Dysfunction In Autism Research Articles

Association of Transcription Factor Gene LMX1B with Autism

Multiple lines of evidence suggest a serotoninergic dysfunction in autism. The role of LMX1B in the development and maintenance of serotoninergic neurons is well known. In order to examine the role, if any, of LMX1B with autism pathophysiology, a trio-based SNP association study using 252 family samples from the AGRE was performed. Using pair-wise tagging method, 24 SNPs were selected from the HapMap data, based on their location and minor allele frequency. Two SNPs (rs10732392 and rs12336217) showed moderate association with autism with p values 0.018 and 0.022 respectively in transmission disequilibrium test. The haplotype AGCGTG also showed significant association (p = 0.008). Further, LMX1B mRNA expressions were studied in the postmortem brain tissues of autism subjects and healthy controls samples. LMX1B transcripts was found to be significantly lower in the anterior cingulate gyrus region of autism patients compared with controls (p = 0.049). Our study suggests a possible role of LMX1B in the pathophysiology of autism. Based on previous reports, it is likely to be mediated through a seretoninergic mechanism. This is the first report on the association of LMX1B with autism, though it should be viewed with some caution considering the modest associations we report.

Atypical Brain Responses to Reward Cues in Autism as Revealed by Event-Related Potentials

Social motivation deficit theories suggest that children with autism do not properly anticipate and appreciate the pleasure of social stimuli. In this study, we investigated event-related brain potentials evoked by cues that triggered social versus monetary reward anticipation in children with autism. Children with autism showed attenuated P3 activity in response to cues associated with a timely reaction to obtain a reward, irrespective of reward type. We attribute this atypical P3 activity in response to reward cues as reflective of diminished motivated attention to reward signals, a possible contributor to reduced social motivation in autism. Thus, our findings suggest a general reward processing deficit rather than a specific social reward dysfunction in autism.

A preliminary transcranial magnetic stimulation study of cortical inhibition and excitability in high‐functioning autism and Asperger disorder

Controversy surrounds the distinction between high-functioning autism (HFA) and Asperger disorder, but motor abnormalities are associated features of both conditions. This study examined motor cortical inhibition and excitability in HFA and Asperger disorder using transcranial magnetic stimulation (TMS). Participants were diagnosed by experienced clinicians strictly according to DSM-IV criteria. Participants with HFA (nine males, two females; mean age 16y 8mo, SD 4y 5mo) or Asperger disorder (11 males, three females; mean age 19y 1mo, SD 4y 2mo) and neurotypical participants (eight males, three females; mean age 19y 0mo, SD 3y 1mo) were administered a paired-pulse TMS paradigm intended to assess motor cortical inhibition and excitability. Responses to TMS were recorded by electromyography. Cortical inhibition was significantly reduced in the HFA group compared with both the Asperger disorder (p<0.001) and neurotypical (p<0.001) groups, suggesting disruption of activity at gamma-aminobutyric acid A (GABA(A)) receptors. There was no group difference in cortical excitability. Cortical inhibition deficits may underlie motor dysfunction in autism, and perhaps even relate to specific clinical symptoms (e.g. repetitive behaviours). These findings provide novel evidence for a possible neurobiological dissociation between HFA and Asperger disorder based on GABAergic function.

Experimental manipulation of face-evoked activity in the fusiform gyrus of individuals with autism

Previous research suggests hypoactivity in response to the visual perception of faces in the fusiform gyri and amygdalae of individuals with autism. However, critical questions remain regarding the mechanisms underlying these findings. In particular, to what degree is the hypoactivation accounted for by known differences in the visual scanpaths exhibited by individuals with and without autism in response to faces? Here, using functional magnetic resonance imaging, we report “normalization” of activity in the right fusiform gyrus, but not the amygdalae, when individuals with autism were compelled to perform visual scanpaths that involved fixating on the eyes of a fearful face. These findings hold important implications for our understanding of social brain dysfunction in autism, theories of the role of the fusiform gyri in face processing, and the design of more effective interventions for autism.

