Monday, November 18, 2013

Asperger's Syndrome Associated with Hyperconnectivity in the Brain - May Result in TOO Much Empathy

Two new studies in the recent issue of Cell Reports document that in those people with Asperger's Syndrome, a high-functioning form of autism, the brain exhibits hyperconnectivity between neurons and not too little connectivity as once thought.
Hyperconnectivity in Children with Autism

The brains of children with autism show more connections than the brains of typically developing children do. What's more, the brains of individuals with the most severe social symptoms are also the most hyper-connected. The findings reported in two independent studies published in the Cell Press journal Cell Reports on Nov. 7 are challenge the prevailing notion in the field that autistic brains are lacking in neural connections. [Cell Reports, Keown et al]
This is an important confirmation of research I read years ago that suggests Asperger's and some other autism-spectrum disorders (ASD) may result from inadequate neural or synaptic pruning in the post-infant years of life (by age two, we have more neurons than we will have at any other time in our lives, with 50% of those being pruned by the time we reach sexual maturity [although it may continue into our 20s]).

More importantly, this may be an important step in proving the Intense World Theory (IWT, formerly the Intense World Syndrome) of autism-spectrum disorders, which posits that ASDs are not the result of inadequate neural connectivity but, rather, an issue of hyperconnectivity. Some people on this spectrum, particularly those with Asperger's Syndrome and high-functioning autism (HFA), do not lack empathy, but instead may feel too deeply.

The IWT model suggests a genetic aspect to the hyperconnectivity that makes neurons more highly sensitive to stimuli. Here is a basic summary of the IWT developed by Kamila and Henry Markram in their 2010 Frontiers in Human Neuroscience paper, "The Intense World Theory – a unifying theory of the neurobiology of autism."
The experimentally based and common neuropathology proposed in the Intense World Theory is hyper-functioning of elementary brain modules, called local neural microcircuits, which are characterized by hyper-reactivity and hyper-plasticity, both of which seem to be caused by a tendency for excitatory neurons to dominate their neighbors. Such hyper-functional microcircuits are proposed to easily become autonomous, leading to runaway information processing, over-specialization in tasks and a hyper-preference syndrome. The proposed core cognitive consequences are hyper-perception, hyper-attention, hyper-memory, functions mediated by the neocortex, and hyper-emotionality, mediated by the hyper-functionality of the limbic system. These four dimensions could potentially explain the full spectrum of symptoms in autism, depending on the severity of the microcircuit pathology in different brain regions. The degree of hyper-functionality in different brain regions could vary in each child depending on genetic personality traits, on unique epigenetic conditions, and unique sequence of postnatal experiences.
This new research seems to suggest the lack of neural pruning model may be more explanatory. The excessive neural and synaptic connections could possibly result in the

Personal Experience

I test high on various Asperger's scales, but I have always been told that I can't have Asperger's because I do not lack empathy nor theory of mind. Here's a quick definition from Wikipedia:
Theory of mind (often abbreviated "ToM") is the ability to attribute mental states—beliefs, intents, desires, pretending, knowledge, etc.—to oneself and others and to understand that others have beliefs, desires, and intentions that are different from one's own.[1] Deficits occur in people with autism spectrum disorders, schizophrenia, attention deficit hyperactivity disorder,[2] as well as neurotoxicity due to alcohol abuse.[3] Though there are philosophical approaches to issues raised in discussions such as this, the theory of mind as such is distinct from the philosophy of mind.
As a child I had some of the common issues of Asperger's children, including language delays followed by proficiency (could not read until 2nd grade, but I was reading at a high school level in 4th grade), clumsiness (baseball was nearly impossible at first, and I once fell 40 feet out of a tree), social awkwardness (a function of poor social learning - social mores have always been a mystery to me), obsessive immersion in interests (I have been called a walking encyclopedia), and a tendency to miss humor or teasing (I am often hyper-literal).

