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Background. Identifying youth who may engage in future substance use could facilitate early identification of substance use disorder vulnerability. We aimed to identify biomarkers that predicted future substance use in psychiatrically unwell youth. Method. LASSO regression for variable selection was used to predict substance use 24.3 months after neuroimaging assessment in 73 behaviorally and emotionally dysregulated youth aged 13.9 (S.D. = 2.0) years, 30 female, from three clinical sites in the Longitudinal Assessment of Manic Symptoms (LAMS) study. Predictor variables included neural activity during a reward task, cortical thickness, and clinical and demographic variables. Results. Future substance use was associated with higher left middle prefrontal cortex activity, lower left ventral anterior insula activity, thicker caudal anterior cingulate cortex, higher depression and lower mania scores, not using antipsychotic medication, more parental stress, older age. This combination of variables explained 60.4% of the variance in future substance use, and accurately classified 83.6%. Conclusions. These variables explained a large proportion of the variance, were useful classifiers of future substance use, and showed the value of combining multiple domains to provide a comprehensive understanding of substance use development. This may be a step toward identifying neural measures that can identify future substance use disorder risk, and act as targets for therapeutic interventions. [ABSTRACT FROM AUTHOR]

Introduction: Attention deficit hyperactivity disorder (ADHD) is characterized by a lack in self-regulation of behaviour, cognition and emotional response. Children with ADHD often experience emotional dysregulation (ED) defined as the inability to regulate emotions and to organize behaviours in response to emotional stimuli. Objectives: The present exploratory study aimed to evaluate possible peculiar sensitivity to emotional stimuli in children with ADHD and ED, revealed by behavioural performances and cortical hemodynamic characteristics measured with functional Near Infrared Spectroscopy (fNIRS). The relationship between haemodynamic activation during task and ADHD and ED symptoms was also investigated. Methods: Eighteen children with ADHD and ED, all drug naïve, and 25 typically developing (TD) peers, aged 6-16 years, underwent fNIRS while performing a visual emotional continuous performance task in which faces with relevant positive, negative and neutral content were presented. ADHD and ED symptoms were evaluated with Conners' parents rating scales (CPRS). Selected fNIRS sources and detectors see figure1 Results: Between groups comparisons revealed worse performances of ADHD children, with a statistically significant difference for positive blocks and total errors. fNIRS analysis showed higher activation inTDgroup, as measured by higher oxygenated-haemoglobin concentration changes, localized in right prefrontal cortex, regardless from the valence of the emotional stimuli. Correlations conducted between fNIRS activation and CPRS revealed several associations between hemodynamic changes in right prefrontal regions and inattention and hyperactivity, but not ED symptoms. Conclusions: Lack of self-regulation and ED impact on ADHD children ability to process emotional stimuli, as revealed by worse performances and haemodynamic peculiarities in right prefrontal cortex. [ABSTRACT FROM AUTHOR]

Background: Children with attention deficit hyperactivity disorder (ADHD) exhibit behavioral inhibition deficits, which often lead to emotional dysregulation (ED) affecting individual ability to control emotions and behavioral responses. In ADHD, ED is associated with poor outcomes and comorbidities, with both externalizing and internalizing disorders. This work aims to evaluate sensitivity to emotional stimuli in children with ADHD using functional Near Infrared Spectroscopy (fNIRS)., Methods: During frontal fNIRS recording, 20 children with ADHD and 25 typically developing (TD) peers performed a visual continuous performance task with stimuli of different emotional content (i.e., positive, negative, neutral, and control stimuli without emotional content). This is a cognitive task designed to evaluate the ability to recognize emotional stimuli and to deal with emotional interference., Results: The ADHD sample showed more variability in response time to stimuli and more false alarms compared to TD group. fNIRS data showed between-group differences in right prefrontal and frontal cortices, with wider hemoglobin concentration changes in the TD group, during positive, negative, and neutral conditions., Limitations: Owing to the limited possibility of near infrared light to penetrate tissue, fNIRS can only measure cortical activations, while it would be of interest to identify the subcortical areas linked to emotional processing, too., Conclusions: Findings suggest the presence of emotional processing deficits in children with ADHD, as suggested by poor performances on the e-CPT task, and of peculiar sensitivity to emotional stimuli, linked to atypical hemodynamics of right prefrontal and frontal areas., (Copyright © 2020. Published by Elsevier B.V.)

