e-book Chapter 25, The Minicolumnopathy of Autism Spectrum Disorders

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Researchers and graduate students alike with an interest in developmental disorders and autism will benefit, as will autism specialists across psychology and medicine looking to expand their expertise. Neuroscientists at all levels interested in neurodevelopmental disorders and autism, autism specialists looking to expand their expertise. Chapter 2. Chapter 3.

Clinicopathological Stratification of Idiopathic Autism and Autism with 15q Chapter 4. Joseph Buxbaum is a world-renowned molecular geneticist who has been intimately affiliated with the Seaver Autism Center since joining the faculty at Mount Sinai in Buxbaum was recruited in part to establish a molecular genetics program in autism spectrum conditions within Mount Sinai. Buxbaum has focused on understanding the molecular and genetic basis of autism spectrum conditions, which will allow for a better understanding of what causes them, leading to the development of novel therapeutics for the negative aspects of these disorders.

Additionally, Dr. Buxbaum heads the Laboratory of Molecular Neuropsychiatry, which has taken the findings of the causes of autism and translated them into animal models where therapeutic approaches can be evaluated. In this context, Dr. Buxbaum has established the Autism Model Systems Initiative, which makes use of multiple experimental systems to develop and evaluate novel therapeutics in autism spectrum conditions. Buxbaum has taken the lead in collaborations with multiple independent sites to ensure that the best science in the service of the families is carried out.

These large Consortia have the benefit of advancing the best science at the fastest pace. As the founder and co-leader of the Autism Sequencing Consortium, Dr. Buxbaum is part of an international group of scientists who share autism samples, data, and ideas in order to accelerate our understanding of the causes and treatments of autism. Buxbaum, the G. Harold and Leila Y. Mathers Professor, has received numerous awards for his research. Efron award for "excellence in research in neuropsychophamacology" , as well as from the Eden Institute Foundation for his "commitment and dedication to improving the quality of life in individuals with autism" In , Dr.

Buxbaum received the Richard D. Buxbaum has published over publications in esteemed journals and his work on autism and related conditions has been published in major journals including Nature, Nature Genetics, Proceedings of the National Academy of Sciences, Molecular Psychiatry, and Biological Psychiatry. He is the co-Editor-in-chief of Molecular Autism, a journal that publishes cutting-edge research in autism genetics. His laboratory has extensive expertise in the pathology of neuropsychiatric disorders and has established an international reputation in quantitative approaches to neuroanatomy and studies of brain evolution.

Hof's research is directed towards the study of selective neuronal vulnerability in dementing illnesses and aging using classical neuropathologic as well as modern quantitative morphologic methods to determine the cellular features that render the human brain uniquely vulnerable to degenerative disorders. Hof also conducts analyses of the distribution and connectivity patterns of pyramidal neuron subpopulations in the macaque monkey cerebral cortex in young and very old animals to study possible age-related changes in the neurochemical characteristics of the neurons of origin of corticocortical projections.

He develops stereologic, high-resolution morphometric, and imaging tools for the quantitative study of neuroanatomical specimens and brain atlas development. Among his major contributions, Dr. Hof is also the curator of a mammalian brain collection that includes a large series of great ape specimens, as well as an extensive sample of marine mammals.

He has contributed considerably to our understanding of the structure of the cetacean brain and has identified, in select mammalian brains, specific neuronal types in parts of the cerebral cortex known to be involved in social awareness, judgment, and attention, that can be considered as markers of adaptive mechanisms and functions in response to particular ecological pressures. We are always looking for ways to improve customer experience on Elsevier.

We would like to ask you for a moment of your time to fill in a short questionnaire, at the end of your visit. The effect can be described as a reduced latency to non-targets and increased latency to target stimuli post-TMS but not after wait period. There were no hemispheric differences observed for P component. There were no group differences in amplitude of the parietal N component.

Latency of N to targets showed post-treatment between group difference in latency to targets The effect was expressed as increased latency for non-target stimuli in the TMS group post-treatment. Post hoc tests showed that in the active treatment group latency increased e. We found between group differences in P3b amplitude that were expressed as more attenuated component post-treatment in TMS as compared to WTL group only to non-Kanisza standards 2. The latency of P3b showed significant effects of Time factor on each stimuli: latency of P3b to targets, Comparison of post-treatment amplitude and latency of N ERP component showed decreased amplitude and prolonged latency to both target and non-target Kanizsa figures in the TMS group, while N magnitude was practically unchanged in the WTL group.

