Compared to their neurotypically developing peers, children and adolescents with autism spectrum disorders tend to have attenuated neural responses in the parietal lobe when attending sensory input, as reflected by a reduced P3b amplitude measured with electroencephalography. However, it is unknown whether a reduced P3b amplitude in autistic children and adolescents is associated with their autism traits, daily functioning, and/or cognitive functions. To address these questions, we assessed 57 children with autism aged 7–14 years and 57 typically developing children with electroencephalography using a binaural auditory oddball paradigm. Participants further underwent cognitive assessment, and parents reported on autistic traits, executive functioning, and adaptive functioning. As expected, children with autism had lower P3b amplitude compared to controls. Across all participants, a lower P3b amplitude was associated with more parent-reported social-communication problems and impairments in daily executive functioning. Children with autism had reduced visual processing speed, which was coupled to a lower P3b amplitude. In conclusion, we found attenuated P3b amplitude in children with autism performing an auditory selective attention task, which generalized to impaired cross-modal processing of visual input and an underlying impairment in allocating attentional resources critical for social and executive functioning. Lay abstract Selective attention to auditory input is reflected in the brain by an electric amplitude called the P3b amplitude, which is measured using electroencephalography. Previous research has shown that children and adolescents with autism have an attenuated P3b amplitude when they have to attend specific sounds while ignoring other sounds. However, it is unknown whether a reduced P3b amplitude in autistic children and adolescents is associated with their autism features, daily functioning and/or cognitive functions. This study aimed to examine these questions. Therefore, we assessed selective attention to auditory input in 57 children with autism aged 7–14 years and 57 neurotypically developing controls while measuring their brain activity with electroencephalography. Participants further underwent cognitive assessment, and parents reported on autistic traits and daily functioning. As expected, children with autism had lower P3b amplitude compared to their neurotypical peers. Importantly, an attenuated P3b amplitude was associated with more parent-reported social-communication problems and difficulties with daily functioning. Children with autism further had reduced processing speed of visual input, which also was coupled to a lower P3b amplitude. In conclusion, we found attenuated P3b amplitude in children with autism performing an auditory selective attention task, which was related to difficulties with processing visual input and allocating attentional resources critical for social and daily functioning. The results suggest that autistic children are more vulnerable to being disturbed when the environment is filled with conflicting sensory input.

Different lines of evidence indicate that the ability to communicate narratives coherently is related to children's social-emotional development. However, it is unknown whether narrative coherence is genre-specific or generalizes across autobiographical memories and fictive stories, and if autobiographical and fictive narratives show different or similar associations with mentalizing language, cognitive functions, social and daily functioning. Addressing these questions may provide important clues about the development of narrative communication skills in children and adolescents. We assessed 86 typically developing children and adolescents aged 7–14, examining narrative coherence and mentalizing complexity in six autobiographical memories and five fictional stories, alongside intellectual functioning and parent and teacher reports on social and adaptive functioning. Results showed that the measures on narrative coherence and mentalizing complexity, respectively, were associated across autobiographical memories and fictional stories. Moreover, narrative coherence and mentalizing complexity was related to each other on both fictive and autobiographical stories. Higher narrative coherence and mentalizing complexity on autobiographical memories were specifically related to better social-emotional reciprocity reported by teachers, who likely have more opportunities than parents to observe the child’s daily interaction with peers. Our findings suggest that narrative coherence and mentalizing language in school-aged children generalize across genres. Being able to communicate personal narratives coherently with use of mentalizing language appears to be important for the social-emotional interplay of children and adolescents.

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.