Normal Movement Selectivity in Autism

It has been proposed that individuals with autism have difficulties understanding the goals and intentions of others because of a fundamental dysfunction in the mirror neuron system. Here, however, we show that individuals with autism exhibited not only normal fMRI responses in mirror system areas during observation and execution of hand movements but also exhibited typical movement-selective adaptation (repetition suppression) when observing or executing the same movement repeatedly. Movement selectivity is a defining characteristic of neurons involved in movement perception, including mirror neurons, and, as such, these findings argue against a mirror system dysfunction in autism.

The immune system's role in the biology of autism

The following is a review of the most recent research concerning the potential role of immune system dysfunction in autism. This body of literature has expanded dramatically over the past few years as researchers continue to identify immune anomalies in individuals with autism. The most exciting of these recent findings is the discovery of autoantibodies targeting brain proteins in both children with autism and their mothers. In particular, circulating maternal autoantibodies directed toward fetal brain proteins are highly specific for autism. This finding has great potential as a biomarker for disease risk and may provide an avenue for future therapeutics and prevention. Additionally, data concerning the cellular immune system in children with autism suggest there may be a defect in signaling pathways that are shared by the immune and central nervous systems. Although studies to explore this hypothesis are ongoing, there is great interest in the commonalities between the neural and immune systems and their extensive interactions. In summary, the exciting research regarding the role of the immune system in autism spectrum disorders may have profound implications for diagnosis and treatment of this devastating disease.

The nature of brain dysfunction in autism: functional brain imaging studies

Functional magnetic resonance imaging studies have had a profound impact on the delineation of the neurobiologic basis for autism. Advances in fMRI technology for investigating functional connectivity, resting state connectivity, and a default mode network have provided further detail about disturbances in brain organization and brain-behavior relationships in autism to be reviewed in this article. Recent fMRI studies have provided evidence of enhanced activation and connectivity of posterior, or parietal-occipital, networks and enhanced reliance on visuospatial abilities for visual and verbal reasoning in high functioning individuals with autism. Evidence also indicates altered activation in frontostriatal networks for cognitive control, particularly involving anterior cingulate cortex, and altered connectivity in the resting state and the default mode network. The findings suggest that the specialization of many cortical networks of the human brain has failed to develop fully in high functioning individuals with autism. This research provides a growing specification of to the neurobiologic basis for this complex syndrome and for the co-occurrence of the signs and symptoms as a syndrome. With this knowledge has come new neurobiologically based opportunities for intervention.

Searching the neural basis of social dysfunction in Autism

To observe the distribution of malaria infection in the tribal area of East Godavari District of Andhra Pradesh, India.The data for the present study was collected from 6 342 and 765 patients who were admitted at tribal hospital and hill forest camps respectively during the study period. The data was collected from the malaria suspected patients admitted in paediatric and adult critical care wards of a tertiary hospital and in interior hill and forest camps in and around the Rampachodavaram. The detailed medical case sheet proforma were prepared and data has been analyz. It was found that RDT's can be helpful to screen Plasmodium falciparum (P. falciparum) inendemic areas and remote tribal belt.A total number of 6 342 and 765 patients were admitted at tribal hospital and hill forest camps respectively during the study period. Among 6 342 of individuals tested, 4 387 individuals were reported for malaria positive. Out of the 4 387 slides examined, 59.0% were positive P. falciparum infection, 19.4% slides showed positive Plasmodium vivax infection and 21.5% had mixed infection. The total P. falciparum burden was estimated as 80.5%. In hill forest camps, out of 765 admitted patients, 650 patients who had clinical history showed suggestive of malaria were examined for malaria parasites.The maximum numbers of malaria infection (4 387) were reported from the tribal based hospital. Malaria is responsible for major health concern in this region, particularly in rainy season. P. falciparum was the major parasite type causing malaria, and most of the complications were due to Plasmodium vivax. Compared to rest of the hills and forest areas, where most of the tribal people reside has the heavy load of malaria mainly P. falciparum. One important finding from the present study was the sex-difference observed in the admission rate. The rate of malaria infection was significantly high for male (53.5%), followed by female (46.5%) and children (33%).

