Search

In this paper we discuss the two-system framework, examine its strengths, point out a fundamental weakness concerning the unity of conscious experience, and then propose a new hypothesis that avoids that weakness and other related concerns. According to our strong emergence hypothesis, what emerges are not merely mental properties in specialized, distributed neural areas, but also a new, irreducibly singular entity (i.e., an emergent self) that functions in a recurrent (or top-down) manner to integrate its mental properties and to rewire its brain. We argue that the former function is suggested, in part, by the effects of anesthetics on sensory integration, and that the latter function is suggested by evidence garnered from the neuroscience of mindfulness, constraint-induced movement therapy for stroke, and neuroimaging data surrounding mental illness. We then discuss how our strong emergence hypothesis relates to the description and treatment of neuropsychiatric disorders. Finally, potential objections are addressed.

Immigration is a rich experience, probably like no other, in relation to both unexpected and even unimagined returns but also colossal difficulties. One of the most fascinating aspects of immigration is learning the language of your newly adopted home. I don't mean simply learning the basics, but attempting to master the nuances of expression, the word play, and the subtleties of phrase choices.

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.

Background: The objective of this study was to examine changes in the activation of the brain reward system following treatment with lisdexamfetamine (LDX) vs. placebo (PL) as a function of clinical improvement in attention deficit/hyperactivity disorder (ADHD) symptoms. Methods: Twenty adults with ADHD were included in a randomized cross-over study. Participants underwent two functional magnetic resonance imaging (fMRI) scans, after receiving 3 to 5 weeks of treatment with both LDX and PL. During scanning, participants performed the passive-avoidance learning task to assess reward-related learning using computational variables (e.g., estimated value and prediction error). Pre-treatment to post-treatment symptom change was assessed via the ADHD Rating Scale (ADHD-RS). The imaging contrasts were Object Choose or Object Refuse during the object choice component of the task, modulated by expected value (reward vs. nonreward cue), and Reward vs. Punishment during feedback, modulated by prediction error (expected vs. actual outcome). To address the primary objective, we performed group-level mass univariate analyses between pre-treatment to post-treatment percent change of the ADHD-RS total scores and the four contrast images under the choice and feedback conditions, with significance set at a whole-brain voxel-wise threshold of p < .05 with family-wise error (FWE) correction and an extent (cluster) threshold of 50 contiguous voxels. Results: Improvement in ADHD symptoms was accompanied by significant increases of brain activation during the Object Refuse, Reward and Punishment contrasts in a widespread network including left caudate and putamen, and right orbitofrontal cortex (i.e., reward-related signaling) and left middle frontal, superior frontal, and precentral gyri (i.e., executive control). Conclusions: These findings are the first to show that the increase in responsiveness of systems engaged in reward processing with LDX treatment is positively related to symptom improvement. Results support the hypothesis that LDX treatment may restore balance to dysfunction (e.g., hypoactivation) within the brain reward circuitry in adults with ADHD.

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. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material.

ObjectiveNo diagnostic biomarkers are available for obsessive-compulsive disorder (OCD). Magnetic resonance imaging (MRI) studies have provided evidence for structural abnormalities in distinct brain regions, but effect sizes are small and have limited clinical relevance. To investigate whether individual patients can be distinguished from healthy controls, we performed multivariate analysis of structural neuroimaging data from the ENIGMA-OCD consortium.MethodWe included 46 data sets with neuroimaging and clinical data from adult (≥18 years) and pediatric (1images from 2,304 OCD patients and 2,068 healthy controls were analyzed using standardized processing to extract regional measures of cortical thickness, surface area and subcortical volume. Machine learning classification performance was tested using cross-validation, and possible effects of clinical variables were investigated by stratification.ResultsClassification performance for OCD versus controls using the complete sample with different classifiers and cross-validation strategies was poor (AUC—0.57 (standard deviation (SD)=0.02;Pcorr=0.19) to 0.62 (SD=0.03;Pcorrcorr>.99) to 0.54 (SD=0.08;Pcorr>.99)). In contrast, good classification performance (>0.8 AUC) was achieved within subgroups of patients split according to their medication status.ConclusionsParcellated structural MRI data do not enable good distinction between patients with OCD and controls. However, classifying subgroups of patients based on medication status enables good identification at the individual subject level. This underlines the need for longitudinal studies on the short- and long-term effects of medication on brain structure.