Bipolar disorder (BD) is highly heritable. Thus, studies in first-degree relatives of individuals with BD could lead to the discovery of objective risk markers of BD. Abnormalities in white matter structure reported in at-risk individuals could play an important role in the pathophysiology of BD. Due to the lack of studies with other at-risk offspring, however, it remains unclear whether such abnormalities reflect BD-specific or generic risk markers for future psychopathology. Using a tract-profile approach, we examined 18 major white matter tracts in 38 offspring of BD parents, 36 offspring of comparison parents with non-BD psychopathology (depression, attention-deficit/hyperactivity disorder), and 41 offspring of healthy parents. Both at-risk groups showed significantly lower fractional anisotropy (FA) in left-sided tracts (cingulum, inferior longitudinal fasciculus, forceps minor), and significantly greater FA in right-sided tracts (uncinate fasciculus and inferior longitudinal fasciculus), relative to offspring of healthy parents (P < 0.05). These abnormalities were present in both healthy and affected youth in at-risk groups. Only offspring (particularly healthy offspring) of BD parents showed lower FA in the right superior longitudinal fasciculus relative to healthy offspring of healthy parents (P < 0.05). We show, for the first time, important similarities, and some differences, in white matter structure between offspring of BD and offspring of non-BD parents. Findings suggest that lower left-sided and higher right-sided FA in tracts important for emotional regulation may represent markers of risk for general, rather than BD-specific, psychopathology. Lower FA in the right superior longitudinal fasciculus may protect against development of BD in offspring of BD parents.

Motor control is a ubiquitous aspect of human function, and from its earliest origins, abnormal motor control has been proposed as being central to schizophrenia. The neurobiological architecture of the motor system is well understood in primates and involves cortical and sub-cortical components including the primary motor cortex, supplementary motor area, dorsal anterior cingulate cortex, the prefrontal cortex, the basal ganglia, and cerebellum. Notably all of these regions are associated in some manner to the pathophysiology of schizophrenia. At the molecular scale, both dopamine and γ-Aminobutyric Acid (GABA) abnormalities have been associated with working memory dysfunction, but particularly relating to the basal ganglia and the prefrontal cortex respectively. As evidence from multiple scales (behavioral, regional and molecular) converges, here we provide a synthesis of the bio-behavioral relevance of motor dysfunction in schizophrenia, and its consistency across scales. We believe that the selective compendium we provide can supplement calls arguing for renewed interest in studying the motor system in schizophrenia. We believe that in addition to being a highly relevant target for the study of schizophrenia related pathways in the brain, such focus provides tractable behavioral probes for in vivo imaging studies in the illness. Our assessment is that the motor system is a highly valuable research domain for the study of schizophrenia., (Copyright © 2017 Elsevier Masson SAS. All rights reserved.)

Background: The ventral striatum (VS) and striatal network supports goal motivated behavior. Identifying how depressed patients differ in their striatal network during the processing of emotionally salient events is a step towards uncovering biomarkers for diagnosis and treatment., Methods: 38 depressed and 30 healthy adults completed a task that examined brain activation to the anticipation and receipt of monetary rewards and losses. Data were collected using a 3T Siemens Trio scanner. Functional connectivity differences were examined with seeds in the Left or Right VS. FC estimates were regressed on specific symptoms., Results: Depressed patients displayed higher functional connectivity between the VS and midline cortical areas during loss versus reward trials. Anhedonia and depressed mood were associated to fairly similar striatal circuits but suicidality was associated to a unique VS-midline structures coupling, while depression severity was linked to higher VS to caudate and precuneus connectivity during loss versus reward trials., Conclusions: Depression is characterized by excessive VS coupling to cognitive control and associative networks during losses versus rewards. High VS to midline cortical structures coupling may index suicidality., (Copyright © 2016 Elsevier B.V. All rights reserved.)