Children and adolescents with autism have increased prevalence of psychosocial disabilities. Studies in autism indicate that key psychosocial factors including adaptive functioning, school absence, special needs education, frequency of peer socialization and participation in organized leisure activities may differ in their relationship with autistic, internalizing and externalizing symptoms, but the findings are so far mixed. Therefore, we examined if these measures of psychosocial functioning displayed specific associations with autistic, internalizing and/or externalizing symptoms in 61 children with autism aged 7–14 years compared to 61 typically developing controls. Multiple linear regression analyses across all participants showed that lower adaptive functioning, frequency of peer socialization and participation in leisure activities were driven by more social communication problems and not internalizing, externalizing or autistic-like symptoms including rigidity, stereotypy and sensory sensitivity. Notably, increased school absence was specifically driven by more internalizing symptoms and not autistic or externalizing symptoms. These associations were observed across all participants, both children with autism and their typically developing peers, and therefore appear to be dimensional and general in nature. Within the autism group, children who received special needs education displayed fewer social communication problems compared to those who attended regular education, while a developmental history of social interaction problems was related to lower adaptive functioning. Our findings suggest that social communication problems are more critical for psychosocial functioning than other autistic-like behaviors, internalizing or externalizing symptoms but that efforts to reduce school absence specifically need to target internalizing symptoms and not autistic-like or externalizing symptoms.

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.

The present article is a theoretical contribution suggesting a simple model of the dynamics involved in the development of neurodevelopmental disorders and the phenomenon of autism offering an explanation of why different individuals have different onset of manifest disease. The model relates to present genetic and epigenetic evidence and previous theoretical models. The dynamic model applies an individualized transdiagnostic and dimensional approach integrating several levels of influence involved in the dynamic interaction between an individual and their environment across time. The dynamic model illustrates the interaction between a basic neurobiological susceptibility, compensating mechanisms, and stress-related releasing mechanisms involved in the development of manifest clinical illness. The model has a particular focus on the dynamics of neurocognitive processes and their relationship to more basic information, psychological and social processes. A basic assumption guiding the model is that even quite normal events related to typical development may increase the risk of enduring stress in cognitively vulnerable individuals, further increasing their risk of developing manifest clinical illness. The model suggests that genetic variation, endogenous epigenetic processes of development, and epigenetic changes influenced by physical/chemical and social environmental risk and resilience factors all may contribute to phenotypical expression. A genetic susceptibility may translate into a biological susceptibility reflected in cognitive impairments. A cognitively vulnerable individual may be at increased risk of misinterpreting sensory inputs, potentially resulting in psychopathological expressions, e.g., autistic symptoms, observed across several neurodevelopmental disorders. The genetically influenced experience of an individual relates to cognitive phenomena occurring at the interfaces between the brain, mind, and society. The severity of clinical illness may differ from the severity of a disorder of reasoning. The dynamic model may help guide future development of personalized medicine in psychiatry and identify relevant points of intervention. A discussion of the implications of the model relating to epigenetic evidence and to previous theoretical models is included at the end of the paper.

Background Attention deficits have been frequently reported in schizophrenia. It has been suggested that treatment with second-generation antipsychotics can ameliorate these deficits. In this study, the influence of 6 months treatment with quetiapine, a compound with less affinity for dopamine D 2 receptors than for serotonergic 5-HT 2A receptors, on electrophysiological parameters of attention was investigated in a group of antipsychotic-naïve, first-episode schizophrenia patients compared with a group of age- and gender-matched healthy controls. Method A total of 34 first-episode, antipsychotic-naïve patients with schizophrenia and an equal number of healthy controls were tested in a selective attention and a typical mismatch negativity (MMN) paradigm at baseline and after 6 months. The patients were treated with quetiapine according to their clinical needs during the period between baseline and follow-up, whereas controls received no treatment. Results Patients showed lower MMN and P200 amplitude than healthy controls in the selective attention paradigm at baseline, while this was not the case for MMN of the typical MMN paradigm. Interestingly, after 6 months treatment, this MMN deficit was only ameliorated in patients treated with above median dosages of quetiapine. Patients had lower P3B amplitude, yet showed similar levels of processing negativity and N100 amplitude compared with healthy controls, both at baseline and follow-up. Conclusions The results indicate that deficits in MMN, P200 and P3B amplitude are present at early stages of schizophrenia, although depending on the paradigm used. Furthermore, the results indicate that 6 months quetiapine treatment ameliorates MMN but not P3B deficits, and only in those subjects on higher dosages.