Neuroimaging has played an important part in advancing our understanding of the neurobiology of obsessive?compulsive disorder (OCD). At the same time, neuroimaging studies of OCD have had notable limitations, including reliance on relatively small samples. International collaborative efforts to increase statistical power by combining samples from across sites have been bolstered by the ENIGMA consortium; this provides specific technical expertise for conducting multi-site analyses, as well as access to a collaborative community of neuroimaging scientists. In this article, we outline the background to, development of, and initial findings from ENIGMA's OCD working group, which currently consists of 47 samples from 34 institutes in 15 countries on 5 continents, with a total sample of 2,323 OCD patients and 2,325 healthy controls. Initial work has focused on studies of cortical thickness and subcortical volumes, structural connectivity, and brain lateralization in children, adolescents and adults with OCD, also including the study on the commonalities and distinctions across different neurodevelopment disorders. Additional work is ongoing, employing machine learning techniques. Findings to date have contributed to the development of neurobiological models of OCD, have provided an important model of global scientific collaboration, and have had a number of clinical implications. Importantly, our work has shed new light on questions about whether structural and functional alterations found in OCD reflect neurodevelopmental changes, effects of the disease process, or medication impacts. We conclude with a summary of ongoing work by ENIGMA-OCD, and a consideration of future directions for neuroimaging research on OCD within and beyond ENIGMA.

Objectives: We will review clinical impacts and explore overlapping symptoms and neurobiological functional domains. Practical approaches to engaging families and a transdiagnostic approach to understanding and treating co-occurring trauma and substance use disorders (SUDs) in adolescents will be presented. Methods: First, Destiny Pegram, MD, will present a case vignette to demonstrate the interaction of early-life trauma and SUD. She will highlight the prevalence, risk factors, and treatment outcome implications of co-occurring trauma and SUD. Iliyan Ivanov, MD, will provide an update on trauma and SUD in the context of the COVID-19 pandemic. Second, Jesse Hinckley, MD, PhD, will discuss the biologic intersections of trauma and SUD. He will present clinical vignettes to illustrate overlapping symptoms and functional domains, review shared neurobiological factors, and explore how these factors may maintain or exacerbate the co-occurring disorders. Third, Abita Raj, MD, will present video clinical vignettes to demonstrate Solution-Focused Brief Therapy as an evidence-based approach to engage families in the treatment of trauma and SUD. Fourth, Liza Suarez, PhD, will present an integrated treatment approach for youth with traumatic stress and co-occurring substance use problems. Steve Berkowitz, MD, director of the Stress, Trauma, Adversity Research, and Treatment (START) Center at the University of Colorado and co-chair of the AACAP Disaster and Trauma Issues Committee will serve as the discussant. Results: At the end of this Clinical Perspectives, participants will identify the importance of co-occurring trauma and SUD and will better understand the clinical and biological factors that maintain or exacerbate co-occurring disorders. Participants will learn best practices and practical approaches for screening in a trauma-informed process and for implementing Solution-Focused Brief Therapy to engage families in treatment. Participants will be introduced to a transdiagnostic approach to understand and treat co-occurring PTSD and SUD in adolescents through an in-depth case presentation. Conclusions: Trauma and SUD commonly co-occur in youth. There is a need for mental health clinicians to implement trauma-informed screening processes and to identify principles of treating these co-occurring disorders. SUD, TRA, FAM

The human brain is arguably the most complex information processing system. It operates by acquiring data from the environment, recognizing patterns of events’ occurrence, anticipating their re-occurrence and in turn generating appropriate behavioral responses. Through the lenses of the free-energy principle any self-organizing system that is at equilibrium with its environment must minimize its free energy either by manipulating the environmental sensory input or by manipulating its internal states thus altering the recognition density of the outside stimuli. However, several sets of challenges interfere with the human brain's ability to learn and adapt in such a theoretically optimal fashion. These may include, and are not limited to, functional inconsistencies related to attention and memory processes, the functions of “fast” and “slow” thinking and responding, and the ability of emotional states to generate unintended behavioral outcomes that are less adaptive or inappropriate. This paper will review literature on the subject of how ideal learning viewed from the free-energy principle perspective may be affected by the above mentioned limitations and will suggest a model of information processing that may have developed as a way of overcoming these challenges. This neurobiological model stipulates that a neuronal network is formed in response to environmental input and is paralleled by at least one and possibly multiple networks that activate intrinsically and represent “virtual responses” to a situation that demands a behavioral response. This model accounts for how the brain generates a multiplicity of potential behavioral responses and may “choose” the one that seems most appropriate and also explains the uncanny ability of humans to socialize and collaborate. Implications for understanding humans’ ability to learn from others, deliberate on opposing constructs and access and utilize information outside of individual minds are also discussed.

The purpose of this review was to understand the impact of second generation antipsychotic (SGA)-induced weight gain on youth with autism spectrum disorders (ASDs), including the clinical evidence, mechanisms, monitoring guidelines, and treatments. To achieve this, multiple MEDLINE/PUBMED and Google database searches were performed and analyzed articles from January 2001 to April 2018. Existing evidences indicates youth with ASDs may be more prone to SGA-induced weight gain than youth with other psychiatric illnesses. The mechanism by which such weight gain occurs is unclear, but is likely multifactorial. Guidelines have been developed to monitor SGA-induced weight gain, though the existing guidelines have had limited adherence by clinicians. The available randomized control trials that have analyzed the benefit of metformin in youth suffering from SGA-induced weight gain have produced conflicting results, but the data looking specifically at youth with ASD have been positive. Increasing data on use of topiramate, melatonin, and zonisamide to treat SGA-induced weight gain in youth also exists and warrants further study. However, overall, the current understanding of the effect of SGA-induced weight gain on youth with ASD and the therapeutic use of medications like metformin is limited, but the existing literature provides useful guidelines for future research. The clinical algorithms for monitoring and managing SGA-induced weight gain have shown promise; however, their utility in routine clinical practice requires further investigation.