The Research Domain Criteria (RDoC) adopts a dimensional approach for examining pathophysiological processes underlying categorically defined psychiatric diagnoses. We used this framework to examine relationships among symptom dimensions, diagnostic categories, and resting state connectivity in behaviorally and emotionally dysregulated youth selected from the Longitudinal Assessment of Manic Symptoms study (n=42) and healthy control youth (n=18). Region of interest analyses examined relationships among resting state connectivity, symptom dimensions (behavioral and emotional dysregulation measured with the Parent General Behavior Inventory-10 Item Mania Scale [PGBI-10M]; dimensional severity measures of mania, depression, anxiety), and diagnostic categories (Bipolar Spectrum Disorders, Attention Deficit Hyperactivity Disorder, Anxiety Disorders, and Disruptive Behavior Disorders). After adjusting for demographic variables, two dimensional measures showed significant inverse relationships with resting state connectivity, regardless of diagnosis: 1) PGBI-10M with amygdala-left posterior insula/bilateral putamen; and 2) depressive symptoms with amygdala-right posterior insula connectivity. Diagnostic categories showed no significant relationships with resting state connectivity. Resting state connectivity between amygdala and posterior insula decreased with increasing severity of behavioral and emotional dysregulation and depression; this suggests an intrinsic functional uncoupling of key neural regions supporting emotion processing and regulation. These findings support the RDoC dimensional approach for characterizing pathophysiologic processes that cut across different psychiatric disorders., (Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.)

Clinical heterogeneity is a confound common to all of schizophrenia research. Deficit schizophrenia has been proposed as a homogeneous disease entity within the schizophrenia syndrome. Utilizing the Schedule for the Deficit Syndrome (SDS) has allowed the definition of a subgroup dominated by persistent clusters of negative symptoms. While a number of studies have appeared over the years examining the electrophysiological correlates of the cluster of negative symptoms in schizophrenia, only a few studies have actually focused on the deficit syndrome (DS). PubMed as well as MEDLINE were searched for all reports indexed for "negative symptoms" or "deficit syndrome" and one of the following electrophysiology assessment tools: electroencephalography (EEG), evoked potentials (EPs), or polysomnography (PSG). While this line of research is evidently in its infancy, two significant trends emerge. First, spectral EEG studies link increased slow wave activity during wakefulness to the prevalence of negative symptoms. Secondly, sleep studies point to an association between decrease in slow wave sleep and prevalence of negative symptoms. Several studies also indicate a relationship of negative symptoms with reduced alpha activity. A host of other abnormalities--including sensory gating and P300 attenuation--are less consistently reported. Two studies specifically addressed electrophysiology of the DS. Both studies provided evidence suggesting that the DS may be a separate disease entity and not simply a severe form of schizophrenia.

Schizophrenia is a complex epigenetic puzzle, the antecedents of which are presumed to lie in neurodevelopmental dysmaturation. This dysmaturation has an impact on children and adolescents at genetic risk for schizophrenia. In this framework, normative mechanisms of brain development that are highly dynamic in adolescence are likely to be disrupted in the at-risk adolescent brain. It is likely that what is affected is the integrity of brain networks that sub-serve fundamental domains of function such as sustained attention. Notably, expansion in proficiency in sustained attention that is characteristic of typical development is likely to be compromised in adolescents at risk for schizophrenia. This confluence of at-risk adolescents and neuro-behavioral domains of inquiry is discussed. We outline the evidence for developmental antecedents of schizophrenia, and their bases in systems and molecular mechanisms in the brain. Then we juxtapose these results against neuro-behavioral evidence of attention deficits in high-risk populations, and fMRI evidence of dysfunctional responses in critical brain regions. We end by advocating the application of systems-based approaches toward understanding the progression of network dysfunction in the adolescent risk-state.

