2. Micro and macro, from synapses to circuits

“I’m very happy to come to the land of Ramon i Cajal and speak about the brain and its connectivity,” explained Sakkubai Naidu, podiatrist and neurologist at the Kennedy Krieger Institute in Baltimore, United States. “He said that neurons are contiguous, not continuous, and that they are dynamic.” The way in which they connect through contiguity is with synapses, and they have been proven to be extremely dynamic. For example, “activity promotes synapses, both in prenatal and postnatal life. And some of the first to mature are those in the sensory cortex: the ones babies need to hear and move their head to feed,” says Naidu.

There are many types of synapses in which various neurotransmitters participate and can be considered the keys to various locks in the brain. Some are excitatory and react to glutamate. Some are inhibitory and react to GABA, the target molecule in most anxiolytics. And some are modulatory, including dopamine, serotonin, adrenaline, etc. And each synapse has its own life cycle: formation, maturation, maintenance and, in many cases, elimination.

Synaptic disruptions lead to a wide range of symptoms and diseases, many of which overlap. Manju Kurian, pediatric neurologist at Great Ormond Street Hospital in London, proposes calling all of these disorders “synaptopathies”, to focus the study. This study is highly necessary but not at all easy. Its complexity can be seen in the fact that hundreds of proteins have been identified in each synapse and the disruption can happen in many different phases, including synthesis of neurotransmitters, their storage or recycling, transport, in the receptors that recognize them, etc.

Amidst this complexity, one of the targets being studied is what are known as neuroligins, a sort of “molecular adhesive” that helps neurons find each other and make the synapses. Several of them are mutated in familiar forms of autism, and scientists speculate that they may be behind several behavioral disorders. This idea was shared by Nils Brose, director of the Department of Molecular Neurobiology at the Max Planck Experimental Medicine Institute, in Germany. For Brose, "One hypothesis that would explain autism is that there is an neuronal imbalance between excitation and inhibition. Certain neuroligins affect the behavior of the GABA inhibitor, which may be a therapeutic target in the future.”

But if the little things are important, so are the big ones: the “wiring” that connects the different areas of the brain and, as a whole, has come to be known as the “connectome”.  In order to visualize this, scientists use ever more sophisticated techniques, which according to co-founder of Mint Labs Paulo Rodrigues, "Allow us to see the networks and nodes, how one part of the brain is connected to another.” In fact, for Rodrigues “the connectome emphasizes the concept that the brain is one large, complex system.”

In terms of pediatrics, these tools “can allow doctors to see the developmental alterations and identify an opportunity/window in which to administer treatment.” One of these alterations is Attention Deficit Hyperactive Disorder (ADHD). Although in many cases it is difficult to firmly establish, Josep Antoni Ramos Quiroga, psychiatrist at the Hospital Vall d'Hebron Barcelona, estimates that nearly 6% of all children have this condition, and that it carries over into just over 3% of adults. Neuroimaging techniques have allowed us to identify that those with this condition have approximately 3% less grey matter, as well as other areas of the brain, and show asymmetrical brain maturing compared to other children.

For Xavier Castellanos, who also researches this disorder, ADHD “has a highly variable prognostic, generally acceptable, but with increased risk of accidents and normally less access to quality jobs.” Interested in the brain networks that cause it, Castellanos and his team use functional magnetic resonance to link the brain structure with its activity. This has led them to suggest that attention deficit in these individuals is the result of “a bad connection between the networks that are active at rest and those that act at the moment of execution. Neuronal activity at rest is giant, up to 60% of the total, but its biological meaning isn't understood yet.”