A lot of these issues were very difficult because most Asperger's children want desperately to fit in and be accepted. I discovered pretty early that chemicals could take the edge off of my social anxiety (resulting from the need to fit and not doing so), particularly alcohol. On the other hand, smoking marijuana made me intensely, overwhelmingly aware of the emotional subtext in communication, to the point of feeling almost paralyzed by that awareness. I could not get stoned with other people and enjoy the experience.

That incredible degree of empathy is something that I had learned to silence in much of my life, or at least to ignore. Frequent marijuana use as a teen and then a five-year or so infatuation with LSD, psilocybin (mushrooms), and mescaline (peyote cactus) took away the ability to turn off the sensitivity to emotions, but it also taught me that I can control my experience.

It has only been the last couple of days that I have become aware of the Intense World Theory of Asperger's and have been integrating that concept into my own experience (of which this post is a part). I have having to change how I think of myself in many ways.

For example, many people with Asperger's exhibit traits that resemble obsessive-compulsive personality disorder (not the Axis I version with rituals - the compulsion part), such as a need for idiosyncratic organization, preferences for specific items (for me it's pens and specific dishes or silverware at home), or a need to categorize things

Anyway, below there is the introduction to Cell Reports on the two Asperger's studies, followed by the abstracts of the studies (both are open access, just follow the title or doi link), and finally, excerpts from and a link to a paper on the Intense World Theory of ASD from 2010.

Convergent Evidence of Brain Overconnectivity in Children with Autism?

Jeffrey David Rudie, Mirella Dapretto

Cell Reports, Volume 5, Issue 3, 565-566, 14 November 2013
doi: 10.1016/j.celrep.2013.10.043

In this issue of Cell Reports, two articles (Keown et al., 2013,Supekar et al., 2013) describe the results of advanced neuroimaging methods used to analyze intrinsic functional brain connectivity in children with autism spectrum disorder (ASD). Although the approaches are quite different, both groups used robust methods to provide a more comprehensive understanding of functional brain organization in ASD. They report that both long- and short-range intrinsic connectivity was increased across multiple brain networks in young children with ASD and that increased connectivity was associated with more severe social deficits. These studies stand in contrast to multiple prior reports of underconnectivity in ASD, suggesting that disrupted brain connectivity in ASD may be dependent on altered age-related trajectories. Critically, the extent to which aberrant patterns of brain connectivity may cause ASD symptomatology instead of resulting from it remains to be determined.

Early studies of brain connectivity in ASD linked widespread underconnectivity to higher-level cognitive deficits observed in autism (e.g., Just et al., 2004). However, these initial reports examined functional connectivity during cognitive tasks. More recent work has used resting-state functional connectivity MRI (rs-fcMRI) to map spontaneous low-frequency fluctuations within cognitive networks that are independent of task performance (and related confounds). These studies have mostly focused on specific networks (i.e., the default mode network) and have generally found reduced long-range connectivity in ASD (see Vissers et al., 2012, for review). Relatively few studies have implemented advanced whole-brain methods for analyzing functional connectivity in ASD (Anderson et al., 2011,Rudie et al., 2013,Di Martino et al., 2013). Importantly, closer methodological scrutiny is now required, given the recent controversy regarding the effects of motion confounds, whereby not appropriately correcting for head motion can lead to both spurious increases in local connectivity and reductions in long-range connectivity (i.e., Power et al., 2012). Thus, it is important to note that both studies previewed here used advanced motion-correction techniques and addressed other major methodological concerns (i.e., global signal regression).

In Keown et al., 2013, the authors focused on local connectivity in adolescents with ASD. Several groups have hypothesized that enhanced local circuit connectivity may provide an explanation for the preservation or enhancement of certain cognitive functions in ASD, such as visual or auditory discrimination (e.g., Geschwind and Levitt, 2007). However, few studies have comprehensively addressed whole-brain local connectivity in ASD. By using methods developed from graph theory, Keown et al., 2013 used rs-fcMRI to compute whole-brain maps of local connectivity. They compared these maps between youths with and without ASD (mean age = 13.8 years) and reported an anterior-posterior gradient of local under- to overconnectivity in ASD. Specifically, occipitotemporal regions showed diffuse overconnectivity in ASD, which was more pronounced in individuals with more severe social deficits, whereas reduced local connectivity was found in frontal regions and was more pronounced in ASD adolescents with less severe social impairments.

