Cortical morphology in patients with the deficit and non-deficit syndrome of schizophrenia: a worldwide meta- and mega-analyses.

Converging evidence suggests that schizophrenia (SZ) with primary, enduring negative symptoms (i.e., Deficit SZ (DSZ)) represents a distinct entity within the SZ spectrum while the neurobiological underpinnings remain undetermined. In the largest dataset of DSZ and Non-Deficit (NDSZ), we conducted a meta-analysis of data from 1560 individuals (168 DSZ, 373 NDSZ, 1019 Healthy Controls (HC)) and a mega-analysis of a subsampled data from 944 individuals (115 DSZ, 254 NDSZ, 575 HC) collected across 9 worldwide research centers of the ENIGMA SZ Working Group (8 in the mega-analysis), to clarify whether they differ in terms of cortical morphology. In the meta-analysis, sites computed effect sizes for differences in cortical thickness and surface area between SZ and control groups using a harmonized pipeline. In the mega-analysis, cortical values of individuals with schizophrenia and control participants were analyzed across sites using mixed-model ANCOVAs. The meta-analysis of cortical thickness showed a converging pattern of widespread thinner cortex in fronto-parietal regions of the left hemisphere in both DSZ and NDSZ, when compared to HC. However, DSZ have more pronounced thickness abnormalities than NDSZ, mostly involving the right fronto-parietal cortices. As for surface area, NDSZ showed differences in fronto-parietal-temporo-occipital cortices as compared to HC, and in temporo-occipital cortices as compared to DSZ. Although DSZ and NDSZ show widespread overlapping regions of thinner cortex as compared to HC, cortical thinning seems to better typify DSZ, being more extensive and bilateral, while surface area alterations are more evident in NDSZ. Our findings demonstrate for the first time that DSZ and NDSZ are characterized by different neuroimaging phenotypes, supporting a nosological distinction between DSZ and NDSZ and point toward the separate disease hypothesis.

Effects of methylphenidate and physiotherapeutic treatment on graphomotor movements in children with ADHD.

In addition to the core symptoms defining ADHD, affected children often experience motor problems; in particular, graphomotor movements including handwriting are affected. However, in clinical settings, there is little emphasis on standardized and objective diagnosing and treatment of those difficulties. The present study investigated for the first time the effects of methylphenidate as well as physiotherapeutic treatment on objectively assessed graphomotor movements compared to a control condition, i.e. parental psychoeducation, in 58 children (mean age: 9.52 ± 1.91 years) newly diagnosed with ADHD in an outpatient clinic for child and adolescent psychiatry. Families were invited to join one of the treatment groups. Before and after 8 weeks of treatment, children performed six different tasks on a digitizing tablet which allowed the objective analysis of three important kinematic parameters of graphomotor movements (fluency, velocity, and pen pressure) in different levels of visual control and automation. Graphomotor movement fluency and velocity improves over time across the groups, especially in tasks with eyes closed. We did not find clear evidence for beneficial effects of methylphenidate or physiotherapeutic treatment on children's overall graphomotor movements suggesting that treatments need to be better tailored towards specific and individual deficits in graphomotor movements.

Hair cortisol-a stress marker in children and adolescents with chronic tic disorders? A large European cross-sectional study.

BACKGROUND: There is clear evidence that tic disorders (TDs) are associated with psychosocial stress as well as emotional and behavioral problems. Studies have shown that individuals with TDs have higher acute physiological stress responses to external, single stressors (as reflected by saliva cortisol). The aim of the present study was to examine a physiological marker of longer-term stress (as reflected by hair cortisol concentration) in children and adolescents with TDs and unaffected siblings of individuals with TDs. METHODS: Two samples of a European cohort were included in this study. In the COURSE sample, 412 children and adolescents aged 3-16 years with a chronic TD including Tourette syndrome according to DSM IV-TR criteria were included. The ONSET sample included 131 3-10 years old siblings of individuals with TDs, who themselves had no tics. Differences in hair cortisol concentration (HCC) between the two samples were examined. Within the COURSE sample, relations of HCC with tic severity and perceived psychosocial stress as well as potential effects and interaction effects of comorbid emotional and behavioral problems and psychotropic medication on HCC were investigated. RESULTS: There were no differences in HCC between the two samples. In participants with TDs, there were no associations between HCC and tic severity or perceived psychosocial stress. No main effects of sex, psychotropic medication status and comorbid emotional and behavioral problems on HCC were found in participants with TDs. CONCLUSION: A link between HCC and TDs is not supported by the present results.

