There he earned a formidable reputation as an experimenter, becoming the first researcher to patch two connected neurons simultaneously. This put him in a position to see how they interacted in response to differently timed electrical signals.
A fundamental postulate of neuroscience is Hebb's rule - that neurons that fire together wire together. However, Markram discovered that the strength of these connections varies according to when impulses arrive and leave. If an input spike of electrical current occurs before an output spike and within a certain time window, on average the input connection was strengthened. However, if the input occurred after the output spike within the same time window, then the connection was weakened. In other words, the wiring of the brain was plastic.
Markram's papers on synaptic plasticity and the microcircuitry of the neural cortex were enough to earn him a full professorship at the age of 40, but his discoveries left him restless and dissatisfied. "The first time I reconstructed an axon and saw that it was touching [dendrites belonging to other neurons] all over, I thought God, how did it decide to put a contact here and there? That's when I realised the scale and complexity of the challenge. I thought this is impossible, how am I ever going to work out how a neuron made a decision to put all those synapses there?"
This professional epiphany was mirrored by a challenge to his family life when his son Kai (Markram has five children from two marriages) was diagnosed with Asperger's, an autism spectrum disorder. The discovery came while Markram was doing his postdoctorate in
Instead, Markram and his wife Kamila, a neuroscientist, performed a series of experiments on rats to test a new theory. Using an anti-epilepsy medicine, valproic acid, that causes birth defects that mimic autism, the Markrams found that certain networks of brain cells in the acid-treated rats were much more sensitive than normal. They also found that the brain cells in autistic rats had notably more connections: their brains were "hyperconnected", enhancing the flow of information. Finally, they discovered that the amygdala, a part of the brain responsible for fear processing, had a tendency to form new connections, possibly explaining the intense fear the autistic rats developed.
The Markrams' hypothesis is that the brains of autistic individuals are similarly hyperconnected and "hyperexcitable". Rather than suffering from a deficit in perceptual abilities, autists experience the world too intensely and so take refuge by turning inward, hence his phrase "intense world theory" to explain the disorder. '"People like Kai have jacked-up brains," he says. "They have to withdraw to protect themselves."
For Markram, using predictive neuroinformatics to reverse-engineer the parts of the brain for which we have little experimental information is only the first stage of his grand scheme. The second is to marry his brain simulation with a medical informatics platform and suck up all the available data on mental diseases from public hospitals and the proprietary databases of pharmaceutical companies. This clinical data, which would include both healthy subjects and patients with widely varying conditions, could then be systematically "mined" to identify clusters of patients with similar changes in the brain.
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