the Blue Brain Project team :-)
Autism is a devastating neurodevelopmental disorder with a polygenetic predisposition that seems to be triggered by multiple envi ronmental factors during embryonic and/or early postnatal life. While significant advances have been made in identifying the neuronal structures and cells affected, a unifying theory that could explain the manifold autistic symptoms has still not emerged. Based on recent synaptic, cellular, molecular, microcircuit, and behavioral results obtained with the valproic acid (VPA) rat model of autism, we propose here a unifying hypothesis where the core pathology of the autistic brain is hyper-reactivity and hyper-plasticity of local neuronal circuits. Such excessive neuronal processing in circumscribed circuits is suggested to lead to hyper-perception, hyper-attention, and hyper-memory, which may lie at the heart of most autistic symptoms. In this view, the autistic spectrum are disorders of hyper-functionality, which turns debilitating, as opposed to disorders of hypo-functionality, as is often assumed. We discuss how excessive neuronal processing may render the world painfully intense when the neocortex is affected and even aversive when the amygdala is affected, leading to social and environmental withdrawal. Excessive neuronal learning is also hypothesized to rapidly lock down the individual into a small repertoire of secure behavioral routines that are obsessively repeated. We further discuss the key autistic neuropathologies and several of the main theories of autism and re-interpret them in the light of the hypothesized Intense World Syndrome.
'But, Hanu, everything dies,' Danlo said softly. He turned to face the scarred, old shih tree, and he pressed his forehead against it. When he looked up, he felt the zig-zag mark where the tree's icy bark had cut into his skin. Hanuman shook his head and continued, 'But why die at all, Danlo? Mightn't there be a new phase of evolution? A new kind of being? Can't you understand?[1] I'm trying to delineate an emergent quality of the brain. New synapses. New connections. A constellation of qualities and abilities, of new levels of existence. Consciousness heightened and exalted in itself, purified. This pure consciousness that we really are. That we struggle to be. For our kind, there's always the burning to be more. The eternal longing. And this is why true human beings feel more pain. Because we are more, but it's never quite enough – never. And we are aware of this neverness inside our souls. And aware of being aware. There is a feedback. Can you understand what this is like? Pain is magnified, infinitely. Each moment of time. Reality becomes almost too real. It blazes. All the universe afire with the possibilities of light, and madness, too. Real pain is the burning that never stops, the frenzy, the lightning.'Minicolumns, genius and autism; the research being reported in the a-shade-of-grey blog article is from Casanova (m0casa02@louisville.edu) (Wp) (researcher), studying the minicolumnar basis of the hierarchical temporal memory (HTM) (cite Jeff Hawkings / On Intelligence) structure of the brain, based on the organization of minicolumns into macrocolumns. In autism, the size of the minicolumn is reduced, the density of the neurons increased, and the number of minicolumns per macrocolumn is therefore increased. This is interesting because a minicolumn is like a processing node, looping back into itself and transferring signals over to neighboring minicolumns, while also up-propagating information. In the linked blog article, it is suggested that too little insulation due to the high density, small neurons can cause amplification of thalamic (sensory) input and even seizures in some of the cases of autism+epilepsy. With the decreased size of the neurons plus increased number of neurons packed into the additional microcolumns, it is more energetically favorable to have short-distance connections due to metabolic constraints. The longer the axon or the dendrite, the more overhead metabolism has to go to the soma of the neuron, and with an increase in the number of neurons, it is simply more favorable to maintain a higher saturation of local connections rather than long-distance connections. Because the minicolumns are smaller and more dense, local information processing is favored, such as the self-referential information that doesn't require long-distance information passing, so there's lots of complex information processing. In some other articles that I have been reading today there was the suggestion that top-down management of information is more complicated in an autist's brain, therefore they shut down and get away from sensory so that they can exert control on the wildly divergent, autonomous and hyperactive minicolumns. The shut-down reaction where autists clamp down all of their senses and do their recursions and perseverations is an attempt to demand control over all of those hyperactive information processing subunits. In "Comparison of the Minicolumnar Morphometry of Three Distinguished Neuroscientists and Controls", 'supernormals' (distinguished polymath-neuroscientists) are shown to have characteristics found in autism and Asperger's but with interpersonal skills. Reduced mean cell spacing (MCS) in neuroscientists v. autists, and the neuroscientists had clustering around the (dimensional/orientation) axis of the minicolumns. Previously, it was assumed that multidimensional cognitive processing involved flexible networks across the entire brain, rather than the more discrete, digital view that the imaging of the neuroscientists found within themselves.