Mapping cortical and subcortical asymmetries in substance dependence: Findings from the ENIGMA Addiction Working Group.

Brain asymmetry reflects left-right hemispheric differentiation, which is a quantitative brain phenotype that develops with age and can vary with psychiatric diagnoses. Previous studies have shown that substance dependence is associated with altered brain structure and function. However, it is unknown whether structural brain asymmetries are different in individuals with substance dependence compared with nondependent participants. Here, a mega-analysis was performed using a collection of 22 structural brain MRI datasets from the ENIGMA Addiction Working Group. Structural asymmetries of cortical and subcortical regions were compared between individuals who were dependent on alcohol, nicotine, cocaine, methamphetamine, or cannabis (n = 1,796) and nondependent participants (n = 996). Substance-general and substance-specific effects on structural asymmetry were examined using separate models. We found that substance dependence was significantly associated with differences in volume asymmetry of the nucleus accumbens (NAcc; less rightward; Cohen's d = 0.15). This effect was driven by differences from controls in individuals with alcohol dependence (less rightward; Cohen's d = 0.10) and nicotine dependence (less rightward; Cohen's d = 0.11). These findings suggest that disrupted structural asymmetry in the NAcc may be a characteristic of substance dependence.

Interactive impact of childhood maltreatment, depression, and age on cortical brain structure: mega-analytic findings from a large multi-site cohort.

BACKGROUND: Childhood maltreatment (CM) plays an important role in the development of major depressive disorder (MDD). The aim of this study was to examine whether CM severity and type are associated with MDD-related brain alterations, and how they interact with sex and age. METHODS: Within the ENIGMA-MDD network, severity and subtypes of CM using the Childhood Trauma Questionnaire were assessed and structural magnetic resonance imaging data from patients with MDD and healthy controls were analyzed in a mega-analysis comprising a total of 3872 participants aged between 13 and 89 years. Cortical thickness and surface area were extracted at each site using FreeSurfer. RESULTS: CM severity was associated with reduced cortical thickness in the banks of the superior temporal sulcus and supramarginal gyrus as well as with reduced surface area of the middle temporal lobe. Participants reporting both childhood neglect and abuse had a lower cortical thickness in the inferior parietal lobe, middle temporal lobe, and precuneus compared to participants not exposed to CM. In males only, regardless of diagnosis, CM severity was associated with higher cortical thickness of the rostral anterior cingulate cortex. Finally, a significant interaction between CM and age in predicting thickness was seen across several prefrontal, temporal, and temporo-parietal regions. CONCLUSIONS: Severity and type of CM may impact cortical thickness and surface area. Importantly, CM may influence age-dependent brain maturation, particularly in regions related to the default mode network, perception, and theory of mind.

Subcortical surface morphometry in substance dependence: An ENIGMA addiction working group study.