In Supekar et al., 2013, the authors used a systematic whole-brain connectivity approach to analyze intrinsic brain connectivity in younger children with ASD (mean age = 10.1 years). By implementing several parcellation schemes and rigorous motion correction techniques, they reported that connectivity was diffusely increased in ASD both within and between different brain networks. This was observed regardless of physical distance, such that both short- and long-range connections were stronger in ASD. Furthermore, they reported that the amount of overconnectivity was associated with increasing levels of social deficits in ASD and replicated both main findings in two additional samples. Interestingly, they also reported that increased connectivity was related to abnormally high amplitudes of low-frequency fluctuations, which they hypothesized to be related to an imbalance of excitation to the inhibition in the brains of children with ASD.

These new findings are not entirely consistent with other recent whole-brain connectivity studies in ASD, although there appears to be more agreement with regards to the findings of Keown et al., 2013. The most relevant data come from a study reporting the establishment of the Autism Brain Imaging Data Exchange (ABIDE), a database which include rs-fcMRI data collected in ASD and neurotypical individuals at 20 different sites (including data from both studies previewed here) (Di Martino et al., 2013). Here, the authors performed several whole-brain connectivity analyses in a sample of over 700 subjects, including analyses of regional homogeneity as a measure of local connectivity. Remarkably, they also found an anterior-posterior gradient of under- to overconnectivity in ASD, similar to what was observed by Keown et al., 2013. Thus, consistent reports of local connectivity alterations in ASD lend support to the hypothesis that increased local connectivity in occipitotemporal regions may be related to islets of superior functioning in sensory systems, whereas reduced local connectivity in frontal regions may relate to disrupted social behavior.

As far as more global connectivity analyses, the findings of Supekar et al., 2013 appear to directly contradict those of Di Martino et al., 2013, who reported widespread reductions in connectivity across multiple systems (except for increased connectivity between primary sensory and subcortical regions). Two other previous studies (Anderson et al., 2011,Rudie et al., 2013) using whole-brain approaches to characterize intrinsic connectivity in ASD also reported widespread reductions in connectivity at both short and long distances. However, a major difference of Supekar et al., 2013 is that the study focused on younger children with ASD (mean age = 10.1) whereas the median age was 14.7 in Di Martino et al., 2013 and the mean ages in Rudie et al., 2013 and Anderson et al., 2011 were 13.5 and 22.7, respectively. This suggests the possibility that early overconnectivity in ASD may give way to underconnectivity across time, particularly at the onset of puberty. However, an rs-fcMRI study of toddlers with ASD found reduced interhemispheric connectivity at this very young age (Dinstein et al., 2011); therefore, connectivity alterations may follow an even more complicated developmental timetable. Additionally, it is important to consider methodological differences (e.g., spiral versus echo planar acquisition and wavelet transformation versus band-pass filter), given that they could have large downstream effects on connectivity data.

Altogether, the new studies by Keown et al., 2013 and Supekar et al., 2013 add considerable weight to the hyperconnectivity side of the current hypo- versus hyperconnectivity debate in ASD while also painting a more complicated story wherein age may play a critical role. It is clear that more studies are needed with younger and longitudinal cohorts in order to obtain a clearer picture of the entire developmental trajectory of altered connectivity in ASD. Lastly, given the heterogeneity of samples and methods used across studies, these new findings highlight the importance of large-scale collaborative efforts such as ABIDE, given that data sharing across multiple sites should help disentangle the impact of several key variables on brain connectivity in typical and atypical development. Continued efforts using advanced analytical approaches, as demonstrated by the studies previewed here, are necessary in order to reach the ultimate goal of using neuroimaging as a clinical biomarker to guide the diagnosis and treatment of complex neuropsychiatric disorders (Fox and Greicius, 2010).

