The Critical Importance of Molecular Biomarkers and Imaging in the Study of Electrohypersensitivity. A Scientific Consensus International Report.

Clinical research aiming at objectively identifying and characterizing diseases via clinical observations and biological and radiological findings is a critical initial research step when establishing objective diagnostic criteria and treatments. Failure to first define such diagnostic criteria may lead research on pathogenesis and etiology to serious confounding biases and erroneous medical interpretations. This is particularly the case for electrohypersensitivity (EHS) and more particularly for the so-called "provocation tests", which do not investigate the causal origin of EHS but rather the EHS-associated particular environmental intolerance state with hypersensitivity to man-made electromagnetic fields (EMF). However, because those tests depend on multiple EMF-associated physical and biological parameters and have been conducted in patients without having first defined EHS objectively and/or endpoints adequately, they cannot presently be considered to be valid pathogenesis research methodologies. Consequently, the negative results obtained by these tests do not preclude a role of EMF exposure as a symptomatic trigger in EHS patients. Moreover, there is no proof that EHS symptoms or EHS itself are caused by psychosomatic or nocebo effects. This international consensus report pleads for the acknowledgement of EHS as a distinct neuropathological disorder and for its inclusion in the WHO International Classification of Diseases.

Prenatal paracetamol exposure and child neurodevelopment: A review.

BACKGROUND: The non-prescription medication paracetamol (acetaminophen, APAP) is currently recommended as a safe pain and fever treatment during pregnancy. However, recent studies suggest a possible association between APAP use in pregnancy and offspring neurodevelopment. OBJECTIVES: To conduct a review of publications reporting associations between prenatal APAP use and offspring neurodevelopmental outcomes. METHODS: Relevant sources were identified through a key word search of multiple databases (Medline, CINAHL, OVID and TOXNET) in September 2016. All English language observational studies of pregnancy APAP and three classes of neurodevelopmental outcomes (autism spectrum disorder (ASD), attention deficit hyperactivity disorder (ADHD), and intelligence quotient (IQ)) were included. One reviewer (AZB) independently screened all titles and abstracts, extracted and analyzed the data. RESULTS: 64 studies were retrieved and 55 were ineligible. Nine prospective cohort studies fulfilled all inclusion criteria. Data pooling was not appropriate due to heterogeneity in outcomes. All included studies suggested an association between prenatal APAP exposure and the neurodevelopmental outcomes; ADHD, ASD, or lower IQ. Longer duration of APAP use was associated with increased risk. Associations were strongest for hyperactivity and attention-related outcomes. Little modification of associations by indication for use was reported. CONCLUSIONS: Together, these nine studies suggest an increased risk of adverse neurodevelopmental outcomes following prenatal APAP exposure. Further studies are urgently needed with; precise indication of use and exposure assessment of use both in utero and in early life. Given the current findings, pregnant women should be cautioned against indiscriminate use of APAP. These results have substantial public health implications.

Somatosensory cortex functional connectivity abnormalities in autism show opposite trends, depending on direction and spatial scale.

Functional connectivity is abnormal in autism, but the nature of these abnormalities remains elusive. Different studies, mostly using functional magnetic resonance imaging, have found increased, decreased, or even mixed pattern functional connectivity abnormalities in autism, but no unifying framework has emerged to date. We measured functional connectivity in individuals with autism and in controls using magnetoencephalography, which allowed us to resolve both the directionality (feedforward versus feedback) and spatial scale (local or long-range) of functional connectivity. Specifically, we measured the cortical response and functional connectivity during a passive 25-Hz vibrotactile stimulation in the somatosensory cortex of 20 typically developing individuals and 15 individuals with autism, all males and right-handed, aged 8-18, and the mu-rhythm during resting state in a subset of these participants (12 per group, same age range). Two major significant group differences emerged in the response to the vibrotactile stimulus. First, the 50-Hz phase locking component of the cortical response, generated locally in the primary (S1) and secondary (S2) somatosensory cortex, was reduced in the autism group (P < 0.003, corrected). Second, feedforward functional connectivity between S1 and S2 was increased in the autism group (P < 0.004, corrected). During resting state, there was no group difference in the mu-α rhythm. In contrast, the mu-ß rhythm, which has been associated with feedback connectivity, was significantly reduced in the autism group (P < 0.04, corrected). Furthermore, the strength of the mu-ß was correlated to the relative strength of 50 Hz component of the response to the vibrotactile stimulus (r = 0.78, P < 0.00005), indicating a shared aetiology for these seemingly unrelated abnormalities. These magnetoencephalography-derived measures were correlated with two different behavioural sensory processing scores (P < 0.01 and P < 0.02 for the autism group, P < 0.01 and P < 0.0001 for the typical group), with autism severity (P < 0.03), and with diagnosis (89% accuracy). A biophysically realistic computational model using data driven feedforward and feedback parameters replicated the magnetoencephalography data faithfully. The direct observation of both abnormally increased and abnormally decreased functional connectivity in autism occurring simultaneously in different functional connectivity streams, offers a potential unifying framework for the unexplained discrepancies in current findings. Given that cortical feedback, whether local or long-range, is intrinsically non-linear, while cortical feedforward is generally linear relative to the stimulus, the present results suggest decreased non-linearity alongside an increased veridical component of the cortical response in autism.

