Biomedical Engineering Reference
In-Depth Information
Figure 15
. Systems biology and nested scales of function. Brain processes can be analogized to a set
of nested scales of function as an approximation. The genome/epigenome is nested in cells (neural and
glial). These cells are nested in neural groups as local circuits. These neural groups are nested in sets
of interconnected groups distributed across the brain, and modulated by monoaminergic and hormonal
systems. The scale of distributed neural groups can be sampled using tomographic imaging modalities
such as fMRI and PET. Multicellular recording techniques can be used to sample local circuits or
neural groups, comprised of excitatory and inhibitory synapses, axonal and dendro-dendritic circuits.
The individual cell, with its intracellular signaling and surface receptors, can be characterized by
measures of local field potential and sequences of action potentials. Across these scales of organiza-
tion, reductionistic explanation of experimental observation has to occur both from "top-down" and
"bottom-up" to be self-sufficient. Given the nesting of scales, dense sampling of one scale of brain
function will reflect processes at the other scales (see Figure 10). Figure adapted with permission from
Breiter and Gasic (32).
representing distributed group function observed with fMRI to similar aversive
and rewarding stimuli (19,37,38). Reverse-engineering how activity is linked
across levels of brain organization will have implications for reductive under-
standing of health and disease. Circuitry-based endophenotypes that have larger
effect sizes, and are more reliable than behavioral phenotypes, should enable
researchers to constrain future genetic association and linkage studies for neuro-
psychiatric illnesses (Figure 16). Such an integrative neuroscience approach
("top-down"; systems to genes) was utilized to find an EEG-based endopheno-
type in individuals susceptible to alcohol dependence, forging an association
with a locus that contains a subunit of the GABA
A
receptor (202,214,264).
The linkage of systems level measures to molecular genetic level descrip-
tors assumes that the probability of illness manifestation will be related to (a) the
probability associated with having a specific allele(s) at a particular locus (loci),
(b) the probability of having a particular endophenotype, and (c) the probability
