Morphometric evaluations based on Voxel Based Morphometry on adolescents with autism spectrum disorders. / Badania morfometryczne oparte o pomiar voksela (Voxel Based Morphometry) u nastolatków z zaburzeniami ze spektrum autyzmu.

OBJECTIVES: Goal: to evaluate changes in the grey matter volume using the VBM method in a group of adolescents with ASD, who met the criteria for Asperger's Syndrome. METHODS: Material and methods: Morphometric evaluations based on Voxel Based Morphometry (VBM) were performed on 37 male adolescents aged 12 to 19 (M = 14.3 ± 2.0), with autism spectrum disorders, who met the DSM-IV-TR criteria for Asperger's Syndrome and 15 neurotypical adolescents matched by age. Significance was set at p<0.007 without FWE correction and p<0.05 with FWE correction. RESULTS: Results: the decrease in the volume of the grey matter was observed in ASD group including the pre- and postcentral gyrus, the superior and middle frontal gyrus, the inferior and superior parietal lobule, the praecuneus, the anterior and posterior cingulate cortex, the fusiform gyrus, the parahippocampal gyrus, the lingual gyrus, the middle occipital region, the cuneus and the angular gyrus, the regions of calcarine sulcus and the cerebellum. The majority of changes was localized bilaterally. CONCLUSIONS: Conclusions: the decrease in the volume of grey matter observed in ASD group can be related functionally with the characteristics of deficits observed in autism spectrum disorders which highlights the role of abnormal organization of numerous CNS structures in the genesis of symptoms observed in cognitive and behavioural domains.

Semantic decisions in adolescents with autism spectrum disorders - functional magnetic resonance imaging study. / Decyzje semantyczne u nastolatków z zaburzeniami ze spektrum autyzmu - badanie czynnosciowym rezonansem magnetycznym.

OBJECTIVES: Goal: to assess fMRI activation during semantic tasks in adolescents with ASD. METHODS: Material: 44 right-handed male adolescents aged 12-19 (mean 14.3 ± 2.0) - 31 with autism spectrum disorders who met DSM-IV-TR criteria for Asperger's syndrome and 13 neurotypical adolescents matched according to age and handiness. Method: Functional testing (fMRI) was performed during semantic decisions tasks and phonological decisions in three categories of tasks: concrete nouns, verbs with plural meanings, words describing states of mind, as a control condition. Statistical analyzes were performed at the level of p <0.05 with FWE (family-wise error) correction and p <0.001. RESULTS: Results: lower BOLD signal was demonstrated in many brain areas including precuneus, posterior cingulate gyrus, angular gyrus, parahippocampal gyrus, regardless of task category and processing method in the ASD group. The smallest differences in semantic processing were found for concrete nouns and the greatest ones for words describing states of mind. CONCLUSIONS: Conclusions: the presence of different activation patterns in the ASD group suggests that far more than just the areas traditionally attributed to language processing, are involved in semantic deficits in ASD.

Functional and structural asymmetry in primary motor cortex in Asperger syndrome: a navigated TMS and imaging study.

Motor functions are frequently impaired in Asperger syndrome (AS). In this study, we examined the motor cortex structure and function using navigated transcranial magnetic stimulation (nTMS) and voxel-based morphometry (VBM) and correlated the results with the box and block test (BBT) of manual dexterity and physical activity in eight boys with AS, aged 8-11 years, and their matched controls. With nTMS, we found less focused cortical representation areas of distinct hand muscles in AS. There was hemispheric asymmetry in the motor maps, silent period duration and active MEP latency in the AS group, but not in controls. Exploratory VBM analysis revealed less gray matter in the left postcentral gyrus, especially in the face area, and less white matter in the precentral area in AS as compared to controls. On the contrary, in the right leg area, subjects with AS displayed an increased density of gray matter. The structural findings of the left hemisphere correlated negatively with BBT score in controls, whereas the structure of the right hemisphere in the AS group correlated positively with motor function as assessed by BBT. These preliminary functional (neurophysiological and behavioral) findings are indicative of asymmetry, and co-existing structural alterations may reflect the motor impairments causing the deteriorations in manual dexterity and other motor functions commonly encountered in children with AS.

Gyrification changes are related to cognitive strengths in autism.