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Full Citation:
Keown, CL, Shih, P, Nair, A, Peterson, N, Mulvey, ME, Müller, RA. (2013, Nov 14). Local Functional Overconnectivity in Posterior Brain Regions Is Associated with Symptom Severity in Autism Spectrum Disorders. Cell Reports; 5(3), 567-572. doi: 10.1016/j.celrep.2013.10.003

Local Functional Overconnectivity in Posterior Brain Regions Is Associated with Symptom Severity in Autism Spectrum Disorders

Christopher Lee Keown [1,2], Patricia Shih [3], Aarti Nair [1,4], Nick Peterson [1,5], Mark Edward Mulvey [1,2], and Ralph-Axel Müller [1,4]
1. Brain Development Imaging Laboratory, Department of Psychology, San Diego State University, San Diego, CA 92120, USA
2. Computational Science Research Center, San Diego State University, San Diego, CA 92182, USA
3. Neuroscience Department, Brown University, Providence, RI 02912, USA
4. Joint Doctoral Program in Clinical Psychology, San Diego State University and University of California, San Diego, San Diego, CA 92182, USA
5. Department of Mathematics and Statistics, San Diego State University, San Diego, CA 92182, USA

This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial-No Derivative Works License, which permits non-commercial use, distribution, and reproduction in any medium, provided the original author and source are credited.


Although growing evidence indicates atypical long-distance connectivity in autism spectrum disorder (ASD), much less is known about local connectivity, despite conjectures that local overconnectivity may be causally involved in the disorder. Using functional connectivity MRI and graph theory, we found that local functional connectivity was atypically increased in adolescents with ASD in temporo-occipital regions bilaterally. Posterior overconnectivity was found to be associated with higher ASD symptom severity, whereas an ASD subsample with low severity showed frontal underconnectivity. The findings suggest links between symptomatology and local connectivity, which vary within the autism spectrum.

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Full Citation:
Supekar, K, Uddin, LQ, Khouzam, A, Phillips, J, Gaillard, WD, Kenworthy, LE, Yerys, BE, Vaidya, CJ, and Menon, V. (2013, Nov 14). Brain Hyperconnectivity in Children with Autism and its Links to Social Deficits. Cell Reports, 5(3), 738-747.doi: 10.1016/j.celrep.2013.10.001

Brain Hyperconnectivity in Children with Autism and its Links to Social Deficits

Kaustubh Supekar [1], Lucina Q. Uddin [1], Amirah Khouzam [1], Jennifer Phillips [1], William D. Gaillard [2], Lauren E. Kenworthy [2], Benjamin E. Yerys [2,3], Chandan J. Vaidya [2,4] and Vinod Menon [1,5,6,7]
1. Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Stanford, CA 94304, USA
2. Center for Autism Spectrum Disorders, Children’s National Medical Center, Washington, DC 20010, USA
3. Center for Autism Research, The Children’s Hospital of Philadelphia, Philadelphia, PA 19146, USA
4. Department of Psychology, Georgetown University, Washington, DC 20057, USA
5. Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA 94304, USA
6. Program in Neuroscience, Stanford University School of Medicine, Stanford, CA 94304, USA
7. Stanford Institute for Neuro-Innovation and Translational Neurosciences, Stanford University School of Medicine, Stanford, CA 94304, USA
This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial-No Derivative Works License, which permits non-commercial use, distribution, and reproduction in any medium, provided the original author and source are credited.


