Atypical Semantic Fluency and Recall in Children and Adolescents with Autism Spectrum Disorders Associated with Autism Symptoms and Adaptive Functioning.

It is unclear whether children with autism spectrum disorders have atypical semantic fluency and lower memory for the semantics of words. Therefore, we examined semantic typicality, fluency and recall for the categories of fruits and animals in 60 children with autism aged 7-15 years (boys: 48/girls: 12) compared to 60 typically developing controls. Relative to controls, the autism group had reduced animal fluency, fruit typicality and recall for fruits. Notably, these measures were associated with more autistic-like symptoms and/or lower adaptive functioning across the autism and control groups. In conclusion, atypical semantics of fruits in the autism group may reflect development of idiosyncratic semantic networks while their lower semantic fluency and recall suggest impaired executive language functions.

Reduced mismatch negativity in children and adolescents with autism spectrum disorder is associated with their impaired adaptive functioning.

Children and adolescents on the autism spectrum display sensory disturbances, rigid and repetitive behavior, social communication problems and a high prevalence of impaired adaptive functioning. Autism is associated with slowed behavioral and neural habituation to repeated sensory input and decreased responses to sensory deviations. Mismatch negativity (MMN) reflects a pre-attentive difference in the neural response to sensory deviations relative to regularities and studies overall suggest that children and adolescents with autism tend to have smaller MMN. However, it remains unclear whether reduced MMN in autism is coupled to severity of specific autistic symptoms or more generally to lower level of adaptive functioning. To address these questions, the present study used electroencephalography (EEG) to assess whether auditory MMN in 59 children and adolescents with autism aged 7-14 years compared to 59 typically developing children and adolescents were related to specific autistic symptoms or level in adaptive functioning. As hypothesized, the autism group had a lower MMN amplitude than controls. Smaller MMN amplitudes were specifically associated with lower adaptive functioning in the autistic subjects but not in controls while no apparent relationships were observed with autistic-like social interaction and communication problems, atypical language, rigidity, stereotypy or sensory sensitivity symptoms. Our findings indicate that a blunted response to changes in sensory input may underlie or contribute to the generalized difficulties with adapting to daily life circumstances seen in children and adolescents with autism. LAY SUMMARY: Children and adolescents on the autism spectrum have a high prevalence of impaired adaptive functioning. Neuroimaging studies have reported that children and adolescents with autism display attenuated brain activity when discriminating sensory input. However, it is unknown whether this attenuation is related to autistic symptoms and/or adaptive functioning. The present study used electroencephalogram (EEG) to show that attenuated brain response in discrimination of novel compared to repetitive sounds in children and adolescents with autism is related to their impaired adaptive functioning.

Autism: a transdiagnostic, dimensional, construct of reasoning?

The concept of autism has changed across time, from the Bleulerian concept, which defined it as one of several symptoms of dementia praecox, to the present-day concept representing a pervasive development disorder. The present theoretical contribution to this special issue of EJN on autism introduces new theoretical ideas and discusses them in light of selected prior theories, clinical examples, and recent empirical evidence. The overall aim is to identify some present challenges of diagnostic practice and autism research and to suggest new pathways that may help direct future research. Future research must agree on the definitions of core concepts such as autism and psychosis. A possible redefinition of the concept of autism may be a condition in which the rationale of an individual's behaviour differs qualitatively from that of the social environment due to characteristic cognitive impairments affecting reasoning. A broad concept of psychosis could focus on deviances in the experience of reality resulting from impairments of reasoning. In this light and consistent with recent empirical evidence, it may be appropriate to redefine dementia praecox as a developmental disorder of reasoning. A future challenge of autism research may be to develop theoretical models that can account for the impact of complex processes acting at the social level in addition to complex neurobiological and psychological processes. Such models could profit from a distinction among processes related to (i) basic susceptibility, (ii) adaptive processes and (iii) decompensating factors involved in the development of manifest illness.

Structural brain correlates of sensorimotor gating in antipsychotic-naive men with first-episode schizophrenia.