Background: Behavioral, cognitive and functional particularities in autism differ according to autism subgroups and might be associated with domain-specific cognitive strengths. It is unknown whether structural changes support this specialization. We investigated the link between cortical folding, its maturation and cognitive strengths in autism subgroups presenting verbal or visuo-spatial peaks of abilities. Methods: We measured gyrification, a structural index related to function, in 55 autistic participants with (AS-SOD, N = 27) or without (AS-NoSOD, N = 28) a speech onset delay (SOD) with similar symptom severity but respectively perceptual and verbal cognitive strengths, and 37 typical adolescents and young adults matched for intelligence and age. We calculated the local Gyrification Index (lGI) throughout an occipito-temporal region of interest and independently modeled age and peak of ability effects for each group. Results: Unique gyrification features in both autistic groups were detected in localized clusters. When comparing the three groups, gyrification was found lower in AS-SOD in a fusiform visual area, whereas it was higher in AS-NoSOD in a temporal language-related region. These particular areas presented age-related gyrification differences reflecting contrasting local maturation pathways in AS. As expected, peaks of ability were found in a verbal subtest for the AS-NoSOD group and in the Block Design IQ subtest for the AS-SOD group. Conclusions: Irrespective of their direction, regional gyrification differences in visual and language processing areas respectively reflect AS-SOD perceptual and AS-NoSOD language-oriented peaks. Unique regional maturation trajectories in the autistic brain may underline specific cognitive strengths, which are key variables for understanding heterogeneity in autism.

Functional network abnormalities consistent with behavioral profile in Autism Spectrum Disorder.

Autism spectrum disorder (ASD) is a neurodevelopmental disorder in which the severity of symptoms varies over subjects. The iCAPs model (innovation-driven co-activation patterns) is a recently developed spatio-temporal model to describe fMRI data. In this study, the iCAPs model was employed to find functional imaging biomarkers for ASD in resting-state fMRI data. MRI data from 125 ASD patients and 243 healthy controls was selected from the online ABIDE data repository. Following standard fMRI preprocessing steps, the iCAP patterns were fitted to the data to obtain network time series. Furthermore, specific combinations of iCAPs were mapped to behavioral domain time series. To quantify to which extent the time series contribute to the fMRI dynamics, their (temporal) standard deviation was calculated and compared between patients and controls. Abnormalities were found in networks involving subcortical and limbic areas and default mode network regions. When mapping the network dynamics to behavioral domain time series, abnormalities were found in emotional and visual behavioral subdomains, and within the ASD spectrum were more pronounced in subjects with autism compared to Asperger's syndrome. Also a trend towards impairment in networks facilitating social cognition was found. The functional imaging abnormalities are consistent with the behavioral impairments typical for ASD.

[Perisylvian magnetoencephalografic impairments in patients with autism spectrum disorders]. / Alteraciones magnetoencefalograficas perisilvianas en pacientes con trastornos del espectro autista.

INTRODUCTION: The perisylvian areas, located around the Sylvian fissure, are constituted by frontal, temporal and parietal brain regions. These are connected forming specialized neural networks and play a primary role in the development of linguistic skills and social cognition. These areas are a possible neuronal substrate of cognitive and behavioral impairments in patients with autism spectrum disorders (ASD). AIM: To locate and quantify epileptiform activity sources through magnetoencephalography in frontal perisylvian areas in children with idiopathic ASD. PATIENTS AND METHODS: Sixty-eight children with idiopathic ASD were studied by magnetoencephalography. The children were classified into two groups: a group of 41 children with autistic disorder and a combined group of 27 children with Asperger syndrome and children with pervasive developmental disorder not otherwise specified. The sources of magnetoencephalografic epileptiform activity detected in the frontal perisylvian were localized and quantified. RESULTS: The amount of epileptiform activity in frontal perisylvian region was significantly higher in children with autistic disorder. CONCLUSIONS: The amount of epileptiform activity in frontal perisylvian areas differed significantly between children with autistic disorder and those with Asperger syndrome and pervasive developmental disorder not otherwise specified.