There were no interaction of N amplitude and latency on Stimulus , Hemisphere and Group factors. The TMS group showed less hemispheric differences post-treatment, while the WTL group had more negative amplitude of N at the right hemisphere. Additionally, post hoc analysis using t -test showed that N latency became statistically more prolonged to target stimuli in TMS group across both hemispheres Frontal P2a components — ms post stimulus is marked with a blue line.

The frontal P2a calculated as a mean difference between P2a amplitude to target Kanizsa minus P2a amplitude to non-target Kanizsa stimuli. Effect can be described as P2d becoming positive post-TMS, i. Paired sample t -test confirmed that P2d amplitude increased significantly post-TMS 3. Difference wave P2d was negative at the baseline in both groups i.

The active TMS showed post-treatment decrease of the P3a bilaterally across all stimuli, whereas WTL group showed no differences at all. There were not detected any main effects or interactions in the latency of the frontal P3a. Two subjects did not show sufficient number of commission errors and were excluded from the analysis. Amplitude and latency of Pe wave in both groups were not significantly changed post-treatment. ERN peak occurring within 40— ms post-error is marked by a blue line. We found a significant decrease in stereotype repetitive and restricted behavior patterns following 18 sessions of bilateral rTMS as measured by the RBS-R Bodfish et al.

Total RBS-R score decreased from There was identified as well a significant reduction in Irritability subscale as measured by the ABC Aman and Singh, , i. Our results show significant changes in behavioral responses accuracy, post-error RT slowing and both early and later-stage ERP indices of task-relevant signal processing as a result of 18 sessions of low frequency rTMS treatment course in children with ASD. Participant in TMS group showed decreased amplitude and prolonged latency of parietal P and N components to all stimuli, more for non-target cues.

In our prior study Sokhadze et al. Latency of the P3b was longer to distracters, without any amplitude group difference to targets and novels. The ASD group had prolonged latencies to novels but not to targets, with effect being better expressed in the right hemisphere. The results indicate the excess of efforts needed for the differentiation of targets from non-target novels in individuals with ASD. TMS treatment enhanced the process of target recognition during performance on task.

Especially informative in this regard was positive change of the frontal P2d difference wave that indicates increase of P2a component to target Kanizsa stimuli vs. In addition, at the same frontal topography N component was more negative to targets as compared to non-target illusory figures and had longer latency resulting in globally higher magnitude of N to targets. Following TMS course the N component at the frontal sites became more negative to targets, and at the same time significantly less negative to both types of non-target stimuli.

The positive frontal P2a component followed by the negative ERP N component both of them peaking within — post-stimulus in visual oddball tests tasks are associated with categorization, perceptual closure and attention focusing ultimately signaling that a perceptual representation has been formed Potts et al. This wave is enhanced if the presented stimulus contains a feature or attribute defining the target in the task according to Potts et al.

It was previous reported Sokhadze et al. In our earlier studies comparing ASD and typical controls we reported that the ASD group showed prolonged N, P, and P3b to targets stimuli, emphasizing a change indicative of abnormalities of sustained attention compared to controls. At the same time, the ASD group exhibited a prolonged P3a to novels, and this can be considered as a marker of impaired orientation to novelty, and ultimately decreased frontal associative and integrative functioning.


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In the current study our results show no differences in amplitude, though the latency of the P3a was still delayed. Over-activation in the parietal cortex at the early stages of processing of non-targets, either standards or infrequent distracters, and at the same time under-activation of integrative frontal regions at the late stages of target processing was found to occur in autism in a similar visual task that was using three-stimuli paradigm with rare novel distracters Sokhadze et al.

Our results in a series of visual oddball tasks indicated enhanced and prolonged early frontal ERPs and a delayed late P3a to non-target stimuli, which would suggest low selectivity in pre-processing and at a later stage under-activation of integrative regions. Overall, this is an indication of an over-connected network where sensory inputs evoke abnormally large evoked potentials for unattended stimuli such as frequent standards and rare novel distracters at all stages of visual signal processing with signs of a reduced selectivity of the activation.

