great promise and have provided clinically meaningful symptom relief these treatments have had less effect on altering the course of these disorders. Research has provided many new insights about the effects of different psychotropic agents on the functions of various brain systems as investigators have embraced the "translational research model." However, this theoretical approach of deconstructing complex behaviors into smaller measurable behavioral units and targeting brain systems that are hypothesized to underlie these discrete behaviors has offered little of practical clinical relevance to significantly improve the treatment of psychiatric disorders in this century. Radical new treatments have not emerged, and available treatments continue to provide symptom relief without resolution of the underlying conditions. Recent publications on the subject have attempted to identify the barriers to progress and have pointed out some of the limitations of the translational approach. It is our position that, given the present limitations of our therapeutic arsenal, both researchers and clinicians would be well-advised to pay closer attention to human specific factors such as the role of language, the creation of personal narratives, and how factors such as these interface with underlying biological diatheses in mental illness. These interactions between pathophysiology and intrapersonal processes may be critical to both the in vivo expression of the underlying biological mechanisms of psychiatric disease states, and to the development of enhancements in therapeutic efficacy. Lastly, we discuss the implications of more coherently integrating neuroscientific research and clinical practice for more effectively addressing the challenges of understanding and treating mental illness., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Ivanov and Schwartz.)

No diagnostic biomarkers are available for obsessive-compulsive disorder (OCD). Here, we aimed to identify magnetic resonance imaging (MRI) biomarkers for OCD, using 46 data sets with 2304 OCD patients and 2068 healthy controls from the ENIGMA consortium. We performed machine learning analysis of regional measures of cortical thickness, surface area and subcortical volume and tested classification performance using cross-validation. Classification performance for OCD vs. controls using the complete sample with different classifiers and cross-validation strategies was poor. When models were validated on data from other sites, model performance did not exceed chance-level. In contrast, fair classification performance was achieved when patients were grouped according to their medication status. These results indicate that medication use is associated with substantial differences in brain anatomy that are widely distributed, and indicate that clinical heterogeneity contributes to the poor performance of structural MRI as a disease marker.

This review summarizes the last decade of work by the ENIGMA (Enhancing NeuroImaging Genetics through Meta Analysis) Consortium, a global alliance of over 1400 scientists across 43 countries, studying the human brain in health and disease. Building on large-scale genetic studies that discovered the first robustly replicated genetic loci associated with brain metrics, ENIGMA has diversified into over 50 working groups (WGs), pooling worldwide data and expertise to answer fundamental questions in neuroscience, psychiatry, neurology, and genetics. Most ENIGMA WGs focus on specific psychiatric and neurological conditions, other WGs study normal variation due to sex and gender differences, or development and aging; still other WGs develop methodological pipelines and tools to facilitate harmonized analyses of "big data" (i.e., genetic and epigenetic data, multimodal MRI, and electroencephalography data). These international efforts have yielded the largest neuroimaging studies to date in schizophrenia, bipolar disorder, major depressive disorder, post-traumatic stress disorder, substance use disorders, obsessive-compulsive disorder, attention-deficit/hyperactivity disorder, autism spectrum disorders, epilepsy, and 22q11.2 deletion syndrome. More recent ENIGMA WGs have formed to study anxiety disorders, suicidal thoughts and behavior, sleep and insomnia, eating disorders, irritability, brain injury, antisocial personality and conduct disorder, and dissociative identity disorder. Here, we summarize the first decade of ENIGMA's activities and ongoing projects, and describe the successes and challenges encountered along the way. We highlight the advantages of collaborative large-scale coordinated data analyses for testing reproducibility and robustness of findings, offering the opportunity to identify brain systems involved in clinical syndromes across diverse samples and associated genetic, environmental, demographic, cognitive, and psychosocial factors.

Longitudinal studies have shown that clinical precursors of antisocial personality disorder (ASPD) include attention-deficit/hyperactivity disorder (ADHD) and more notably comorbid ADHD and conduct disorder (CD). Despite existing evidence for the purported role of abnormal serotonergic function in aggressive youth and adults, little evidence exists on the role of serotonin in the progression from childhood disruptive behavior disorders to adult psychopathology, including ASPD. This study examined the relation between serotonergic function in children diagnosed with ADHD and the development of ASPD in early adulthood. We hypothesized that low serotonin response to a pharmacological probe in childhood would predict the development of adult ASPD. Towards this goal we divided 40 adults (M = 37, F = 3), ages 23-26 (m-24.57, sd-2.33) diagnosed with childhood ADHD into 2 groups: participants with (n = 21) and without (n = 19) ASPD. We used logistic regression to assess whether serotonergic measures in childhood assessed via prolactin and cortisol responses to a fenfluramine challenge, would selectively predict the development of ASPD in early adulthood. Logistic regression models showed that low central serotonergic response in childhood indexed by cortisol response significantly predicted adult ASPD (Wald = 4.427, p = .035) but not ADHD diagnosis in adulthood. Adults without ASPD had the highest serotonergic response whereas adults with adolescent ASPD (i.e. early onset ASPD) had the lowest response. Thus we provide new evidence of the link between low serotonergic function in childhood and the development of ASPD in adulthood, particularly for boys with adolescent onset of ASPD. These findings are relevant for understanding the contribution of childhood neurobiology to risk for later ASPD., (Copyright © 2018. Published by Elsevier B.V.)