Correlation of Fractional Anisotropy With Motor Recovery in Patients With Stroke After Postacute Rehabilitation.

OBJECTIVE: To investigate the relation between fractional anisotropy (FA), a suggested biomarker for tissue integrity, and motor recovery in patients with stroke after postacute rehabilitation. DESIGN: Retrospective study. SETTING: Acute rehabilitation hospital. PARTICIPANTS: Subjects (N=43) diagnosed with ischemic stroke (n=28) and hemorrhagic stroke (n=15). The average age for subjects was 68±14 years. INTERVENTIONS: Magnetic resonance imaging and diffusion tensor imaging were conducted on all patients. MAIN OUTCOME MEASURES: The admission and discharge motor subscores of the FIM were obtained from medical records, and relative gain was calculated using the Montebello Rehabilitation Factor Score (MRFS). K-means cluster analysis (K=3) using both the MRFS and the gain of the FIM motor subscore (ΔFIM) was performed. Analysis of variance was used to determine the difference in FA among the clusters. Spearman analysis was conducted to examine the relation between FA, ΔFIM, and MRFS in each cluster. RESULTS: FA was significantly higher in the clusters of good and moderate recovery in the corticospinal tract (CST), peduncle, and posterior limb of the internal capsule bilaterally (all P<.05) compared with the poor recovery group. Significant positive correlations were observed in multiple regions along the CST between FA, ΔFIM, and MRFS in the clusters of good and moderate recovery, but not in the poor recovery group. CONCLUSIONS: Our results showed an association between FA values within the corticospinal tract and motor recovery in patients with stroke undergoing postacute rehabilitation. This finding may help to identify novel targets for new interventions to promote stroke recovery.

Local and long-range functional connectivity is reduced in concert in autism spectrum disorders.

Long-range cortical functional connectivity is often reduced in autism spectrum disorders (ASD), but the nature of local cortical functional connectivity in ASD has remained elusive. We used magnetoencephalography to measure task-related local functional connectivity, as manifested by coupling between the phase of alpha oscillations and the amplitude of gamma oscillations, in the fusiform face area (FFA) of individuals diagnosed with ASD and typically developing individuals while they viewed neutral faces, emotional faces, and houses. We also measured task-related long-range functional connectivity between the FFA and the rest of the cortex during the same paradigm. In agreement with earlier studies, long-range functional connectivity between the FFA and three distant cortical regions was reduced in the ASD group. However, contrary to the prevailing hypothesis in the field, we found that local functional connectivity within the FFA was also reduced in individuals with ASD when viewing faces. Furthermore, the strength of long-range functional connectivity was directly correlated to the strength of local functional connectivity in both groups; thus, long-range and local connectivity were reduced proportionally in the ASD group. Finally, the magnitude of local functional connectivity correlated with ASD severity, and statistical classification using local and long-range functional connectivity data identified ASD diagnosis with 90% accuracy. These results suggest that failure to entrain neuronal assemblies fully both within and across cortical regions may be characteristic of ASD.

Autism and EMF? Plausibility of a pathophysiological link part II.