The results of the current study indicate that rTMS may have facilitated attention and target discrimination by improving conflict resolutions during processing task-relevant and task-irrelevant stimuli. The latency of posterior P3b was prolonged to targets but reduced to both non-target Kanzisa and non-Kanizsa stimuli following rTMS.

The P3b has been linked to task-relevance and the decision- related character of the stimulus as it indicates memory-updating and individual trial processing closure Picton, Earlier we Sokhadze et al. The auditory and visual sensory information processing abnormalities been described in ASD by different researchers Kemner et al. However, most of these studies analyzed and reported outcomes of late cognitive potentials such as centro-parietal P3b Courchesne et al.

Majority of these studies emphasize over-activation as well as an abnormal pattern of basic perceptual processes such as low selectivity regardless of modality, abnormal top-down attentional control including delayed attentional orienting to novel stimuli, and deficits in information integration processes Belmonte and Yurgelun-Todd, In typically developing children the fronto-central P3a occurs earlier in time as compared to parietal P P3b , but in autistic subjects the P3a and P3b components were found to peak almost simultaneously over the frontal and parietal sites in a spatial attention test Townsend et al.

The latency of P3a is thought to be associated with the speed of attentional orienting to significant novel stimulus and reflects working memory processes in the prefrontal cortex. Centro-parietal P3b is usually described as a cognitive component that indexes context update and closure. This cognitive potential was found to be delayed but was not significantly attenuated in the group of children with autism as compared to typical controls Sokhadze et al.

The results of the study may indicate facilitation of visual target discrimination processes and enhanced habituation to task-irrelevant distracters post-TMS. We report significant improvement in the accuracy of MTs, lower total error rate and improved normative post-error RT slowing following 18 session long rTMS course. These result support our earlier findings outlining improvement in attention, executive control, and irrelevant response inhibition post-TMS treatment in autism.

In our initial rTMS pilot studies Sokhadze et al. In a very similar manner, our current study also found a notable reduction in the frontal N and altered latency of the parietal P3b to task-irrelevant stimuli. Additionally, similar to the present investigation we also found a significant reduction in the response errors rate following a shorter courses of the prefrontal rTMS Sokhadze et al.

It might be stated that we found even more pronounced changes in cognitive ERPs such as P2d, Nand P3b in this study that had the greater number of rTMS treatments 18 sessions. In another study using this time 12 sessions of rTMS we found a significant reduction in repetitive and restricted behavior patterns as well as a significant reduction in irritability according to clinical and behavioral questionnaires Casanova et al. The results of current 18 session-long rTMS treatment confirm and expand our prior findings of reduced repetitive behaviors Sokhadze et al.

It should be noted that we found significant reductions in irritability only as a result of 12 sessions of bilateral stimulation Baruth et al. The DLPFC processes components of working memory, decision making process, and regulates the ability to focus attention on task-relevant goals while inhibiting responses to distracters Gray et al. Suggested disruption in the ratio between cortical excitation and inhibition especially within the prefrontal cortex in individuals with autism Casanova et al. Among other defects, individuals with autism have well known perceptual processing abnormalities, including a hypersensitivity to auditory, visual and tactile stimulation Gomot et al.

Studies of perceptual systems in animal models may provide useful insights into mechanisms underlying sensory disturbances in autism. In particular, investigations of auditory development in rats using modulated noise manipulation showed that the representation of sound inputs in the cortex remains poorly differentiated when the cortex is undergoing development under very poor signal-to-noise conditions Chang and Merzenich, Neurodevelopmental abnormalities may lead to increased number, morphology or functional balance of excitatory vs.

Excessive noise in cortical structures processing information also negatively affects development of normally differentiated representations. Relatively undifferentiated representations of orienting signals or significant stimuli would result in larger and less selective response. Such over-representation by non-differentiated responses could account for the strong aversive reactions to auditory, tactile and visual stimuli that are common in autism.

Casanova et al. More specifically, their minicolumns have less peripheral neuropil space, which is the conduit for inhibitory local circuit projections. The authors concluded that GABAergic interneurons are vital for sensory signal processing e.