"Spindle cells appear to play a central role in the development of intelligent behavior and adaptive response to changing conditions and cognitive dissonance. They emerge postnatally [emphasis added] and eventually become widely connected with diverse parts of the brain, evidencing their essential contributions to the superior capacity of hominids to focus on difficult problems." Spindle neurons are known to be found in reduced numbers in those with ASD. Perhaps they helped the neuroscientists compensate for – and even exploit the benefits of – the bias towards local processing inherent in reduced width minicolumns?- autism acquisition within the first 40 days of fetal development?
The genesis of minicolumns, their total number and constituent cells, is defined during brain development. Symmetrical divisions of germinal cells provide for the total number of minicolumns (Rakic & Kornack, 2001). A second phase of asymmetrical divisions provides for daughter cells that migrate into the cortex along radial scaffoldings with successive divisions accounting for the total number of cells within each minicolumn. Rakic and Kornack have enumerated a number of defining events that can alter minicolumnar phenotype (Rakic & Kornack, 2001):
Another component of minicolumns are various types of GABAergic inhibitory interneurons (i.e. neurons that produce GABA as their neurotransmitter), which tend to be aligned one on top of the other and modulate the activity of minicolumn pyramidal cells. Double bouquet cells are present in all layers, but are most dense in layers 2 and 3. The axon bundles (long projections that conduct electrical impulses away from the cell body) of these cells are projected deep into the cortex from layer 2 to layer 5, terminating on pyramidal cells as well as other inhibitory interneurons. They create a narrow vertical stream of inhibition through the cortex, as well as a vertically directed disinhibition of those pyramidal cells upon which the other inhibitory interneurons project. Other interneurons include Chandelier cells [GABAergic fast spiking parvalbumin-containing cortical interneurons with cartridge-shaped axons ' ... the cartridges are immunoreactive to an isoform of the GABA membrane transporter, GAT-1, and this serves as their identifying feature.[1][2] GAT-1 is involved in the process of GABA reuptake into nerve terminals, thus helping to terminate its synaptic activity.'], which synapse directly onto the axon hillock (base of the axon projection from the cell body) of pyramidal cells, modulating cell output and participating in intra-columnar inhibition, and basket cells, which contacts the soma and dendrites of pyramidal cells, modulating input to these cells. Although these interneurons make up a small fraction of the total number of minicolumn cells, they play a significant role in finely tuning cortical information processing. A simplified representation of a minicolumn is thus of a processing core surrounded by a GABAergic interneuron circumferential zone of inhibitory and disinhibitory activity.Also, minicolumnar width plays a factor (perhaps - see Casanova 2006), but more importantly, see the reduction of inhibition effects within minicolumns in ASD.
In effect, a brain with narrower minicolumns may be less robust, and therefore more vulnerable to the complications that could come with deviation from the narrow tolerances within which the brain functions. In a brain with wider minicolumns, a loss of inhibition would not have as significant an impact, as minicolumnar width (and therefore distance between minicolumn information processing cores) would still exist to reduce intercolumnal spill, and thalamic projections would result in fewer minicolumns per macrocolumn to be affected.
The minicolumn-macrocolumn relationship may be linked in part to both the termination of projections from the thalamus, which span a fixed distance and may serve to link together minicolumns that receive input from the same thalamocortical fibers, and by the effects of serotonin, changing columnar development in the cortex during brain development (Casanova 2006).Ian Parker suggests a connection between the number of minicolumns and evolution of intelligence, but I don't quite see the point of this sort of claim: what would it help us with? Would we try to track down the genes responsible for these changes? It occurs to me that it would be rather difficult to track down the genes that evolutionary history has recently been working on, the 'scratchpad' so-to-speak. But if those genes were to be found anyway, what better could we do than the permutation (mutation) and recombination that nature does? How would we enhance upon the abilities of natural selection in this regard? Perhaps the Markram supercomputer simulations can show us interesting modifications to make. Implementation could be through viral gene therapy. But I still don't see the reason to explicitly relate this to the concepts in evolution (whether micro or macro).