Objective: The functioning of neural systems supporting emotion processing and regulation in youth with bipolar disorder not otherwise specified (BP-NOS) remains poorly understood. We sought to examine patterns of activity and connectivity in youth with BP-NOS relative to youth with bipolar disorder type I (BP-I) and healthy controls (HC)., Method: Participants (18 BP-I youth, 16 BP-NOS youth, and 18 HC) underwent functional magnetic resonance imaging while performing two emotional-face gender labeling tasks (happy/neutral, fearful/neutral). Analyses focused on a priori neural regions supporting emotion processing (amygdala) and emotion regulation (ventromedial prefrontal cortex (VMPFC), dorsolateral prefrontal cortex (DLPFC). Connectivity analyses used VMPFC as a seed region., Results: During the happy-face task, BP-I youth had greater amygdala, VMPFC, and DLPFC activity to happy faces whereas BP-NOS youth had reduced VMPFC and DLPFC activity to neutral faces relative to HC, and reduced amygdala, VMPFC, and DLPFC activity to neutral faces versus BP-I. During the fearful-face task, BP-I youth had reduced DLPFC activity to fearful faces whereas BP-NOS youth had reduced DLPFC activity to neutral faces relative to HC. BP-NOS youth showed greater VMPFC-DLPFC connectivity to happy faces relative to HC and BP-I youth. BP-I youth showed reduced VMPFC-amygdala connectivity to fearful faces relative to HC and BP-NOS youth., Conclusions: This is the first study to document differential patterns of abnormal neural activity in, and connectivity between, neural regions supporting emotion processing and regulation in BP-NOS versus BP-I youth. Findings suggest that despite similarities in symptom presentation, there are differential patterns of abnormal neural functioning in BP-NOS and BP-I relative to HC, which might reflect an "intermediate state" in the course of BP-I illness. Future longitudinal studies are needed to relate these findings with future conversion to BP-I/II., (Copyright © 2011 American Academy of Child and Adolescent Psychiatry. Published by Elsevier Inc. All rights reserved.)

Neurocognitive deficits in schizophrenia (SZ) are thought to be stable trait markers that predate the illness and manifest in relatives of patients. Adolescence is the age of maximum vulnerability to the onset of SZ and may be an opportune "window" to observe neurocognitive impairments close to but prior to the onset of psychosis. We reviewed the extant studies assessing neurocognitive deficits in young relatives at high risk (HR) for SZ and their relation to brain structural alterations. We also provide some additional data pertaining to the relation of these deficits to psychopathology and brain structural alterations from the Pittsburgh Risk Evaluation Program (PREP). Cognitive deficits are noted in the HR population, which are more severe in first-degree relatives compared to second-degree relatives and primarily involve psychomotor speed, memory, attention, reasoning, and social-cognition. Reduced general intelligence is also noted, although its relationship to these specific domains is underexplored. Premorbid cognitive deficits may be related to brain structural and functional abnormalities, underlining the neurobiological basis of this illness. Cognitive impairments might predict later emergence of psychopathology in at-risk subjects and may be targets of early remediation and preventive strategies. Although evidence for neurocognitive deficits in young relatives abounds, further studies on their structural underpinnings and on their candidate status as endophenotypes are needed.