Elevated fetal steroidogenic activity in autism | Molecular Psychiatry

The hierarchical basis of the modular organization of the cerebral cortex is well recognized in the literature. The cerebral cortex originates during brain development as germinal cells from the ventricular and later on the subventricular zones divide asymmetrically and the resulting neuroblasts migrate towards the pial surface for review see Casanova and Trippe, The resulting vertical arrangement of cells within this dynamic system serves as an attractor for satellite interneurons to populate its peripheral neuropil space.

Radially migrating neurons provide for future pyramidal cells while those that follow a tangential path, primarily from the ganglionic eminences, are destined to be interneurons.

Introduction

Recent studies indicate that higher cognitive functions including our executive functions derive from the workings of these modules or minicolumns Opris et al. Topographical studies of minicolumnar morphometry in ASD have shown the greatest deviance from neurotypicals within the prefrontal cortex Casanova et al. Some investigators have explained this fact as resulting from the prolonged maturation time of this structure which thus provides a larger time window of opportunity for exogenous factors to alter its development Opris and Casanova, Within the rostral brain region abnormalities within the DLPFC could serve as a pathological correlate to observed executive function deficits in autism Opris and Casanova, Given the vertical orientation of inhibitory elements within the periphery of the minicolumns e.

Since the dorsolateral prefrontal cortex has been a source of significant minicolumnopathy in published postmortem studies it could be viewed as a target for stimulation using rTMS Casanova et al. Furthermore, considering the trans-synaptic effects of rTMS, the large number of DLPFC connections could provide a therapeutic cascading effect in other parts of the brain. In autism computerized image analysis suggests the presence of a minicolumnopathy characterized by an increased density of modules and a diminution in their peripheral neuropil space Casanova et al.

The deficits previously described by our group have been corroborated using a variety of neuronomorphometric techniques e. The diminished width of the minicolumnar peripheral neuropil space is seen throughout laminae II-VI, suggesting a deficit of an anatomical element in-common to all layers Casanova et al. Since inhibitory elements populate all layers of the lateral compartment of the minicolumn pathology involving these elements could contribute to a deficit in the lateral or peripheral inhibitory surround of these modules.

It is plausible to propose that low frequency rTMS is increasing inhibitory tone and improving lateral inhibition, and this may result in an enhancement of executive functions. Executive function deficits were always in the center of attention in autism research. Executive function of behavioral performance monitoring comprises error detection and response conflict monitoring, functions that can be measured using response-locked ERPs such as ERN and Pe Gehring et al. The ERN is a well-studied component whose parameters were investigated under different experimental task conditions, and its ties to error processing have been well established Carter et al.

There is an increased number of research studies examining ERN during commission errors in children Davies et al. It is established that executive functions normally improve with age Huizinga et al. Furthermore, the studying error processing maturation can be used to understand mechanisms of various neurodevelopmental disorders, such as ADHD and ASD, which feature impairments in execute control Liotti et al.

The ERN abnormalities are interpreted as reflecting early error processing impairments. A number of studies have investigated the functional relationship between the ERN and the fronto-central stimulus-locked N, while some suggest that they represent distinct neurophysiological processes Ridderinkhof et al. One of the most important findings of current study was replication of the increase of ERN amplitude and shortened latency post-TMS reported in previous study using 12 sessions of rTMS Sokhadze et al.

In accord with our previous study Sokhadze et al. This component has a more posterior topography and is expressed as a positivity elicited after the ERN Falkenstein et al. Facilitation of target recognition following TMS treatment and more effective early inhibition of non-target distracters leads to less pronounced carryover of non-target over-processing.

We suggested earlier that more expressed positive neuromodulation effects in the early ERPs rather than in the late ERPs might be due to enhanced suppression of task- irrelevant stimuli and less effortful discrimination of targets from non-targets during attention task performance.

One more critical methodological issue to be considered in absence of significant TMS effects on Pe in autism might be related to the number of commission errors as this measure depends on the actual number of committed errors Franken et al. It is feasible to suggest that the magnitude of the Pe was affected by the reduced number of commission errors in active TMS group. There is a possibility of a dissociation of ERN and Pe effects since generation of Pe wave might be affected by the absence of feedback about the accuracy of the MR resulting in that lower awareness of error Hewig et al.