Autism spectrum conditions (ASCs) are defined behaviorally, but they also involve multileveled disturbances of underlying biology that find striking parallels in the physiological impacts of electromagnetic frequency and radiofrequency radiation exposures (EMF/RFR). Part I (Vol 776) of this paper reviewed the critical contributions pathophysiology may make to the etiology, pathogenesis and ongoing generation of behaviors currently defined as being core features of ASCs. We reviewed pathophysiological damage to core cellular processes that are associated both with ASCs and with biological effects of EMF/RFR exposures that contribute to chronically disrupted homeostasis. Many studies of people with ASCs have identified oxidative stress and evidence of free radical damage, cellular stress proteins, and deficiencies of antioxidants such as glutathione. Elevated intracellular calcium in ASCs may be due to genetics or may be downstream of inflammation or environmental exposures. Cell membrane lipids may be peroxidized, mitochondria may be dysfunctional, and various kinds of immune system disturbances are common. Brain oxidative stress and inflammation as well as measures consistent with blood-brain barrier and brain perfusion compromise have been documented. Part II of this paper documents how behaviors in ASCs may emerge from alterations of electrophysiological oscillatory synchronization, how EMF/RFR could contribute to these by de-tuning the organism, and policy implications of these vulnerabilities. It details evidence for mitochondrial dysfunction, immune system dysregulation, neuroinflammation and brain blood flow alterations, altered electrophysiology, disruption of electromagnetic signaling, synchrony, and sensory processing, de-tuning of the brain and organism, with autistic behaviors as emergent properties emanating from this pathophysiology. Changes in brain and autonomic nervous system electrophysiological function and sensory processing predominate, seizures are common, and sleep disruption is close to universal. All of these phenomena also occur with EMF/RFR exposure that can add to system overload ('allostatic load') in ASCs by increasing risk, and can worsen challenging biological problems and symptoms; conversely, reducing exposure might ameliorate symptoms of ASCs by reducing obstruction of physiological repair. Various vital but vulnerable mechanisms such as calcium channels may be disrupted by environmental agents, various genes associated with autism or the interaction of both. With dramatic increases in reported ASCs that are coincident in time with the deployment of wireless technologies, we need aggressive investigation of potential ASC-EMF/RFR links. The evidence is sufficient to warrant new public exposure standards benchmarked to low-intensity (non-thermal) exposure levels now known to be biologically disruptive, and strong, interim precautionary practices are advocated.

Autism and EMF? Plausibility of a pathophysiological link - Part I.

Although autism spectrum conditions (ASCs) are defined behaviorally, they also involve multileveled disturbances of underlying biology that find striking parallels in the physiological impacts of electromagnetic frequency and radiofrequency exposures (EMF/RFR). Part I of this paper will review the critical contributions pathophysiology may make to the etiology, pathogenesis and ongoing generation of core features of ASCs. We will review pathophysiological damage to core cellular processes that are associated both with ASCs and with biological effects of EMF/RFR exposures that contribute to chronically disrupted homeostasis. Many studies of people with ASCs have identified oxidative stress and evidence of free radical damage, cellular stress proteins, and deficiencies of antioxidants such as glutathione. Elevated intracellular calcium in ASCs may be due to genetics or may be downstream of inflammation or environmental exposures. Cell membrane lipids may be peroxidized, mitochondria may be dysfunctional, and various kinds of immune system disturbances are common. Brain oxidative stress and inflammation as well as measures consistent with blood-brain barrier and brain perfusion compromise have been documented. Part II of this paper will review how behaviors in ASCs may emerge from alterations of electrophysiological oscillatory synchronization, how EMF/RFR could contribute to these by de-tuning the organism, and policy implications of these vulnerabilities. Changes in brain and autonomic nervous system electrophysiological function and sensory processing predominate, seizures are common, and sleep disruption is close to universal. All of these phenomena also occur with EMF/RFR exposure that can add to system overload ('allostatic load') in ASCs by increasing risk, and worsening challenging biological problems and symptoms; conversely, reducing exposure might ameliorate symptoms of ASCs by reducing obstruction of physiological repair. Various vital but vulnerable mechanisms such as calcium channels may be disrupted by environmental agents, various genes associated with autism or the interaction of both. With dramatic increases in reported ASCs that are coincident in time with the deployment of wireless technologies, we need aggressive investigation of potential ASC - EMF/RFR links. The evidence is sufficient to warrant new public exposure standards benchmarked to low-intensity (non-thermal) exposure levels now known to be biologically disruptive, and strong, interim precautionary practices are advocated.

Statistical adjustments for brain size in volumetric neuroimaging studies: some practical implications in methods.