TITLE: Alteraciones magnetoencefalograficas perisilvianas en pacientes con trastornos del espectro autista.Introduccion. Las areas perisilvianas se situan alrededor de la cisura de Silvio y estan constituidas por regiones cerebrales frontales, temporales y parietales. Estas regiones estan conectadas formando redes neurales especializadas y desempeñan una funcion elemental en el desarrollo de las habilidades linguisticas y de la cognicion social. Estas areas son un posible sustrato neural de las alteraciones cognitivas y conductuales en los pacientes con trastornos del espectro autista (TEA). Objetivo. Localizar y cuantificar las fuentes de actividad epileptiforme mediante magnetoencefalografia en areas frontales perisilvianas en niños con TEA primario. Pacientes y metodos. Se estudio a 68 niños con TEA idiopatico mediante magnetoencefalografia. Se clasificaron en dos grupos: uno de 41 niños con trastorno autista y un grupo combinado de 27 niños con sindrome de Asperger y niños con trastorno generalizado del desarrollo no especificado. Se localizaron y se cuantificaron las fuentes de actividad epileptiforme magnetoencefalografica detectadas en las areas frontales perisilvianas. Resultados. La actividad epileptiforme en la region perisilviana frontal fue significativamente mayor en el grupo de niños con trastorno autista. Conclusiones. La localizacion y cantidad de actividad epileptiforme en areas frontales perisilvianas difirieron significativamente entre los niños con trastorno autista y aquellos con sindrome de Asperger y trastorno generalizado del desarrollo no especificado.

Working memory network alterations in high-functioning adolescents with an autism spectrum disorder.

AIM: People with autism spectrum disorder (ASD) typically have deficits in the working memory (WM) system. WM is found to be an essential chain in successfully navigating in the social world. We hypothesize that brain networks for WM have an altered network integrity in ASD compared to controls. METHODS: Thirteen adolescents (one female) with autistic disorder (n = 1), Asperger's disorder (n = 7), or pervasive developmental disorder not otherwise specified (n = 5), and 13 typically developing healthy control adolescents (one female) participated in this study. Functional magnetic resonance imaging (MRI) was performed using an n-back task and in resting state. RESULTS: The analysis of the behavioral data revealed deficits in WM performance in ASD, but only when tested to the limit. Adolescents with ASD showed lower binary global efficiency in the WM network than the healthy control group with n-back and resting-state data. This correlated with diagnostic scores for total problems, reciprocity, and language. CONCLUSION: Adolescents with higher-functioning autism have difficulty with the WM system, which is typically compensated. Functional MRI markers of brain network organization in ASD are related to characteristics of autism as represented in diagnostic scores. Therefore, functional MRI provides neuronal correlates for memory difficulties in adolescents with ASD.

Neuroanatomical Markers of Neurological Soft Signs in Recent-Onset Schizophrenia and Asperger-Syndrome.

Neurological soft signs (NSS) are frequently found in psychiatric disorders of significant neurodevelopmental origin. Previous MRI studies in schizophrenia have shown that NSS are associated with abnormal cortical, thalamic and cerebellar structure and function. So far, however, no neuroimaging studies investigated brain correlates of NSS in individuals with Asperger-Syndrome (AS) and the question whether the two disorders exhibit common or disease-specific cortical correlates of NSS remains unresolved. High-resolution MRI data at 3 T were obtained from 48 demographically matched individuals (16 schizophrenia patients, 16 subjects with AS and 16 healthy individuals). The surface-based analysis via Freesurfer enabled calculation of cortical thickness, area and folding (local gyrification index, LGI). NSS were examined on the Heidelberg Scale and related to cortical measures. In schizophrenia, higher NSS were associated with reduced cortical thickness and LGI in fronto-temporo-parietal brain areas. In AS, higher NSS were associated with increased frontotemporal cortical thickness. This study lends further support to the hypothesis that disorder-specific mechanisms contribute to NSS expression in schizophrenia and AS. Pointing towards dissociable neural patterns may help deconstruct the complex processes underlying NSS in these neurodevelopmental disorders.

The 5-HT(2A) receptor and serotonin transporter in Asperger's disorder: A PET study with [¹¹C]MDL 100907 and [¹¹C]DASB.

Evidence from biochemical, imaging, and treatment studies suggest abnormalities of the serotonin system in autism spectrum disorders, in particular in frontolimbic areas of the brain. We used the radiotracers [(11)C]MDL 100907 and [(11)C]DASB to characterize the 5-HT(2A) receptor and serotonin transporter in Asperger's Disorder. Seventeen individuals with Asperger's Disorder (age=34.3 ± 11.1 years) and 17 healthy controls (age=33.0 ± 9.6 years) were scanned with [(11)C]MDL 100907. Of the 17 patients, eight (age=29.7 ± 7.0 years) were also scanned with [¹¹C]DASB, as were eight healthy controls (age=28.7 ± 7.0 years). Patients with Asperger's Disorder and healthy control subjects were matched for age, gender, and ethnicity, and all had normal intelligence. Metabolite-corrected arterial plasma inputs were collected and data analyzed by two-tissue compartment modeling. The primary outcome measure was regional binding potential BP(ND). Neither regional [¹¹C]MDL 100907 BP(ND) nor [¹¹C]DASB BP(ND) was statistically different between the Asperger's and healthy subjects. This study failed to find significant alterations in binding parameters of 5-HT(2A) receptors and serotonin transporters in adult subjects with Asperger's disorder.

