Non-pharmacological treatment of Attention Deficit Disorder with or without Hyperactivity (ADHD). Overview and report of the first international symposium on the non-pharmacological management of ADHD.

Attention Deficit Disorder with or without Hyperactivity (ADHD is a neurodevelopmental disorder which affects the day-to-day functioning of children and adults with this condition. Pharmacological treatment can reduce the symptoms associated with ADHD, but it has some limitations. The objective of this symposium is to determine the effects of non-pharmacological approaches on ADHD symptoms. Results indicate that the following intervention are promising approaches: cognitive behavioral therapy (CBT), mindfulness-based interventions (MBI), yoga, cognitive and metacognitive intervention, neurofeedback and parental training programs. Current research advocates multimodal approaches in conjunction with school or work accommodations integrating innovative technologies.

Increased Connectivity Between the Nucleus Accumbens and the Default Mode Network in Patients With Schizophrenia During Cigarette Cravings.

Objective: Compared to the general population, tobacco smoking cessation rates are lower in populations with schizophrenia. Unfortunately, the potential neurophysiologic mechanisms underlying these low cessation rates in schizophrenia have been seldom studied using functional neuroimaging. Recently, it has been shown that tobacco cravings are increased in smokers with schizophrenia compared to smokers with no comorbid psychiatric disorder. Given the critical role of the brain reward system in the neurobiology of addiction, we sought to examine the functional connectivity of core regions of this system in smokers with schizophrenia during the viewing of appetitive smoking cues. Methods: Smokers with (n = 18) and without (n = 24) schizophrenia were scanned using functional magnetic resonance imaging while viewing appetitive cigarette images. Functional connectivity analyses were performed using the bilateral nucleus accumbens as the seed regions. Results: Smokers with schizophrenia and smokers with no psychiatric comorbidity did not differ in subjective cravings in response to appetitive smoking cues. However, in smokers with schizophrenia relative to control smokers, we found an increased connectivity between the nucleus accumbens and regions involved in the default mode network (e.g., middle temporal gyrus and precuneus), which are involved in self-referential processes. Moreover, a positive correlation was observed between the left nucleus accumbens and left middle temporal gyrus connectivity and cigarette cravings across both groups of smokers. Conclusions: These results highlight a key role of the nucleus accumbens in cigarette craving in schizophrenia and suggest that the subjective valuation of cigarette cues is increased in this population. Similar neurofunctional studies on cravings for other psychoactive substances in schizophrenia are warranted.

The Impact of the in utero and Early Postnatal Environments on Grey and White Matter Volume: A Study with Adolescent Monozygotic Twins.

Prenatal and early postnatal adversities have been shown to be associated with brain development. However, we do not know how much of this association is confounded by genetics, nor whether the postnatal environment can moderate the impact of in utero adversity. This study used a monozygotic (MZ) twin design to assess (1) the association between birth weight (BW) and brain volume in adolescence, (2) the association between within-twin-pair BW discordance and brain volume discordance in adolescence, and (3) whether the association between BW and brain volume in adolescence is mediated or moderated by early negative maternal parenting behaviours. These associations were assessed in a sample of 108 MZ twins followed longitudinally since birth and scanned at age 15. The total grey matter (GM) and white matter (WM) volumes were obtained using the Diffeomorphic Anatomical Registration Through Exponentiated Lie Algebra (DARTEL) toolbox in the Statistical Parametric Mapping version 8 (SPM8). We found that the BW was significantly associated with the total GM and WM volumes, particularly in the superior frontal gyrus and thalamus. Within-twin-pair discordance in BW was also significantly associated with within-pair discordance in both the GM and the WM volumes, supporting the hypothesis that the specific in utero environment is associated with brain development independently of genetics. Early maternal hostile parenting behaviours and depressive symptoms were associated with total GM volume but not WM volume. Finally, greater early maternal hostility may moderate the association between the BW and GM volume in adolescence, since the positive association between the BW and total GM volume appeared stronger at higher levels of maternal hostility (trend). Together, these findings support the importance of the in utero and early environments for brain development.

MRI Surface-Based Brain Morphometry in Egyptian Autistic and Typically Developing Children.

OBJECTIVES: The verbal abilities of autistic children differ from those of typically developing ones and they also differ among autistic children themselves. Neuroanatomical changes and an abnormal organization of functional networks are expected to accompany such a neurodevelopmental disorder. The aim of this study was to delineate the brain neuroanatomical changes in Egyptian children with autism and to compare them with previous studies in order to add more insight into the global brain imaging deviations linked to autism. PATIENTS AND METHODS: Twenty-five autistic children and 25 typically developing children underwent MRI. Further analysis was performed using surface-based morphometry to obtain cortical thickness, brain volume, and cortical complexity. RESULTS: MRI analysis results revealed significantly greater cortical thickness, cortical complexity, and gray matter volume in the autistic as compared to the control group. On the other hand, the white matter volume was significantly smaller. CONCLUSION: These findings generally align with findings in previous studies, except for occasional differences.

