The neural correlates of performance in adolescents at risk for schizophrenia: Inefficiently increased cortico-striatal responses measured with fMRI

Abstract

Background fMRI studies indicate that schizophrenia patients and their adult relatives require greater prefrontal activation to maintain performance at levels equal to controls, but studies have not established if this pattern of inefficiency is observed in child and adolescent offspring of schizophrenia patients (SCZ-Off). Methods Using a task with visual working memory demands, we investigated activation in cortico-striatal networks and dorsal prefrontal modulation of regions underlying visual working memory in a group of SCZ-Off (n=19) and controls with no family history of psychosis (n=25 subjects) using an event-related design. Trials were divided based on memory performance (correct vs. incorrect) to specifically identify the neural correlates of correct working memory performance. Results Whereas groups did not differ in terms of behavioral accuracy, SCZ-Off demonstrated significantly increased fMRI-measured activation in dorsal prefrontal cortex and the caudate nucleus during correct, relative to incorrect memory performance. Whereas activation in SCZ-Off was high and independent of performance in each region, in controls the fMRI response was related to behavioral proficiency in the caudate. Further, exploratory analyses indicated that this inefficiency in the dorsal prefrontal cortex response increased with age in SCZ-Off (but in no other regions or group). Finally, these differences were not based in differences in dorsal prefrontal modulation of other regions during successful performance. Discussion These results are consistent with observed patterns in adult patients and first-degree relatives. Inefficient fronto-striatal responses during working memory may characterize the schizophrenia diathesis and may reflect the effects of the illness and vulnerability for the illness.

Hyperactivity of caudate, parahippocampal, and prefrontal regions during working memory in never-medicated persons at clinical high-risk for psychosis

“…Results of this study are provocative, as left PHP, left caudate, and right DLPFC are strongly implicated in studies of CHR, schizophrenia, and familial risk for psychosis (e.g., (Diwadkar et al, 2012; Fusar-Poli et al, 2011d; Kuepper et al, 2013; Seidman et al, 2003; Seidman et al, 2006; Tamminga et al, 2010; Tandon et al, 2013; Thermenos et al, 2013). Converging evidence points to both structural, functional and/or neurochemical abnormalities in these three regions in CHR.…”

Neural activity changes in unaffected children of patients with schizophrenia: A resting-state fMRI study

“…PET studies have found increased striatal dopamine neurotransmission in schizophrenia patients (Abi-Dargham et al, 1998Kegeles et al, 2010), individuals with prodromal signs of schizophrenia Howes et al, 2009), and their unaffected first-degree relatives (Hirvonen et al, 2005;Huttunen et al, 2008). Taskbased functional neuroimaging studies have also found altered striatal activity in high risk subjects during various tasks, including inhibitory control tasks , anti-saccades , as well as tasks of sustained attention (Diwadkar et al, 2011) and visual working memory (Diwadkar et al, 2012). However, striatal findings in schizophrenia have been mixed.…”

“…For example, using PET, Hirvonen et al report increased caudate D2 receptor availability in unaffected co-twins of patients with schizophrenia (Hirvonen et al, 2005). Furthermore, a recent t-fMRI study of children of patients with schizophrenia suggests inefficient frontostriatal responses during a working memory task (Diwadkar et al, 2012). Alterations in cortico-subcortical functioning may characterize schizophrenia diathesis and reflect vulnerability for the illness.…”

Structural brain abnormalities and suicidal behavior in borderline personality disorder

“…All statistical analyses were conducted using a cluster-level correction approach that has been formally characterized (Ward, 2000) and utilized in several imaging related studies (Ladouceur et al, In Press; Hagler et al, 2006; Bakshi et al, 2011; Diwadkar et al, 2011a; 2011b; Diwadkar et al, In Press). The approach is based on “n” Monte Carlo simulations of the process of image generation, spatial correlations of voxels (i.e., clusters), voxel intensity thresholding (voxel-level values), probability thresholding, and minimum cluster size thresholding where the probability of a true positive detection of a significant cluster is determined from the simulations themselves.…”