Autism spectrum disorder (ASD), a neurodevelopmental disorder affecting nearly 1 in 88 children, is thought to result from aberrant brain connectivity. Remarkably, there have been no systematic attempts to characterize whole-brain connectivity in children with ASD. Here, we use neuroimaging to show that there are more instances of greater functional connectivity in the brains of children with ASD in comparison to those of typically developing children. Hyperconnectivity in ASD was observed at the whole-brain and subsystems levels, across long- and short-range connections, and was associated with higher levels of fluctuations in regional brain signals. Brain hyperconnectivity predicted symptom severity in ASD, such that children with greater functional connectivity exhibited more severe social deficits. We replicated these findings in two additional independent cohorts, demonstrating again that at earlier ages, the brain of children with ASD is largely functionally hyperconnected in ways that contribute to social dysfunction. Our findings provide unique insights into brain mechanisms underlying childhood autism.
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Full Citation:
Markra, K, and Markram, H. (2010, Dec 21). The Intense World Theory – a unifying theory of the neurobiology of autism. Frontiers in Human Neuroscience, 4:224. doi: 10.3389/fnhum.2010.00224

The Intense World Theory of Autism

The challenge for any unified theory of autism is to understand the common cause for the wide spectrum of autistic disorders and the autistic traits that are found in other disorders, if there is one. The Intense World Theory proposes that autistic traits could emerge if a molecular syndrome is activated that sensitizes gene expression pathways to respond excessively to environmental stimulation. Under normal conditions such pathways would enable enriched environments to nurture brain development, but if these pathways are sensitized, then environmental stimulation may cause exaggerated and accelerated development of the brain in general and the glutamatergic system of neural microcircuits in particular. Microcircuit glutamatergic hyper-functionality in the neocortex could cause hyper-perception, hyper-attention, and hyper-memory, which are proposed as the core triad of cognitive traits common to all autistic symptoms. Microcircuit hyper-functionality in the limbic system could cause hyper-emotionality adding a forth dimension that could scale the cognitive impact of the triad pathology. The severity on each of these four axes could perhaps account for autism on any part of the spectrum. The sensitivity to the environment could drive the brain to develop in a premature sequence and in a manner that enhances functionality. At its peak, the environment could become excessively intense and set in motion a systematic regression to where the brain is forced to take refuge in a highly specialized “cocoon” where extremes and surprises are actively avoided and blocked out.

The specific molecular cascade that drives hyper-functionality in brain microcircuits is not thought to be necessarily the same in different parts of the brain since there may be different ways to produce hyper-functionality in different regions and we therefore propose a common syndrome rather than a common specific molecular cascade, for all brain regions. The characteristics of the syndrome could be an exaggerated response to stimulation. In the brain, this common molecular syndrome is proposed to have a dual effect of causing hyper-reactivity and hyper-plasticity of microcircuits to produce hyper-functionality (Figure 5).


Figure 5. The hyper-functional circuits in autism. As suggested by the Intense World Theory three etiological factors (a genetic predisposition; an epigenetics attack in form of a toxic insult; environmental factors during postnatal development) cause autism by activating a molecular syndrome that may be different across different brain regions, but that leads to hyper-functional microcircuits (expressed as hyper-reactivity and hyper-plasticity) in all brain regions. Two regions known to be affected include the neocortex and amygdala and we hypothesize that other regions may be similarly affected. The consequences on cognitive processing include hyper-sensitivity, -perception, -attention, -memory, -fear, and -emotionality. We propose that this leads to an intense, fragmented, and aversive world syndrome for the autistic child, which could account for a spectrum of behavioral abnormalities.
In the neocortex, the consequences could be severe, because microcircuits lie within functional modules called neocortical columns and if these columns are hyper-functional, the delicate balance between intra- and inter-columnar processing would be upset. The approximately million neocortical columns in humans each need to be precisely excited and inhibited to coordinate higher brain functions and complex behavior. Excessive intra-columnar processing, particularly during development, could enhance the most elementary sensory, motor, and cognitive processes at the expense of being able to orchestrate “symphonies” of higher cognitive functions. With excessive learning and memory processes, sensory regions could consolidate into overspecialized modules and lead to hyper-preference processing. During early development, this may lead to excessive flow of information from sensory areas to the higher integration areas such as the association cortices and prefrontal lobe which may cause prematurely accelerated growth of these higher order brain areas, as indeed observed in autism (Courchesne et al., 2001; Carper et al., 2002), but this is only one out of several possible explanations for this phenomenon. Deficits in higher brain functions such as executive control and holistic processing may also be better explained by overly autonomous elementary modules rather than deficits in these areas or weak long-range connectivity. Indeed, structural MRI indicates higher levels of white matter in the cerebrum and cerebellum in young children with autism (Courchesne et al., 2001; Carper et al., 2002), which – in the light of the Intense World Theory – could be interpreted as a compensatory action to coordinate excessive activity in columns within and between different brain areas.