[Asperger syndrome with highly exceptional calendar memory: a case report]. / Gelismis Takvim Bellegi Becerisi Sergileyen Bir Asperger Sendromu Olgusu.

Some patients with pervasive developmental disorders develop unusual talents, which are characterized as savant syndrome. Herein we present neuropsychological examination and brain imaging (fMRI and brain SPECT) findings of an 18-year-old male with Asperger syndrome and highly unusual calendar memory. Neuropsychological evaluation of the case indicated mild attention, memory, and problem solving deficits, and severe executive function deficits that included conceptualization, category formation, and abstraction. Functional MRI findings showed activation above the baseline level (P<0.05) in the bilateral inferior parietal lobule, precuneus, superior and middle frontal gyri, and medial frontal cortex. Brain SPECT findings, in comparison to rest-SPECT findings, showed that there was hypoperfusion in some brain regions, including the right frontal cortex and right parietal cortex. Baseline blood perfusion in the left frontal cortex was also observed, as well as hypoperfusion in the right parietal-occipital cortex and in the right basal ganglion (compared to the left side). The results of the present study and further research will contribute to our understanding of calendar memory and savant syndrome.

Volumetric analysis and three-dimensional glucose metabolic mapping of the striatum and thalamus in patients with autism spectrum disorders.

OBJECTIVE: In patients with autism, behavioral deficits as well as neuroimaging studies of the anterior cingulate cortex suggest ventral rather than dorsal striatal and thalamic abnormalities in structure and function. The authors used imaging studies to map volumetric and metabolic differences within the entire dorsoventral extent of the striatum and thalamus. METHOD: Magnetic resonance imaging (MRI) and positron emission tomography (PET) were used to measure volumes and metabolic activity in the thalamus, caudate, and putamen in 17 patients with autism or Asperger's disorder and 17 age- and sex-matched comparison subjects. Subjects performed a serial verbal learning test during the [(18)F]-fluorodeoxyglucose uptake period. The regions of interest were outlined on contiguous axial MRI slices. After PET/MRI coregistration, region-of-interest coordinates were applied to the PET scan for each individual. Between-group differences in metabolism were assessed by three-dimensional statistical probability mapping. RESULTS: The patients with autism spectrum disorders had greater volumes of the right caudate nucleus than comparison subjects as well as a reversal of the expected left-greater-than-right hemispheric asymmetry. Patients also had lower relative glucose metabolic rates bilaterally in the ventral caudate, putamen, and thalamus. Patients with autism had lower metabolic activity in the ventral thalamus than those with Asperger's disorder, but they did not differ from comparison subjects in metabolic activity in the caudate nucleus. CONCLUSIONS: These results are consistent with a deficit in the anterior cingulate-ventral striatum-anterior thalamic pathway in patients with autism spectrum disorders. The results also suggest an important role for the caudate in helping support working-memory demands.

Cortical serotonin 5-HT2A receptor binding and social communication in adults with Asperger's syndrome: an in vivo SPECT study.

OBJECTIVE: The cause of autistic spectrum disorder (i.e., autism and Asperger's syndrome) is unknown. The serotonergic (5-HT) system may be especially implicated. However, cortical 5-HT2A receptor density in adults with the disorder has not been examined, to the authors' knowledge. METHOD: The authors investigated cortical 5-HT2A receptor binding in eight adults with Asperger's syndrome and in 10 healthy comparison subjects with single photon emission computed tomography and the selective 5-HT2A receptor ligand 123I iodinated 4-amino-N-[1-[3-(4-fluorophenoxy)propyl]-4-methyl-4-piperidinyl]-5-iodo-2-methoxybenzamide (123I-5-I-R91150). RESULTS: People with Asperger's syndrome had a significant reduction in cortical 5-HT2A receptor binding in the total, anterior, and posterior cingulate; bilaterally in the frontal and superior temporal lobes; and in the left parietal lobe. Also, reduced receptor binding was significantly related to abnormal social communication. CONCLUSIONS: The authors' findings suggest that adults with Asperger's syndrome have abnormalities in cortical 5-HT2A receptor density and that this deficit may underlie some clinical symptoms.

Increased presynaptic dopamine function in Asperger syndrome.