Smaller minicolumns would skew information processing (noise/signal) in favour of signal, potentially enhancing the ability to process stimuli that require discrimination, but also potentially at the expense of generalizing the salience of a particular stimulus. Smaller and more densely packed minicolumns could also allow for more complex information processing. As an example, the smaller minicolumns in the visual cortex may support added functionality, e.g. depth or color perception. This may be due to the overlap of neuronal projections allowed for when neuronal dendrites and axons remain the same size but the distance to neighbouring minicolumns is reduced (Casanova - Abnormalities Of Cortical Circuitry In The Brains Of Autistic Individuals).hypersensitivity results from reductions in the peripheral zone of inhibitory and disinhibitory activity allowing spill-over (stimuli spill) from one minicolumn to the next and allowing an amplification effect, " ... so a reduction in GABAergic inhibitory activity could also result in a loss of inhibition and greater amplification."
An additional cost is that imposed by a reduction in neuron size. The ability of a neuron to sustain a connection over distance is related to the size of its cell body. Smaller neurons result in a metabolic bias favouring shorter connections at the expense of both longer distance and inter-hemispheral connectivity. The result is that autistic brains have a bias towards local (intra-regional) over global (inter-regional) connectivity and processing. Short intra-regional processing functions include mathematical calculations and visual processing. Cognitive functions that require inter-regional processing would be less metabolically efficient, including language, face recognition, and joint attention (Casanova - Abnormalities Of Cortical Circuitry In The Brains Of Autistic Individuals).That is interesting. The favorability of small size due to metabolism restrictions on the neuron also mimic the obsessive compulsive hoarding on the more cognitive levels in autists, such as those autists that much rather prefer to cache information for themselves rather than relying on outside sources to back them up.
The total number of minicolumns in the human brain is defined during the first forty days of fetal development. Symmetrical divisions of germinal cells determine the total number of minicolumns, and a second phase of asymmetrical divisions provides for cell migration into the cortex, with successive divisions determining the number of cells in each minicolumn. This is a complex process, defined by a large number of genes interacting with the environment. The result is that a higher number of minicolumns is not something that someone can ‘acquire’ or be vulnerable to within the post-natal period. It is possible for disruptions during the narrow window of fetal development (e.g. rubella, thalidomide, tuberous sclerosis) to also result in an increase in the number of minicolumns, by influencing this process (Casanova - Abnormalities Of Cortical Circuitry In The Brains Of Autistic Individuals; Casanova 2006).Henry Markram has found an interesting way to interrupt the development process re: valproic acid and his other studies.
Autism is a devastating neurodevelopmental disorder with a polygenetic predisposition that seems to be triggered by multiple envi ronmental factors during embryonic and/or early postnatal life. While significant advances have been made in identifying the neuronal structures and cells affected, a unifying theory that could explain the manifold autistic symptoms has still not emerged. Based on recent synaptic, cellular, molecular, microcircuit, and behavioral results obtained with the valproic acid (VPA) rat model of autism, we propose here a unifying hypothesis where the core pathology of the autistic brain is hyper-reactivity and hyper-plasticity of local neuronal circuits. Such excessive neuronal processing in circumscribed circuits is suggested to lead to hyper-perception, hyper-attention, and hyper-memory, which may lie at the heart of most autistic symptoms. In this view, the autistic spectrum are disorders of hyper-functionality, which turns debilitating, as opposed to disorders of hypo-functionality, as is often assumed. We discuss how excessive neuronal processing may render the world painfully intense when the neocortex is affected and even aversive when the amygdala is affected, leading to social and environmental withdrawal. Excessive neuronal learning is also hypothesized to rapidly lock down the individual into a small repertoire of secure behavioral routines that are obsessively repeated. We further discuss the key autistic neuropathologies and several of the main theories of autism and re-interpret them in the light of the hypothesized Intense World Syndrome.
'But, Hanu, everything dies,' Danlo said softly. He turned to face the scarred, old shih tree, and he pressed his forehead against it. When he looked up, he felt the zig-zag mark where the tree's icy bark had cut into his skin. Hanuman shook his head and continued, 'But why die at all, Danlo? Mightn't there be a new phase of evolution? A new kind of being? Can't you understand?[1] I'm trying to delineate an emergent quality of the brain. New synapses. New connections. A constellation of qualities and abilities, of new levels of existence. Consciousness heightened and exalted in itself, purified. This pure consciousness that we really are. That we struggle to be. For our kind, there's always the burning to be more. The eternal longing. And this is why true human beings feel more pain. Because we are more, but it's never quite enough – never. And we are aware of this neverness inside our souls. And aware of being aware. There is a feedback. Can you understand what this is like? Pain is magnified, infinitely. Each moment of time. Reality becomes almost too real. It blazes. All the universe afire with the possibilities of light, and madness, too. Real pain is the burning that never stops, the frenzy, the lightning.'You realize what Markram is doing, right? He has been simulating microcolumns on a supercomputer with 400 comp-neurosci packages spliced together. This is interesting in light of autism and increasing repetitive behavior, and indeed it may shed some light on what engineering can be done to enhance, engineer, even program one's recursions.
