Annual research review: Current limitations and future directions in MRI studies of child- and adult-onset developmental psychopathologies.

BACKGROUND: The widespread use of Magnetic Resonance Imaging (MRI) in the study of child- and adult-onset developmental psychopathologies has generated many investigations that have measured brain structure and function in vivo throughout development, often generating great excitement over our ability to visualize the living, developing brain using the attractive, even seductive images that these studies produce. Often lost in this excitement is the recognition that brain imaging generally, and MRI in particular, is simply a technology, one that does not fundamentally differ from any other technology, be it a blood test, a genotyping assay, a biochemical assay, or behavioral test. No technology alone can generate valid scientific findings. Rather, it is only technology coupled with a strong experimental design that can generate valid and reproducible findings that lead to new insights into the mechanisms of disease and therapeutic response. METHODS: In this review we discuss selected studies to illustrate the most common and important limitations of MRI study designs as most commonly implemented thus far, as well as the misunderstanding that the interpretations of findings from those studies can create for our theories of developmental psychopathologies. RESULTS: Common limitations of MRI study designs are in large part responsible thus far for the generally poor reproducibility of findings across studies, poor generalizability to the larger population, failure to identify developmental trajectories, inability to distinguish causes from effects of illness, and poor ability to infer causal mechanisms in most MRI studies of developmental psychopathologies. For each of these limitations in study design and the difficulties they entail for the interpretation of findings, we discuss various approaches that numerous laboratories are now taking to address those difficulties, which have in common the yoking of brain imaging technologies to studies with inherently stronger designs that permit more valid and more powerful causal inferences. Those study designs include epidemiological, longitudinal, high-risk, clinical trials, and multimodal imaging studies. CONCLUSIONS: We highlight several studies that have yoked brain imaging technologies to these stronger designs to illustrate how doing so can aid our understanding of disease mechanisms and in the foreseeable future can improve clinical diagnosis, prevention, and treatment planning for developmental psychopathologies.

Aberrant hippocampus and amygdala morphology associated with cognitive deficits in schizophrenia.

Background: Working memory deficits are thought to be a primary disturbance in schizophrenia. We aimed to identify differences in morphology of the hippocampus and amygdala in patients with schizophrenia compared with healthy controls (HCs), and in patients who were either neuropsychologically near normal (NPNN) or neuropsychologically impaired (NPI). Morphological disturbances in the same subfields of the hippocampus and amygdala, but of greater magnitude in those with NPI, would strengthen evidence for the centrality of these limbic regions and working memory deficits in the pathogenesis of schizophrenia. Methods: We acquired anatomical MRIs in 69 patients with schizophrenia (18 NPNN, 46 NPI) and 63 age-matched HC participants. We compared groups in hippocampus and amygdala surface morphologies and correlated morphological measures with clinical symptoms and working memory scores. Results: Schizophrenia was associated with inward deformations of the head and tail of the hippocampus, protrusion of the hippocampal body, and widespread inward deformations of the amygdala. In the same regions where we detected the effects of schizophrenia, morphological measures correlated positively with the severity of symptoms and inversely with working memory performance. Patients with NPI displayed a similar pattern of anatomical abnormality compared to patients with NPNN. Conclusion: Our findings indicate that anatomical abnormalities of the hippocampus relate to working memory performance and clinical symptoms in persons with schizophrenia. Moreover, NPNN and NPI patients may lie on a continuum of severity, both in terms of working memory abilities and altered brain structure, with NPI patients being more severe than NPNN patients in both domains.

Morphological Biomarkers in the Amygdala and Hippocampus of Children and Adults at High Familial Risk for Depression.

Major Depressive Disorder (MDD) is highly familial, and the hippocampus and amygdala are important in the pathophysiology of MDD. Whether morphological markers of risk for familial depression are present in the hippocampus or amygdala is unknown. We imaged the brains of 148 individuals, aged 6 to 54 years, who were members of a three-generation family cohort study and who were at either high or low familial risk for MDD. We compared surface morphological features of the hippocampus and amygdala across risk groups and assessed their associations with depression severity. High- compared with low-risk individuals had inward deformations of the head of both hippocampi and the medial surface of the left amygdala. The hippocampus findings persisted in analyses that included only those participants who had never had MDD, suggesting that these are true endophenotypic biomarkers for familial MDD. Posterior extension of the inward deformations was associated with more severe depressive symptoms, suggesting that a greater spatial extent of this biomarker may contribute to the transition from risk to the overt expression of symptoms. Significant associations of these biomarkers with corresponding biomarkers for cortical thickness suggest that these markers are components of a distributed cortico-limbic network of familial vulnerability to MDD.

Social functioning in young people at risk for schizophrenia.

Deficits in social functioning are potential risk factors for schizophrenia. Social functioning was assessed in 55 individuals "at risk" for schizophrenia, 16 first episode patients with schizophrenia and 45 normal comparison subjects. The Social Adjustment Inventory for Children and Adolescents (SAICA) was administered to adolescents <18 and the Social Adjustment Scale (SAS-SR) to young adults >17. The at risk and first episode groups significantly differed from the normal subjects on measures of social functioning in the domains of peer, family, work and school relationships. Individuals at risk for schizophrenia have significant functional deficits which may be potential indicators of increased vulnerability for psychosis.

Treatment implications of the schizophrenia prodrome.

Schizophrenia is a debilitating neurodevelopmental disorder that strikes at a critical period of a young person's life. Early identification of individuals in the prodromal phase of a psychotic illness can lead to earlier treatment and perhaps prevention of many of the devastating effects of a first psychotic episode. International research efforts have demonstrated the success of community outreach and education regarding the schizophrenia prodrome and it is now possible to use empirically defined clinical and demographic criteria to identify individuals at a substantially increased risk for a psychotic illness. The development of clinical staging criteria for psychosis that incorporates type and severity of clinical symptoms, level of global and social functioning, family history, substance use, neurocognitive functioning, and perhaps neurobiological information, could help to specify appropriate treatment for vulnerable individuals at different phases of the prodrome. Preliminary psychosocial and pharmacologic treatment studies report initial success in reducing severity of prodromal symptoms in "at-risk" samples, but further work is needed to refine the prodromal criteria and perform well controlled treatment studies in adequately powered samples. Treatment algorithms can then be tailored to presenting symptoms, number of risk factors present, and evidence of progression of the illness, to assure appropriate, safe and effective interventions in the early stages of psychosis.