Computational models can be used to enhance the description of behavioral responses that arise from the interaction between the brain and its immediate environment, and mathematical approaches are increasingly being utilized in the attempt to understand how the brain processes sensory data to elicit various behavioral responses. Computational psychiatry is the application of computational models to understanding psychopathology, with the modelling of mood and anxiety disorders becoming an area of particular interest. Various approaches to constructing these models have been suggested. For example, some investigators have proposed that distinguishing between “mood” and “emotions” is a key to computational modeling in studying depression, while others have pointed out that clinical phenomena related to the experience of depression and anxiety may be best accounted for by computational approaches to narratives patients construct to attempt to “make sense” of their biological condition. The growth and dynamic interaction of these various approaches has become an area with increasing potential for clinical application. This paper presents a broad overview of the existing literature on the use of computational modeling in mood and anxiety disorders, as well as recent publications outlining the application of other related translational methods in psychiatry. We also present some original ideas on how Bayesian computational approaches can help explain the effects of attentional focus on brain function, and the how this relates to the utility of computational modeling for enhancing treatment interventions.

In this article, we review several new psychosocial and psychopharmacologic treatment approaches for attention deficit hyperactivity disorder (ADHD). Several of the treatments reviewed are promising and offer opportunities for augmenting current evidence-based approaches. However, others are not yet ready for prime time. Consequently, existing algorithms for ADHD treatment should still be followed. Current guidelines include those from the American Academy of Pediatrics (Wolraich et al. Pediatrics. 128 5:1007–22 2011), the American Academy of Child and Adolescent Psychiatry (AACAP) (Pliszka S and AACAP Work Group on Quality Issues. J Am Acad Child Adolesc Psychiatry. 46 7:894–921 2007), and the Texas Department of Mental Health and Mental Retardation (Pliszka et al. J Am Acad Child Adolesc Psychiatry. 45 6:642–57 2006). These treatment recommendations and algorithms are based on results from both controlled clinical trials and expert opinion. For core symptoms, medication is considered superior to psychosocial treatment. However, the full range of ADHD-associated impairments is best addressed by combined treatment, with an emphasis on behavioral interventions as first-line approaches when treating preschool children with ADHD. The availability of an evidence-based organizational skills training program is a welcome addition for targeting problems with organization and attention-related impairments in children. Among available medication treatments, stimulants are considered to have the most robust effects on core symptoms; however several non-stimulant medications are available and others are being investigated for possible utility. Combined pharmacotherapy with stimulants and α2 agonists is now an FDA-approved treatment and can be considered in youth who are not fully responsive to stimulants or who have other problems which may represent indications for α2 agonist treatment. Combined treatment with stimulants plus risperidone has merit in youth with severe aggressive behavior but remains off-label and should generally be considered when other options fail. The potential risk and benefits of stimulant treatment for subsequent substance abuse remains an important topic. In the main, stimulant treatment is considered safe and may even provide protection against development of substance abuse. However, the possibility that stimulant exposure could be problematic in youth with elevated risk for substance abuse disorders should be considered.

Summary 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.

The long-term effects of blast exposure are a major health concern for combat veterans returning from the recent conflicts in Iraq and Afghanistan. We used an optimized diffusion tensor imaging tractography algorithm to assess white matter (WM) fractional anisotropy (FA) in blast-exposed Iraq and Afghanistan veterans (n = 40) scanned on average 3.7 years after deployment/trauma exposure. Veterans diagnosed with a blast-related mild traumatic brain injury (mTBI) were compared to combat veterans with blast exposure but no TBI diagnosis. Blast exposure was associated with decreased FA in several WM tracts. However, total blast exposure did not correlate well with neuropsychological testing performance and there were no differences in FA based on mTBI diagnosis. Yet, veterans with mTBI performed worse on every neurocognitive test administered. Multiple linear regression across all blast-exposed veterans using a six-factor prediction model indicated that the amount of blast exposure accounted for 11–15% of the variability in composite FA scores such that as blast exposure increased, FA decreased. Education accounted for 10% of the variability in composite FA scores and 25–32% of FA variability in the right cingulum, such that as level of education increased, FA increased. Total blast exposure, age, and education were significant predictors of FA in the left cingulum. We did not find any effect of post-traumatic stress disorder on cognition or composite FA. In summary, our findings suggest that greater total blast exposure is a contributing factor to poor WM integrity. While FA was not associated with neurocognitive performance, we hypothesize that FA changes in the cingulum in veterans with multiple combat exposures and no head trauma prior to deployment may represent a marker of vulnerability for future deficits. Future work needs to examine this longitudinally.