BACKGROUND: Prepulse inhibition (PPI) of the startle reflex is modulated by a complex neural network. Prepulse inhibition impairments are found at all stages of schizophrenia. Previous magnetic resonance imaging (MRI) studies suggest that brain correlates of PPI differ between patients with schizophrenia and healthy controls; however, these studies included only patients with chronic illness and medicated patients. Our aim was to examine the structural brain correlates of PPI in antipsychotic-naive patients with first-episode schizophrenia. METHODS: We performed acoustic PPI assessment and structural MRI (1.5 and 3 T) in men with first-episode schizophrenia and age-matched controls. Voxel-based morphometry was used to investigate the association between PPI and grey matter volumes. RESULTS: We included 27 patients and 38 controls in the study. Patients had lower PPI than controls. The brain areas in which PPI and grey matter volume correlated did not differ between the groups. Independent of group, PPI was significantly and positively associated with regional grey matter volume in the right superior parietal cortex. Prepulse inhibition and grey matter volume associations were also observed in the left rostral dorsal premotor cortex, the right presupplementary motor area and the anterior medial superior frontal gyrus bilaterally. Follow-up analyses suggested that the rostral dorsal premotor cortex and presupplementary motor area correlations were driven predominantly by the controls. LIMITATIONS: We used 2 different MRI scanners, which might have limited our ability to find subcortical associations since interscanner consistency is low for subcortical regions. CONCLUSION: The superior parietal cortex seems to be involved in the regulation of PPI in controls and antipsychotic-naive men with first-episode schizophrenia. Our observation that PPI deficits in schizophrenia may be related to the rostral dorsal premotor cortex and presupplementary motor area, brain areas involved in maintaining relevant sensory information and voluntary inhibition, warrants further study.

P50 suppression and its neural generators in antipsychotic-naive first-episode schizophrenia before and after 6 months of quetiapine treatment.

BACKGROUND: Numerous studies have demonstrated sensory gating deficits in schizophrenia. However, only a few longitudinal studies report on the effects of antipsychotic treatment on sensory gating deficits and their results are inconsistent. In the present study, P50 suppression and its neural generators were investigated in antipsychotic-naïve first-episode patients with schizophrenia before and after 6 months of treatment with quetiapine. METHODS: Thirty-four antipsychotic-naïve first-episode schizophrenia patients and age and gender matched healthy controls were tested in an auditory sensory gating paradigm at baseline and after 6 months. During this period, the patients were treated with quetiapine, while controls received no treatment. Sixteen patients completed the study. RESULTS: Patients showed significant reduced P50 suppression compared with controls at baseline but not at follow-up. Furthermore, a significant positive correlation between baseline P50 suppression and dose of quetiapine at follow-up was found. P50 suppression in patients receiving above median dosages of quetiapine increased significantly from baseline to follow-up. At baseline, a frontocentral source was significantly more active in patients than in controls at the time of the testing stimulus. CONCLUSIONS: The present findings suggest that P50 suppression deficits are already present at an early stage of schizophrenia. Furthermore, particularly those patients with more severe gating deficits appeared to need higher dosages of quetiapine, although their clinical symptoms did not seem to indicate this. Quetiapine treatment significantly improved these gating deficits. Furthermore, a frontocentral source in the brain appeared to be involved in the deficient P50 gating of the patients.

Neural markers of negative symptom outcomes in distributed working memory brain activity of antipsychotic-naive schizophrenia patients.

Since working memory deficits in schizophrenia have been linked to negative symptoms, we tested whether features of the one could predict the treatment outcome in the other. Specifically, we hypothesized that working memory-related functional connectivity at pre-treatment can predict improvement of negative symptoms in antipsychotic-treated patients. Fourteen antipsychotic-naive patients with first-episode schizophrenia were clinically assessed before and after 7 months of quetiapine monotherapy. At baseline, patients underwent functional magnetic resonance imaging while performing a verbal n-back task. Spatial independent component analysis identified task-modulated brain networks. A linear support vector machine was trained with these components to discriminate six patients who showed improvement in negative symptoms from eight non-improvers. Classification accuracy and significance was estimated by leave-one-out cross-validation and permutation tests, respectively. Two frontoparietal and one default mode network components predicted negative symptom improvement with a classification accuracy of 79% (p = 0.003). Discriminating features were found in the frontoparietal networks but not the default mode network. These preliminary data suggest that functional patterns at baseline can predict negative symptom treatment-response in schizophrenia. This information may be used to stratify patients into subgroups thereby facilitating personalized treatment.

