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.2010 Dec 21:4:224.
doi: 10.3389/fnhum.2010.00224. eCollection 2010.

The intense world theory - a unifying theory of the neurobiology of autism

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The intense world theory - a unifying theory of the neurobiology of autism

Kamila Markram et al. Front Hum Neurosci..

Abstract

Autism covers a wide spectrum of disorders for which there are many views, hypotheses and theories. Here we propose a unifying theory of autism, the Intense World Theory. The proposed neuropathology is hyper-functioning of local neural microcircuits, best characterized by hyper-reactivity and hyper-plasticity. Such hyper-functional microcircuits are speculated to become autonomous and memory trapped leading to the core cognitive consequences of hyper-perception, hyper-attention, hyper-memory and hyper-emotionality. The theory is centered on the neocortex and the amygdala, but could potentially be applied to all brain regions. The severity on each axis depends on the severity of the molecular syndrome expressed in different brain regions, which could uniquely shape the repertoire of symptoms of an autistic child. The progression of the disorder is proposed to be driven by overly strong reactions to experiences that drive the brain to a hyper-preference and overly selective state, which becomes more extreme with each new experience and may be particularly accelerated by emotionally charged experiences and trauma. This may lead to obsessively detailed information processing of fragments of the world and an involuntarily and systematic decoupling of the autist from what becomes a painfully intense world. The autistic is proposed to become trapped in a limited, but highly secure internal world with minimal extremes and surprises. We present the key studies that support this theory of autism, show how this theory can better explain past findings, and how it could resolve apparently conflicting data and interpretations. The theory also makes further predictions from the molecular to the behavioral levels, provides a treatment strategy and presents its own falsifying hypothesis.

Keywords: NMDA; amygdala; animal model; attention; autism; connectivity; emotion; glutamate; memory; neocortex; neural circuitry; perception; plasticity; valproic acid.

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Figures

Figure 1
Figure 1
Hyper-reactivity and hyper-connectivity in VPA-treated offspring. Depicted are schematic neural microcircuits from control (top) and VPA-treated offspring (bottom). Brain slices were electrically stimulated through multiple stimulation electrodes underneath the slice – a multi-electrode array. The responsiveness to this network stimulation was recorded from individually patched cells. In comparison to controls, neurons from VPA-treated offspring were excessively reacting to the stimulation as depicted in the exemplary voltage traces. Further examination by recording from pairs of neurons revealed that this hyper-reactivity was due to the excessive connectivity in VPA-treated microcircuits (schematically depicted by the red half-circles). The connection probability was increased by approximately 50% in microcircuits from VPA-treated offspring.
Figure 2
Figure 2
Cellular hyper-plasticity in VPA-treated offspring. Long-term potentiation (LTP) is increased in neurons from VPA-treated offspring as compared to controls. The graphs depict the percentual increase in response amplitude recorded from neurons before and after a strong electrical stimulation. Increases are at least two to four times higher in VPA-treated offspring than controls across all three recorded brain regions, the somatosensory cortex (S1), the medial prefrontal cortex (mPFC) and the lateral amygdala. Results rearranged from original research articles (Rinaldi et al., , ; Markram et al., 2008), with permission fromPNAS,Neurospychopharmacology, andFrontiers in Neural Circuits.
Figure 3
Figure 3
Microcircuit hyper-plasticity in VPA-treated offspring. Depicted are schematic neural microcircuits from control (top) and VPA-treated offspring (bottom). In this experiment, brain slices were perfused for 12 h with a glutamate solution in order to stimulate the circuits and induce rewiring of connections (red and blue half-circles). The connectivity probability between neurons was accessed before (left panels) and after (right panels) the glutamate stimulation. In controls, the connection probability increased significantly within a range of less than 50 μm (red half-circles), which is the mini-columnar range, but did not change in ranges higher than 50 μm (measured up to 200 μm, blue half-circles), which is a columnar range. In VPA-treated offspring, the connections probability was already increased within the short mini-columnar range (below 50 μm, red half-circles) before the glutamate stimulation and did not increase any further after the stimulation (right panel), because the connection capacity was already boosted and probably saturated to a maximum at baseline levels. Indeed, controls only reached a similarly high connectivity probability within the mini-columnar range as VPA-treated offspring already exhibited at baseline levels after the 12 h stimulation was applied. However, in VPA-treated offspring, the connectivity probability increased significantly at ranges above 50 μm (right panel, blue half-circles), revealing a further remarkable rewiring capacity at the columnar range due to stimulation – a feature “normal” control microcircuits did not exhibit.
Figure 4
Figure 4
Enhanced fear memories in VPA-treated offspring. Offspring of VPA-treated dams exhibits normal fear conditioning during training, but enhanced fear memories to the tone and context 1, 30, and 90 days after training, with the differences becoming more pronounced with time. Results rearranged from original research article (Markram et al., 2008) with permission ofNeurospychopharmacology.
Figure 5
Figure 5
The hyper-functional circuits in autism. As suggested by theIntense 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.
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