Background: Impaired awareness of the self and others (i.e., metacognitive evaluations) are seen in schizophrenia. We compared patterns of activation in schizophrenia (SZ) and nonclinical subjects during a functional magnetic resonance imaging (fMRI) task of metacognitive evaluations that has been demonstrated to engage the neural circuitry of the self in healthy subjects., Methods: Eleven SZ subjects (7 males, mean age 26.6+/-8) and 10 healthy control subjects (4 males, mean age 29.6+/-8.4) were enrolled. Participants completed two runs of a metacognitive evaluation task (self vs. other vs. word meaning). fMRI data was obtained using a full body Bruker MedSped 4.0Tesla system. Group contrasts were performed using an uncorrected p<0.005 with a 50voxel extent threshold., Results: We observed a significant hypoactivation in the left superior temporal sulcus (STS) during metacognitive evaluations of others (OE) vs. semantic positivity evaluations (SPE) and a trend toward significant hypoactivation in the OE vs. self evaluations (SE) in the SZ group. Significant hypoactivation was also seen in the right inferior temporal gyrus (ITG) in the OE vs. SE contrasts in the SZ group. A trendworthy hypoactivation was seen in the SZ group in the right middle frontal gyrus and pole of the left STS during OE vs. SPE and SE contrasts respectively., Conclusions: These results extend previous findings of impaired metacognitive evaluative processes in schizophrenia to aberrations of the neural circuitry implicated in self/other awareness among SZ patients. Greater understanding of the neural basis of deficits of self/other awareness in early schizophrenia may contribute to improvements in the identification and treatment of individuals at risk for the illness., (2009 Elsevier B.V. All rights reserved.)

Alterations of verbal fluency may correlate with deficits of gray matter volume and hemispheric lateralization of language brain regions like the pars triangularis (PT) in schizophrenia. Examining non-psychotic individuals at high genetic risk (HR) for schizophrenia may clarify if these deficits represent heritable trait markers or state dependent phenomena. We assessed adolescent and young adult HR subjects (N=60) and healthy controls (HC; N=42) using verbal fluency tests and Freesurfer to process T1-MRI scans. We hypothesized volumetric and lateralization alterations of the PT and their correlation with verbal fluency deficits. HR subjects had letter verbal fluency deficits (controlling for IQ), left PT deficits (p=.00), (controlling ICV) and reversal of the L>R PT asymmetry noted in HC. Right Heschl's (p=.00), left supramarginal (p=.00) and right angular gyrii (p=.02) were also reduced in HR subjects. The L>R asymmetry of the Heschl's gyrus seen in HC was exaggerated and asymmetries of L>R of supramarginal and R>L of angular gyri, seen in HC were attenuated in HR subjects. L>R asymmetry of the PT predicted better verbal fluency across the pooled HR and HC groups. Young relatives of schizophrenia patients have verbal fluency deficits, gray matter volume deficits and reversed asymmetry of the pars triangularis. A reversed structural asymmetry of the PT in HR subjects may impair expressive language abilities leading to verbal fluency deficits. Volumetric deficits and altered asymmetry in inferior parietal and Heschl's gyrii may accompany genetic liability to schizophrenia.

Background: Previous research has demonstrated that heavy prenatal alcohol exposure affects the size and shape of the corpus callosum (CC) and compromises interhemispheric transfer of information. The aim of this study was to confirm the previous reports of poorer performance on a finger localization test (FLT) of interhemispheric transfer in a cohort of heavily exposed children and to extend these findings to a cohort of moderately exposed young adults., Methods: In Study 1, the FLT was administered to 40 heavily exposed and 23 nonexposed children from the Cape Coloured community of Cape Town, South Africa, who were evaluated for fetal alcohol syndrome (FAS) dysmorphology and growth. Anatomical images of the CC were obtained using structural MRI on a subset of these children. In Study 2, the FLT was administered to a cohort of 85 moderate-to-heavily exposed young adults participating in a 19-year follow-up assessment of the Detroit Prenatal Alcohol Exposure cohort, whose alcohol exposure had been ascertained prospectively during gestation., Results: In Study 1, children with FAS showed more transfer-related errors than controls after adjustment for confounding, and increased transfer-related errors were associated with volume reductions in the isthmus and splenium of the CC. In Study 2, transfer-related errors were associated with quantity of alcohol consumed per occasion during pregnancy. More errors were made if the mother reported binge drinking (> or =5 standard drinks) during pregnancy than if she drank regularly (M > or = 1 drink/day) without binge drinking., Conclusions: These findings confirm a previous report of impaired interhemispheric transfer of tactile information in children heavily exposed to alcohol in utero and extend these findings to show that these deficits are also seen in more moderately exposed individuals, particularly those exposed to binge-like pregnancy drinking.

