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Abstract: Repetitive transcranial magnetic stimulation (rTMS) can interfere with linguistic performance when delivered over language areas. At low frequency (1 Hz), rTMS is assumed to decrease cortical excitability; however, the degree of TMS effect on cortical language areas may depend on the localization of the stimulation coil with respect to the inter-individual anatomo-functional variations. Hence, we aimed at investigating individual brain areas involved in semantic and phonological auditory processes. We hypothesized that active rTMS targeted over Wernicke''s area might modify the performance during a language-fragment-detection task. Sentences in native or foreign languages were presented to 12 right-handed male healthy volunteers during functional magnetic resonance imaging (fMRI). 3D-functional maps localized the posterior temporal activation (Wernicke) in each subject and MRI anatomical cortical landmarks were used to define Broca''s pars opercularis (F3Op). A frameless stereotaxy system was used to guide the TMS coil position over Wernicke''s and F3Op areas in each subject. Active and placebo randomized rTMS sessions were applied at 1 Hz, 110% of motor threshold, during the same language-fragment-detection task. Accuracy and response time (RT) were recorded. RT was significantly decreased by active rTMS compared to placebo over Wernicke''s area, and was more decreased for native than for foreign languages. No significant RT change was observed for F3Op area. rTMS conditions did not impair participants'' accuracy. Thus, low-frequency rTMS over Wernicke''s area can speed-up the response to a task tapping on native language perception in healthy volunteers. This individually-guided stimulation study confirms that facilitatory effects are not confined to high-frequency rTMS. [Copyright &y& Elsevier]

1/In juvenile patients, a cross-sectional ALE meta-analysis of both brain structure and function regional deviations in 270 articles allowed to cluster the diagnosed disorders into three sets with respectively marked affective, cognitive, and psychomotor phenomenology. The group with affective phenomenology was characterized by abnormalities of the frontal-limbic regions; the group with “cognition deficits” (incl. schizophrenia) mainly related to cortex abnormalities; and the psychomotor condition was associated with abnormalities in the basal ganglia. Therefore, early regional brain abnormalities might interact with the analysis of subsequent treatments effects in MR studies of brain structure and function of chronic mental disorders. 2/In chronic patients, brain imaging studies of antipsychotic drugs using dopamine receptor radioligands &PET scanner have consistently demonstrated the prevalence of their dose-dependent action in basal ganglia. This information has led to theoretical windows for optimal drug dosage. Recent measures of the dopamine transporter in chronic antipsychotic treatment, or in chronic use of drugs of addiction (e.g. tobacco, cannabis) suggest opposite changes of the adioligand uptake in both conditions. Therefore, control for the associated confounding addictions is required for in vivo analysis of antipsychotic action on the dopamine regulation in cortex and subcortical regions. 3/In treatment-resistant patients, MR & PET imaging studies have detected deviations of both brain structure and function, therefore suggesting biomarker of treatment response. 4/Conclusion: stage of illness, addictions, multimodal imaging, should be considered as covariates for brain imaging determinations of treatment effects in patients with chronic mental disorders. [ABSTRACT FROM AUTHOR]

Objective The idea of cortical surface anomalies in subjects with intellectual disability (mental retardation) and schizophrenia can be traced back to early 20th century qualitative observations. Since it is unknown whether modern quantitative measures of cortical complexity and folding would retrieve those early empirical observations, we measured fractal dimension and sulcal span index in photographs of human brains taken in the 1910's. Method Brain photographs were compared between 36 patients with mental retardation and 21 patients with dementia praecox for the fractal dimension and sulcal span index. Also, a mental retardation subgroup with no-or-non-understandable speech ( n = 12) was compared with a subgroup with comprehensible speech ( n = 23). Results Mental retardation group had a lower whole-brain fractal dimension than dementia praecox, and a higher sulcal span index in left posterior cortex. The mental retardation subgroup with comprehensible speech had a lower fractal dimension in left hemisphere than the subgroup with no-or-non-understandable speech and a lower sulcal index in left posterior cortex. Conclusion Measures of cortical complexity and folding suggest differences between mental retardation and dementia praecox, and regional variations according to language abilities in mental retardation. The findings provide a unique picture of cortical surface changes in their original untreated form, one century ago. [ABSTRACT FROM AUTHOR]

