Biomedical Engineering Reference
In-Depth Information
Figure 17
. (
a
) Attempts at a "top-down" approach to integrative neuroscience have frequently started from the
delineation of behaviorally defined exophenotypes, which are theoretically related to circuitry-based phenotypes
(endophenotypes). Illness category can stand in for any number of American Psychiatric Associations Diagnos-
tic Statistical Manual Axis I neuropsychiatric disorders, such as subtypes of major depressive disorder, or co-
caine abuse and dependence. Altered function in a distributed set of neural groups (referred to in the figure as
"circuits") is symbolized by an asterisk after the circuit number. This altered function may include diminished or
increased circuitry activity, or substitution of an alternative circuitry to fulfill a functional deficit. There may be
a number of altered functions or metric traits, determined by altered circuitry performance, which determine a
particular neuropsychiatric disorder. This is highly likely given the use of multiple signs and symptoms currently
used to define neuropsychiatric exophenotypes using the American Psychiatric Associations Diagnostic Statisti-
cal Manual (5). Given the embedding of scales of brain function, "top-down" approaches starting from continu-
ous quantitative measures of systems biology, would, with the appropriate subject sample size, have the
potential to identify all polymorphic traits and temporal adaptations for a behavioral variant. (
b
) "Bottom-up"
approaches evaluate one genetic polymorphism at a time to determine how it leads to an altered profile of cir-
cuitry function.
responsible for generating behavior, but it is heavily dependent on ge-
netic/epigenetic function. Weinberger and colleagues have demonstrated with
fMRI that genetic variations in COMT and 5HT transporter are correlated with
fMRI signal changes in human amygdala and prefrontal cortex, respectively
(86,112). These types of studies represent a "bottom-up" approach to comple-
ment findings from the "top-down" approach (Figure 17). In some diseases,
such as Huntington's, a single major disease locus may be enough to produce the
endophenotypes and exophenotypes that characterize the illness. In contrast,
oligogenetic and polygenic diseases (16), such as Parkinson's disease and most