Cognition and lobar morphology in full mutation boys with fragile X syndrome.

The aims of the present study are twofold: (1) to examine cortical morphology (CM) associated with alterations in cognition in fragile X syndrome (FXS); (2) to characterize the CM profile of FXS versus FXS with an autism diagnosis (FXS+Aut) as a preliminary attempt to further elucidate the behavioral distinctions between the two sub-groups. We used anatomical magnetic resonance imaging surface-based morphometry in 21 male children (FXS N=11 and age [2.27-13.3] matched controls [C] N=10). We found (1) increased whole hemispheric and lobar cortical volume, cortical thickness and cortical complexity bilaterally, yet insignificant changes in hemispheric surface area and gyrification index in FXS compared to C; (2) linear regression analyses revealed significant negative correlations between CM and cognition; (3) significant CM differences between FXS and FXS+Aut associated with their distinctive behavioral phenotypes. These findings are critical in understanding the neuropathophysiology of one of the most common intellectual deficiency syndromes associated with altered cognition as they provide human in vivo information about genetic control of CM and cognition.

Neuroanatomy of childhood disruptive behavior disorders.

Our aims were to (1) examine possible neuroanatomical abnormalities associated with the Disruptive Behavior Disorders (DBDs) as a group and (2) assess neuroanatomical anomalies specific to each DBD (i.e., conduct disorder [CD] and oppositional defiant disorder). Cortical thickness analysis and voxel-based morphometry were analyzed in 47 8-year-old boys (22 DBDs with and without CD and/or ODD and 25 healthy controls) from Magnetic Resonance Imaging brain scans. DBD symptoms were assessed using the Dominic-R. In DBD subjects relative to controls, we found (1) a decreased overall mean cortical thickness; (2) thinning of the cingulate, prefrontal and insular cortices; and (3) decreased gray matter density (GMd) in the same brain regions. We also found that scores on the Dominic-R were negatively correlated with GMd in the prefrontal and precuneus/superior temporal regions. There was a subdiagnostic main effect for CD, related to thinning of the middle/medial frontal, and for ODD in the left rectal/orbitofrontal. Findings suggest that thinning and decreased GMd of the insula disorganizes prefrontal circuits, diminishing the inhibitory influence of the prefrontal cortex on anger, aggression, cruelty, and impulsivity, and increasing a person's likelihood of aggressive behavior. These findings have implications for pathophysiologic models of the DBDs, their diagnostic classification system, and for designing more effective intervention programs.

Lateralized genetic and environmental influences on human brain morphology of 8-year-old twins.

It has been increasing rapidly interest in understanding genetic effects on brain structure and function in recent years. In this study, we examined the genetic and environmental influences on the variation in cortical thickness and specific tissue volumes in a large cohort of 8-year-old healthy twins. The present study can provide a better estimation of the genetic and environmental effects by virtue of the homogeneously aged pediatric twin pairs with a similar growing environment. We found that common environmental factors contributed significantly to the variations of the right lateral ventricle (36%) and corpus callosum (36%) volumes while genetic factors accounted for most of the phenotypic variance in other brain tissue volumes. In the case of cortical thickness, several regions in the left hemisphere showed statistically significant additive genetic factors, including the middle and inferior frontal gyri, lateral fronto-orbital and occipitotemporal gyri, pars opercularis, planum temporale, precentral and parahippocampal gyri and the medial region of the primary somatosensory cortex. Relatively high common environmental influence (>50%) was observed in the right anterior cingulate cortex and insula. Our findings indicate that the genetic and common environmental influences on individual human brain structural differences are lateralized, with the language-dominant left cerebral cortex under stronger genetic control than the right.

Violent Behavior Is Associated With Emotion Salience Network Dysconnectivity in Schizophrenia.