Abnormalities in white-matter (WM) microstructure, as lower fractional anisotropy (FA), have been reported in adolescent-onset bipolar disorder and in youth at familial risk for bipolarity. We sought to determine whether healthy adolescents with subthreshold bipolar symptoms (SBP) would have early WM microstructural alterations and whether those alterations would be associated with differences in gray-matter (GM) volumes. Forty-two adolescents with three core manic symptoms and no psychiatric diagnosis, and 126 adolescents matched by age and sex, with no psychiatric diagnosis or symptoms, were identified after screening the IMAGEN database of 2223 young adolescents recruited from the general population. After image quality control, voxel-wise statistics were performed on the diffusion parameters using tract-based spatial statistics in 25 SBP adolescents and 77 controls, and on GM and WM images using voxel-based morphometry in 30 SBP adolescents and 106 controls. As compared with healthy controls, adolescents with SBP displayed lower FA values in a number of WM tracts, particularly in the corpus callosum, cingulum, bilateral superior and inferior longitudinal fasciculi, uncinate fasciculi and corticospinal tracts. Radial diffusivity was mainly higher in posterior parts of bilateral superior and inferior longitudinal fasciculi, inferior fronto-occipital fasciculi and right cingulum. As compared with controls, SBP adolescents had lower GM volume in the left anterior cingulate region. This is the first study to investigate WM microstructure and GM morphometric variations in adolescents with SBP. The widespread FA alterations in association and projection tracts, associated with GM changes in regions involved in mood disorders, suggest altered structural connectivity in those adolescents. [ABSTRACT FROM AUTHOR]

Background. Failure to resist chronic obsessive-compulsive symptoms may denote an altered state of cognitive control. We searched for the cerebral regions engaged in this dysfunction.Method. Differences in brain regional activity were examined by event-related functional magnetic regional imaging (fMRI) in a group of adolescents or young adults (n=12) with childhood-onset obsessive-compulsive disorder (OCD), relative to healthy subjects. Subjects performed a conflict task involving the presentation of two consecutive and possibly conflicting prime and target numbers. Patients' image dataset was further analysed according to resistance or non-resistance to symptoms during the scans.Results. Using volume correction based on a priori hypotheses, an exploratory analysis revealed that, within the prime-target repetition condition, the OCD subjects activated more than healthy subjects a subregion of the anterior cingulate gyrus and the left parietal lobe. Furthermore, compared with 'resistant' patients, the 'non-resistant' OCD subjects activated a bilateral network including the precuneus, pulvinar and paracentral lobules.Conclusions. Higher regional activations suggest an abnormal amplification process in OCD subjects during the discrimination of repetitive visual stimuli. The regional distribution of functional changes may vary with the patients' ability to resist obsessions. [ABSTRACT FROM AUTHOR]

Objective Repetitive transcranial magnetic stimulation ( rTMS) over the left temporo-parietal region has been proposed as a treatment for resistant auditory verbal hallucinations ( AVH), but which patients are more likely to benefit from rTMS is still unclear. This study sought to assess the effects of rTMS on AVH, with a focus on hallucination phenomenology. Method Twenty-seven patients with schizophrenia and medication-resistant AVH participated to a randomized, double-blind, placebo-controlled, add-on rTMS study. The stimulation targeted a language-perception area individually determined using functional magnetic resonance imaging and a language recognition task. AVH were assessed using the hallucination subscale of the Scale for the Assessment of Positive Symptoms ( SAPS). The spatial location of AVH was assessed using the Psychotic Symptom Rating Scales. Results A significant improvement in SAPS hallucination subscale score was observed in both actively treated and placebo-treated groups with no difference between both modalities. Patients with external AVH were significantly more improved than patients with internal AVH, with both modalities. Conclusions A marked placebo effect of rTMS was observed in patients with resistant AVH. Patients with prominent external AVH may be more likely to benefit from both active and placebo interventions. Cortical effects related to non-magnetic stimulation of the auditory cortex are suggested. [ABSTRACT FROM AUTHOR]

Background. Resilience is the capacity of individuals to resist mental disorders despite exposure to stress. Little is known about its neural underpinnings. The putative variation of white-matter microstructure with resilience in adolescence, a critical period for brain maturation and onset of high-prevalence mental disorders, has not been assessed by diffusion tensor imaging (DTI). Lower fractional anisotropy (FA) though, has been reported in the corpus callosum (CC), the brain's largest white-matter structure, in psychiatric and stress-related conditions. We hypothesized that higher FA in the CC would characterize stress-resilient adolescents. Method. Three groups of adolescents recruited from the community were compared: resilient with low risk of mental disorder despite high exposure to lifetime stress (n = 55), at-risk of mental disorder exposed to the same level of stress (n = 68), and controls (n = 123). Personality was assessed by the NEO-Five Factor Inventory (NEO-FFI). Voxelwise statistics of DTI values in CC were obtained using tract-based spatial statistics. Regional projections were identified by probabilistic tractography. Results. Higher FA values were detected in the anterior CC of resilient compared to both non-resilient and control adolescents. FA values varied according to resilience capacity. Seed regional changes in anterior CC projected onto anterior cingulate and frontal cortex. Neuroticism and three other NEO-FFI factor scores differentiated non-resilient participants from the other two groups. Conclusion. High FA was detected in resilient adolescents in an anterior CC region projecting to frontal areas subserving cognitive resources. Psychiatric risk was associated with personality characteristics. Resilience in adolescence may be related to white-matter microstructure. [ABSTRACT FROM AUTHOR]