Volumetric magnetic resonance imaging (MRI) brain data provide a valuable tool for detecting structural differences associated with various neurological and psychiatric disorders. Analysis of such data, however, is not always straightforward, and complications can arise when trying to determine which brain structures are "smaller" or "larger" in light of the high degree of individual variability across the population. Several statistical methods for adjusting for individual differences in overall cranial or brain size have been used in the literature, but critical differences exist between them. Using agreement among those methods as an indication of stronger support of a hypothesis is dangerous given that each requires a different set of assumptions be met. Here we examine the theoretical underpinnings of three of these adjustment methods (proportion, residual, and analysis of covariance) and apply them to a volumetric MRI data set. These three methods used for adjusting for brain size are specific cases of a generalized approach which we propose as a recommended modeling strategy. We assess the level of agreement among methods and provide graphical tools to assist researchers in determining how they differ in the types of relationships they can unmask, and provide a useful method by which researchers may tease out important relationships in volumetric MRI data. We conclude with the recommended procedure involving the use of graphical analyses to help uncover potential relationships the ROI volumes may have with head size and give a generalized modeling strategy by which researchers can make such adjustments that include as special cases the three commonly employed methods mentioned above.

Contributions of the environment and environmentally vulnerable physiology to autism spectrum disorders.

PURPOSE OF REVIEW: This review presents a rationale and evidence for contributions of environmental influences and environmentally vulnerable physiology to autism spectrum disorders (ASDs). RECENT FINDINGS: Recent studies suggest a substantial increase in ASD prevalence above earlier Centers for Disease Control figures of one in 150, only partly explicable by data artifacts, underscoring the possibility of environmental contributors to increased prevalence. Some gene variants in ASD confer altered vulnerability to environmental stressors and exposures. De-novo mutations and advanced parental age as a risk factor for ASD also suggest a role for environment. Systemic and central nervous system pathophysiology, including oxidative stress, neuroinflammation, and mitochondrial dysfunction can be consistent with a role for environmental influence (e.g. from air pollution, organophosphates, heavy metals) in ASD, and some of the underlying biochemical disturbances (such as abnormalities in glutathione, a critical antioxidant and detoxifier) can be reversed by targeted nutritional interventions. Dietary factors and food contaminants may contribute risk. Improvement and loss of diagnosis in some with ASD suggest brain circuitry amenable to environmental modulation. SUMMARY: Prevalence, genetic, exposure, and pathophysiological evidence all suggest a role for environmental factors in the inception and lifelong modulation of ASD. This supports the need for seeking targets for early and ongoing medical prevention and treatment of ASD.

Offering to share: how to put heads together in autism neuroimaging.

Data sharing in autism neuroimaging presents scientific, technical, and social obstacles. We outline the desiderata for a data-sharing scheme that combines imaging with other measures of phenotype and with genetics, defines requirements for comparability of derived data and recommendations for raw data, outlines a core protocol including multispectral structural and diffusion-tensor imaging and optional extensions, provides for the collection of prospective, confound-free normative data, and extends sharing and collaborative development not only to data but to the analytical tools and methods applied to these data. A theme in these requirements is the need to preserve creative approaches and risk-taking within individual laboratories at the same time as common standards are provided for these laboratories to build on.

Anatomic brain magnetic resonance imaging of the basal ganglia in pediatric bipolar disorder.

BACKGROUND: Basal ganglia (BG) enlargement has been found in studies of adults with bipolar disorder (BPD), while the few studies of BPD youths have had mixed findings. The BG (caudate, putamen, globus pallidus, nucleus accumbens) is interconnected with limbic and prefrontal cortical structures and therefore may be implicated in BPD. METHODS: Sixty-eight youths (46 with BPD, 22 healthy controls) received neurological and psychiatric assessment, semi-structured interviews, and neuropsychological testing, followed by anatomic magnetic resonance imaging on a 1.5 Tesla scanner. After image segmentation, log BG volumes and asymmetry indices were analyzed using MANOVAs controlling for the effects of cerebral volume, age, sex, and diagnosis. These omnibus tests were followed by univariate linear regression models of each BG structure. RESULTS: Youths with BPD had a trend for larger right nucleus accumbens (NA) volumes (p = 0.089). There were no significant group asymmetry differences, nor volume differences in the caudate, putamen, and globus pallidus. When analyzed separately by pubertal status, the prepubertal group had significantly larger total NA (p = 0.035) versus healthy controls, while the pubertal group did not show significant differences in the NA versus healthy controls. LIMITATIONS: The size of the control group is relatively small, possibly limiting our power to detect significant group differences. The inter-rater reliability for the NA is not as strong as the other structures; the finding of volume differences in this structure is preliminary and warrants replication. CONCLUSIONS: Youths with BPD had larger right NA volumes; this enlargement was most pronounced in the prepubertal group. The differences between these findings and those seen in adult BPD imply a neurodevelopmental phenomenon.

