Post by Amtram on Jun 23, 2014 10:25:57 GMT -5
The miswired brain: making connections from neurodevelopment to psychopathology by Kevin Mitchell
The hubs of the human connectome are generally implicated in the anatomy of brain disorders
Both articles are full-text. While the Human Connectome Project is still new, scientists are seeing a lot of potential in studying the electrical signalling in the brain. It's not as easy to figure out and mediate as the chemical signalling, but it has a better potential for specifically targeted treatments with fewer side effects. Even though this won't become a treatment in my lifetime, it's still fascinating to look at, because neuroscience is amazing.
The convergence of psychiatry and developmental neurobiology
Mutations in many different genes controlling cell migration, axon guidance and especially synaptogenesis are being found at an increasing rate in patients with schizophrenia, autism, epilepsy, mental retardation and other disorders [1]. These discoveries are prompting a paradigm shift regarding models of the genetic architecture of these disorders, which can be seen to be highly heterogeneous and primarily due to rare mutations in any of a large number of different loci [2]. They also indicate that these distinct clinical categories share overlapping etiologies and strongly implicate neurodevelopmental processes in a significant proportion of cases.
In this context, investigating the genetics of neurodevelopment in animals assumes greater importance. Many researchers have used genetic approaches in model organisms to dissect how neurodevelopmental processes work - to infer the normal function of a protein and to identify the cellular processes it is involved in. The application of these approaches in mice has revealed a wealth of information on how the brain gets wired. The converse question - how the brain can be miswired - has received less direct attention.
With the evidence of relevance to human disease, the phenotypes that arise in mice due to mutations in neurodevelopmental genes become of interest in themselves, not just as indicators of the normal function of the gene. It is important to ask: what happens to brain circuitry when a mutation affecting a process such as cell migration or synaptogenesis is mutated? The primary defects due to impairment of that protein are just the start of the story. How does miswiring of the circuit affect its function? What are the secondary consequences of altered activity in developing circuits? How does the developing brain react to such changes? How does the ultimate anatomical outcome affect brain functions, as indexed by physiology and behavior? Answering these questions will be a major challenge for the future and will require an integration of expertise from diverse fields and disciplinary traditions [3].
Mutations in many different genes controlling cell migration, axon guidance and especially synaptogenesis are being found at an increasing rate in patients with schizophrenia, autism, epilepsy, mental retardation and other disorders [1]. These discoveries are prompting a paradigm shift regarding models of the genetic architecture of these disorders, which can be seen to be highly heterogeneous and primarily due to rare mutations in any of a large number of different loci [2]. They also indicate that these distinct clinical categories share overlapping etiologies and strongly implicate neurodevelopmental processes in a significant proportion of cases.
In this context, investigating the genetics of neurodevelopment in animals assumes greater importance. Many researchers have used genetic approaches in model organisms to dissect how neurodevelopmental processes work - to infer the normal function of a protein and to identify the cellular processes it is involved in. The application of these approaches in mice has revealed a wealth of information on how the brain gets wired. The converse question - how the brain can be miswired - has received less direct attention.
With the evidence of relevance to human disease, the phenotypes that arise in mice due to mutations in neurodevelopmental genes become of interest in themselves, not just as indicators of the normal function of the gene. It is important to ask: what happens to brain circuitry when a mutation affecting a process such as cell migration or synaptogenesis is mutated? The primary defects due to impairment of that protein are just the start of the story. How does miswiring of the circuit affect its function? What are the secondary consequences of altered activity in developing circuits? How does the developing brain react to such changes? How does the ultimate anatomical outcome affect brain functions, as indexed by physiology and behavior? Answering these questions will be a major challenge for the future and will require an integration of expertise from diverse fields and disciplinary traditions [3].
The hubs of the human connectome are generally implicated in the anatomy of brain disorders
Brain networks or ‘connectomes’ include a minority of highly connected hub nodes that are functionally valuable, because their topological centrality supports integrative processing and adaptive behaviours. Recent studies also suggest that hubs have higher metabolic demands and longer-distance connections than other brain regions, and therefore could be considered biologically costly. Assuming that hubs thus normally combine both high topological value and high biological cost, we predicted that pathological brain lesions would be concentrated in hub regions. To test this general hypothesis, we first identified the hubs of brain anatomical networks estimated from diffusion tensor imaging data on healthy volunteers (n = 56), and showed that computational attacks targeted on hubs disproportionally degraded the efficiency of brain networks compared to random attacks. We then prepared grey matter lesion maps, based on meta-analyses of published magnetic resonance imaging data on more than 20 000 subjects and 26 different brain disorders. Magnetic resonance imaging lesions that were common across all brain disorders were more likely to be located in hubs of the normal brain connectome (P < 10−4, permutation test). Specifically, nine brain disorders had lesions that were significantly more likely to be located in hubs (P < 0.05, permutation test), including schizophrenia and Alzheimer’s disease. Both these disorders had significantly hub-concentrated lesion distributions, although (almost completely) distinct subsets of cortical hubs were lesioned in each disorder: temporal lobe hubs specifically were associated with higher lesion probability in Alzheimer’s disease, whereas in schizophrenia lesions were concentrated in both frontal and temporal cortical hubs. These results linking pathological lesions to the topological centrality of nodes in the normal diffusion tensor imaging connectome were generally replicated when hubs were defined instead by the meta-analysis of more than 1500 task-related functional neuroimaging studies of healthy volunteers to create a normative functional co-activation network. We conclude that the high cost/high value hubs of human brain networks are more likely to be anatomically abnormal than non-hubs in many (if not all) brain disorders.
Both articles are full-text. While the Human Connectome Project is still new, scientists are seeing a lot of potential in studying the electrical signalling in the brain. It's not as easy to figure out and mediate as the chemical signalling, but it has a better potential for specifically targeted treatments with fewer side effects. Even though this won't become a treatment in my lifetime, it's still fascinating to look at, because neuroscience is amazing.