While imaging studies have demonstrated volumetric differences in subcortical structures associated with dependence on various abused substances, findings to date have not been wholly consistent. Moreover, most studies have not compared brain morphology across those dependent on different substances of abuse to identify substance-specific and substance-general dependence effects. By pooling large multinational datasets from 33 imaging sites, this study examined subcortical surface morphology in 1628 nondependent controls and 2277 individuals with dependence on alcohol, nicotine, cocaine, methamphetamine, and/or cannabis. Subcortical structures were defined by FreeSurfer segmentation and converted to a mesh surface to extract two vertex-level metrics-the radial distance (RD) of the structure surface from a medial curve and the log of the Jacobian determinant (JD)-that, respectively, describe local thickness and surface area dilation/contraction. Mega-analyses were performed on measures of RD and JD to test for the main effect of substance dependence, controlling for age, sex, intracranial volume, and imaging site. Widespread differences between dependent users and nondependent controls were found across subcortical structures, driven primarily by users dependent on alcohol. Alcohol dependence was associated with localized lower RD and JD across most structures, with the strongest effects in the hippocampus, thalamus, putamen, and amygdala. Meanwhile, nicotine use was associated with greater RD and JD relative to nonsmokers in multiple regions, with the strongest effects in the bilateral hippocampus and right nucleus accumbens. By demonstrating subcortical morphological differences unique to alcohol and nicotine use, rather than dependence across all substances, results suggest substance-specific relationships with subcortical brain structures.

The neural correlates of Childhood Trauma Questionnaire scores in adults: A meta-analysis and review of functional magnetic resonance imaging studies.

Childhood maltreatment, including abuse and neglect, may have sustained effects on the integrity and functioning of the brain, alter neurophysiological responsivity later in life, and predispose individuals toward psychiatric conditions involving socioaffective disturbances. This meta-analysis aims to quantify associations between self-reported childhood maltreatment and brain function in response to socioaffective cues in adults. Seventeen functional magnetic resonance imaging studies reporting on data from 848 individuals examined with the Childhood Trauma Questionnaire were included in a meta-analysis of whole-brain findings, or a review of region of interest findings. The spatial consistency of peak activations associated with maltreatment exposure was tested using activation likelihood estimation, using a threshold of p < .05 corrected for multiple comparisons. Adults exposed to childhood maltreatment showed significantly increased activation in the left superior frontal gyrus and left middle temporal gyrus, and decreased activation in the left superior parietal lobule and the left hippocampus. Although hyperresponsivity to socioaffective cues in the amygdala and ventral anterior cingulate cortex in correlation with maltreatment severity is a replicated finding in region of interest studies, null results are reported as well. The findings suggest that childhood maltreatment has sustained effects on brain function into adulthood, and highlight potential mechanisms for conveying vulnerability to development of psychopathology.

Distinct intrinsic functional brain network abnormalities in methamphetamine-dependent patients with and without a history of psychosis.

Chronic methamphetamine use is associated with executive functioning deficits that suggest dysfunctional cognitive control networks (CCNs) in the brain. Likewise, abnormal connectivity between intrinsic CCNs and default mode networks (DMNs) has also been associated with poor cognitive function in clinical populations. Accordingly, we tested the extent to which methamphetamine use predicts abnormal connectivity between these networks, and whether, as predicted, these abnormalities are compounded in patients with a history of methamphetamine-associated psychosis (MAP). Resting-state fMRI data were acquired from 46 methamphetamine-dependent patients [19 with MAP, 27 without (MD)], as well as 26 healthy controls (CTRL). Multivariate network modelling and whole-brain voxel-wise connectivity analyses were conducted to identify group differences in intrinsic connectivity across four cognitive control and three DMN networks identified using an independent components analysis approach (meta-ICA). The relationship of network connectivity and psychotic symptom severity, as well as antipsychotic treatment and methamphetamine use variables, was also investigated. Robust evidence of hyper-connectivity was observed between the right frontoparietal and anterior DMN networks in MAP patients, and 'normalized' with increased duration of treatment with antipsychotics. Attenuation of anticorrelated anterior DMN-dorsal attention network activity was also restricted to this group. Elevated coupling detected in MD participants between anterior and posterior DMN networks became less apparent with increasing duration of abstinence from methamphetamine. In summary, we observed both alterations of RSN connectivity between DMN networks with chronic methamphetamine exposure, as well as DMN-CCN coupling abnormalities consistent with possible MAP-specific frontoparietal deficits in the biasing of task-appropriate network activity.