Brain abnormalities in language disorders and in autism.

It has been speculated that autism and specific language impairment share common underlying neural substrates because of the overlap in language impairment issues and evidence suggesting parallels in other domains and implying a possible shared genetic risk. Anatomically the two sets of disorders have generally been studied using different methodologies, but when identical methodologies have been used substantial similarities have been noted. Functionally there is a growing body of literature suggesting sensory perception abnormalities that have parallels in both conditions and that may be upstream of language abnormalities. Finding upstream mechanisms that impact language and non-language abnormalities in autism and specific language impairment would impact the orientation taken by translational attempts to use science to design treatments.

Connecting the dots: Overlaps between autism and cancer suggest possible common mechanisms regarding signaling pathways related to metabolic alterations.

Common features between autism spectrum disorders (ASDs) and cancer have been discerned using methodologies from a number of disciplines, including genetics, bioinformatics and epidemiological studies. To understand such apparent overlaps between these two conditions and the mechanisms that may underlie these linkages, it is important to look at their multi-level systems context. Here we discuss ASDs and cancer linkages across levels ranging from genes to pathways and systems, as well as from the vantage points of mechanism and of clinical and epidemiological studies. Review of existing findings yielded evidence that ASDs and cancer overlap extensively in signal transduction pathways that are involved in metabolic processes. We hypothesize that further studies focusing on illuminating the relationships between ASDs and cancer, specifically with regard to signaling pathways that regulate metabolic activities, could help shed new insight on these conditions and develop treatment strategies that, by targeting underlying mechanisms, may be more efficient and effective for both conditions.

The role of oxidative stress, inflammation and acetaminophen exposure from birth to early childhood in the induction of autism.

The wide range of factors associated with the induction of autism is invariably linked with either inflammation or oxidative stress, and sometimes both. The use of acetaminophen in babies and young children may be much more strongly associated with autism than its use during pregnancy, perhaps because of well-known deficiencies in the metabolic breakdown of pharmaceuticals during early development. Thus, one explanation for the increased prevalence of autism is that increased exposure to acetaminophen, exacerbated by inflammation and oxidative stress, is neurotoxic in babies and small children. This view mandates extreme urgency in probing the long-term effects of acetaminophen use in babies and the possibility that many cases of infantile autism may actually be induced by acetaminophen exposure shortly after birth.

Auditory processing in noise is associated with complex patterns of disrupted functional connectivity in autism spectrum disorder.

Autism spectrum disorder (ASD) is associated with difficulty in processing speech in a noisy background, but the neural mechanisms that underlie this deficit have not been mapped. To address this question, we used magnetoencephalography to compare the cortical responses between ASD and typically developing (TD) individuals to a passive mismatch paradigm. We repeated the paradigm twice, once in a quiet background, and once in the presence of background noise. We focused on both the evoked mismatch field (MMF) response in temporal and frontal cortical locations, and functional connectivity with spectral specificity between those locations. In the quiet condition, we found common neural sources of the MMF response in both groups, in the right temporal gyrus and inferior frontal gyrus (IFG). In the noise condition, the MMF response in the right IFG was preserved in the TD group, but reduced relative to the quiet condition in ASD group. The MMF response in the right IFG also correlated with severity of ASD. Moreover, in noise, we found significantly reduced normalized coherence (deviant normalized by standard) in ASD relative to TD, in the beta band (14-25 Hz), between left temporal and left inferior frontal sub-regions. However, unnormalized coherence (coherence during deviant or standard) was significantly increased in ASD relative to TD, in multiple frequency bands. Our findings suggest increased recruitment of neural resources in ASD irrespective of the task difficulty, alongside a reduction in top-down modulations, usually mediated by the beta band, needed to mitigate the impact of noise on auditory processing. Autism Res 2016,. © 2016 International Society for Autism Research, Wiley Periodicals, Inc. Autism Res 2017, 10: 631-647. © 2016 International Society for Autism Research, Wiley Periodicals, Inc.

