New hope for Mis-wired minds

auditoryHallucinationAlmost no new drugs have been developed for psychiatric conditions in over sixty years, because the causes of those conditions are mostly unknown. That is about to change because gene mutations have been found that correspond to subsets of schizophrenia, depression, and autism.
These mutations sometimes affect a single gene. Other times they duplicate a section of a chromosome, or delete a section. A surprising finding is that a particular mutation may manifest itself as Schizophrenia in one person, autism in another, and intellectual disability or epilepsy in a third.

Another important point is that psychiatric conditions can arise many different ways. Many different mutations can produce a syndrome that psychiatrists give a single name such as “depression”. Some people believe that mental illness genes must have an upside, because they persist in the population, but there are so many de novo mutations that can affect the brain, that the diseases would exist even if the gene variants that cause them provide no advantage.

The finding of such genes gives hope for curing some types of mental illness, because for example, if you give a brain MRI to many patients with “Schizophrenia” you are really imaging many different syndromes, but if you know that a subset of the patients have the same mutation, you can study them as one group, and perhaps find a common pattern in brain images.

I would expect that if a gene only affects transmission between neurons, then it might be possible to fix the problem when the gene is ineffective, or only partly effective.
However, many of the genes affect how the brain grows. As the brain develops, genes specify the proteins that tell cells where to migrate, where their axons and dendrites project, which cells they will connect with and how the connections change as they are used in life. So the actual brain of an afflicted person might look so different than the brain of a normal person that fixing any problems would impossible (in my view).

A recurring theme in the diseases is an unbalance in the functions of two main classes of neurons, those who excite other neurons, and those who inhibit other neurons from firing. This imbalance occurs in epilepsy — the uncontrolled firing of large populations of neurons — as you would expect. But inhibitory neurons also control many aspects of “information processing” as well – such as:

  • Filtering (removing unwanted information, noise, and redundant information)
  • Gain control – you might want a steady level of output, despite varying level of inputs
  • Spatial integration – neurons add and subtract the inputs from a spatial area
  • Temporal integration – neurons may sum up their inputs over a time period before firing.
  • Orchestration of synchronous firing of ensembles of neurons
  • Orchestration oscillating firing of ensembles of neurons

For instance, if you know someone who is poor at social interactions, is hyperactive, and can’t stand loud noises, it could be because he has a mutation in the gene that encodes FMRP (a protein). The protein puts brakes on a process that affects synapse plasticity. So without it, neurons become hyper-connected, and the cortex becomes hyper-excitable with altered patterns of activity.

The above is mostly from a chapter by Kevin Mitchell titled The Miswired Brain, Genes and Mental Illness in an anthology called The Future of The Brain.  

We can speculate that criminality, which can be genetic as shown by studies of adopted twins, might also involve a mutation that mis-wires the brain. In fact,  Adriane Raine, a neuro-criminologist,  says this:

My graduate student Angela Scarpa showed that our young psychopaths… were hooked on rewards, confirming previous studies showing the same in adult psychopaths… We found that our psychopathic individuals showed a 10 percent increase in the volume of the striatum [bloggers note: reward-related] compared with controls. Rewards are important to offenders, and to them money doesn’t just talk—it swears. It’s very salient to them. A full 45 percent of psychopaths are motivated by money in the crimes they perpetrate. Studies also show that it takes less money to push psychopaths into violating moral principles than non-psychopaths.’ But more troublingly, aggressive, conduct-disordered kids show increased activity of the striatum when they view images of other people in pain.’ ….However we interpret structural deficits of the amygdala, hippo-campus, corpus callosum, and striatum in psychopathic and antisocial offenders, one thing stands out. These structural abnormalities are likely not the result of some discrete disease process or obvious trauma. Such causes would if anything result in overall volume reductions to these structures. Our findings are much more complex than that. The right hippocampus is larger than the left in psychopaths. The striatum is larger. The corpus callosum also has a bigger volume.

This certainly sounds as if some gene that affects the self-assembly of the brain is not working correctly.

There may be more subtle problems with genes that have trade-offs. For example numerous studies have demonstrated correlations between creative occupations and people living with mental illness. You don’t need to have mental problems (or have a relative with mental problems) to be creative, but in some cases their seems to be a relationship.  Another example is that a few adults have had phenomenal memories but in extreme cases, like those of Solomon Shereshevsky and Kim Peek, memory skills can reportedly hinder social skills. Psychology Today explains: “It may also be no accident that none of the five had stable marriages. Living with someone who never forgets, and therefore rarely loses an argument, can be a drag.”

The good side of all this is that in some cases partial cures can be found. In the case of FMRP, you can block the function of the resulting overactive pathway with drugs, which in mice at least, reverses many of the bad effects.

The Anatomy of Violence: The Biological Roots of Crime by Adriane Raine (2014)
The Future of the Brain : Essays by the’s leading Neuroscientists (Kevin Mitchell’s chapter was in this book) (2015)
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