More specifically, each neocortical column is known to be involved in processing multiple features of stimuli. In the visual cortex for example, such features include the orientation, spatial frequency, contrast or color (Hubel and Wiesel, 1962; Tootell et al., 1981). The emphasis that each column must place on processing the different features is carefully crafted to allow the neocortex to simultaneously specialize in processing many different features locally and generalize in combining features globally. Hyper-reactivity and hyper-plasticity could act synergistically during experiences to enhance sensitivity to features and consolidate memories of features processed. Selective feature sensitivity would more easily allow specific features to trigger column processing, but could make it more difficult to activate other features (and tasks) and to interrupt any processing, once started. Overly strong consolidation of memories of the processing of features in development could also rapidly lead to dominance of the earliest features (“impressions”) and avoidance of processing of other features (manifesting in higher thresholds). Such hyper-autonomous and overly selective columns could make bottom-up control of the activation of columns from the thalamus and top-down control from higher associational areas more difficult leaving the neocortex fragmented into independent modules that are difficult to control and coordinate – an exaggerated and runaway response to stimulation.

Hyper-preference processing in the sensory domain could lead to exaggerated selectivity, sensitivity, and specialization of sensory features and hence hyper-perception, while hyper-preference processing in cognitive processing in general could lead to hyper-attention and in the memory domain, to hyper-memory. Therefore, the degree of hyper-preference processing in neocortical regions, areas and columns and the normal variation of individuals, could contribute a spectrum of autistic traits all manifesting as part of an Intense World Syndrome.

The molecular syndrome, however, also seems to extend beyond the neocortex. While in the neocortex this drives hyper-functionality by hyper-connecting neighboring neurons to produce excessive excitation and by hyper-expressing NMDA receptors to produce excessive plasticity, in the amygdala inhibition is also reduced. The amygdala contains relatively higher numbers of inhibitory interneurons than in the neocortex and reducing inhibition may be more effective in causing hyper-functionality than hyper-connecting through glutamatergic synapses. Hyper-functionality in the amygdala (and related emotion centers) could add a very important hyper-emotional dimension to the triad pathology to render the already intense world progressively more painful and aversive with each experience leading to a progressive lock down and social withdrawal.

While the Intense World Theory is primarily based on experimental data derived from the neocortex and the amygdala, we do not exclude that the same molecular syndrome driving hyper-reactivity and hyper-plasticity could be active in other structures of the forebrain or the mid- and hindbrain as well. For example, it is well established that the cerebellum is strongly affected in autism with decreased numbers of the inhibitory Purkinje cells (Ritvo et al., 1986; Bailey et al., 1998; Bauman and Kemper, 2005), which would predict hyper-reactivity. It is also known that there are increased white matter volumes (Courchesne et al., 2001) which would increase activation of brain regions from other regions. Indeed, others already postulated a disinhibition of the cerebellum that would lead to increased reactivity and could alter connectivity not only within the cerebellum, but also across the cerebello-thalamo-corticial circuits (Carper and Courchesne, 2000; Belmonte et al., 2004b; Boso et al., 2010).

In summary, autonomously acting hyper-functional microcircuits in the neocortex may cause exaggerated perception to fragments of a sensory world that must normally be holistically processed, and may cause hyper-focusing on fragments of the sensory world with exaggerated and persistent attention. This hyper-attention could become difficult to shift to new stimuli due to the difficulty for bottom-up and top-down mechanisms to coordinate the overly autonomous low-level neocortical columns. The hyper-plasticity component may also drive exaggerated memories to further amplify hyper-attention toward the same stimulus and drive over-generalization of attention to all related forms of the stimulus. The positive consequences are exceptional capabilities for elementary and specific tasks while the negative consequences are impairment of holistic processing, a rapid lock to a limited repertoire of behavioral routines, which are then repeated obsessively.