Background: Despite the known importance of impaired social functioning in the pathway to psychosis, there is no clear understanding about the etiological underpinnings of this relationship. A number of hypothesis have been proposed, including the idea that (1) social impairment is an independent contributor to psychosis risk, (2) social impairment and psychosis are two independent outings of the same genetic vulnerability, and that (3) social impairment may be the confounding results from brain abnormalities that are directly associated with psychosis risk. Our objective was to combine imaging, clinical and genome-wide association data to dissect how early disruptions in social functioning are related to psychotic experiences.

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.

The cerebellum is emerging as a key anatomical structure underlying normal attentional and cognitive control mechanisms. Dysregulation within cerebellar circuits may contribute to the core symptoms of Attention Deficit/Hyperactivity Disorder (ADHD). In the present study we aimed to characterize surface morphological features of the cerebellum in ADHD and healthy comparison youths. Further, we studied the association of cerebellar morphology with the severity of ADHD symptoms and the effects of stimulant treatment. We examined 46 youths with ADHD and 59 comparison youths 8–18 years of age in a cross-sectional, case–control study using magnetic resonance imaging. Measures of cerebellar surface morphology were the primary outcome. Relative to comparison participants, youths with ADHD exhibited smaller regional volumes corresponding to the lateral surface of the left anterior and the right posterior cerebellar hemispheres. Stimulant medication was associated with larger regional volumes over the left cerebellar surface, whereas more severe ADHD symptoms were associated with smaller regional volumes in the vermis. We used optimized measures of morphology to detect alterations in cerebellar anatomy specific to ADHD, dimensions of symptomology, and stimulant treatment. Duration of treatment correlated positively with volumes of specific cerebellar subregions, supporting a model whereby compensatory morphological changes support the effects of stimulant treatment.

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 ( F 1,30 = 17.00; p 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 ( F 1,30 = 14.99; p 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.

Several models have been proposed to explain the progression from drug experimentation to regular use and addiction in persons with heritable risk. These include a two-factor model of the relationship between behavioral activation (i.e., decreased reward sensitivity) and behavioral control (i.e., decreased behavioral control). However, a more complex model suggests that different groups of individuals at risk exhibit different patterns of behavioral deficits. For instance, some at-risk individuals may show increased reward/sensation seeking and preference for smaller immediate rewards when others may show decreased reward sensitivity but also compromised ability to withhold behaviors that lead to negative outcomes. Physiological and neuroimaging studies have identified brain regions in individuals with familial substance use disorders (SUDs) that show different structural and functional patterns compared to unaffected controls. Although existing evidence prevents us from drawing a firm conclusion as to whether over- or underresponsive reward systems mediate the familial risk for developing SUDs, it is plausible that alterations in reward processing and behavioral control present a common deficit in individuals at familial risk for SUD.

Existing evidence suggests that reward and attentional networks function in concert and that activation in one system influences the other in a reciprocal fashion; however, the nature of these influences remains poorly understood. We therefore developed a three-component task to assess the interaction effects of reward anticipation and conflict resolution on the behavioral performance and the activation of brain reward and attentional systems. Sixteen healthy adult volunteers aged 21–45 years were scanned with functional magnetic resonance imaging (fMRI) while performing the task. A two-way repeated measures analysis of variance (ANOVA) with cue (reward vs. non-reward) and target (congruent vs. incongruent) as within-subjects factors was used to test for main and interaction effects. Neural responses to anticipation, conflict, and reward outcomes were tested. Behaviorally there were main effects of both reward cue and target congruency on reaction time. Neuroimaging results showed that reward anticipation and expected reward outcomes activated components of the attentional networks, including the inferior parietal and occipital cortices, whereas surprising non-rewards activated the frontoinsular cortex bilaterally and deactivated the ventral striatum. In turn, conflict activated a broad network associated with cognitive control and motor functions. Interaction effects showed decreased activity in the thalamus, anterior cingulated gyrus, and middle frontal gyrus bilaterally when difficult conflict trials (e.g., incongruent targets) were preceded by reward cues; in contrast, the ventral striatum and orbitofrontal cortex showed greater activation during congruent targets preceded by reward cues. These results suggest that reward anticipation is associated with lower activation in attentional networks, possibly due to increased processing efficiency, whereas more difficult, conflict trials are associated with lower activity in regions of the reward system, possibly because such trials are experienced as less rewarding.

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-naive 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-naive 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-naive 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.