Impaired temporoparietal deactivation with working memory load in antipsychotic-naïve patients with first-episode schizophrenia.

OBJECTIVES: Neuroimaging studies have shown abnormal task-related deactivations during working memory (WM) in schizophrenia patients with recent emphasis on brain regions within the default mode network. Using fMRI, we tested whether antipsychotic-naïve schizophrenia patients were impaired at deactivating brain regions that do not subserve WM. METHODS: Twenty-three antipsychotic-naïve patients with first-episode schizophrenia and 35 healthy individuals underwent whole-brain 3T fMRI scans while performing a verbal N-back task including 0-back (no WM load), 1-back (low WM load), and 2-back (high WM load) conditions. RESULTS: Contrasting the 2-back and 0-back conditions revealed that patients deactivated default mode network regions to a similar degree as controls. However, patients were impaired in deactivating large bilateral clusters centred on the superior temporal gyrus with increasing WM load. These regions activated with the no WM load condition (0-back) in both groups. CONCLUSIONS: Because 0-back activation reflects verbal attention processes, patients' persistent activation in the 1-back and 2-back conditions may reflect an inability to shift cognitive strategy with onset of WM demands. Since patients were antipsychotic-naïve and task performance was equal to controls, we infer that this impaired temporoparietal deactivation may represent a primary dysfunction in schizophrenia.

Progressive striatal and hippocampal volume loss in initially antipsychotic-naive, first-episode schizophrenia patients treated with quetiapine: relationship to dose and symptoms.

First-generation antipsychotics have been associated with striatal volume increases. The effects of second-generation antipsychotics (SGAs) on the striatum are unclear. Moreover, SGAs may have neuroprotective effects on the hippocampus. Dose-dependent volumetric effects of individual SGAs have scarcely been investigated. Here we investigated structural brain changes in antipsychotic-naive, first-episode schizophrenia patients after 6 months treatment with the SGA, quetiapine. We have recently reported on baseline volume reductions in the caudate nucleus and hippocampus. Baseline and follow-up T1-weighted images (3 T) from 22 patients and 28 matched healthy controls were analysed using tensor-based morphometry. Non-parametric voxel-wise group comparisons were performed. Small volume correction was employed for striatum, hippocampus and ventricles. Dose-dependent medication effects and associations with psychopathology were assessed. Patients had significant bilateral striatal and hippocampal loss over the 6-month treatment period. When compared to controls the striatal volume loss was most pronounced with low quetiapine doses and less apparent with high doses. Post-hoc analyses revealed that the striatal volume loss was most pronounced in the caudate and putamen, but not in accumbens. Conversely, hippocampal volume loss appeared more pronounced with high quetiapine doses than with low doses. Clinically, higher baseline positive symptoms were associated with more striatal and hippocampal loss over time. Although patients' ventricles did not change significantly, ventricular increases correlated with less improvement of negative symptoms. Progressive regional volume loss in quetiapine-treated, first-episode schizophrenia patients may be dose-dependent and clinically relevant. The mechanisms underlying progressive brain changes, specific antipsychotic compounds and clinical symptoms warrant further research.

Cognitive effects of six months of treatment with quetiapine in antipsychotic-naïve first-episode schizophrenia.

