Biomedical Engineering Reference
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endophenotypes would have implications for the nested genetic, molecular, sub-
cellular, and cellular mechanisms that produce them (53,86,112,125,161).
To develop a unitary nosology for neuropsychiatric illness based on func-
tional and structural circuitry measures, it is likely that more than one or
two motivation subprocesses will need to be studied. Strong evidence exists
that disorders such as schizophrenia involve abnormalities in multiple cortical
regions and functional domains separate from the circuitry implicated in the
subprocess of reward/aversion assessment (220,235). The classification of neu-
ropsychiatric illnesses using abnormalities in the circuitry for reward/aversion
assessment may be one dimension of a multidimensional schema for circuitry-
based (or systems-based) characterization of neuropsychiatric illnesses. Per Fig-
ure 4, other dimensions might include processes involved with sensory percep-
tion (29), or processes for attention and memory (79,231,261). At the systems
biology interface between genome, epigenome, and environment (Figure 14), a
substantial combination of brain subprocesses involved with motivated behavior
may be dysfunctional in concert with that of reward/aversion assessment to pro-
duce neuropsychiatric signs and symptoms.
6.
LINKING THE DISTRIBUTED NEURAL GROUPS
PROCESSING REWARD
/
AVERSION INFORMATION
TO THE GENE NETWORKS THAT ESTABLISH AND
MODULATE THEIR FUNCTION
An organism arises from a complex set of interactions between its genome-
epigenome and its environment. Disease states can be conceptualized as an or-
ganism's failure to adapt effectively to its environment. A new nosology for psy-
chiatric illness could consider these adaptation failures at multiple spatio-
temporal scales of brain function beginning with common circuitry alterations,
which represent adaptation failures on an immediate timescale (Figures 12 and
13). Alterations in genome-epigenome, molecular machinery, and cellular func-
tion, which represent adaptation failures on a broader timescale, would also be
relevant in this classification system. Although deleterious to the individual,
these changes, which appear at the genetic, molecular, and organelle levels, can
be viewed as the byproduct of the "capacitors" and "gain-controls" responsible
for species-wide adaptations to a changing environment over time (17,135,
205,217,252,260). Although circuitry and molecular genetic functions are inter-
related, systems-level descriptors (e.g., the reward/aversion systems described
above) and molecular genetic-level descriptors will both be essential compo-
nents for the characterization of all neuropsychiatric illnesses.
A view of how future characterization of psychiatric diseases might incor-
porate molecular-genetic descriptors can be obtained from characterizations of
other less prevalent neuropsychiatric diseases with neurodegenerative (2) or