Genetic variation in a genomic region on chromosome 15q25.1, which encodes the alpha5, alpha3, and beta4 subunits of the cholinergic nicotinic receptor genes, confers risk to smoking and nicotine dependence (ND). Neural reward-related responses have previously been identified as important factors in the development of drug dependence involving ND. Applying an imaging genetics approach in two cohorts (N=487; N=478) of healthy non-smoking adolescents, we aimed to elucidate the impact of genome-wide significant smoking-associated variants in the CHRNA5-CHRNA3-CHRNB4 gene cluster on reward-related neural responses in central regions such as the striatum, orbitofrontal and anterior cingulate cortex (ACC), and personality traits related to addiction. In both samples, carriers of the rs578776 GG compared with AG/AA genotype showed a significantly lower neural response to reward outcomes in the right ventral and dorsal ACC but not the striatum or the orbitofrontal cortex. Rs578776 was unrelated to neural reward anticipation or reward magnitude. Significantly higher scores of anxiety sensitivity in GG compared with AG/AA carriers were found only in sample 1. Associations with other personality traits were not observed. Our findings suggest that the rs578776 risk variant influences susceptibility to ND by dampening the response of the ACC to reward feedback, without recruiting the striatum or orbitofrontal cortex during feedback or anticipation. Thus, it seems to have a major role in the processing of and behavioral adaptation to changing reward outcomes. [ABSTRACT FROM AUTHOR]

Background: Brain models of drug addiction are being tackled in humans, using PET and MRI. Results: [1.] Whereas tobacco and cannabis do not interact directly with dopamine sites, positron emission tomography detected lower availability in sites regulating the catecholamines homeostasis, notably in dopamine transporter sites in striatal and in extrastriatal regions. This further supports repeated and long term substance use progress towards an adaptative diminished basal dopamine level that would contribute to the switch to an addicted brain. [2.] Alcohol: abnormalities in brain macro- and micro- structure were searched in detoxified alcohol-dependents with preserved psychosocial functioning: [-] Brain function (fMRI): fronto-cerebellar overactivation detected during an auditory language task in alcohol-dependents may reflect the compensatory effort required for patients to maintain the same level of performance as controls. [-] Brain macrostructure (MRI). Widespread lower white matter volumes, and lower grey matter volumes in the frontal lobe, insula, hippocampus, thalami and cerebellum, were detected. Poorer neuropsychological performance correlated with smaller grey matter volumes in these regions and with lower white matter volume in the brainstem. [-] Brain microstructure (DTI): tractography of white matter fiber bundles revealed that brainstem bundles alteration may contribute to cognitive flexibility impairment. Regression analyses showed memory scores were related to brain microstructure in parahippocampal areas, frontal cortex, and left temporal cortex. This suggest diffusion imaging (DTI) is a useful probe to early alcohol-induced brain alterations. Conclusion: While indices of dopamine down-regulation are consistency detected in several drug addictions, even “socially-adapted” alcohol dependence may induce change in brain structure. Psychol Med. 1998 28:1039-48. Neuropsychopharmacology. 2007 32:429-38. IEEE Trans Med Imaging. 2007 26:553-65 J Nucl Med. 2007 48:538-46. Neuropsychopharmacology (Chanraud S et al., 2008 Jul 9. [Epub ahead of print]). J Clin Psychopharmacol (Leroy C et al, in press). [Copyright &y& Elsevier]

Background: Analysis of cortical folding may provide insight into neurodevelopment deviations, which, in turn, can predispose to depression that responds particularly poorly to medications. We hypothesized that patients with treatment-resistant depression would exhibit measurable alterations in cortical folding. Methods: We computed hemispheric global sulcal indices (g-SIs) in T1-weighted magnetic resonance images obtained from 76 patients and 70 healthy controls. We separately searched for anatomic deviations in patients with bipolar disorder (16 patients with treatment-resistant depression, 25 with euthymia) and unipolar depression (35 patients with treatment-resistant depression). Results: Compared with healthy controls, both groups of patients with treatment-resistant depression exhibited reduced g-SIs: in the right hemisphere among patients with bipolar disorder and in both hemispheres among those with unipolar depression. Patients with euthymic bipolar disorder did not differ significantly from depressed patients or healthy controls. Among patients with bipolar disorder who were taking lithium, we found positive correlations between current lithium dose and g-SIs in both hemispheres. Limitations: We cannot estimate the extent to which the observed g-SI reductions are linked to treatment resistance and to what extent they are state-dependent. Furthermore, we cannot disentangle the impact of medications from that of the affective disorder. Finally, there is interindividual variation and overlap of g-SIs among patients and healthy controls that need to be considered when interpreting our results. Conclusion: Reduced global cortical folding surface appears to be characteristic of patients with treatmentresistant depression, either unipolar or bipolar. In patients with bipolar disorder, treatment with lithium may modify cortical folding surface. [ABSTRACT FROM AUTHOR]

