Active and placebo transcranial magnetic stimulation effects on external and internal auditory hallucinations of schizophrenia.

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.

Resilience and corpus callosum microstructure in adolescence.

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.

White-matter microstructure and gray-matter volumes in adolescents with subthreshold bipolar symptoms.

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.

1910s' brains revisited. Cortical complexity in early 20th century patients with intellectual disability or with dementia praecox.

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.

Inter-hemispheric asymmetry of motor corticospinal excitability in major depression studied by transcranial magnetic stimulation.

BACKGROUND: Imaging and electroencephalographic studies have reported inter-hemispheric asymmetries in frontal cortical regions associated with depression. This study aimed at comparing motor corticospinal excitability assessed by methods of transcranial magnetic stimulation (TMS) between the right and left hemispheres in patients with major depression and healthy controls. METHOD: Patients with major depression (n=35) and healthy controls (n=35) underwent a bilateral study of various motor corticospinal excitability parameters, including rest motor threshold (RMT), corticospinal silent period (CSP) duration and intra-cortical inhibition (ICI) and facilitation (ICF). Indexes of asymmetry were calculated, and the relationships between excitability parameters and clinical scores of depression were statistically analyzed. RESULTS: Depressed patients showed a reduced excitability of both excitatory (RMT, ICF) and inhibitory (CSP, ICI) processes in the left hemisphere, compared to the right hemisphere and to healthy controls. CONCLUSION: The present results confirmed the existence of inter-hemispheric asymmetries in frontal cortex activities of depressed patients in favor of a left-sided reduced excitability. This neurophysiological approach may help to guide repetitive TMS procedures in the treatment of depressive disorders.

Disentangling the autism-anxiety overlap: fMRI of reward processing in a community-based longitudinal study.

Up to 40% of youth with autism spectrum disorder (ASD) also suffer from anxiety, and this comorbidity is linked with significant functional impairment. However, the mechanisms of this overlap are poorly understood. We investigated the interplay between ASD traits and anxiety during reward processing, known to be affected in ASD, in a community sample of 1472 adolescents (mean age=14.4 years) who performed a modified monetary incentive delay task as part of the Imagen project. Blood-oxygen-level dependent (BOLD) responses to reward anticipation and feedback were compared using a 2x2 analysis of variance test (ASD traits: low/high; anxiety symptoms: low/high), controlling for plausible covariates. In addition, we used a longitudinal design to assess whether neural responses during reward processing predicted anxiety at 2-year follow-up. High ASD traits were associated with reduced BOLD responses in dorsal prefrontal regions during reward anticipation and negative feedback. Participants with high anxiety symptoms showed increased lateral prefrontal responses during anticipation, but decreased responses following feedback. Interaction effects revealed that youth with combined ASD traits and anxiety, relative to other youth, showed high right insula activation when anticipating reward, and low right-sided caudate, putamen, medial and lateral prefrontal activations during negative feedback (all clusters PFWE<0.05). BOLD activation patterns in the right dorsal cingulate and right medial frontal gyrus predicted new-onset anxiety in participants with high but not low ASD traits. Our results reveal both quantitatively enhanced and qualitatively distinct neural correlates underlying the comorbidity between ASD traits and anxiety. Specific neural responses during reward processing may represent a risk factor for developing anxiety in ASD youth.

Improvement of some schizophrenic deficit symptoms with low doses of amisulpride.

OBJECTIVE: The authors assessed the effects on primary negative symptoms of low doses of amisulpride, a substituted benzamide neuroleptic with high affinity for D2 and D3 dopamine receptors. METHOD: Young, drug-free schizophrenic patients with pure negative symptoms participated in a 6-week double-blind trial of placebo (N = 10) or low-dose amisulpride (N = 10). They were assessed with the Scale for the Assessment of Negative Symptoms. RESULTS: Amisulpride significantly improved negative symptoms. Improvement in avolition, attentional impairment, and retardation was significantly greater with amisulpride than with placebo. CONCLUSIONS: These findings suggest that some primary negative symptoms may be directly affected by low doses of benzamide neuroleptics.

Binding of antipsychotic drugs to cortical 5-HT2A receptors: a PET study of chlorpromazine, clozapine, and amisulpride in schizophrenic patients.

OBJECTIVE: This study examined the binding to cortical serotonin 5-HT2A receptors of conventional doses of the typical neuroleptic chlorpromazine in comparison with clozapine, the prototype atypical antipsychotic, and amisulpride, a specific dopamine D2-D3 blocker. METHOD: Seventeen schizophrenic patients treated with chlorpromazine (75-700 mg/day), four treated with clozapine (200-600 mg/day), and five treated with amisulpride (200-1200 mg/day) were studied. Cortical 5-HT2A binding was estimated by reference to the values for 14 antipsychotic-free schizophrenic subjects with the use of positron emission tomography and [18F]setoperone, a high-affinity radioligand for cortical 5-HT2A receptors. RESULTS: A dose-dependent decrease in the number of available cortical binding sites for [18F] setoperone was demonstrated in the chlorpromazine group; for the highest dose, there was a virtual lack of sites available for binding. A very low percentage of available binding sites was also observed in the clozapine-treated patients at all doses. This suggests a high level of 5-HT2A blockade with both clozapine and high doses of chlorpromazine. No significant binding of amisulpride to 5-HT2A receptors was detected. CONCLUSIONS: A high level of 5-HT2A receptor blockade does not appear specific to clozapine in comparison with high doses of chlorpromazine, suggesting that the distinct clinical profiles of both drugs are unrelated to 5-HT2A blockade itself.