Morphological examination of 3D reconstructions of biocytin stained pyramidal neurons did not show any significant differences in the extent of axonal or dendritic arbors, in the spine or bouton densities, and in the size of pyramidal neuron somata. There was also no change in the number of pyramidal neurons. Hyper-reactivity of the neocortical microcircuitry is therefore not caused by larger or more elaborate neurons, more excitable neurons, an increase in neuron numbers, more powerful synapses between neurons, nor by a loss of inhibition. Indeed, changes in these parameters seem to act in the opposite direction, perhaps part of a compensatory strategy.But hyperconnectivity within a radius of 50 micrometers was observed.
An intriguing aspect of this hyper-connectivity is the finding that pyra- midal neurons target more neurons even at the expense of deploying less synapses per connection. This form of hyper-connectivity is, therefore, not a general hypertrophy of synapse formation, but rather a hypertro- phy of connectivity between neurons. We, therefore, propose that a novel molecular mechanism involved in “target dominance” is enhanced in the VPA-treated neocortex and this molecular syndrome triggered by VPA exposure causes hyper-reactivity.In the above blockquote there's the line "... the finding that pyramidal neurons target more neurons even at the expense of deploying less synapses per connection." How many synapses per connection would be possible otherwise? One neuron has one axon, therefore only one synapse and one connection, yes? What is this alternative that the authors are proposing? Perhaps they are just trying to distinguish between synapse hypertrophy and locally-connective hypertrophy.
Since memory processes are also altered in autism, we examined whether synaptic plasticity is affected in the VPA-treated neocortex (Rinaldi et al., 2007b). The results are summarized in Table 5. Synaptic responses recorded in pyramidal neurons following a Hebbian pairing stimulation protocol caused more than a two-fold increase in the subsequent synap- tic responses (i.e., enhanced long term potentiation). The results were also found for both layer 2/3 and in layer 5 pyramidal neurons and a closer examination revealed that the boosted plasticity was a postsynap- tic form of plasticity. The presynaptic form of plasticity that is normally observed between these neurons was normal in the VPA treated slices. These results indicate that glutamatergic synapses are hyper-plastic in this animal model of autism.
the VPA-treated offspring (Markram et al., 2007). We found that the lateral amygdala microcircuit was also extremely hyper-reactive when stimulated with progressively stronger electrical stimulations using the MEA stimu- lator (Table 5). The amygdala responded differently from the neocortex in that stimulation easily produced prolonged episodes of up-state-like bursts. The number, frequency and duration of these evoked up-states were all greatly enhanced in slices from VPA-treated animals. When we isolated the inhibition, we found that, unlike in the neocortex, inhibition was greatly reduced. We have not yet been able to obtain sufficient data to determine whether the excitatory cells of the amygdala are hyper- connected as in the neocortex, but the cellular and synaptic alterations are such that they also result in hyper-reactivity.Interesting. Interpretations?
We examined whether synaptic plasticity was affected in the amygdala and found an equally significant enhancement of long-term potentiation (Markram et al., 2007) (Table 5) as in the neocortex. Interestingly amygdala disinhibition induced either by GABAergic blockade (Isoardi et al., 2004), genetic knockout of the GABAB(1a)-receptor subtype (Shaban et al., 2006), benzodiazepine withdrawal (Isoardi et al., 2004), dopamine receptor acti- vation (Bissiere et al., 2003), or stress (Rodriguez Manzanares et al., 2005), can result in amygdaloid hyper-excitability (Isoardi et al., 2004; Rodriguez Manzanares et al., 2005) and facilitate LTP induction (Bissiere et al., 2003; Rodriguez Manzanares et al., 2005; Shaban et al., 2006), which has been associated not only with enhanced fear memories (Isoardi et al., 2004; Rodriguez Manzanares et al., 2005), but also with over-generalization of conditioned fear to neutral stimuli (Shaban et al., 2006).Hm.
