A Critical Period for Prefrontal Network Configurations Underlying Psychiatric Disorders and Addiction

Modeling of human neuropsychiatric disorders in animals is extremely challenging given the subjective nature of many symptoms, the lack of biomarkers and objective diagnostic tests, and the early state of the relevant neurobiology and genetics. Nonetheless, progress in understanding pathophysiology and in treatment development would benefit greatly from improved animal models. Here we review the current state of animal models of mental illness, with a focus on schizophrenia, depression and bipolar disorder. We argue for areas of focus that might increase the likelihood of creating more useful models, at least for some disorders, and for explicit guidelines when animal models are reported.

Illicit drug use is identified in Healthy People 2010 as a leading health indicator because it is associated with multiple deleterious health outcomes, such as sexually transmitted diseases, human immunodeficiency virus, viral hepatitis, and numerous social problems among adolescents and adults. Improved understanding of the influence of stressful or traumatic childhood experiences on initiation and development of drug abuse is needed. We examined the relationship between illicit drug use and 10 categories of adverse childhood experiences (ACEs) and total number of ACEs (ACE score). A retrospective cohort study of 8613 adults who attended a primary care clinic in California completed a survey about childhood abuse, neglect, and household dysfunction; illicit drug use; and other health-related issues. The main outcomes measured were self-reported use of illicit drugs, including initiation during 3 age categories: or=19 years); lifetime use for each of 4 birth cohorts dating back to 1900; drug use problems; drug addiction; and parenteral drug use. Each ACE increased the likelihood for early initiation 2- to 4-fold. The ACE score had a strong graded relationship to initiation of drug use in all 3 age categories as well as to drug use problems, drug addiction, and parenteral drug use. Compared with people with 0 ACEs, people with >or=5 ACEs were 7- to 10-fold more likely to report illicit drug use problems, addiction to illicit drugs, and parenteral drug use. The attributable risk fractions as a result of ACEs for each of these illicit drug use problems were 56%, 64%, and 67%, respectively. For each of the 4 birth cohorts examined, the ACE score also had a strong graded relationship to lifetime drug use. The ACE score had a strong graded relationship to the risk of drug initiation from early adolescence into adulthood and to problems with drug use, drug addiction, and parenteral use. The persistent graded relationship between the ACE score and initiation of drug use for 4 successive birth cohorts dating back to 1900 suggests that the effects of adverse childhood experiences transcend secular changes such as increased availability of drugs, social attitudes toward drugs, and recent massive expenditures and public information campaigns to prevent drug use. Because ACEs seem to account for one half to two third of serious problems with drug use, progress in meeting the national goals for reducing drug use will necessitate serious attention to these types of common, stressful, and disturbing childhood experiences by pediatric practice.

An information-processing model is outlined that predicts that performance on non-routine tasks can be impaired independently of performance on routine tasks. The model is related to views on frontal lobe functions, particularly those of Luria. Two methods of obtaining more rigorous tests of the model are discussed. One makes use of ideas from artificial intelligence to derive a task heavily loaded on planning abilities. A group of patients with left anterior lesions has a specific deficit on the task. Subsidiary investigations support the inference that this is a planning impairment.