Social cognition and aggression in methamphetamine dependence with and without a history of psychosis.

In substance use and psychotic disorders, socially problematic behaviours, such as high aggression may, in part, be explained by deficits in social cognition skills, like the detection of emotions or intentions in others. The aim of this study was to assess the magnitude of social cognition impairment and its association with aggression in individuals with methamphetamine (MA) dependence, methamphetamine-associated psychosis (MAP), and healthy controls (CTRL). A total of 20 MAP participants, 21 MA-dependent participants without psychosis, and 21 CTRL participants performed a facial morphing emotion recognition task (ERT) across four basic emotions (anger, fear, happiness and sadness) and the reading the mind in the eyes task (RMET), and completed the aggression questionnaire. Both MA-dependent groups showed impairment in social cognition in terms of lower RMET scores relative to CTRL participants (MA; p = .047; MAP: p < .001). Additionally, performance decrements were significantly greater in MAP (p = .040), compared to MA-dependent participants. While deficits in recognising emotional expressions were restricted to anger in the MA group (p = .020), a generalized impairment across all four emotions was observed in MAP (all p ≤ .001). Additionally, both patient groups demonstrated higher levels of aggression than CTRLs, yet no association was found with social cognition. This study supported the notion of deficits in recognising facial emotional expressions and inferring mental states of others in MA dependence, with additional impairments in MAP. Failure to detect an association between social cognitive impairment and aggressive behaviour may implicate independent disturbances of the two phenomena in MA dependence.

White matter microstructure and impulsivity in methamphetamine dependence with and without a history of psychosis.

BACKGROUND: Methamphetamine (MA) use may lead to white matter injury and to a range of behavioral problems and psychiatric disorders, including psychosis. The present study sought to assess white matter microstructural impairment as well as impulsive behavior in MA dependence and MA-associated psychosis (MAP). METHODS: Thirty patients with a history of MAP, 39 participants with MA dependence and 40 healthy controls underwent diffusion tensor imaging (DTI). Participants also completed the UPPS-P impulsive behavior questionnaire. We applied tract-based spatial statistics (TBSS) to investigate group differences in mean diffusivity (MD), fractional anisotropy (FA), axial (λ‖ ) and radial diffusivity (λ⊥ ), and their association with impulsivity scores and psychotic symptoms. RESULTS: The MAP group displayed widespread higher MD, λ‖ and λ⊥ levels compared to both controls and the MA group, and lower FA in extensive white matter areas relative to controls. MD levels correlated positively with negative psychotic symptoms in MAP. No significant DTI group differences were found between the MA group and controls. Both clinical groups showed high levels of impulsivity, and this dysfunction was associated with DTI measures in frontal white matter tracts. CONCLUSIONS: MAP patients show distinct patterns of impaired white matter integrity of global nature relative to controls and the MA group. Future work to investigate the precise nature and timing of alterations in MAP is needed. The results are further suggestive of frontal white matter pathology playing a role in impulsivity in MA dependence and MAP. Hum Brain Mapp 37:2055-2067, 2016. © 2016 Wiley Periodicals, Inc.

Frontal white matter changes and aggression in methamphetamine dependence.