To examine late adolescent substance use outcomes in relation to childhood conduct disorder (CD) and psychostimulant treatment in urban youth found to have attention-deficit/hyperactivity disorder (ADHD) in childhood.Ninety-seven adolescents, evaluated during childhood, were seen for follow-up on average 9.30 (SD = 1.65) years later along with a well-matched never-ADHD control group. Stimulant treatment history was coded: Never (n = 28), up to 1 year (n = 19), 1 to 5 years (n = 28), and greater than 5 years (n = 22). Substance use at outcome was coded dimensionally for severity (frequency × intensity) and categorically for substance use disorders (SUDs).Individuals with ADHD+CD in childhood had significantly higher rates of SUD and substance use severity than those with childhood ADHD and controls. The ADHD and control groups did not differ significantly. Among those with childhood ADHD, there were no significant differences in SUD status or substance use severity as a function of medication history.Within an ethnically diverse urban sample, the increased rate of substance use associated with ADHD was fully accounted for by the presence of CD. These results extend previous findings indicating little impact of psychostimulant treatment on later substance use to an ethnically diverse urban sample and to individuals who received treatment for up to 12 years.

The role of the thalamus in the genesis of attention deficit hyperactivity disorder (ADHD) remains poorly understood. The authors used anatomical MRI to examine the morphology of the thalamus in youths with ADHD and healthy comparison youths.The authors examined 46 youths with ADHD and 59 comparison youths 8-18 years of age in a cross-sectional case-control study. Conventional volumes and measures of surface morphology of the thalamus served as the main outcome measures.A mixed-effects model comparing whole thalamic volumes revealed no significant differences between groups. Maps of the thalamic surface revealed significantly smaller regional volumes bilaterally in the pulvinar in youths with ADHD relative to comparison subjects. Post hoc analyses showed that ADHD patients who received stimulants (N=31) had larger conventional thalamic volumes than untreated youths with ADHD, and maps of the thalamic surface showed enlargement over the pulvinar in those receiving stimulants. Smaller regional volumes in the right lateral and left posterior thalamic surfaces were associated with more severe hyperactivity symptoms, whereas larger regional volumes in the right medial thalamic surfaces were associated with more severe symptoms of inattention.These findings demonstrate reduced pulvinar volumes in youths with ADHD and indicate that this same area is relatively enlarged in patients treated with stimulants compared to those untreated. Associations of hyperactivity scores with smaller regional volumes on the lateral thalamic surface and inattention scores with larger regional volumes on the medial thalamic surface suggest the differential involvement of thalamic subcircuits in the pathogenesis of differing ADHD symptoms.

Developmental stuttering is a neuropsychiatric condition of incompletely understood brain origin. Our recent functional magnetic resonance imaging study indicates a possible partial basis of stuttering in circuits enacting self-regulation of motor activity, attention, and emotion.To further characterize the neurophysiology of stuttering through in vivo assay of neurometabolites in suspect brain regions.Proton chemical shift imaging of the brain was performed in a case-control study of children and adults with and without stuttering. Recruitment, assessment, and magnetic resonance imaging were performed in an academic research setting.Ratios of N-acetyl-aspartate plus N-acetyl-aspartyl-glutamate (NAA) to creatine (Cr) and choline compounds (Cho) to Cr in widespread cerebral cortical, white matter, and subcortical regions were analyzed using region of interest and data-driven voxel-based approaches.Forty-seven children and adolescents aged 5 to 17 years (22 with stuttering and 25 without) and 47 adults aged 21 to 51 years (20 with stuttering and 27 without) were recruited between June 2008 and March 2013. The mean (SD) ages of those in the stuttering and control groups were 12.2 (4.2) years and 13.4 (3.2) years, respectively, for the pediatric cohort and 31.4 (7.5) years and 30.5 (9.9) years, respectively, for the adult cohort. Region of interest-based findings included lower group mean NAA:Cr ratio in stuttering than nonstuttering participants in the right inferior frontal cortex (-7.3%; P = .02), inferior frontal white matter (-11.4%; P .001), and caudate (-10.6%; P = .04), while the Cho:Cr ratio was higher in the bilateral superior temporal cortex (left: +10.0%; P = .03 and right: +10.8%; P = .01), superior temporal white matter (left: +14.6%; P = .003 and right: +9.5%; P = .02), and thalamus (left: +11.6%; P = .002 and right: +11.1%; P = .001). False discovery rate-corrected voxel-based findings were highly consistent with region of interest findings. Additional voxel-based findings in the stuttering sample included higher NAA:Cr and Cho:Cr ratios (regression coefficient, 197.4-275; P .001) in the posterior cingulate, lateral parietal, hippocampal, and parahippocampal cortices and amygdala, as well as lower NAA:Cr and Cho:Cr ratios (regression coefficient, 119.8-275; P .001) in the superior frontal and frontal polar cortices. Affected regions comprised nodes of the Bohland speech-production (motor activity regulation), default-mode (attention regulation), and emotional-memory (emotion regulation) networks. Regional correlations were also observed between local metabolites and stuttering severity (r = 0.40-0.52; P = .001-.02).This spectroscopy study of stuttering demonstrates brainwide neurometabolite alterations, including several regions implicated by other neuroimaging modalities. Prior ascription of a role in stuttering to inferior frontal and superior temporal gyri, caudate, and other structures is affirmed. Consistent with prior functional magnetic resonance imaging findings, these results further intimate neurometabolic aberrations in stuttering in brain circuits subserving self-regulation of speech production, attention, and emotion.