SynCAM1 expression correlates with restoration of central synapses on spinal motoneurons after two different models of peripheral nerve injury

SynCAM1 and neuroligins (NLGs) are adhesion molecules that govern synapse formation in vitro. In vivo, the molecules are expressed during synaptogenesis, and altered NLG function is linked to synapse dysfunction in autism. Less is known about SynCAM1 and NLGs in adult synapse remodeling. CNS synapse elimination occurs after peripheral nerve injury, which causes a transient decrease in synapse number on spinal motoneurons. Here we have studied the expression of SynCAM1 and NLGs in relation to changes in synaptic covering on spinal motoneurons. We performed sciatic nerve transection (SNT) or crush (SNC), axotomy models that result in poor or good conditions for axon regeneration, respectively. The two lesions resulted in similar synapse elimination and in poor (SNT) and good (SNC) return of synapses after 70 days. Functional recovery was good after SNC but absent after SNT. SynCAM1 mRNA decreased after 14 days in both models and was restored 70 days after SNC, but not after SNT. NLG2 and -3 mRNAs decreased to a smaller degree after SNC than after SNT. Synaptophysin immunoreactivity correlated with SynCAM1 mRNA 70 days after SNT and NLG2 mRNA 70 days after SNC. Surprisingly, an inverse correlation was seen between NLG3 mRNA and Vglut2, a marker for excitatory synapses, 70 days after SNT. We conclude that 1) SynCAM1 mRNA levels seem to reflect the loss and restoration of synapses on motoneurons, 2) down-regulation of NLGs is not a prerequisite for synapse elimination, and 3) expression of SynCAM1 and NLGs is regulated by different mechanisms during regeneration.

Electrophysiological signs of supplementary‐motor‐area deficits in high‐functioning autism but not Asperger syndrome: an examination of internally cued movement‐related potentials

Motor dysfunction is common to both autism and Asperger syndrome, but the underlying neurophysiological impairments are unclear. Neurophysiological examinations of motor dysfunction can provide information about likely sites of functional impairment and can contribute to the debate about whether autism and Asperger syndrome are variants of the same disorder or fundamentally distinct neurodevelopmental conditions. We investigated the neurophysiology of internally determined motor activity in autism and Asperger syndrome via examination of movement-related potentials (MRPs). We used electroencephalography to investigate MRPs, via an internally cued movement paradigm, in the following three groups: (1) individuals with high-functioning autism (14 males, one female; mean age 13 y 1 mo, SD 4 y 2 mo, range 7 y 8 mo to 20 y 9 mo; mean Full-scale IQ 93.40, SD 20.72); (2) individuals with Asperger syndrome (10 males, two females; mean age 13 y 7 mo, SD 3 y 9 mo, range 8 y 11 mo to 20 y 4 mo; mean Full-scale IQ 103.25, SD 19.37), and (3) a healthy control group (13 males, seven females; mean age 14 y 0 mo, SD 3 y 11 mo; range 8 y 4 mo to 21 y 0 mo; mean Full-scale IQ 114.25, SD 11.29). Abnormal MRPs can reflect disruption of motor-related neural networks involving the basal ganglia, thalamus, and supplementary motor area. There was evidence for abnormal MRPs in autism (e.g. increased post-movement cortical activity, abnormal peak time) but not in Asperger syndrome. The results support basal ganglia, thalamus, and supplementary motor area involvement as a likely source of motor dysfunction in autism, and provide further evidence for the neurobiological separateness of autism and Asperger syndrome.

Sensory Processing Subtypes in Autism: Association with Adaptive Behavior

Children with autism are frequently observed to experience difficulties in sensory processing. This study examined specific patterns of sensory processing in 54 children with autistic disorder and their association with adaptive behavior. Model-based cluster analysis revealed three distinct sensory processing subtypes in autism. These subtypes were differentiated by taste and smell sensitivity and movement-related sensory behavior. Further, sensory processing subtypes predicted communication competence and maladaptive behavior. The findings of this study lay the foundation for the generation of more specific hypotheses regarding the mechanisms of sensory processing dysfunction in autism, and support the continued use of sensory-based interventions in the remediation of communication and behavioral difficulties in autism.