Background: Gulf War veterans were exposed to environmental toxins not present in other combat theaters resulting in a unique biological signature that only partially resembles that seen in other combat veterans with PTSD. Thus it is important to determine if brain abnormalities seen in non-Gulf War veterans with PTSD are also present in Gulf War veterans. In this pilot study, diffusion tensor imaging (DTI) tractography was used to assess the ultra-structural integrity of fronto-limbic white matter connections in Gulf War veterans with and without PTSD. The effects of chronic multisymptom illness on DTI measures was also evaluated., Methods: Subjects were 20 previously studied Gulf War veterans on whom MRIs had been obtained. Mean diffusivity (MD) and fractional anisotropy (FA) were determined for left and right cingulum bundle by DTI tractography and compared in separate analyses for 12 veterans with, and 8 without PTSD. The effect of chronic multisymptom illness and it's interaction with PTSD, were similarly investigated using multivariate ACOVA. Partial correlations were used to test the associations of both DTI indices with PTSD severity and plasma cortisol, controlling for whole brain volume., Results: Significantly lower MD was demonstrated in the right cingulum bundle among Gulf War veterans with PTSD. There were no significant differences in MD or FA in the left cingulum bundle. The presence of chronic multisymptom illness significantly attenuated the PTSD associated decrement in right cingulum MD. Clinician and self-rated PTSD symptom severity scores were significantly associated with reduced MD and increased FA in the right cingulum. Similar associations were observed for 8am plasma cortisol in a subset of participants., Conclusions: The preliminary findings indicate increased structural integrity - supporting enhanced connectivity - between right amygdala and anterior cingulate cortex in PTSD. This effect was strongest among Gulf War veterans without chronic multisymptom illness. The association of both MD and FA in the right cingulum with PTSD severity, and with heightened glucocorticoid responsivity, suggests that these DTI findings are a reflection of current PTSD illness expression. Although based on a small sample, these microstructural observations are consistent with a functional model suggesting increased amygdala responsivity in association with anterior cingulate modulation in PTSD., (Copyright © 2014. Published by Elsevier Ltd.)

Psychostimulants, such as methylphenidate, are thought to improve information processing in motivation-reward and attention-activation networks by enhancing the effects of more relevant signals and suppressing those of less relevant ones; however the nature of such reciprocal influences remains poorly understood. To explore this question, we tested the effect of methylphenidate on performance and associated brain activity in the Anticipation, Conflict, Reward (ACR) task. Sixteen healthy adult volunteers, ages 21-45, were scanned twice using functional magnetic resonance imaging (fMRI) as they performed the ACR task under placebo and methylphenidate conditions. A three-way repeated measures analysis of variance, with cue (reward vs. non-reward), target (congruent vs. incongruent) and medication condition (methylphenidate vs. placebo) as the factors, was used to analyze behaviors on the task. Blood oxygen level dependent (BOLD) signals, reflecting task-related neural activity, were evaluated using linear contrasts. Participants exhibited significantly greater accuracy in the methylphenidate condition than the placebo condition. Compared with placebo, the methylphenidate condition also was associated with lesser task-related activity in components of attention-activation systems irrespective of the reward cue, and less task-related activity in components of the reward-motivation system, particularly the insula, during reward trials irrespective of target difficulty. These results suggest that methylphenidate enhances task performance by improving efficiency of information processing in both reward-motivation and in attention-activation systems., (Published by Elsevier B.V.)