Chronic methamphetamine (MA) use can lead to white matter (WM) changes and increased levels of aggression. While previous studies have examined WM abnormalities relating to cognitive impairment, associations between WM integrity and aggression in MA dependence remain unclear. Diffusion Tensor Imaging (DTI) was used to investigate WM changes in 40 individuals with MA dependence and 40 matched healthy controls. A region of interest (ROI) approach using tract based spatial statistics (TBSS) in FSL was performed. We compared fractional anisotropy (FA), mean diffusivity (MD), parallel diffusivity (λ║) and perpendicular diffusivity (λ┴) in WM tracts of the frontal brain. A relationship of WM with aggression scores from the Buss & Perry Questionnaire was investigated. Mean scores for anger (p < 0.001), physical aggression (p = 0.032) and total aggression (p = 0.021) were significantly higher in the MA group relative to controls. ROI analysis showed increased MD (U = 439.5, p = 0.001) and λ┴ (U = 561.5, p = 0.021) values in the genu of the corpus callosum, and increased MD (U = 541.5, p = 0.012) values in the right cingulum in MA dependence. None of the WM changes were significantly associated with aggression scores. This study provides evidence of frontal WM changes and increased levels of aggression in individuals with MA dependence. The lack of significant associations between WM and aggressive behaviour may reflect methodological issues in measuring such behaviour, or may indicate that the neurobiology of aggression is not simply correlated with WM damage but is more complex.

First-Rank Symptoms in Methamphetamine Psychosis and Schizophrenia.

BACKGROUND: Methamphetamine psychosis (MAP) symptomatology has been described as indistinguishable from that of schizophrenia (SZ), yet research comparing these two disorders on specific psychotic symptoms such as schneiderian first-rank symptoms (FRS) is lacking. We aimed to determine and compare the occurrence and associations of FRS in patients diagnosed with MAP and with SZ. SAMPLING AND METHOD: Data from SCID-I interviews performed on patients with either a diagnosis of SZ or MAP were compared. We calculated the prevalence of different FRS between MAP and SZ patients and used logistic regression to assess the association between FRS and diagnosis. RESULTS: 102 patients were included in the study (MAP = 33, SZ = 69). Thought broadcasting occurred significantly more often in SZ (42%) than in MAP (24.2%) patients (adjusted OR = 3.02; 95% CI: 1.12-8.15; p = 0.028), while auditory hallucinations (voices conversing) were significantly higher in MAP (48.5%) than in SZ (20.3%) patients (adjusted OR = 0.27; 95% CI: 0.10-0.66; p = 0.004). However, there was no significant difference in the occurrence of one or more FRS in MAP and SZ, with most FRS showing overlap. CONCLUSIONS: We found that first-rank auditory hallucinations were more prevalent in MAP, whereas first-rank delusions of thought broadcasting were more prevalent in SZ. However, there was a substantial overlap in MAP and SZ for most FRS. This is consistent with the finding that FRS may have limited diagnostic specificity and that there is significant overlap in the symptoms of MAP and SZ. Future research into the neurobiology of delusions and hallucinations needs to take FRS into account.

Hair Cortisol and Perceived Stress-Predictors for the Onset of Tics? A European Longitudinal Study on High-Risk Children.

Some retrospective studies suggest that psychosocial stressors trigger the onset of tics. This study examined prospective hypothalamic-pituitary-adrenal (HPA) axis activity and perceived stress prior to tic onset. In the present study, 259 children at high risk for developing tics were assessed for hair cortisol concentration (HCC) and parent-on-child-reported perceived stress four-monthly over a three-year period. We used (i) generalised additive modelling (GAM) to investigate the time effects on HCC (hair samples n = 765) and perceived stress (questionnaires n = 1019) prior to tic onset and (ii) binary logistic regression to predict tic onset in a smaller subsample with at least three consecutive assessments (six to nine months before, two to five months before, and at tic onset). GAM results indicated a non-linear increasing course of HCC in children who developed tics, and a steady HCC course in those without tics, as well as a linear-increasing course of perceived stress in both groups. Logistic regression showed that with a higher HCC in hair samples collected in a range of two to five months before tic onset (which refers to cortisol exposure in a range of four to eight months), the relative likelihood of tic onset rose. Our study suggests increased stress prior to tic onset, as evidenced by higher HCC several months before tic onset.

Recalibrating single-study effect sizes using hierarchical Bayesian models.

