The Neuropathology of Autism

Department of Psychiatry and Behavioral Sciences, University of Louisville, Louisville, KY 40292, USA.
Brain Pathology (Impact Factor: 3.84). 11/2007; 17(4):422-33. DOI: 10.1111/j.1750-3639.2007.00100.x
Source: PubMed


Autism is a brain disorder characterized by abnormalities in how a person relates and communicates to others. Both post-mortem and neuroimaging studies indicate the presence of increased brain volume and, in some cases, an altered gray/white matter ratio. Contrary to established gross findings there is no recognized microscopic pathology to autism. Early studies provided multiple leads none of which have been validated. Clinicopathological associations have been difficult to sustain when considering possible variables such as use of medications, seizures, mental retardation and agonal/pre-agonal conditions. Research findings suggest widespread cortical abnormalities, lack of a vascular component and an intact blood-brain barrier. Many of the previously mentioned findings can be explained in terms of a mini-columnopathy. The significance of future controlled studies should be judged based on their explanatory powers; that is, how well do they relate to brain growth abnormalities and/or provide useful clinicopathological correlates.

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    • "Reduced cortical inhibitory tone and an increased E/I ratio could adversely affect patterns of cortical activation, possibly resulting in isolated islands of coordinated excitatory activity and in a high comorbidity rate of ASD and epilepsy (Tuchman and Rapin, 1997). We believe that a course of 18 neuromodulatory sessions of low frequency rTMS may restore the cortical E/I balance by selective activation of double-bouquet cells at the periphery of cortical minicolumns (Casanova et al., 2006a,b; Casanova, 2007). It was shown that minicolumnar abnormalities in autism are most significant within the prefrontal cortex, more specifically, the DLPFC and the ACC (Fernandez-Duque et al., 2000; Mesulam, 2000; Casanova et al., 2002b, 2006a,b). "
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    ABSTRACT: Objectives: Reports in autism spectrum disorders (ASD) of a minicolumnopathy with consequent deficits of lateral inhibition help explain observed behavioral and executive dysfunctions. We propose that neuromodulation based on low frequency repetitive Transcranial Magnetic Stimulation (rTMS) will enhance lateral inhibition through activation of inhibitory double bouquet interneurons and will be accompanied by improvements in the prefrontal executive functions. In addition we proposed that rTMS will improve cortical excitation/inhibition ratio and result in changes manifested in event-related potential (ERP) recorded during cognitive tests. Materials and methods: Along with traditional clinical behavioral evaluations the current study used ERPs in a visual oddball task with illusory figures. We compared clinical, behavioral and electrocortical outcomes in two groups of children with autism (TMS, wait-list group). We predicted that 18 session long course in autistic patients will have better behavioral and ERP outcomes as compared to age- and IQ-matched WTL group. We used 18 sessions of 1 Hz rTMS applied over the dorso-lateral prefrontal cortex in 27 individuals with ASD diagnosis. The WTL group was comprised of 27 age-matched subjects with ASD tested twice. Both TMS and WTL groups were assessed at the baseline and after completion of 18 weekly sessions of rTMS (or wait period) using clinical behavioral questionnaires and during performance on visual oddball task with Kanizsa illusory figures. Results: Post-TMS evaluations showed decreased irritability and hyperactivity on the Aberrant Behavior Checklist (ABC), and decreased stereotypic behaviors on the Repetitive Behavior Scale (RBS-R). Following rTMS course we found decreased amplitude and prolonged latency in the frontal and fronto-central N100, N200 and P300 (P3a) ERPs to non-targets in active TMS treatment group. TMS resulted in increase of P2d (P2a to targets minus P2a to non-targets) amplitude. These ERP changes along with increased centro-parietal P100 and P300 (P3b) to targets are indicative of more efficient processing of information post-TMS treatment. Another important finding was decrease of the latency and increase of negativity of error-related negativity (ERN) during commission errors that may reflect improvement in error monitoring and correction function. Enhanced information processing was also manifested in lower error rate. In addition we calculated normative post-error treaction time (RT) slowing response in both groups and found that rTMS treatment was accompanied by post-error RT slowing and higher accuracy of responses, whereas the WTL group kept on showing typical for ASD post-error RT speeding and higher commission and omission error rates. Conclusion: RESULTS from our study indicate that rTMS improves executive functioning in ASD as evidenced by normalization of ERP responses and behavioral reactions (RT, accuracy) during executive function test, and also by improvements in clinical evaluations.
    Frontiers in Systems Neuroscience 08/2014; 8:134. DOI:10.3389/fnsys.2014.00134
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    • "In contrast, our cerebellar results show significantly lower expression of all four microglial cell specific markers in autistic brains. While other studies have identified microglial activation in the cerebellum of autistic tissue [33], no study has attempted to specifically quantify microglial cells in the cerebellum using the markers assessed here, and therefore histopathologic studies in the cerebellum are needed to confirm these findings. One report described increased microglial cell activation in the cerebellum, assessed via HLA-DR staining in the white matter and granular cell layer of the cerebellum [7], and another showed increased microglial activation throughout the brain (although most prominently in the cerebellum) using an in vivo PET metabolic radiotracer [13]. "