Effects of quetiapine on cognition were assessed in a group of first-episode antipsychotic-naïve patients with schizophrenia (N=24). A comprehensive battery of neuropsychological tests was administered at baseline and after 6 months of treatment with quetiapine. In order to examine retest effects, a matched healthy control group (N=24) was also tested at baseline and after 6 months. Only few differential changes were observed between patients and healthy controls. Of 8 cognitive domains examined, only significant changes in executive function suggested possible ameliorating effects of quetiapine. Patients also improved on speed of processing; however, this was parallel to the retest effects found in healthy controls. When covaried for differences at baseline, patients showed smaller improvements in speed of processing than the retest effects found in controls, as well as a lack of retest effects on sustained attention and working memory that were found in healthy controls. The main result of the study is that there was very little evidence of efficacy of quetiapine on cognition. The study also indicated a lack of normal retest effects in patients compared to controls.

Serotonin2A receptor blockade and clinical effect in first-episode schizophrenia patients treated with quetiapine.

RATIONALE: We have previously reported decreased frontal cortical serotonin2A receptor binding in 30 antipsychotic naïve first-episode schizophrenic patients and a relationship between this binding and positive psychotic symptoms. Until now, no longitudinal studies of serotonin2A receptor in first-episode antipsychotic-naïve schizophrenia patients have reported on the relationship between serotonin2A receptor occupancy and treatment effect after sustained treatment with a specific atypical antipsychotic compound. OBJECTIVES: Here, we measured serotonin2A receptor occupancy with [(18)F]altanserin PET in 15 first-episode antipsychotic-naïve schizophrenia patients before and after 6 months of quetiapine treatment. Moreover, we investigated possible relationships between clinical efficacy, oral dose, and plasma levels of quetiapine RESULTS: Significant nonlinear relationships were found between serotonin2A receptor occupancy, quetiapine dose, and plasma concentration. There was a modest effect on positive symptoms up until a serotonin2A receptor occupancy level of approximately 60%. A receptor occupancy level between 60% and 70% appeared to exert the optimal serotonin2A receptor related treatment effect on positive symptoms whereas no additional serotonin2A receptor associated treatment effect was obtained above a receptor occupancy of 70%. CONCLUSIONS: Taken together, the data point to a therapeutic role of the serotonin2A receptor in the treatment of subgroups of patients with schizophrenia. Specifically, the study indicates a serotonin2A receptor associated therapeutic window on positive symptoms in responding patients in the range between 60% and 70% occupancy in antipsychotic-naïve first-episode schizophrenia. We speculate that non-responding patients need higher dopamine D(2) receptor blockade. Future studies with concurrent measurement of interactions with the dopamine system are, however, warranted to clarify this.

Sensorimotor gating and habituation in antipsychotic-naive, first-episode schizophrenia patients before and after 6 months' treatment with quetiapine.

Impaired prepulse inhibition of the startle reflex (PPI) in schizophrenia has been replicated in many studies. However, previous results may have been influenced by course of illness, and antipsychotic medication. Studies on antipsychotic-naive, first-episode schizophrenia patients are lacking, since these patients are so difficult to recruit. Furthermore, longitudinal studies are few, and their results are inconsistent: some results indicating a reduction of PPI deficits by treatment with atypical antipsychotics, while others do not. This study reports on PPI, habituation and sensitization of the human startle reflex in a large group of antipsychotic-naive, first-episode schizophrenia patients, and the effect of subsequent treatment with quetiapine. Thirty-four antipsychotic-naive, first-episode schizophrenia patients (24 males, 10 females), and age- and gender-matched healthy controls were tested in a psychophysiological test battery at baseline and again after 6 months. During this period, the patients were treated with quetiapine, while the controls received no treatment. Sixteen patients completed the study. At baseline, male patients showed significantly lower PPI than controls. Treatment with quetiapine for 6 months increased male PPI to a level where it was no longer statistically different from the controls. The much smaller group of females did not show PPI deficits at baseline. In addition, compared to controls, patients appeared highly aroused and showed a strong yet non-significant trend for reduced sensitization at baseline, but not at follow-up. Patients and controls showed similar levels of habituation, both at baseline, and at follow-up. These findings indicate that PPI deficits are already present from the earliest stage of clinical onset of schizophrenia, before the patients have received any antipsychotic treatment. In addition, following 6 months' treatment with quetiapine these PPI deficits were normalized. Furthermore, the results suggest that schizophrenia patients in the antipsychotic-naive state show reduced levels of sensitization, yet normal levels of habituation.