Introduction: There are growing concerns about commonly inflated effect sizes in small neuroimaging studies, yet no study has addressed recalibrating effect size estimates for small samples. To tackle this issue, we propose a hierarchical Bayesian model to adjust the magnitude of single-study effect sizes while incorporating a tailored estimation of sampling variance. Methods: We estimated the effect sizes of case-control differences on brain structural features between individuals who were dependent on alcohol, nicotine, cocaine, methamphetamine, or cannabis and non-dependent participants for 21 individual studies (Total cases: 903; Total controls: 996). Then, the study-specific effect sizes were modeled using a hierarchical Bayesian approach in which the parameters of the study-specific effect size distributions were sampled from a higher-order overarching distribution. The posterior distribution of the overarching and study-specific parameters was approximated using the Gibbs sampling method. Results: The results showed shrinkage of the posterior distribution of the study-specific estimates toward the overarching estimates given the original effect sizes observed in individual studies. Differences between the original effect sizes (i.e., Cohen's d) and the point estimate of the posterior distribution ranged from 0 to 0.97. The magnitude of adjustment was negatively correlated with the sample size (r = -0.27, p < 0.001) and positively correlated with empirically estimated sampling variance (r = 0.40, p < 0.001), suggesting studies with smaller samples and larger sampling variance tended to have greater adjustments. Discussion: Our findings demonstrate the utility of the hierarchical Bayesian model in recalibrating single-study effect sizes using information from similar studies. This suggests that Bayesian utilization of existing knowledge can be an effective alternative approach to improve the effect size estimation in individual studies, particularly for those with smaller samples.

Estimating multimodal brain variability in schizophrenia spectrum disorders: A worldwide ENIGMA study.

Objective: Schizophrenia is a multifaceted disorder associated with structural brain heterogeneity. Despite its relevance for identifying illness subtypes and informative biomarkers, structural brain heterogeneity in schizophrenia remains incompletely understood. Therefore, the objective of this study was to provide a comprehensive insight into the structural brain heterogeneity associated with schizophrenia. Methods: This meta- and mega-analysis investigated the variability of multimodal structural brain measures of white and gray matter in individuals with schizophrenia versus healthy controls. Using the ENIGMA dataset of MRI-based brain measures from 22 international sites with up to 6139 individuals for a given brain measure, we examined variability in cortical thickness, surface area, folding index, subcortical volume and fractional anisotropy. Results: We found that individuals with schizophrenia are distinguished by higher heterogeneity in the frontotemporal network with regard to multimodal structural measures. Moreover, individuals with schizophrenia showed higher homogeneity of the folding index, especially in the left parahippocampal region. Conclusions: Higher multimodal heterogeneity in frontotemporal regions potentially implies different subtypes of schizophrenia that converge on impaired frontotemporal interaction as a core feature of the disorder. Conversely, more homogeneous folding patterns in the left parahippocampal region might signify a consistent characteristic of schizophrenia shared across subtypes. These findings underscore the importance of structural brain variability in advancing our neurobiological understanding of schizophrenia, and aid in identifying illness subtypes as well as informative biomarkers.

Executive function in methamphetamine users with and without psychosis.

Methamphetamine abuse is associated with cognitive deficits across a wide range of domains. It is unclear, however, whether methamphetamine-dependent individuals with co-occurring psychosis are more impaired than those without psychosis on tests assessing executive function. We therefore aimed to compare the executive function performance of three groups: methamphetamine-dependent individuals with methamphetamine-induced psychosis (MA+; n = 20), methamphetamine-dependent individuals without psychosis (MA-; n = 19), and healthy controls (HC; n = 20). All participants were administered a neuropsychological test battery that assessed executive functioning across six sub domains (problem solving, working memory, verbal generativity, inhibition, set switching, and decision making). Analyses of covariance (controlling for between-group differences in IQ) detected significant between-group differences on tests assessing verbal generativity and inhibition, with MA+ participants performing significantly more poorly than HC. The finding that methamphetamine-induced psychosis is associated with performance impairments in particular subdomains of executive function may have implications for treatment adherence and relapse prevention.