Background: Despite individuals with schizophrenia being at an elevated risk of violence compared to the general population, limited efforts have been invested in investigating the neurobiological etiology explaining the increase. Among the few studies examining functional disruptions pertaining to violent schizophrenia patients using fMRI, only one study has considered functional connectivity. The current state of knowledge does not allow to infer deficits in functional connectivity specific to distinct cognitive/emotional states that have been associated with the emergence of violence in schizophrenia, such as negative emotion processing. This study sought to identify disrupted connectivity among men with schizophrenia and a history of violence (SCZ+V), compared to men with schizophrenia without a history of violence (SCZ-V) and healthy controls, during negative emotion processing using fMRI. Methods: Twenty SCZ+V, 19 SCZ-V, and 21 healthy men were scanned while viewing negative images. Results: Negative images elicited an increased connectivity between the dorsal anterior cingulate cortex (dACC) and the bilateral rostral prefrontal cortex (rPFC), as well as a decreased functional connectivity between the frontal regions (bilateral rPFC and dACC) and the putamen and hippocampus in SCZ+V men as compared to SCZ-V men and healthy controls. Concurrently, the centrality of the dACC within the network was reduced in SCV+V subjects. Conclusions: These results suggest an inefficient integration of the information by the dACC between frontal and limbic regions in SCZ+V men during negative emotion processing and highlight the importance of the ACC in the neurobiological bases of violent behavior in schizophrenia.

Increased grey matter densities in schizophrenia patients with negative symptoms after treatment with quetiapine: a voxel-based morphometry study.

Among new-generation antipsychotics, quetiapine was found to be associated with a partial 'normalization' of reduced functional activation in prefrontal and temporal areas and studies conducted by our group found a clinical improvement in negative symptoms in addition to restoration of frontal activation in schizophrenia patients with blunted affect after treatment with quetiapine. Here we investigated the parallelism between improved clinical symptoms and grey mater density (GMD) changes in the frontal region after quetiapine treatment in 15 schizophrenia patients. We hypothesize that improvement in clinical symptoms will be associated with change in GMD in prefrontal regions of interest. By using voxel-based morphometry, paired t-test random-effect analysis showed a significant increase in GMD bilaterally in the inferior frontal cortex/orbitofrontal gyrus and anterior cingulate cortex after 5.5 months of treatment with quetiapine. This GMD increase was associated with a significant improvement in negative symptoms. When GMD was correlated with psychiatric assessment scores, there was a negative correlation between GMD in the anterior cingulate cortex and the Rating Scale for Emotional Blunting score (r=-665, P=0.008) and between the orbitofrontal gyrus and the total Positive and Negative Syndrome Scale negative score (r=-764, P=0.001). Results suggest that increased GMD in some frontal regions are associated with an improvement of negative symptoms. Although not unique to quetiapine, it would be reasonable to attribute the GMD changes in the study to treatment.

Thinning of the motor-cingulate-insular cortices in siblings concordant for Tourette syndrome.

Fraternal twin studies on normal subjects have demonstrated low heritability (intra-class correlation coefficient) estimates for frontal brain regions (r = 0.43). Here we aimed to investigate the relatedness/similarity estimates of the frontal brain regions in fraternal subjects concordant for Tourette syndrome (TS). We sought to identify regional brain similarities between siblings concordant for TS as an exploratory step towards the identification of potential brain structures involved in the TS phenotype. The identified brain structures may then serve in subsequent molecular genetic and linkage studies. In addition, we regressed cortical thickness and TS clinical severity scores to assess the relation between TS clinical symptoms and cortical structures. Sixteen sibling pairs concordant for TS were scanned using a 1.5 T magnetic resonance imaging scanner (age range 10-25, mean 17.19 +/- 4.1). Brain morphology was assessed using the fully automated Civet pipeline at the Montreal Neurological Institute. TS was assessed using the Children's Yale-Brown Obsessive Compulsive Scale (CY-BOCS), Yale Global Tic Severity Scale (YGTSS) and the Goetz Tic Scale. We report high relatedness/similarity estimates for fraternal siblings concordant for TS (r = 0.86-0.60) in the middle frontal-motor/cingulate/insular cortices. Regression analysis revealed significant negative correlations in the right insula with the YGTSS (r = -0.41, F = 6.09, P < 0.02) and the left cingulated cortex with the (CY-BOCS) (r = -0.35, F = 4.30, P < 0.05). Since previous findings have concluded that normal fraternal siblings are less alike in frontal cortices, the present findings may be attributed to TS. We speculate that the high ICC between siblings and the negative correlation between TS symptoms severity and cortical thickness measurements are related to the disturbances in the maturation of the motor-cingulate-insular cortical neural system that mediate self-regulatory processes. Such delayed maturation may consequently contribute to the development of TS by releasing motor and vocal tics from regulatory control. These findings may have important genetic implications.

Serotonin transporter promoter methylation in peripheral cells and neural responses to negative stimuli: A study of adolescent monozygotic twins.