Accessing Other Minds: The Role of Temporo-Parietal Junction and its Dysfunction in Autism

Accessing Other Minds: The Role of Temporo-Parietal Junction and its Dysfunction in Autism

Serotonin and dopamine transporter binding in children with autism

See related article on page 593 In recounting research results in the field of autism over the past 50 years, the most consistent and well-replicated finding remains that of elevated whole blood serotonin. Aberrant serotonin function has consistently been found to contribute to the genetics, neuropharmacology, and brain metabolism of persons with autism.1 In addition, some but not all randomized controlled trials have shown selective serotonin reuptake inhibitors (SSRIs) to improve specific associated symptoms (e.g. interfering repetitive behavior) in children and adults with autism.2 The data presented in this issue’s article by Makkonen and colleagues build upon this series of findings related to serotonin dysfunction in autism. Single-photon emission computed tomography (SPECT) with [123I] nor-β-CIT (a labeled tracer that has been used to determine serotonin [SERT] and dopamine [DAT] transporter binding capacity) was utilized to image 15 children with autism and 10 non-autistic comparison children. Due to concerns about unnecessary radiation exposure in healthy children, the comparison children had a number of different neurological diagnoses. Reduced SERT binding capacity was found in the medial frontal cortex (MFC), midbrain, and temporal lobe areas of the children with autism compared with the comparison children. After adjustment for age and correction for the assumed effects of sedation, only the reduction in the MFC remained significant. No difference was identified in DAT binding capacity between the groups. As the authors acknowledge, there are a number of limitations to their study. These include the lack of a healthy age- and sex-matched comparison group, for reasons addressed above; the need for sedation in the children with autism; the lack of use of a criterion standard autism diagnostic instrument, such as the Autism Diagnostic Interview-Revised; the relatively small sample size; and the unusually high level of cognitive functioning (mean Full-scale IQ=89) of the children with autism. On the other hand, there are a number of strengths to this investigation. Published brain imaging studies of neurochemical binding are extremely rare in pediatric populations, including children with autism, due to appropriate concerns regarding radiation exposure. For this reason, these preliminary data are unique, valuable, and a potentially important contribution to the literature. In fact, this study is believed to be the first investigation of SERT and DAT binding capacity in children and adolescents with autism. The authors speculate that the reduced SERT binding observed in the children with autism may represent less synapse sprouting and a sparse synaptic density in serotonergic pathways in autistic individuals. They conclude that the most evident reason for the reduced SERT binding capacity is a lesser number of serotonergic synapses and SERTs themselves. Autism is a ‘syndrome’ and its causes will ultimately be linked to a multitude of biological factors related to both nature and nurture. As the study by Makkonen et al. demonstrates, neuroimaging techniques, including SPECT, have the potential to contribute substantially to furthering our understanding of the pathophysiology of autism. It is unlikely that a single neurochemical, such as serotonin, will be determined to be central to the cause of autism. Undoubtedly, excitatory and inhibitory amino acids, neuropeptides such as oxytocin and vasopressin, and neurotrophic and other factors essential to brain development may be involved.3 It is interesting, though, that serotonin is believed to play a critical interactive and modulatory role with each of these systems. The involvement of serotonin in the pathophysiology and, potentially, the treatment of autism has withstood the test of time. An important next step to build upon the work of Makkonen and colleagues would be to consider a positron emission tomography investigation of SERT and/or serotonin receptor binding capacity in adults with autism. Studying an adult population would minimize the risks of radiation exposure and allow for the inclusion of a healthy control group. Adults with autism might also be better able to participate in the scans without the need for sedation. For such a study to proceed it would be imperative to ensure that the participants and/or their legal guardians were engaged fully in the informed written assent and consent process.

Evidence of Mitochondrial Dysfunction in Autism and Implications for Treatment

Classical mitochondrial diseases occur in a subset of individuals with autism and are usually caused by genetic anomalies or mitochondrial respiratory pathway deficits. However, in many cases of autism, there is evidence of mitochondrial dysfunction (MtD) without the classic features associated with mitochondrial disease. MtD appears to be more common in autism and presents with less severe signs and symptoms. It is not associated with discernable mitochondrial pathology in muscle biopsy specimens despite objective evidence of lowered mitochondrial functioning. Exposure to environ- mental toxins is the likely etiology for MtD in autism. This dysfunction then contributes to a number of diagnostic symptoms and comorbidities observed in autism including: cognitive impairment, language deficits, abnormal energy metabolism, chronic gastrointestinal problems, abnormalities in fatty acid oxidation, and increased oxidative stress. MtD and oxidative stress may also explain the high male to female ratio found in autism due to increased male vulnerability to these dysfunctions. Biomarkers for mitochondrial dysfunction have been identified, but seem widely under-utilized despite available therapeutic interventions. Nutritional supplementation to decrease oxidative stress along with factors to improve reduced glutathione, as well as hyperbaric oxygen therapy (HBOT) represent supported and rationale approaches. The underlying pathophysiology and autistic symptoms of affected individuals would be expected to either improve or cease worsening once effective treatment for MtD is implemented.