Working memory control in patients with schizophrenia: a PET study during a random number generation task.

OBJECTIVE: The authors' goal was to investigate brain regions involved in the deficiency of working memory control processes in patients with schizophrenia. METHOD: Regional cerebral blood flow was measured with positron emission tomography in eight men with stabilized schizophrenia and eight healthy men while they were performing a graded random number generation task. Twelve scans were made for each subject. Covariations between randomness of responses and regional activation were analyzed. RESULTS: The pattern of covariation between randomness of responses and activation in the anterior cingulate and superior parietal regions differed between patients and healthy subjects. CONCLUSIONS: These results suggest a cinguloparietal dysfunction underlying the impairment of working memory control processes during a random number generation task in patients with schizophrenia.

In vivo characteristics of dopamine D2 receptor occupancy by amisulpride in schizophrenia.

The relationship between the daily oral dose of the benzamide amisulpride and the striatal D2-dopamine receptors occupancy was investigated in 11 schizophrenic patients using positron emission tomography with 76Br-bromolisuride. The patients were studied before and during chronic treatment with amisulpride over a wide range of doses. The test-retest variability of the method was estimated to be 5.8% in a group of four patients receiving placebo. A curvilinear relationship was demonstrated between the amisulpride doses and the D2-receptor occupancy. A range of 70-80% occupancy of the striatal D2 receptors, suggested as an optimal interval for therapeutic action on positive psychotic symptoms, was obtained with doses of amisulpride ranging between 630 and 910 mg per day, while an occupancy of 85%, suggested to be associated with pronounced extrapyramidal side-effects, was reached with 1,100 mg per day.

No serotonin 5-HT2A receptor density abnormality in the cortex of schizophrenic patients studied with PET.

To investigate putative abnormalities of cortical 5-HT2A receptor density in schizophrenia, we used positron emission tomography and [18F]setoperone, a high-affinity 5-HT2A receptor radioligand, in 14 neuroleptic-free or -naive schizophrenic patients and in 15 normal controls. No significant difference between the groups was observed in the whole or regional cortical binding potential of [18F]setoperone, indicating an absence of major 5-HT2A receptor cortical density abnormalities in schizophrenics.

Temporal order and spatial memory in schizophrenia: a parametric study.

Spatial working memory has been shown to be impaired in schizophrenia. In contrast, memory for temporal order has been poorly studied in patients with schizophrenia. The aim of this study was to compare and to further characterize spatial working memory and sequence reproduction deficits in patients with schizophrenia under stable medication by manipulating cues (pattern versus sequence), delay, set-size and response type in various recall and recognition tasks. This allowed us to dissociate processes as encoding, retention and retrieval and to compare the performance of patients with schizophrenia to the performance of patients with prefrontal lesions, who have been previously tested in the same tasks. Our results show that increase of the set-size and of the delay decreased performance of both groups, and that these factors had larger detrimental effects in patients with schizophrenia than in controls. Furthermore, comparison between tasks revealed retention and retrieval deficits in schizophrenia. Finally, patients with schizophrenia showed impairments not only in recall but also in sequence recognition tasks with delay. This is in contrast to patients with prefrontal lesions, who have previously been shown to have intact recognition of sequences after a delay. These results suggest that the working memory deficit in schizophrenia cannot be restricted to a prefrontal dysfunction.

Presynaptic dopaminergic function in the striatum of schizophrenic patients.

The dopaminergic hypothesis of schizophrenia postulates increased brain dopaminergic activity. Two previous studies reported increased 18F-DOPA uptake with positron emission tomography in schizophrenic patients (n = 5, n = 7). In the present study, striatal dopaminergic function was assessed in vivo in six untreated schizophrenics and seven control subjects, comparable for age and sex. The 18F-fluoro-L-DOPA (18F-DOPA) uptake rate constant Ki was determined in the caudate and putamen using coregistered positron emission tomography and magnetic resonance imaging. No difference between groups for mean Ki was found. The variability of the 18F-DOPA uptake values was higher in the caudate (p < 0.01) and in the putamen (p < 0.001) in schizophrenic patients than in control subjects, suggesting that schizophrenia is a disorder involving heterogeneous states of the striatal presynaptic dopaminergic function.

A prognostic study of clinical dimensions in adolescent-onset psychoses.