Hippocampal and caudate volume reductions in antipsychotic-naive first-episode schizophrenia.

BACKGROUND: Enlarged ventricles and reduced hippocampal volume are consistently found in patients with first-episode schizophrenia. Studies investigating brain structure in antipsychotic-naive patients have generally focused on the striatum. In this study, we examined whether ventricular enlargement and hippocampal and caudate volume reductions are morphological traits of antipsychotic-naive first-episode schizophrenia. METHODS: We obtained high-resolution 3-dimensional T1-weighted magnetic resonance imaging scans for 38 antipsychotic-naive first-episode schizophrenia patients and 43 matched healthy controls by use of a 3-T scanner. We warped the brain images to each other by use of a high-dimensional intersubject registration algorithm. We performed voxel-wise group comparisons with permutation tests. We performed small volume correction for the hippocampus, caudate and ventricles by use of a false discovery rate correction (p < 0.05) to control for multiple comparisons. We derived and analyzed estimates of brain structure volumes. We grouped patients as those with (n = 9) or without (n = 29) any lifetime substance abuse to examine the possible effects of substance abuse. RESULTS: We found that hippocampal and caudate volumes were decreased in patients with first-episode schizophrenia. We found no ventricular enlargement, differences in global volume or significant associations between tissue volume and duration of untreated illness or psychopathology. The hippocampal volume reductions appeared to be influenced by a history of substance abuse. Exploratory analyses indicated reduced volume of the nucleus accumbens in patients with first-episode schizophrenia. LIMITATIONS: This study was not a priori designed to test for differences between schizophrenia patients with or without lifetime substance abuse, and this subgroup was small. CONCLUSION: Reductions in hippocampal and caudate volume may constitute morphological traits in antipsychotic-naive first-episode schizophrenia patients. However, the clinical implications of these findings are unclear. Moreover, past substance abuse may accentuate hippocampal volume reduction. Magnetic resonance imaging studies addressing the potential effects of substance abuse in antipsychotic-naive first-episode schizophrenia patients are warranted.

Decreased frontal serotonin2A receptor binding in antipsychotic-naive patients with first-episode schizophrenia.

CONTEXT: Postmortem investigations and the receptor affinity profile of atypical antipsychotics have implicated the participation of serotonin(2A) receptors in the pathophysiology of schizophrenia. Most postmortem studies point toward lower cortical serotonin(2A) binding in schizophrenic patients. However, in vivo studies of serotonin(2A) binding report conflicting results, presumably because sample sizes have been small or because schizophrenic patients who were not antipsychotic-naive were included. Furthermore, the relationships between serotonin(2A) binding, psychopathology, and central neurocognitive deficits in schizophrenia are unclear. OBJECTIVES: To assess in vivo brain serotonin(2A) binding potentials in a large sample of antipsychotic-naive schizophrenic patients and matched healthy controls, and to examine possible associations with psychopathology, memory, attention, and executive functions. DESIGN: Case-control study. SETTING: University hospital, Denmark. PARTICIPANTS: A sample of 30 first-episode, antipsychotic-naive schizophrenic patients, 23 males and 7 females, and 30 matched healthy control subjects. INTERVENTIONS: Positron emission tomography with the serotonin(2A)-specific radioligand fluorine 18-labeled altanserin and administration of a neuropsychological test battery. MAIN OUTCOME MEASURES: Binding potential of specific tracer binding, scores on the Positive and Negative Syndrome Scale, and results of neuropsychological testing. RESULTS: Schizophrenic patients had significantly lower serotonin(2A) binding in the frontal cortex than did control subjects. A significant negative correlation was observed between frontal cortical serotonin(2A) binding and positive psychotic symptoms in the male patients. No correlations were found between cognitive functions and serotonin(2A) binding. CONCLUSION: The results suggest that frontal cortical serotonin(2A) receptors are involved in the pathophysiology of schizophrenia. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00207064.