Detection of IL-17 and IL-23 in Plasma Samples of Children with Autism.

Interleukin-23 (IL-23) is a survival factor for a newly described population of T lymphocytes, namely Th-17 cells, that secrete IL-17, tumor necrosis factor- alpha (TNFα) and IL-6. It has been shown that Th-17 cells are a pathogenic T cell subset involved in autoimmune and chronic inflammatory diseases. Based on the increasing evidence of immune dysfunction in autism, including possible autoimmune and inflammatory processes, we hypothesized that Th-17 cells, a T cell lineage that has not been previously examined in this disorder, may be altered in autism. To assess the potential role, if any, of Th-17 cells in autism, we analyzed plasma samples obtained from children ranging in age from 2-5 years with a diagnosis of autism and age-matched typically developing controls for the presence of IL-17 and IL-23 cytokines. Plasma samples from 40 children with autism including 20 children with a regressive form of autism, 20 with early onset and no regression and 20 typically developing age-matched control children were analyzed for IL-17 and IL-23, under the hypothesis that altered number and function of Th-17 cells would directly correlate with altered levels of IL-17 and IL-23 in the plasma. In this study, we were able to demonstrate that IL-23 cytokine levels were significantly different in children with autism compared with age-matched controls, a finding primarily driven by children with early onset autism. In contrast, there were no statistical differences in IL-17 levels autism compared with age-matched typically developing controls. This is the first study to report altered IL-23 production in autism. The decreased plasma IL-23 production observed in children with autism warrants further research as to its affect on the generation and survival of Th-17 cells, a subset important in neuroinflammatory conditions that may include autism.

Charting the typical and atypical development of the social brain

We describe recent progress in our program of research that aims to use functional magnetic resonance imaging (fMRI) to identify and delineate the brain systems involved in social perception and to chart the development of those systems and their roles as mechanisms supporting the development of social cognition in children, adolescents, and adults with and without autism. This research program was initiated with the intention of further specifying the role of the posterior superior temporal sulcus (STS) region in the network of neuroanatomical structures comprising the social brain. Initially, this work focused on evaluating STS function when typically developing adults were engaged in the visual analysis of other people's actions and intentions. We concluded that that the STS region plays an important role in social perception via its involvement in representing and predicting the actions and social intentions of other people from an analysis of biological-motion cues. These studies of typically developing people provided a set of core findings and a methodological approach that informed a set of fMRI studies of social perception dysfunction in autism. The work has established that dysfunction in the STS region, as well as reduced connectivity between this region and other social brain structures including the fusiform gyrus and amygdala, play a role in the pathophysiology of social perception deficits in autism. Most recently, this research program has incorporated a developmental perspective in beginning to chart the development of the STS region in children with and without autism.