Several studies have examined associations between peripheral DNA methylation patterns of the serotonin transporter gene (SLC6A4) promoter and symptoms of depression and anxiety. The SLC6A4 promoter methylation has also been associated with frontal-limbic brain responses to negative stimuli. However, it is unclear how much of this association is confounded by DNA sequence variations. We utilized a monozygotic-twin within-pair discordance design, to test whether DNA methylation at specific CpG sites in the SLC6A4 promoter of peripheral cells is associated with greater frontal-limbic brain responses to negative stimuli (sadness and fear), independently of DNA sequence effects. In total 48 pairs of healthy 15-year-old monozygotic twins from the Quebec Newborn Twin Study, followed regularly since birth, underwent functional magnetic resonance imaging while conducting an emotion-processing task. The SLC6A4 promoter methylation level was assessed in saliva samples using pyrosequencing. Relative to the co-twins with lower SLC6A4 promoter methylation levels, twins with higher peripheral SLC6A4 methylation levels showed greater orbitofrontal cortical (OFC) activity and left amygdala-anterior cingulate cortex (ACC) and left amygdala-right OFC connectivity in response to sadness as well as greater ACC-left amygdala and ACC-left insula connectivity in response to fearful stimuli. By utilising a monozygotic-twin design, we provided evidence that associations between peripheral SLC6A4 promoter methylation and frontal-limbic brain responses to negative stimuli are, in part, independent of DNA sequence variations. Although causality cannot be determined here, SLC6A4 promoter methylation may be one of the mechanisms underlying how environmental factors influence the serotonin system, potentially affecting emotional processing through frontal-limbic areas.

Sex, Age, Symptoms and Illness Duration and Their Relation with Gyrification Index in Schizophrenia.

INTRODUCTION: The Gyrification Index (GI) represents the degree of cortical folding and is of special interest in schizophrenia, since alterations in cortical folding indirectly reflect white matter development and axonal connectivity underneath. To the best of our knowledge, very few studies have investigated the effect of sex on GI in schizophrenia. Differences in the GI between patients with schizophrenia and healthy controls and the relation between sex, age symptoms and duration of illness with GI were investigated. METHODS: T1-images were acquired from schizophrenia patients (24 males [SZ-M] and 24 females [SZ-F]) and healthy volunteers (24 males [NC-M] and 24 females [NC-F]) matched for age, sex and handedness. GI analyses were performed using the fully automated CIVET pipeline. RESULTS: Significantly lower GI was found in patients relative to controls bilaterally in frontal, temporal, and parietal cortex. Sex differences were found: negative correlation was found between the duration of illness and the right parietal GI and right occipital GI in SZ-M, while SZ-F was found in the left frontal and bilateral temporal GI. Patients, regardless of sex, showed positive correlations between negative symptoms and GI in the right occipital. NC-F had greater GI values than SZ-F and both male groups. CONCLUSIONS: Since GI reflects, in part, alterations in cerebral development and connectivity, the decrease in GI observed in patients is in agreement with the neurodevelopmental model of disconnectivity in schizophrenia; in addition, we emphasize the importance of sex differences in schizophrenia.

Increased striatal gray matter densities in patients with schizophrenia and substance use disorder: a voxel-based morphometry study.

We sought to investigate the link between substance abuse and increased striatal gray matter densities (GMD) in schizophrenia, using voxel-based morphometry (VBM). Increased striatal GMD were found in patients with schizophrenia and substance use disorder (n=12), but not schizophrenia only patients (n=11), compared to healthy volunteers (n=15).

Neural correlates of the affect regulation model in schizophrenia patients with substance use history: a functional magnetic resonance imaging study.

BACKGROUND: The lifetime prevalence of substance use disorders among schizophrenia patients is close to 50%. The negative consequences of substance abuse in schizophrenia are well documented, but the etiology of this comorbid condition remains unknown. According to the affect regulation model, schizophrenia patients abuse drugs in order to cope with their negative affects. Supporting the model, clinical studies have shown that dual-diagnosis patients have less blunting of affect and that they experience more negative affect. We hypothesized that patients with a history of substance use would have increased cerebral activations in response to aversive stimuli when compared to abstinent patients. METHOD: Schizophrenia patients were divided into 2 groups: patients with (SCZ-SU group; N = 12) and without (SCZ group; N = 11) a current or past substance use disorder (alcohol, cannabis, and/or LSD). Diagnoses were made according to DSM-IV criteria. Using functional magnetic resonance imaging (fMRI), patients were scanned during passive viewing of emotionally negative pictures (International Affective Picture System). Data were gathered from September 2001 to December 2003. RESULTS: Subjectively, the emotional experience induced by viewing the negative pictures was rated significantly higher in the SCZ-SU group than in the SCZ group (p = .008). Neurally, in the SCZ-SU group, significant loci of activation were identified in the right medial prefrontal cortex (Brodmann's area [BA] 10), left medial prefrontal cortex (BA 10), right orbitofrontal cortex (BA 47), and left amygdala. No significant loci of activation were observed in the SCZ group. CONCLUSIONS: These results suggest that the functioning of the medial prefrontal cortex, thought to be impaired in patients with prominent negative symptoms, is more preserved in dual-diagnosis schizophrenia. This relative preservation could be primary or secondary to substance use.