Background : Attention deficit hyper activity disorder (ADHD) is a developmental disorder, most often diagnosed in childhood, and characterized by hyperactivity and inattention that negatively impacts one’s ability to function and fulfill social and personal obligations. Individuals with past history of ADHD may enlist in the military under certain conditions, however the full impact of military training and deployment of later in life ADHD symptoms is unclear. It is of particular interest how military experience may affect ADHD in remission and if such individuals might be at elevated risk for relapse of ADHD symptoms. Method : We performed a systematic review f the available literature including the Department of Defense (DOD) guidelines for both eligibility to enlist and fitness for deployment based on reported history and current symptomatology of ADHD. Results : The after care for veterans with ADHD relapse is inconsistent and presents with number of challenges. We evaluate the DOD policies regarding the implications of ADHD for fitness for military service and post-combat mental health. Conclusion : The full extend of the interaction between pre-existing ADHD and post-combat PTSD are not fully understood. The development of comprehensive and clear algorithms for diagnosing and treating ADHD in the military before and after deployment will have a strong positive impact on the quality of care delivered to soldiers and veterans. Keywords : ADHD; military; PTSD Responsible Editor: Eric Vermetten, Central Military Hospital, University Medical Center Utrecht, Netherlands. This paper is part of the Special Issue: PTSD in the military: prevalence, pathophysiology, treatment . More papers from this issue can be found at http://www.eurojnlofpsychotraumatol.net (Published: 14 August 2014) Citation : European Journal of Psychotraumatology 2014, 5 : 23894 - http://dx.doi.org/10.3402/ejpt.v5.23894

CONTEXT Attention-deficit/hyperactivity disorder (ADHD) is a highly prevalent and impairing psychiatric disorder that affects both children and adults. There are Food and Drug Administration-approved stimulant and nonstimulant medications for treating ADHD; however, little is known about the mechanisms by which these different treatments exert their therapeutic effects. OBJECTIVE To contrast changes in brain activation related to symptomatic improvement with use of the stimulant methylphenidate hydrochloride vs the nonstimulant atomoxetine hydrochloride. DESIGN Functional magnetic resonance imaging before and after 6 to 8 weeks of treatment with methylphenidate (n = 18) or atomoxetine (n = 18) using a parallel-groups design. SETTING Specialized ADHD clinical research program at Mount Sinai School of Medicine, New York, New York. PARTICIPANTS Thirty-six youth with ADHD (mean [SD] age, 11.2 [2.7] years; 27 boys) recruited from randomized clinical trials. MAIN OUTCOME MEASURES Changes in brain activation during a go/no-go test of response inhibition and investigator-completed ratings on the ADHD Rating Scale-IV-Parent Version. RESULTS Treatment with methylphenidate vs atomoxetine was associated with comparable improvements in both response inhibition on the go/no-go test and mean (SD) improvements in ratings of ADHD symptoms (55% [30%] vs 57% [25%]). Improvement in ADHD symptoms was associated with common reductions in bilateral motor cortex activation for both treatments. Symptomatic improvement was also differentially related to gains in task-related activation for atomoxetine and reductions in activation for methylphenidate in the right inferior frontal gyrus, left anterior cingulate/supplementary motor area, and bilateral posterior cingulate cortex. These findings were not attributable to baseline differences in activation. CONCLUSIONS Treatment with methylphenidate and atomoxetine produces symptomatic improvement via both common and divergent neurophysiologic actions in frontoparietal regions that have been implicated in the pathophysiology of ADHD. These results represent a first step in delineating the neurobiological basis of differential response to stimulant and nonstimulant medications for ADHD.

This chapter examines how the behavioral trait of impulsivity, when present in childhood as feature of disruptive behavior disorders such as attention deficit/hyperactivity disorder (ADHD) and conduct disorder (CD), may contribute to the development of substance abuse disorders in adolescence. We discuss the relationship between the constructs of impulsivity and inhibitory control deficits and review their clinical manifestations in youth with ADHD and CD. We also review evidence suggesting that high levels of impulsivity in children can be viewed as a predictor of later substance abuse, and provide information about the possible biological underpinnings of such risk factors. The hypotheses that biological factors could potentially mediate the transition from drug experimentation to drug abuse and dependence is important for the development of prevention and treatment strategies to combat different types of addiction. Clinical considerations related to biological and psychological therapeutic interventions for impulsive types of behaviors in childhood and adolescence are also discussed.