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    ABSTRACT: The cellular mechanism(s) underlying autism spectrum disorders (ASDs) are not completely understood, but ASDs are thought to ultimately result from disrupted synaptogenesis. However, studies have also shown that glial cell numbers and function are abnormal in post-mortem brain tissue from autistic patients. Direct assessment of glial cells in post-mortem human brain tissue is technically challenging, limiting glial research in human ASD studies. Therefore, we attempted to determine if glial cell-type specific markers may be altered in autistic brain tissue in a manner that is consistent with known cellular findings, such that they could serve as a proxy for glial cell numbers and/or activation patterns. We assessed the relative expression of five glial-specific markers and two neuron-specific markers via qRT-PCR. We studied tissue samples from the prefrontal cortex (PFC) and cerebellum of nine post-mortem autistic brain samples and nine neurologically-normal controls. Relative fold-change in gene expression was determined using the DeltaDeltaCt method normalized to housekeeping gene beta-actin, with a two-tailed Student's t-test P <0.05 between groups considered as significant. Both astrocyte- and microglial-specific markers were significantly more highly expressed in autistic PFC as compared to matched controls, while in the cerebellum only astrocyte markers were elevated in autistic samples. In contrast, neuron-specific markers showed significantly lower expression in both the PFC and cerebellum of autistic patients as compared to controls. These results are in line with previous findings showing increased glial cell numbers and up-regulation of glial cell gene expression in autistic post-mortem brain tissue, particularly in the PFC, as well as decreased number of neurons in both the PFC and cerebellum of autistic patients. The concordance of these results with cell-level studies in post-mortem autistic brain tissue suggests that expression of glial cell-type specific markers may serve as a useful alternative to traditional cellular characterization methods, especially when appropriately-preserved post-mortem tissue is lacking. Additionally, these results demonstrate abnormal glial-specific gene expression in autistic brains, supporting previous studies that have observed altered glial cell numbers or activation patterns in ASDs. Future work should directly assess the correlation between cell-type specific marker levels and cell number and activation patterns.
    Molecular Autism 01/2014; 5(1):3. DOI:10.1186/2040-2392-5-3 · 5.41 Impact Factor
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    • "The brunt of dysplastic changes appears to be within the neocortex wherein abnormalities of gyrification and laminar architecture are often found. These findings include effacement of the normal lamination pattern, minicolumnar abnormalities, and variations in neuronal density [1-4]. In addition to the previously mentioned microscopic changes, at gross examination, brains of autistic individuals have shown malformations in the form of hyperconvolution [5], misdirected gyri [6], and polymicrogyria [7]. "
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    ABSTRACT: Previous reports indicate the presence of histological abnormalities in the brains of individuals with autism spectrum disorders (ASD) suggestive of a dysplastic process. In this study we identified areas of abnormal cortical thinning within the cerebral cortex of ASD individuals and examined the same for neuronal morphometric abnormalities by using computerized image analysis. The study analyzed celloidin-embedded and Nissl-stained serial full coronal brain sections of 7 autistic (ADI-R diagnosed) and 7 age/sex-matched neurotypicals. Sections were scanned and manually segmented before implementing an algorithm using Laplace's equation to measure cortical width. Identified areas were then subjected to analysis for neuronal morphometry. Results of our study indicate the presence within our ASD population of circumscribed foci of diminished cortical width that varied among affected individuals both in terms of location and overall size with the frontal lobes being particularly involved. Spatial statistic indicated a reduction in size of neurons within affected areas. Granulometry confirmed the presence of smaller pyramidal cells and suggested a concomitant reduction in the total number of interneurons. The neuropathology is consistent with a diagnosis of focal cortical dysplasia (FCD). Results from the medical literature (e.g., heterotopias) and our own study suggest that the genesis of this cortical malformation seemingly resides in the heterochronic divisions of periventricular germinal cells. The end result is that during corticogenesis radially migrating neuroblasts (future pyramidal cells) are desynchronized in their development from those that follow a tangential route (interneurons). The possible presence of a pathological mechanism in common among different conditions expressing an autism-like phenotype argue in favor of considering ASD a "sequence" rather than a syndrome. Focal cortical dysplasias in ASD may serve to explain the high prevalence of seizures and sensory abnormalities in this patient population.
    10/2013; 1(1):67. DOI:10.1186/2051-5960-1-67
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