Haloperidol and ifenprodil are N-methyl-D-aspartate (NMDA) receptor (NR) antagonists with preference for the NR1/NR2B subunit combination. Previous investigations utilizing 125I-MK801 binding assays with recombinant receptors distinguished certain structural determinants on the NR2B subunit for these two drugs, with glutamate 201 being critical for haloperidol sensitivity and arginine 337 being important for ifenprodil block. Other studies, however, suggested that these two sites pharmacologically overlap. In an attempt to resolve these discrepancies, we have characterized the actions of haloperidol and CP101,606, an ifenprodil analog, on the single-channel properties of NR1/NR2B(E201R) receptors transiently expressed in Chinese hamster ovary cells, because receptors formed by NR1/NR2B(R337K) appear to be nonfunctional. Haloperidol (10 µM) inhibited wild-type NR1/NR2B channels by decreasing the frequency of channel opening, whereas CP101,606 (0.5 µM) antagonized NR1/NR2B channel activity by decreasing both the open dwell time and the frequency of channel opening. The inhibitory actions of both drugs were virtually absent in the mutant NR1/NR2B(E201R) receptors. These results suggest that glutamate 201 is critical for both haloperidol and CP101,606 inhibition, thus demonstrating common features in the action of these two antagonists.Anxiolytics tend to not effect NR2B but rather NR2A.
distance between synapses - spillover from one input is almost impossible to avoid, to another one. Within 200 nm there's another synapse that is related to a different neuron. What the brain is trying to do is control the voltage within a certain voxel compartment - not so much a particular neuron. This would be an attempt to control pain/energy/action. Electromagnetic dendritic objects. We do not see the world. What we do is we use any clue that our senses can provide us is to build a virtual analog model in our brain; the world we see is the world we build. (51:05). "So it may just be, what the brain is trying to do is control the voltage within a certain voxel compartment. So if we summarize, let's look at the world as electromagnetic dendritic object."Would this imply that the brain is attempting to bring the voltage gating systems into equilibrium?
Items removed from the house included rope, baby carriages, a doll carriage, rakes, umbrellas, rusted bicycles, old food, potato peelers, a collection of guns, glass chandeliers, bowling balls, camera equipment, the folding top of a horse-drawn carriage, a sawhorse, three dressmaking dummies, painted portraits, pinup girl photos, plaster busts, Mrs. Collyer's hope chests, rusty bed springs, the kerosene stove, a checkerboard, a child's chair (the brothers were lifelong bachelors and childless), more than 25,000 books (including thousands of books about medicine and engineering and more than 2,500 on law), human organs pickled in jars, eight live cats, a beaded lampshade, the chassis of the old Model T Langley had been tinkering with, one British and six American flags, tapestries, hundreds of yards of unused silks and fabric, clocks, fourteen pianos (both grand and upright), a clavichord, two organs, banjos, violins, bugles, accordions, a gramophone and records, and, of course, countless bundles of newspapers and magazines, some of them decades old. Near the spot where Homer died, police also found 34 bank account passbooks with a total of $3,007.18.So, disposophobia. In many mystical spiritualities, the world and universe is seen as a natural extension to one's subjective viewpoint; if this is so, then wouldn't "throwing things away" be akin to cutting off limbs?
At present, Dr. Casanova is well published in a multitude of postmortem techniques including neuronal morphometry immunocytochemistry, neurochemistry, and autoradiography.
You know how to get eternal life
in the center of the lightening-speed waltz.
Feel your soul cut by a rusty knife
as you head for the self-destructive edge.
Our satori are just floating in the core
where we can spiritually go through the door.
We'll know how to get eternal life
while we catch the pulse from unknown satellites
If we get the transient facts,
then we feel the info high.
If we get the transient facts,
then we are really free
to fly high
in space.
We know how to get an internal high
in the center of the lightening-speed waltz.
See our soul struggling to survive,
As we head down for the self-destructive edge.
Sayonara to intrusive noise.
No more childish play and no more toys.
We know how to get eternal life
while we feel and sense mother nature's strong might.
If we get the transient facts,
then we feel the info high.
If we get the transient facts,
then we feel the info high.
If we get the transient facts,
then we feel the info high.
If we get the transient facts,
then we are really free
to fly high
in space.