Disturbances in the basal ganglia portions of cortico-striato-thalamo-cortical circuits likely contribute to the symptoms of attention deficit hyperactivity disorder (ADHD). The authors examined the morphologic features of the basal ganglia nuclei (caudate, putamen, and globus pallidus) in children with ADHD.A total of 104 individuals (combined-type ADHD patients: N=47; healthy comparison subjects: N=57), aged 7 to 18 years, were examined in a cross-sectional case-control study using anatomical magnetic resonance imaging. Conventional volumes and the surface morphology for the basal ganglia were measured.Overall volumes were significantly smaller only in the putamen. Analysis of the morphological surfaces revealed significant inward deformations in each of the three nuclei, localized primarily in portions of these nuclei that are components of limbic, associative, and sensorimotor pathways in the cortico-striato-thalamo-cortical circuits in which these nuclei reside. The more prominent these inward deformations were in the patient group, the more severe the ADHD symptoms. Surface analyses also demonstrated significant outward deformations of all basal ganglia nuclei in the ADHD children treated with stimulants compared with those ADHD youth who were untreated. These stimulant-associated enlargements were in locations similar to the reduced volumes detected in the ADHD group relative to the comparison group. The outward deformations associated with stimulant medications attenuated the statistical effects of the primary group comparisons.These findings potentially represent evidence of anatomical dysregulation in the circuitry of the basal ganglia in children with ADHD and suggest that stimulants may normalize morphological features of the basal ganglia in children with the disorder.

This study compared the methylphenidate (MPH) dose-response profiles of children with the Predominantly Inattentive (PI) and Combined (CB) subtypes of attention-deficit/hyperactivity disorder (ADHD). It is the first such study to enroll a sample comprised exclusively of children, all but one of whom had no prior exposure to ADHD medications.The design was a double-blind crossover with 1-week exposures to placebo and low, medium, and high, fixed, three times daily (t.i.d.) dosage regimens of immediate-release MPH, administered in random order. Parents and teachers completed weekly behavioral questionnaires (Conners, Swanson, Kotkin, Agler, M-Flynn and Pelham Scale [SKAMP]) and a child psychiatrist provided weekly ratings of symptom severity (ADHD Rating Scale [ADHD-RS]), side effects (Side Effects Rating Scale), and a Clinical Global Impressions-Severity (CGI-S). In addition, laboratory measures of vigilance (Continuous Performance Test [CPT]) and resistance to cognitive interference (Stroop) were administered weekly.Twenty-five children (15 CB, 10 PI), who met rigorous diagnostic criteria for their ADHD subtype, completed the study. Groups did not differ on demographic variables or severity at baseline. Behavioral questionnaires and clinical ratings indicated significant improvement on MPH for both subtypes but no differences in response profiles of the two groups. Drug effects were predominantly linear for both subtypes. Effects of MPH were significant for the CPT, but not the Stroop, instrument with no differences between ADHD subtypes.Results support the clinical utility of MPH in the treatment of the PI subtype and provide no evidence of differences in response between the subtypes.

Polymorphisms in the 3′ UTR variable number tandem repeat (VNTR) of exon 15 of the dopamine transporter gene (DAT1) have been linked to attention-deficit hyperactivity disorder (ADHD); moreover, variability in DAT1 3′UTR genotype may contribute to both heterogeneity of the ADHD phenotype and differences in response to stimulant medications. The impact of this VNTR on neuronal function in individuals with ADHD remains unclear despite evidence that the polymorphisms influence dopamine transporter expression. Thus, we used event-related functional magnetic resonance imaging to examine the impact of DAT1 3′UTR genotype on brain activation during response inhibition in unmedicated children and adolescents with ADHD. Twenty-one youth with ADHD who were homozygous for the 10-repeat (10R) allele of the DAT1 3′UTR and 12 youth who were carriers of the 9-repeat (9R) allele were scanned while they performed a Go/No-Go task. Response inhibition was modeled by contrasting activation during correct No-Go trials versus correct Go trials. Participants who were homozygous for the DAT1 3′UTR 10R allele and those who had a single 9R allele did not differ on percent of trials with successful inhibition, which was the primary measure of inhibitory control. Yet, youth with the DAT1 3′UTR 10R/10R genotype had significantly greater inhibitory control-related activation than those with one 9R allele in the left striatum, right dorsal premotor cortex, and bilaterally in the temporoparietal cortical junction. These findings provide preliminary evidence that neural activity related to inhibitory control may differ as a function of DAT1 3′UTR genotype in youth with ADHD.

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.

