This is a competitive renewal application for an Independent Scientist award (K02). The Principal Investigator (PI) has previously been funded for a level 1 (K01) and a level (K02) award to investigate brain abnormalities and clinical symptoms in schizophrenia (SZ). Continuation of the K02 will support the PI's research efforts at a crucial time period in her career development. Activities during this time will include: (1) expanding the scope and breadth of understanding of magnetic resonance (MRI) imaging and image processing tools; (2) visiting prominent laboratories outside the current site to increase understanding of different approaches to brain imaging; (3) developing further warping techniques and shape models of regions of interest (ROI) to determine the extent to which automated ROI measures can replace manual measures; (4) presenting research findings at professional meetings to receive feedback from other investigators; (5) applying transcranial magnetic stimulation for the purpose of mapping cognitive speech areas in SZ; (6) delineating further brain abnormalities and their specificity to SZ (see RO1); (7) determining whether brain abnormalities are related to cognitive and clinical symptom clusters (see R01); (8) determining whether any, all, or only some of these abnormalities are static and/or progressive (see RO1); and, (9) determining whether shape deformations are better discriminators than volume measures (see RO1). We will evaluate MRI frontal, temporal, parietal, basal ganglia, thalamus, CSP, PT, cerebellum, fornix, corpus callosum, and sulco-gyral pattern abnormalities in chronic SZ (n=50; 1/2 more positive symptoms and 1/2 more negative symptoms), first episode psychotic patients (n=60 SZs, n=60 bipolar), and controls (n=50 for chronics; n=75 for first episodes). We will conduct MR scans at 1.5 and 3 years to determine which brain regions, in which patient groups, progress over time. It is hypothesized that SZ with more positive symptoms and formal thought disorder will demonstrate MR left-lateralized temporal lobe volume reductions, and cognitive impairments characterized by selective deficits in verbal processes, memory, and associations. In contrast, SZ with more negative/deficit symptoms will demonstrate bilateral temporal and frontal lobe volume reductions that will progress over time, and more cognitive impairments, particularly attention and working memory. Moreover, patients with a greater number and severity of neurodevelopmental abnormalities (e.g., CSP, PT, sulco-gyral pattern) will show a negative symptom pattern (see above), while patients with fewer and less severe neurodevelopmental abnormalities will shoe a positive symptom pattern (see above). We make similar predictions for first episode SZs, though we expect them to show the greatest volume reduction over time. It is expected that these abnormalities and clinical correlates to be specific to SZ and not bipolar disorder.

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
Research Scientist Development Award - Research (K02)
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Clinical Psychopathology Review Committee (CPP)
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Meinecke, Douglas L
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Harvard University
Schools of Medicine
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Lee, Sang-Hyuk; Niznikiewicz, Margaret; Asami, Takeshi et al. (2016) Initial and Progressive Gray Matter Abnormalities in Insular Gyrus and Temporal Pole in First-Episode Schizophrenia Contrasted With First-Episode Affective Psychosis. Schizophr Bull 42:790-801
Nestor, Paul G; Nakamura, Motoaki; Niznikiewicz, Margaret et al. (2015) Attentional Control and Intelligence: MRI Orbital Frontal Gray Matter and Neuropsychological Correlates. Behav Neurol 2015:354186
Ohtani, Toshiyuki; Levitt, James J; Nestor, Paul G et al. (2014) Prefrontal cortex volume deficit in schizophrenia: a new look using 3T MRI with manual parcellation. Schizophr Res 152:184-90
Nestor, Paul G; Nakamura, Motoaki; Niznikiewicz, Margaret et al. (2013) In search of the functional neuroanatomy of sociality: MRI subdivisions of orbital frontal cortex and social cognition. Soc Cogn Affect Neurosci 8:460-7
Araki, Tsuyoshi; Niznikiewicz, Margaret; Kawashima, Toshiro et al. (2013) Disruption of function-structure coupling in brain regions sub-serving self monitoring in schizophrenia. Schizophr Res 146:336-43
Nestor, Paul G; Kubicki, Marek; Nakamura, Motoaki et al. (2013) Neuropsychological variability, symptoms, and brain imaging in chronic schizophrenia. Brain Imaging Behav 7:68-76
Asami, Takeshi; Bouix, Sylvain; Whitford, Thomas J et al. (2012) Longitudinal loss of gray matter volume in patients with first-episode schizophrenia: DARTEL automated analysis and ROI validation. Neuroimage 59:986-96
Sampaio, Adriana; Sousa, Nuno; FĂ©rnandez, Montse et al. (2010) Williams syndrome and memory: a neuroanatomic and cognitive approach. J Autism Dev Disord 40:870-7
Yoshida, Takeshi; McCarley, Robert W; Nakamura, Motoaki et al. (2009) A prospective longitudinal volumetric MRI study of superior temporal gyrus gray matter and amygdala-hippocampal complex in chronic schizophrenia. Schizophr Res 113:84-94
Kawashima, Toshiro; Nakamura, Motoaki; Bouix, Sylvain et al. (2009) Uncinate fasciculus abnormalities in recent onset schizophrenia and affective psychosis: a diffusion tensor imaging study. Schizophr Res 110:119-26

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