OBJECTIVE: Although euthymic bipolar patients show minimal manic and depressive symptoms, they continue to show impaired emotional regulation and cognitive functioning. Few studies have directly examined the interference of emotional information with cognitive processes and its underlying cerebral mechanisms in euthymic bipolar patients. The authors examined the emotional modulation of cognitive processes and its underlying neural mechanisms in euthymic bipolar patients. METHOD: Seventeen euthymic bipolar patients and 17 healthy comparison subjects underwent functional magnetic resonance imaging (MRI) while performing an emotional and nonemotional go/nogo task. Neural responses associated with the overall task performance, as well as with the impact of emotional information on the task performance, were assessed. RESULTS: Bipolar disorder patients exhibited increased activity in the temporal cortex, specifically to emotional go/nogo conditions, as well as in the orbitofrontal cortex, the insula, the caudate nuclei, and the dorsal anterior and posterior cingulate cortices when inhibiting emotional stimuli compared with neutral stimuli. Conversely, no global attentional deficits were observed on either a behavioral or neural response level, indicated by similar task performances for all task conditions and similar brain activation patterns when comparing all the go/nogo conditions with the resting state. CONCLUSIONS: The present study provides evidence of an altered emotional modulation of cognitive processing in euthymic bipolar patients, indicated by an overactivation in ventral-limbic, temporal, and dorsal brain structures during emotional go/nogo conditions in patients relative to comparison subjects. [ABSTRACT FROM AUTHOR]

The underlying neurobiology of autism, a severe pervasive developmental disorder, remains unknown. Few neocortical brain MRI abnormalities have been reported. Using rest functional brain imaging, two independent studies have described localized bilateral temporal hypoperfusion in children with primary autism. In order to search for convergent evidence of anatomical abnormalities in autistic children, we performed an anatomical MRI study using optimized whole-brain voxel-based morphometry (VBM). High-resolution 3-D T1-weighted MRI data sets were acquired in 21 children with primary autism (mean age 9.3 ± 2.2 years) and 12 healthy control children (mean age 10.8 ± 2.7 years). By comparing autistic children to normal children, we found bilaterally significant decreases of grey matter concentration located in superior temporal sulcus (STS) (P < 0.05 corrected, after small volume correction; SVC). Children with autism were also found to have a decrease of white matter concentration located in the right temporal pole and in cerebellum (P < 0.05, corrected) compared to normal children. These results suggest that autism is associated with bilateral anatomical abnormalities localized in the STS and are remarkably consistent with functional hypoperfusion previously reported in children with autism. The multimodal STS areas are involved in highest level of cortical integration of both sensory and limbic information. Moreover, the STS is now recognized as a key cortical area of the “social brain” and is implicated in social perceptual skills that are characteristically impaired in autism. Therefore, the convergent anatomical and functional temporal abnormalities observed in autism may be important in the understanding of brain behavior relationships in this severe developmental disorder. [Copyright &y& Elsevier]

Introduction: Although neuroimaging studies suggest brain regional abnormalities in depressive disorders, it remains unclear whether abnormalities are present at illness onset or reflect disease progression. Objectives: We hypothesized that cerebral variations were present in adolescents with subthreshold depression known to be at high risk for later full-blown depression. Aims: We examined brain structural and diffusion-weighted magnetic resonance images of adolescents with subthreshold depression. Methods: The participants were extracted from the European IMAGEN study cohort of healthy adolescents recruited at age 14. Subthreshold depression was defined as a distinct period of abnormally depressed or irritable mood, or loss of interest, plus two or more depressive symptoms but without diagnosis of Major Depressive Episode. Comparisons were performed between adolescents meeting these criteria and control adolescents within the T1-weighted imaging modality (118 and 475 adolescents respectively) using voxel-based morphometry and the diffusion tensor imaging modality (89 ad 422 adolescents respectively) using tract-based spatial statistics. Whole brain analyses were performed with a statistical threshold set to p< 0.05 corrected for multiple comparisons. Results: Compared with controls, adolescents with subthreshold depression had smaller gray matter volume in caudate nuclei, medial frontal and cingulate cortices; smaller white matter volume in anterior limb of internal capsules, left forceps minor and right cingulum; and lower fractional anisotropy and higher radial diffusivity in the genu of corpus callosum. Conclusions: The findings suggest that adolescents with subthreshold depression have volumetric and microstructural gray and white matter changes in the emotion regulation frontal-striatal-limbic network. [Copyright &y& Elsevier]