As a consequence the autistic person would remain with a fragmented and amplified perception of bits and pieces of the world. The intense world that the autistic person faces could also easily become aversive if the amygdala and related emotional areas are significantly affected with local hyper-functionality. The lack of social interaction in autism may therefore not be because of deficits in the ability to process social and emotional cues, but because a sub-set of cues are overly intense, compulsively attended to, excessively processed and remembered with frightening clarity and intensity. Typical autistic symptoms, such as averted eye gaze, social withdrawal, and lack of communication, may be explained by an initial over-awareness of sensory and social fragments of the environment, which may be so intense, that avoidance is the only refuge. This active avoidance strategy could be triggered at a very early stage in a child’s development and could progress rapidly with each experience manifesting as a regression, which is striking in some cases. With such early over-specialization, many other important elementary certain skills may never be properly developed to enable normal navigation in a socially rich world with an appropriate understanding of social cues and communication. As already stated by other authors (for example Frith, 2003) “autism affects development, and in turn development affects autism” (p. 2). Compiling higher order functions such as abstract thought and language when the elementary alphabet of features is so overly attended to may become difficult if not impossible in severe cases.
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Predictions of the Intense World Theory

The Intense World Theory is not only consistent with a large number of previous studies, and has the explanatory power to reconcile a large number of apparently contradictory data and interpretations, but also has significant predictive power because it is grounded at the molecular, cellular and circuit levels. The set of some testable predictions derived from the Intense World Theory are listed below.


• Circuit level:

○ Some level of hyper-reactive and hyper-plastic circuits in all brain regions. This can be tested by progressively increasing the intensity of multi-site stimulation of a brain region. The molecular, synaptic, and cellular causes may differ in different regions.
○ The loss of inhibition and hence hyper-reactivity also in sub-cortical regions where inhibitory neurons are more prominent such as in the cerebellum.
• System level:
The variance, as opposed to the mean, of the pixel intensities in fMRI measures should be higher in autistic subjects with the upper and lower intensities being greater than in neurotypical subjects. Higher upper pixel intensities may even be present in under-activated brain regions. These predictions would best be tested using fMRI at the highest spatial resolution.
Enhanced low-level feature processing in primary sensory brain regions. This could manifest in greater peaks in some tuning curves for different features as well as lower detection thresholds.
• Cognitive and emotional levels:
○ Highly idiosyncratic stimulus preference to activate brain areas, which should become more idiosyncratic with progression of the disorder.
○ Vulnerability to sensory overflow. Consequential behavior would be panic, aggression, and withdrawal as already suggested by anecdotal reports.
• Associated Pathologies:
○ A lower threshold for stimulus-induced epilepsy (such as stroboscopically induced epilepsy).
○ Neglect syndrome.
○ Learning impairments correlated to the degree and variance of associations required.
○ Panic attacks and phobias triggered by uniquely personal situations (as originally noted by Leo Kanner).
○ Post-traumatic stress disorder.


• Circuit level:

○ Abnormally high levels of persistent reverberant activity within circuits that is difficult to interrupt.
• Systems level:
○ Amplified neocortical response during thalamic stimulation.
○ Abnormally high degree of synchronization between the mPFC with some brain regions and abnormally low synchronization, with other regions.
○ Abnormally high tendency for phase locking with smaller phase lags indicating a higher degree of oscillations and coherence across those brain areas engaged.
• Cognitive level:
○ Enhanced sustained attention to material of interest (as anecdotally reported).
○ Once attention is captured, impaired shifting of attention to different features or tasks, because of internal hyper-processing (as also suggested by the difficulty to engage the attention of an autistic child).
○ Attention to arbitrary fragments related strongly to early life experiences.
○ Strongly enhanced focused on internal processes.
• Associated Pathologies:
○ Attention deficit disorder (ADD) or Attention deficit hyperactivity disorder (ADHD).
○ Learning impairments in some cases and super-learning in others.
○ May seem distracted and disengaged, but are actually hyper-focused on internal processes.