Warning signals evoke an alert state of readiness that prepares for a rapid response by priming a thalamo-frontal-striatal network that includes the dorsolateral prefrontal cortex (DLPFC). Animal models indicate that noradrenergic input is essential for this stimulus-driven activation of DLPFC, but the precise mechanisms involved have not been determined. We tested the role that postsynaptic alpha(2A) adrenoceptors play in the activation of DLPFC evoked by warning cues using a placebo-controlled challenge with the alpha(2A) agonist guanfacine.Sixteen healthy young adults were scanned twice with event-related functional magnetic resonance imaging (fMRI), while performing a simple cued reaction time (RT) task following administration of a single dose of oral guanfacine (1 mg) and placebo in counterbalanced order. The RT task temporally segregates the neural effects of warning cues and motor responses and minimizes mnemonic demands.Warning cues produced a marked reduction in RT accompanied by significant activation in a distributed thalamo-frontal-striatal network, including bilateral DLPFC. Guanfacine selectively increased the cue-evoked activation of the left DLPFC and right anterior cerebellum, although this increase was not accompanied by further reductions in RT. The effects of guanfacine on DLPFC activation were specifically associated with the warning cue and were not seen for visual- or target-related activation.Guanfacine produced marked increases in the cue-evoked activation of DLPFC that correspond to the well-described actions of postsynaptic alpha(2) adrenoceptor stimulation. The current procedures provide an opportunity to test postsynaptic alpha(2A) adrenoceptor function in the prefrontal cortex in the pathophysiology of several psychiatric disorders.

The spontaneously hypertensive rat (SHR) is a widely accepted rodent model of Attention Deficit/Hyperactivity Disorder (ADHD), and methylphenidate (MP) is a central nervous system stimulant that has been shown to have a dose-related positive effect on attention task performance in humans with ADHD. The current study was undertaken to compare SHR to its typical control strain, Wistar–Kyoto (WKY) rats, on the performance of a Visual Stimulus Position Discrimination Task (VSPDT) as well as of the responsiveness of the two rat strains to MP treatment. The rats were initially trained on the VSPDT, in which a light cue was presented randomly at three different cue-light intervals (1 s, 300 ms and 100 ms) over one of two levers, and presses on the lever corresponding to the light cue were reinforced with a food pellet. Once rats reached stable performance, the treatment phase of the study began, during which they received daily intraperitoneal (IP) injections of saline, 2 mg/kg, 5 mg/kg, and 10 mg/kg of MP in a randomized order immediately prior to being tested on the VSPDT. Baseline performance accuracy on the VSPDT did not differ between the groups. Furthermore, a striking strain dissociation was evident in the response of the two strains to treatment; VSPDT performance was substantially disrupted by the 5 and 10 mg/kg dose in the WKY rats but only mildly in the SHR rats. Response omissions were also increased only in WKY rats. Finally, both strains had increased locomotor activity in the operant chamber following MP treatment. These findings point to an important difference in response tendency to MP in the two strains that supports a view that a critical difference between these strains may suggest neurochemical and neuroadaptive differences associated with the behavioral impairments of ADHD.

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.

Anatomical and functional disturbances in corticostriatothalamocortical (CSTC) circuits are thought to contribute to the pathogenesis of Tourette syndrome (TS). Previous imaging studies have suggested the presence of hypoplasia in motor portions of these loops, particularly in the caudate nucleus1,2 and in inferior portions of sensory, motor, and premotor cortices.3 Enlargement in other portions of CSTC circuits, including the frontal and parietal cortices, the hippocampus, and their associated commissural pathways,4–6 are thought to compensate for disturbances in motor pathways and thereby reduce the severity of tic symptoms in persons with TS. The thalamus is an integral component of the CSTC circuits that are involved in the genesis of tic symptoms and their associated compensatory responses. A previous functional magnetic resonance imaging study demonstrated activation of the thalamus, together with the basal ganglia and frontal and parietal cortices, during the willful suppression of tic symptoms.7 The change in activity of the thalamus correlated with the change inactivity of basal ganglia nuclei, suggesting that a coordinated effort between the thalamus and basal ganglia (defined as the striatum, globus pallidus, substantia nigra, and subthalamic nucleus)8 is required to suppress tics. In addition, inducing lesions in or stimulating thalamic subregions may attenuate tics,9,10 whereas space-occupying lesions of the thalamus seem to exacerbate them.11 These and other findings have prompted some to hypothesize that dysregulation of thalamocortical activity may generate tic behaviors.12 Several preliminary anatomical studies have yielded contradictory findings for overall thalamic volume. One reported an increased size of the left hemithalamus in 18 treatment-naive boys with TS.13 Another in which treatment history was unspecified found decreased thalamic volumes in 23 children with TS.14 A third study detected no morphological differences in the thalamus of 15 neuroleptic-naive adults.15 The small numbers of participants, their differing histories of medication use, the differing age and sex compositions of the samples, and the markedly differing image-processing techniques across these studies renders a coherent interpretation of their findings impossible. A large-scale study is needed to clarify the effects of TS on thalamic morphology. We assessed overall thalamic volumes and localized morphological features over individual thalamic subregions in a large sample of children and adults to improve our understanding of the role of the thalamus in the pathophysiological processes of TS. We hypothesized that the volumes of the thalamus and its subregions would differ between diagnostic groups.