Adjustment for whole brain and cranial size in volumetric brain studies: a review of common adjustment factors and statistical methods.

In this article we address analytic challenges inherent in brain volumetrics (i.e., the study of volumes of brains and brain regions). It has sometimes been assumed in the literature that deviations in regional brain size in clinical samples are directly related to maldevelopment or pathogenesis. However, this assumption may be incorrect; such volume differences may, instead, be wholly or partly attributable to individual differences in overall dimension (e.g., for head, brain, or body size). What quantitative approaches can be used to take these factors into account? Here, we provide a review of volumetric and nonvolumetric adjustment factors. We consider three examples of common statistical methods by which one can adjust for the effects of body, head, or brain size on regional volumetric measures: the analysis of covariance, the proportion, and the residual approaches. While the nature of the adjustment will help dictate which method is most appropriate, the choice is context sensitive, guided by numerous considerations-chiefly the experimental hypotheses, but other factors as well (including characteristic features of the disorder and sample size). These issues come into play in logically framing the assessment of putative abnormalities in regional brain volumes.

Pathway Network Analyses for Autism Reveal Multisystem Involvement, Major Overlaps with Other Diseases and Convergence upon MAPK and Calcium Signaling.

We used established databases in standard ways to systematically characterize gene ontologies, pathways and functional linkages in the large set of genes now associated with autism spectrum disorders (ASDs). These conditions are particularly challenging--they lack clear pathognomonic biological markers, they involve great heterogeneity across multiple levels (genes, systemic biological and brain characteristics, and nuances of behavioral manifestations)-and yet everyone with this diagnosis meets the same defining behavioral criteria. Using the human gene list from Simons Foundation Autism Research Initiative (SFARI) we performed gene set enrichment analysis with the Kyoto Encyclopedia of Genes and Genomes (KEGG) Pathway Database, and then derived a pathway network from pathway-pathway functional interactions again in reference to KEGG. Through identifying the GO (Gene Ontology) groups in which SFARI genes were enriched, mapping the coherence between pathways and GO groups, and ranking the relative strengths of representation of pathway network components, we 1) identified 10 disease-associated and 30 function-associated pathways 2) revealed calcium signaling pathway and neuroactive ligand-receptor interaction as the most enriched, statistically significant pathways from the enrichment analysis, 3) showed calcium signaling pathways and MAPK signaling pathway to be interactive hubs with other pathways and also to be involved with pervasively present biological processes, 4) found convergent indications that the process "calcium-PRC (protein kinase C)-Ras-Raf-MAPK/ERK" is likely a major contributor to ASD pathophysiology, and 5) noted that perturbations associated with KEGG's category of environmental information processing were common. These findings support the idea that ASD-associated genes may contribute not only to core features of ASD themselves but also to vulnerability to other chronic and systemic problems potentially including cancer, metabolic conditions and heart diseases. ASDs may thus arise, or emerge, from underlying vulnerabilities related to pleiotropic genes associated with pervasively important molecular mechanisms, vulnerability to environmental input and multiple systemic co-morbidities.

Large brains in autism: the challenge of pervasive abnormality.

The most replicated finding in autism neuroanatomy-a tendency to unusually large brains-has seemed paradoxical in relation to the specificity of the abnormalities in three behavioral domains that define autism. We now know a range of things about this phenomenon, including that brains in autism have a growth spurt shortly after birth and then slow in growth a few short years afterward, that only younger but not older brains are larger in autism than in controls, that white matter contributes disproportionately to this volume increase and in a nonuniform pattern suggesting postnatal pathology, that functional connectivity among regions of autistic brains is diminished, and that neuroinflammation (including microgliosis and astrogliosis) appears to be present in autistic brain tissue from childhood through adulthood. Alongside these pervasive brain tissue and functional abnormalities, there have arisen theories of pervasive or widespread neural information processing or signal coordination abnormalities (such as weak central coherence, impaired complex processing, and underconnectivity), which are argued to underlie the specific observable behavioral features of autism. This convergence of findings and models suggests that a systems- and chronic disease-based reformulation of function and pathophysiology in autism needs to be considered, and it opens the possibility for new treatment targets.