Restoration of frontal activation during a treatment with quetiapine: an fMRI study of blunted affect in schizophrenia.

This study investigated changes in cerebral activation related to emotion processing in schizophrenia patients with blunted or flat affect (FA+) during treatment with quetiapine. Using functional magnetic resonance imaging (fMRI), brain activation in 12 FA+ schizophrenia patients during passive viewing of sad film excerpts was studied before and after a median of 5.5-months treatment with quetiapine. Random-effects 'paired sample t-test' analyses of brain activation before quetiapine (contrast=sad-neutral, before-after) revealed significant activation in the brainstem (pons, medulla). After quetiapine, the same contrast showed significant prefrontal activation (BA 9, 10 and 11). Activation of key prefrontal areas involved in emotion processing and significant symptoms improvement as measured by the subjective rating scale and PANSS suggests the potential effect of quetiapine in improving blunted affect related symptoms (i.e., passive withdrawal, emotional withdrawal, social avoidance) in schizophrenia.

Brain activity during emotionally negative pictures in schizophrenia with and without flat affect: an fMRI study.

The aim of this functional magnetic resonance imaging (fMRI) study was to compare regional brain activity in schizophrenia subjects with (FA+) and without (FA-) flat affect during the viewing of emotionally negative pictures. Thirteen FA+ subjects and 11 FA- subjects were scanned while being presented with a series of emotionally negative and neutral pictures. Experientially, the viewing of the negative pictures induced a negative emotional state whose intensity was significantly greater in the FA- group than in the FA+ group. Neurally, the Negative minus Neutral contrast revealed, in the FA- group, significant loci of activation in the midbrain, pons, anterior cingulate cortex, insula, ventrolateral orbitofrontal cortex, anterior temporal pole, amygdala, medial prefrontal cortex, and extrastriate visual cortex. In the FA+ group, this contrast produced significant loci of activation in the midbrain, pons, anterior temporal pole, and extrastriate visual cortex. When the brain activity measured in the FA+ group was subtracted from that measured in the FA- group, only the lingual gyrus was significantly activated. Perhaps in FA+ subjects an amygdaloid malfunction rendered the amygdala unable to correctly evaluate the emotional meaning of the pictures presented, thus preventing effective connectivity linking the amygdala to the brain regions implicated in the physiological and experiential dimensions of emotion. Alternatively, a disturbance of effective connectivity in the neural networks linking the midbrain and the medial prefrontal system may have been responsible for the quasi absence of emotional reaction in FA+ subjects, and the abnormal functioning of the medial prefrontal cortex and anterior cingulate cortex in the FA+ group.

Paternal age and sporadic schizophrenia: evidence for de novo mutations.

Schizophrenia is an etiologically heterogeneous syndrome. It has a strong genetic component and exists in clinically indistinguishable familial and nonfamilial (sporadic) forms. A significant role for de novo genetic mutations in genetic schizophrenia vulnerability is suggested by a strong monotonic increase in schizophrenia risk with advancing paternal age. However, an alternative explanation for the paternal age effect in schizophrenia is that childbearing is delayed in fathers who themselves have genetic schizophrenia vulnerability. In this study, we compared paternal birth ages between patient groups with familial (n = 35) and sporadic (n = 68) patients with DSM-IV schizophrenia from an inpatient schizophrenia research unit. If later age of fathering children is related to having some genetic schizophrenia vulnerability, then paternal birth age should be later in familial schizophrenia cases than in sporadic cases, and any association of father's age and schizophrenia risk in offspring would be a spurious finding, unrelated to etiology. However, if de novo mutations cause sporadic schizophrenia, then patients without a family history of schizophrenia would have older fathers than familial patients. We found that patients without a family history of schizophrenia had significantly older fathers (4.7 years) than familial patients; so later childbirth was not attributable to parental psychiatric illness. These findings support the hypothesis that de novo mutations contribute to the risk for sporadic schizophrenia.