Adolescent-onset psychoses often raise diagnostic difficulties because of the mixture of schizophrenic and affective features. This study examined prospectively which clinical dimensions contribute to difficulty in initial diagnosis and which clinical features have predictive value for outcomes of schizophrenia or affective disorders, and for eventual psychosocial functioning. Thirty-six adolescents consecutively admitted for a psychotic episode were followed up for 1 to 4 years. Symptoms were assessed at admission, at discharge, and once a year. DSM-III-R (APA 1989) diagnoses were assessed at admission and once a year. Comparisons were performed across initial and followup diagnostic groups. Positive symptoms did not differentiate the initial clinical pictures, while negative symptoms, manic symptoms, and disorganization differentiated the manic and depressive episodes in the acute phase. When initial positive symptoms (mainly delusions) were severe, they predicted a final diagnosis in the schizophrenia spectrum. Poor outcome was associated with more anhedonia-associality and lower functioning scores at admission. Results suggest (1) a higher vulnerability to positive symptoms in adolescents who will further develop schizophrenia and (2) the low specificity of affective symptoms at this age.

Altered hemispheric functional dominance during word generation in negative schizophrenia.

Functional brain imaging studies have reported decreased frontal activations in schizophrenia, but hemispheric dominance for language has rarely been assessed. To investigate regional activation and lateralization during word production, we determined normalized regional cerebral blood flow (rCBF) variations with positron emission tomography (PET) and H2(15)O (water labeled with the isotope oxygen 15) in 14 negative schizophrenia patients and 14 volunteers. Subjects were scanned during two trials of three conditions: rest, vocalized verbal fluency, and spontaneous word production. Images were analyzed using an anatomical volumes of interest method, and the two groups' changes were compared, using rest as a baseline. Differences in the lateralization of changes were detected in homologous frontal and inferior parietal regions. The lateralization effects in patients arose from lower activations in the left frontal regions, abnormal right inferior frontal activations, and weaker right inferior parietal deactivation, during the word production tasks. The right hemisphere changes correlated negatively with the performance in verbal fluency. Thus in negative schizophrenia patients, while the activations were less focused on the left hemisphere regions usually engaged in word generation, rCBF changes in the right hemisphere might reflect a compensatory functional pattern.

[Use of electroconvulsive therapy in adolescence]. / Utilisation de l'ECT chez l'adolescent.

Few studies report the use of ECT in adolescents. Within a period of 3 years, 9 patients aged 15 to 19 were treated by ECT in our department. Indications were acute schizophrenia, delusional depression and delusional mania, resistant to usual medication. ECT proved to be a safe treatment with good short-term outcome. Long-term outcome did not seem to be modified by treatment. These results are discussed in relation to the use of ECT in adults and adolescents reported in the literature.

[Persecution syndrome after the use of interferon: a case report]. / Syndrome de persécution sous interféron: à propos d'un cas.

The interferon has been used for fifteen years as a viral and carcinomatous pathology treatment, however it has some spychiatric secondary effects. In this paper we present a psychotic reaction in a patient without any psychiatric history. A depression with specific characteristics was also detected. It appears just after injection and goes away quickly forming an interesting "on-off" depression model.

Brain imaging findings in children and adolescents with mental disorders: a cross-sectional review.

BACKGROUND: While brain imaging studies of juvenile patients has expanded in recent years to investigate the cerebral neurophysiologic correlates of psychiatric disorders, this research field remains scarce. The aim of the present review was to cluster the main mental disorders according to the differential brain location of the imaging findings recently reported in children and adolescents reports. A second objective was to describe the worldwide distribution and the main directions of the recent magnetic resonance imaging (MRI) and positron tomography (PET) studies in these patients. METHODS: A survey of 423 MRI and PET articles published between 2005 and 2008 was performed. A principal component analysis (PCA), then an activation likelihood estimate (ALE) meta-analysis, were applied on brain regional information retrieved from articles in order to cluster the various disorders with respect to the cerebral structures where alterations were reported. Furthermore, descriptive analysis characterized the literature production. RESULTS: Two hundred and seventy-four articles involving children and adolescent patients were analyzed. Both the PCA and ALE methods clustered, three groups of diagnosed psychiatric disorders, according to the brain structural and functional locations: one group of affective disorders characterized by abnormalities of the frontal-limbic regions; a group of mental disorders with "cognition deficits" mainly related to cortex abnormalities; and one psychomotor condition associated with abnormalities in the basal ganglia. The descriptive analysis indicates a focus on attention deficit hyperactivity disorders and autism spectrum disorders, a general steady rise in the number of annual reports, and lead of US research. CONCLUSION: This cross-sectional review of child and adolescent mental disorders based on neuroimaging findings suggests overlaps of brain locations that allow to cluster the diagnosed disorders into three sets with respectively marked affective, cognitive, and psychomotor phenomenology. Furthermore, the brain imaging research effort was unequally distributed across disorders, and did not reflect their prevalence.