Background: Neurological Examination Abnormalities (NEA, often called "neurological soft signs") have been observed in early schizophrenia and may be heritable. We investigated the prevalence, and neurocognitive and psychopathological correlates of NEA among offspring of schizophrenia patients who are at increased genetic risk for this illness., Methods: Neurological examinations were conducted on high risk (HR, n=74) and healthy comparison subjects (HS, n=86), using the Heinrichs-Buchanan scale. Cognitive-perceptual (CogPer) and repetitive motor (RepMot) subscores, and total NEA scores were computed. All HR and HS were assessed using K-SADS/SCID for diagnoses. Schizotypy was measured using the Magical Ideation and the Perceptual Aberration subscales (Chapman scale), attention using Continuous Performance Test (CPT-IP) and executive functions using the Wisconsin Card Sorting Test (WCST)., Results: CogPer (F(1,160)=7.14, p=0.008) but not RepMot NEA scores were higher in HR subjects compared to HS after controlling for age and sex. CogPer NEA scores were higher in HR subjects with axis I psychopathology compared to those without (F(2,170)-6.41, p=0.002). HR subjects had higher schizotypy scores (composite of the magical ideation and perceptual aberration scales) (F(1,141)=23.25, p=0.000004). Schizotypy scores were negatively correlated with sustained attention and executive functions. In addition, schizotypy was positively correlated with CogPer NEA scores., Conclusions: Young relatives at increased genetic risk for schizophrenia show more frequent NEA. CogPer but not RepMot NEA scores were elevated, consistent with our prior observation of CogPer NEA being relatively specific for schizophrenia. The observed relationships between NEA, cognitive impairments, schizotypy and axis I disorders suggest that NEA may characterize a subgroup of HR offspring at an elevated risk for psychopathology.

Imaging studies using region-of-interest morphometry and positron emission tomography have contributed to our understanding of structural and functional abnormalities in borderline personality disorder (BPD); however, both methods have practical limitations to their usefulness for exploratory studies of brain-behavior relationships. We used voxel-based morphometry (VBM) in 34 subjects with BPD and 30 healthy control (HC) subjects to study effects of diagnosis, gender, childhood sexual abuse, depressed mood, impulsivity and aggression on group differences. VBM is a computer-based method for whole brain analysis that combines the advantages of a functional study with a structural method. The BPD subjects, diagnosed with the Diagnostic Interview for Borderline Patients and the International Personality Disorders Examination, were compared with 30 HC subjects, with age and gender covaried. Analyses were repeated separately by gender and, in women, by histories of childhood sexual abuse. Depressed mood, impulsivity, and aggression were covaried in separate analyses. Compared with HC, BPD subjects had significant bilateral reductions in gray matter concentrations in ventral cingulate gyrus and several regions of the medial temporal lobe, including the hippocampus, amygdala, parahippocampal gyrus, and uncus. BPD women (and abused BPD women), but not BPD men, had significant reductions in medial temporal lobe, including the amygdala. BPD men, but not BPD women, showed diminished gray matter concentrations in the anterior cingulate gyrus compared with findings in HC subjects. Covarying for depressed mood rendered group differences non-significant in the ventral cingulate but had little effect on differences in medial temporal cortex. Covarying for aggression (LHA) had relatively little effect on group differences, while covarying for impulsivity, as determined by the Barratt Impulsiveness Scale, rendered all previously noted voxel-level group differences non-significant. Diminished gray matter in the prefrontal cortex and the medial temporal cortex may mediate the dysregulation of impulse and affect in BPD. Group differences varied greatly by gender, levels of depression, and impulsivity. VBM is an efficient method for exploratory study of brain-behavior relationships.