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.

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Rasmussen, Hans PhD; Ebdrup, Bjørn H. MD, PhD; Aggernaes, Bodil MD, PhD; Lublin, Henrik MD, DMSc; Oranje, Bob PhD; Pinborg, Lars H. MD, DMSc; Knudsen, Gitte M. MD, DMSc; Glenthøj, Birte MD, DMSc Author Information

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.

BACKGROUND:Impaired cognition is a prominent feature of schizophrenia. To what extent the heterogeneous cognitive impairments can be accounted for by considering only a single underlying impairment or a small number of core impairments remains elusive. This study examined whether cognitive impairments in antipsychotic-naïve, first-episode schizophrenia patients may be determined by a relative slower speed of information processing.METHOD:Forty-eight antipsychotic-naïve patients with first-episode schizophrenia and 48 matched healthy controls were administered a comprehensive battery of neuropsychological tests to assess domains of cognitive impairments in schizophrenia. Composite scores were calculated, grouping tests into cognitive domains.RESULTS:There were significant differences between patients and healthy controls on global cognition and all cognitive domains, including verbal intelligence, processing speed, sustained attention, working memory, reasoning and problem solving, verbal learning and memory, visual learning and memory, and reaction time. All these significant differences, except for verbal intelligence and global cognition, disappeared when processing speed was included as a covariate.CONCLUSION:At the first stage of illness, antipsychotic-naïve patients with schizophrenia display moderate/severe impairments in all the cognitive domains assessed. The results support the contention of a global cognitive dysfunction in schizophrenia that to some extent may be determined by impaired processing speed.

Progressive atrophy occurs in brain regions involved in the working memory network along the schizophrenia's course, but without parallel evolution of working memory impairment. We investigated the functional organization inside this network at different stages of the disease.Twenty-eight patients with schizophrenia (16 with long disease duration (> 60 months) and 12 with short disease duration (< 60 months)) and eleven healthy controls underwent structural and functional MRI during an n-back task to determine atrophy and activation patterns.At similar n-back performances and relative to short disease duration patients, long disease duration patients activated more frontal temporal parietal and frontal network during 0-back and 1-back tasks respectively. n-back scores were correlated to atrophy in the frontal–temporal areas.Functional reorganization in the working memory network may play a compensatory role during the first ten years of schizophrenia.

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 quetiapineRESULTS: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.

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.

Asparaginase and steroids can cause hypertriglyceridaemia in children with acute lymphoblastic leukaemia (ALL). There are no guidelines for screening or management of patients with severe hypertriglyceridaemia (>1000 mg/dL) during ALL therapy.Fasting lipid profiles were obtained prospectively at four time-points for 257 children consecutively enrolled on a frontline ALL study. Risk factors were evaluated by the exact chi-square test. Details of adverse events and management of hypertriglyceridaemia were extracted retrospectively.Eighteen of 257 (7%) patients developed severe hypertriglyceridaemia. Older age and treatment with higher doses of asparaginase and steroids on the standard/high-risk arm were significant risk factors. Severe hypertriglyceridaemia was not associated with pancreatitis after adjustment for age and treatment arm or with osteonecrosis after adjustment for age. However, patients with severe hypertriglyceridaemia had a 2.5–3 times higher risk of thrombosis compared to patients without, albeit the difference was not statistically significant. Of the 30 episodes of severe hypertriglyceridaemia in 18 patients, seven were managed conservatively while the others with pharmacotherapy. Seventeen of 18 patients continued to receive asparaginase and steroids. Triglyceride levels normalised after completion of ALL therapy in all 12 patients with available measurements.Asparaginase- and steroid-induced transient hypertriglyceridaemia can be adequately managed with dietary modifications and close monitoring without altering chemotherapy. Patients with severe hypertriglyceridaemia were not at increased risk of adverse events, with a possible exception of thrombosis. The benefit of pharmacotherapy in decreasing symptoms and potential complications requires further investigation.