It is hypothesized that the development of substance abuse (SA) may be due to imbalance in functions of the motivation-reward and behavioral inhibition systems in the brain. This speaks to the search for biological risk factors for SA in drug-naïve children who also exhibit motivational and inhibitory control deficits; however, this type of research is currently lacking. The objective of this study was to establish a neurobiological basis for addiction vulnerability using functional magnetic resonance imaging (fMRI) in drug-naïve youth with attention deficit/hyperactivity disorder (ADHD). We hypothesized that children with ADHD alone would show higher activity in regions of the motivation-reward and behavioral inhibition systems than children with ADHD and a parental history of SA. Toward this goal we scanned 20 drug-naïve children with ADHD ages 8-13 while performing an event-related reward task. High (N=10) and low (N=10) risk subjects were identified, based on parental history of SA. The effects of anticipation, conflict, and reward were assessed with appropriate linear contrasts, and between-group differences were assessed using statistical parametric mapping. The two groups did not differ on behavioral measures of the task. The fMRI results show heightened activation in the brain motivational-reward system and reduced activation of the inhibitory control system in high-risk compared to low-risk children. These results suggest that a functional mismatch between these two systems may represent one possible biological underpinning of SA risk, which is conferred by a parental history of addiction., (Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.)

Neurodegenerative dementias represent among the most clinically and pathologically complex syndromes in neuropsychiatry. Phenomenologically protean, and often initially presenting with subtle subsyndromal characteristics, neurodegenerative behavioral syndromes can manifest with an assortment of cognitive, mood, personality, and comportmental changes, often alloyed with elementary neurologic (e.g., motor) signs. A range of pathogenic mechanisms (e.g., amyloid plaques, Pick bodies, etc) typically underlie corresponding clinical syndromes. However, overlap in both clinical expression and histopathologic comorbidities frequently exist among cortical and subcortical neurodegenerative disorders. Moreover, secondary central nervous system pathologies (e.g., cerebrovascular disease) commonly coexist with neurodegenerative processes, further complicating clinical phenomenology-based nosologic categorization. Evolving insight into the etiologic mechanisms of neurodegenerative dementias, and correspondingly improving potential for intervention, require more precise differentiation among dementia subtypes and comprehensive identification of contemporaneous neurodegenerative processes. Increasing appreciation of this diagnostic complexity is prompting the need for renovation of existing diagnostic schemas. We address these issues by reviewing the atypical dementia type known as posterior cortical atrophy. We then use posterior cortical atrophy as an exemplar for renovating neuropsychiatric diagnostic classification to better account for the layered complexity of clinical and pathologic domains needing to be characterized to accurately and completely diagnose neuropsychiatric disturbances., (Copyright © 2011. Published by Elsevier Inc.)

Context: The basal ganglia and thalamus together connect in parallel closed-loop circuits with the cortex. Previous imaging studies have shown modifications of the basal ganglia and cortical targets in individuals with Tourette syndrome (TS), but less is known regarding the role of the thalamus in TS pathogenesis., Objective: To study the morphological features of the thalamus in children and adults with TS., Design: A cross-sectional, case-control study using anatomical magnetic resonance imaging., Setting: University research center., Participants: The 283 participants included 149 with TS and 134 normal control individuals aged 6 to 63 years., Main Outcome Measures: Conventional volumes and measures of surface morphology of the thalamus., Results: Analyses of conventional volumes and surface morphology were consistent in demonstrating an enlargement in TS-affected thalami. Overall volumes were 5% larger in the group composed of children and adults with TS. Statistical maps of surface contour demonstrated enlargement over the lateral thalamus. Post hoc testing indicated that differences in IQ, comorbid illnesses, and medication use did not account for these findings., Conclusions: Morphological abnormalities in the thalamus, together with the disturbances reported in the sensorimotor cortex, striatum, and globus pallidus, support the hypothesis of a circuitwide disorder within motor pathways in TS. The connectivity and function of the numerous and diverse thalamic nuclei within cortical-subcortical circuits constitute an anatomical crossroad wherein enlargement of motor nuclei may represent activity-dependent hypertrophy within this component of cortical-subcortical motor circuits, or an adaptive response within a larger putative compensatory system that could thereby directly modulate activity in motor circuits to attenuate the severity of tics.

Identification of neurobiological factors that confer risk for the development of addiction may substantially advance development of new prevention and treatment strategies to combat substance use disorders. This review focuses on the relationship between impulsivity - a behavior that is common to the clinical picture of both substance use disorders (SUD) and childhood disruptive behavior disorders - and neurobiological risk for SUD. It further examines various behaviors within the over-arching domain of impulsivity, ultimately focusing on the more narrowly defined and measurable construct of inhibitory control, and concluding that underlying deficits in inhibitory control may be central to many of the behaviors associated with high risk for SUD. Targeted cross-sectional study of the neural basis of inhibitory dyscontrol in subjects at high risk for SUD, who have not yet begun to abuse drugs, has the potential to generate important hypotheses regarding the neurobiological underpinnings of SUD risk. Hypotheses developed using this approach can be more definitively evaluated in longitudinal studies with these same populations, extending through the period of maximal risk for SUD in adolescence and early adulthood.