Increased motor cortex white matter volume predicts motor impairment in autism

Careful consideration of motor impairments, such as those documented in autism, can afford valuable insights into the neurological basis of developmental disorders. Motor signs are highly quantifiable and reproducible and can serve as markers for deficits in parallel systems important for socialization and communication. Correlations of motor signs with anatomic MRI (aMRI) measures therefore offer an important means of investigating brain abnormalities contributing to autism. Prior aMRI studies have revealed increased cerebral volume in young children with autism, particularly in 'outer zone' radiate white matter; however functional correlates of these findings have not been reported. In this study, we examined whether radiate white matter within the primary motor cortex would predict impaired motor performance in children with autism. Subjects included children ages 8-12 years: 20 with autism, 36 typically developing (TD) controls and 20 clinical controls with attention-deficit/hyperactivity disorder (ADHD). Regional tissue volumes were measured using an automated tissue classification algorithm followed by a semi-automated parcellation method. Motor performance was assessed using the Physical and Neurologic Examination of Subtle Signs (PANESS), with higher scores indicating poorer performance. Independent linear regression analyses revealed that for TD controls there was a significant negative correlation between total PANESS score and primary motor cortex white matter volume in both the right and left hemispheres, such that increased white matter volume predicted improved motor skill. In contrast, children with autism showed a robust positive correlation between total PANESS score and left hemisphere primary motor and premotor white matter volumes, such that increased white matter volume predicted poorer motor skill. No significant correlations were found for ADHD. Multivariate regression analyses revealed that the correlation between PANESS score and left motor cortex white matter volume in children with autism significantly differed from those in both ADHD and TD children. The correlation in ADHD did not significantly differ from that in TD children. The findings for the first time demonstrate an association between increasing radiate white matter volume and functional impairment in children with autism, in this case basic motor skill impairment. The observed association, which appears specific to autism, may be representative of global patterns of brain abnormality that not only contribute to motor dysfunction in autism, but also deficits in socialization and communication that define the disorder.

Sensory correlations in autism

This study examined the relationship between auditory, visual, touch, and oral sensory dysfunction in autism and their relationship to multisensory dysfunction and severity of autism. The Sensory Profile was completed on 104 persons with a diagnosis of autism, 3 to 56 years of age. Analysis showed a significant correlation between the different processing modalities using total scores. Analysis also showed a significant correlation between processing modalities for both high and low thresholds, with the exception that auditory high threshold processing did not correlate with oral low threshold or touch low threshold processing. Examination of the different age groups suggests that sensory disturbance correlates with severity of autism in children, but not in adolescents and adults. Evidence from this study suggests that: all the main modalities and multisensory processing appear to be affected; sensory processing dysfunction in autism is global in nature; and sensory processing problems need to be considered part of the disorder.

Evidence for Cortical Dysfunction in Autism: A Proton Magnetic Resonance Spectroscopic Imaging Study

Although brain imaging studies have reported neurobiological abnormalities in autism, the nature and distribution of the underlying neurochemical irregularities are unknown. The purpose of this study was to examine cerebral gray and white matter cellular neurochemistry in autism with proton magnetic resonance spectroscopic imaging (MRSI). Proton MRSI examinations were conducted in 26 males with autism (age 9.8 +/- 3.2 years) and 29 male comparison subjects (age 11.1 +/- 2.4 years). Estimates of cerebral gray and white matter concentrations of N-acetylaspartate (NAA), creatine + phosphocreatine, choline-containing compounds, myo-inositol, and glutamate + glutamine (Glx) were made by linear regression analysis of multi-slice MRSI data and compared between groups. Regional estimates of metabolite concentration were also made with multivariate linear regression, allowing for comparisons of frontal, temporal, and occipital gray matter, cerebral white matter, and the cerebellum. Patients with autism exhibited significantly lower levels of gray matter NAA and Glx than control subjects. Deficits were widespread, affecting most cerebral lobes and the cerebellum. No significant differences were detected in cerebral white matter or cerebellar metabolite levels. These results suggest widespread reductions in gray matter neuronal integrity and dysfunction of cortical and cerebellar glutamatergic neurons in patients with autism.

Brief Report: High Frequency of Biochemical Markers for Mitochondrial Dysfunction in Autism: No Association with the Mitochondrial Aspartate/Glutamate Carrier SLC25A12 Gene

In the present study we confirm the previously reported high frequency of biochemical markers of mitochondrial dysfunction, namely hyperlactacidemia and increased lactate/pyruvate ratio, in a significant fraction of 210 autistic patients. We further examine the involvement of the mitochondrial aspartate/glutamate carrier gene (SLC25A12) in mitochondrial dysfunction associated with autism. We found no evidence of association of the SLC25A12 gene with lactate and lactate/pyruvate distributions or with autism in 241 nuclear families with one affected individual. We conclude that while mitochondrial dysfunction may be one of the most common medical conditions associated with autism, variation at the SLC25A12 gene does not explain the high frequency of mitochondrial dysfunction markers and is not associated with autism in this sample of autistic patients.