In general, our findings are in concordance with a recent review of rTMS applications in autism research and treatment Oberman et al. In that review the authors concluded that, though results of published studies are promising suggesting that specific rTMS protocols Enticott et al. Some limitations to the study should be taken into account. It is often reported in rTMS studies that effects of magnetic stimulation usually do not wash out in approximately one week.

We believe that switching to once per week session regimen, e. Probably the length of staying in the rTMS treatment rather than intensity is one of the main keys of behavioral and electrocrtical improvements that we observe in our later rTMS trials in ASD Baruth et al. However, it must be mentioned that other known TMS protocols were targeting psychopathologies such as treatment-resistant major depression, or neurological disorders such as for instance Parkinson disease in adults.

One more limitation of the study is the use a waiting-list group as a control group rather than using a randomized clinical trial RCT design with a sham rTMS condition. Even though our group has a custom-made sham Magstim TMS coil and interface enabling blinding of TMS delivery, we considered this study as a preliminary pilot with a WTL group design, and plan to consider progression to a RCT design on the future stages. It is possible to consider as a limitation also the difficulty of proving in non-invasive human brain research that low frequency rTMS is activating primarily double-bouquet inter-neurons.

We hope that future neurophysiological studies on animal models would be able to find support for our hypothesis. We also found significant reductions in both repetitive and stereotypic behaviors, reduced repetitive behaviors, hyperactivity and irritability scores according to social and behavioral clinical evaluations post-TMS. We consider that it is possible to conclude that neuromodulation using low frequency, inhibitory rTMS improved executive functioning and behavior in autism.

This study provides further support to the statement that TMS can be regarded as a perspective treatment targeting core symptoms of ASD such as executive function deficits. The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Historical...

Europe PMC requires Javascript to function effectively. Recent Activity. Reports in autism spectrum disorders ASD of a minicolumnopathy with consequent deficits of lateral inhibition help explain observed behavioral and executive dysfunctions. Along with traditional clinical behavioral evaluations the current study used ERPs in a visual oddball task with illusory figures. The snippet could not be located in the article text. This may be because the snippet appears in a figure legend, contains special characters or spans different sections of the article.

Front Syst Neurosci. Published online Aug 6. PMID: Estate M. El-Baz , 2 Lonnie L. Sears , 3 Ioan Opris , 4 and Manuel F. Casanova 1. Ayman S. Lonnie L. Manuel F.


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  • Received Jan 25; Accepted Jul 9. The use, distribution or reproduction in other forums is permitted, provided the original author s or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

    This article has been cited by other articles in PMC. Abstract Objectives: Reports in autism spectrum disorders ASD of a minicolumnopathy with consequent deficits of lateral inhibition help explain observed behavioral and executive dysfunctions. Introduction Autism Spectrum Disorders ASD are featured by severe deficits in social communication, social interaction, and restricted, repetitive patterns of behaviors, interests and activities APA, Three-stimuli oddball task with Kanizsa figures The stimuli employed in the test were Kanizsa square target , Kanizsa triangle non-target , non-Kanizsa square, and non-Kanizsa triangle standards Kanizsa, Open in a separate window.

    Figure 1. Clinical social and behavioral evaluation outcomes For the evaluation of social and behavioral functioning we utilized caregiver reports and clinician ratings of improvement. Figure 2. N There were no group differences in amplitude of the parietal N component. Figure 3. P P3b We found between group differences in P3b amplitude that were expressed as more attenuated component post-treatment in TMS as compared to WTL group only to non-Kanisza standards 2.

    Figure 4. P2d The frontal P2a calculated as a mean difference between P2a amplitude to target Kanizsa minus P2a amplitude to non-target Kanizsa stimuli. Figure 5.

    Response-locked frontal and fronto-central ERN and Pe Two subjects did not show sufficient number of commission errors and were excluded from the analysis. Figure 6. Figure 7. Figure 8. Figure 9. Discussion Our results show significant changes in behavioral responses accuracy, post-error RT slowing and both early and later-stage ERP indices of task-relevant signal processing as a result of 18 sessions of low frequency rTMS treatment course in children with ASD.

    Conflict of interest statement The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. References Aman M. Management of hyperactivity and other acting out problems in patients with autism spectrum disorder.

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