• Molecular:

○ Enhanced NMDA receptor subunit expression in the neocortex. Alterations in the adult, after critical periods, may be absent and increases may still be observable following stimulation.
○ Other markers associated with synaptic plasticity may follow a similar pattern as some NMDA receptor subunits.
• Cellular:
○ NMDA mediated Ca2+ toxicity in adult and aged autistics. This will have consequences for the enhanced learning and memory postulate of the Intense World Theory, which may be less pronounced in aged autistics.
• Cognitive level:
○ Strong imprint of early life experiences and learning material, which is highly resistant to extinction and dominates over new learning challenges. E.g., this could potentially show in high interference in learning semantic material.
○ Enhanced simple associative learning (conditioning), which is resistant to extinction. This should be particularly well observable early in life. Later in life strong early life memory traces will over-shadow further learning attempts.
○ Learning impairments are predicted for all negatively associated stimuli and resistance to rehabilitation is predicted because of fear of previous negative associations. The Intense World Theory predicts that all children with autism will display greater than average memory performance for the tasks that the autistic has chosen as non-threatening.
○ Enhanced learning and memory should be most observable in very young autistic children and less so in progressively older autistics. In elderly autistics – due to the neurotoxicity effects of enhanced NMDA signaling throughout in particular the early lifespan – learning and memory impairments may become more evident.
• Related Pathologies:
○ Idiosyncratic, albeit exceptional memory capabilities.
○ Repetitive tendencies.
○ Obsession compulsive disorder.
○ Stronger and more persistent memories following conditioning.
○ Behavioral inflexibility.


• Cellular:

○ Cell toxicity in brain areas that are easily excitable such as the amygdala and hippocampus due to over-excitation.
• Circuit:
○ Hyper-reactive and hyper-plastic amygdala and other limbic structures.
• Systems:
○ Enhanced amygdala activation when autistics are instructed by teachers or parents.
○ Enhanced amygdala activation when autistics view eyes, faces or social scenes.
○ Enhanced sympathetic responses to social content such as eyes, faces, social situations etc. This could be tested with measures of the autonomic system, such as skin conductance, heart measures or stress and anxiety hormone levels.
○ Enhanced sympathetic responses to novel and sensory rich situations.
○ Enhanced sympathetic responses to negatively associated stimuli.
• Cognitive level:
○ Enhanced fear conditioning in autistics – most pronounced in young children.
○ Enhanced generalization of fear responses to similar content.
○ Resistance to fear extinction.
○ Enhanced active avoidance of fear-associated material.
○ Enhanced active avoidance of high-emotion content such as eyes, emotional faces, social encounters.
○ Enhanced active avoidance of novel environments is predicted due to fear of surprises that arise from over-generalization of previous negative associations.
○ At the behavioral level unpredictable, exaggerated, extreme, and inappropriate reactions to surprising situations.
• Associated Pathologies:
○ Anxiety.
○ Panic attacks and phobias.
○ Post-traumatic stress disorder.
○ Paranoia.
○ Depression.
○ Hyper-emotionality.
○ Behavioral inflexibility.
○ Repetitive tendencies.

Psychological Scores

• The Intense World Theory predicts higher variance in any set of scores from a large psychophysical test battery as compared to controls with the highest and lowest scores. In particular, since columns are hyper-reactive, but highly selective, the reaction times to a battery of tests should display a higher variance with the longest and shortest reaction times. The theory predicts that the key parameter to measure is the variance of performance on different scores rather than focusing on any one task, on absolute values, or on the average performance of many tasks. The theory predicts the same high variance characteristic for cognitive profiling.

• High measures of variance on cognitive battery tests should be independent of intelligence, but due to the proposed highly idiosyncratic feature over-selectivity of neural columns.

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