RESUMO
The purpose of this study was to examine measures of anatomical connectivity between the thalamus and lateral prefrontal cortex (LPFC) in schizophrenia and to assess their functional implications. We measured thalamocortical connectivity with diffusion tensor imaging (DTI) and probabilistic tractography in 15 patients with schizophrenia and 22 age- and sex-matched controls. The relationship between thalamocortical connectivity and prefrontal cortical blood-oxygenation-level-dependent (BOLD) functional activity as well as behavioral performance during working memory was examined in a subsample of 9 patients and 18 controls. Compared with controls, schizophrenia patients showed reduced total connectivity of the thalamus to only one of six cortical regions, the LPFC. The size of the thalamic region with at least 25% of model fibers reaching the LPFC was also reduced in patients compared with controls. The total thalamocortical connectivity to the LPFC predicted working memory task performance and also correlated with LPFC BOLD activation. Notably, the correlation with BOLD activation was accentuated in patients as compared with controls in the ventral LPFC. These results suggest that thalamocortical connectivity to the LPFC is altered in schizophrenia with functional consequences on working memory processing in LPFC.
Assuntos
Córtex Pré-Frontal/patologia , Córtex Pré-Frontal/fisiopatologia , Esquizofrenia/patologia , Esquizofrenia/fisiopatologia , Psicologia do Esquizofrênico , Tálamo/patologia , Adulto , Atrofia/patologia , Estudos de Casos e Controles , Imagem de Tensor de Difusão/métodos , Imagem de Tensor de Difusão/psicologia , Feminino , Humanos , Imageamento por Ressonância Magnética/métodos , Imageamento por Ressonância Magnética/psicologia , Masculino , Memória de Curto Prazo/fisiologia , Vias Neurais/patologia , Vias Neurais/fisiopatologia , Neuroimagem/métodos , Neuroimagem/psicologiaRESUMO
Organized neuronal firing is crucial for cortical processing and is disrupted in schizophrenia. Using rapid amplification of 5' complementary DNA ends in human brain, we identified a primate-specific isoform (3.1) of the ether-a-go-go-related K(+) channel KCNH2 that modulates neuronal firing. KCNH2-3.1 messenger RNA levels are comparable to full-length KCNH2 (1A) levels in brain but three orders of magnitude lower in heart. In hippocampus from individuals with schizophrenia, KCNH2-3.1 expression is 2.5-fold greater than KCNH2-1A expression. A meta-analysis of five clinical data sets (367 families, 1,158 unrelated cases and 1,704 controls) shows association of single nucleotide polymorphisms in KCNH2 with schizophrenia. Risk-associated alleles predict lower intelligence quotient scores and speed of cognitive processing, altered memory-linked functional magnetic resonance imaging signals and increased KCNH2-3.1 mRNA levels in postmortem hippocampus. KCNH2-3.1 lacks a domain that is crucial for slow channel deactivation. Overexpression of KCNH2-3.1 in primary cortical neurons induces a rapidly deactivating K(+) current and a high-frequency, nonadapting firing pattern. These results identify a previously undescribed KCNH2 channel isoform involved in cortical physiology, cognition and psychosis, providing a potential new therapeutic drug target.