The etiology of Asperger syndrome is essentially unknown, but abnormality of the dopamine system has been shown in clinically overlapping disorders. The present study was designed to investigate the presynaptic dopamine function in Asperger syndrome. Eight healthy, drug-free males with Asperger syndrome and five healthy male controls were examined with positron emission tomography using 6-[18F]fluoro-L-DOPA ([18F]FDOPA) as a tracer. In the Asperger syndrome group, the [18F]FDOPA influx (Ki) values were increased in the striatum, i.e. in the putamen and caudate nucleus and in the frontal cortex. The results indicate that the dopamine system is affected in subjects with Asperger syndrome. Partially similar results have also been obtained in schizophrenia, suggesting an overlap not only of the clinical features but also of pathogenesis.

Changes in cerebral blood flow in Asperger syndrome during theory of mind tasks presented by the auditory route.

Lack of theory of mind (ToM) has been considered to be a key feature in Asperger syndrome (AS). The main aim of the present study was to determine whether an exclusively auditory input of ToM stories activated the same brain areas as demonstrated previously using visual stimuli. Eight right-handed otherwise healthy men with AS and eight healthy right-handed male controls participated in a PET activation study using auditory given ToM stories and stories about physical events for induction. Both subjects with AS and controls showed increased activation in the occipitotemporal area bilaterally and in thalamus during ToM tasks. Both groups also showed activation in the medial frontal area during ToM tests.However, this activation was more intensive and extensive in the control group, especially when a more sensitive analysis method was used. As a group, unrelated to the tasks, the AS subjects showed increased activation of the cerebellum. It was concluded that the activation pattern was mainly in agreement with earlier studies using comparable stimuli administered differently. There was no support for a right hemisphere specific dysfunction.

Effect of fluoxetine on regional cerebral metabolism in autistic spectrum disorders: a pilot study.

The regional metabolic effects of fluoxetine were examined in patients with autism spectrum disorders. Six adult patients with DSM-IV and Autism Diagnostic Interview (ADI) diagnoses of autism (n = 5) and Asperger's syndrome (n = 1), entered a 16-wk placebo-controlled cross-over trial of fluoxetine. The patients received (18)F-deoxyglucose positron emission tomography with co-registered magnetic resonance imaging at baseline and at the end of the period of fluoxetine administration. After treatment, the patients showed significant improvement on the scores of the Yale--Brown Obsessive--Compulsive Scale -- Obsessions subscale and the Hamilton Anxiety Scale; Clinical Global Impressions -- Autism scores showed 3 of the patients much improved and 3 unchanged. Relative metabolic rates were significantly higher in the right frontal lobe following fluoxetine, especially in the anterior cingulate gyrus and the orbitofrontal cortex. Patients with higher metabolic rates in the medial frontal region and anterior cingulate when unmedicated were more likely to respond favourably to fluoxetine. These results are consistent with those in depression indicating that higher cingulate gyrus metabolic rates at baseline predict SRI response.

Limbic circuitry in patients with autism spectrum disorders studied with positron emission tomography and magnetic resonance imaging.

OBJECTIVE: Cytoarchitectonic changes in the anterior cingulate cortex, hippocampus, subiculum, entorhinal cortex, amygdala, mammillary bodies, and septum were reported in a postmortem study of autism. Previously, the authors found smaller cingulate volume and decreased metabolism of the cingulate in seven autistic patients. In this study, they measured the volume and glucose metabolism of the amygdala, hippocampus, and cingulate gyrus in an expanded group of 17 patients with autism spectrum disorders (autism [N=10] or Asperger's disorder [N=7]) and 17 age- and sex-matched healthy volunteers. METHOD: Subjects performed a serial verbal learning test during (18)F-deoxyglucose uptake. The amygdala, hippocampus, and cingulate gyrus were outlined on magnetic resonance imaging scans, volumes of the structures were applied to matching coregistered positron emission tomography scans, and three-dimensional significance probability mapping was performed. RESULTS: Significant metabolic reductions in both the anterior and posterior cingulate gyri were visualized in the patients with autism spectrum disorders. Both Asperger's and autism patients had relative glucose hypometabolism in the anterior and posterior cingulate as confirmed by analysis of variance; regional differences were also found with three-dimensional significance probability mapping. No group differences were found in either the metabolism or the volume of the amygdala or the hippocampus. However, patients with autism spectrum disorders showed reduced volume of the right anterior cingulate gyrus, specifically in Brodmann's area 24'. CONCLUSIONS: Compared with age- and sex-matched healthy volunteers, patients with autism spectrum disorders showed significantly decreased metabolism in both the anterior and posterior cingulate gyri.