Functional integration between the posterior hippocampus and prefrontal cortex is impaired in both first episode schizophrenia and the at risk mental state

Abstract

Recent neuroimaging studies have reported deficits in functional integration between prefrontal cortex and the hippocampal formation in schizophrenia. It is unclear whether these alterations are a consequence of chronic illness or its treatment, and whether they are also evident in non-psychotic subjects at increased risk of the disorder. We addressed these issues by investigating prefrontal-hippocampal interactions in patients with first episode schizophrenia and subjects with an At Risk Mental State (ARMS). Using functional Magnetic Resonance Imaging, we measured brain responses from 16 individuals with an ARMS, 10 patients with first episode schizophrenia and 14 healthy controls during a delayed matching to sample task. Dynamic causal modelling was used to estimate the effective connectivity between prefrontal cortex and anterior and posterior hippocampal regions. The normal pattern of effective connectivity from the right posterior hippocampus to the right inferior frontal gyrus was significantly decreased in both first episode patients and subjects with an ARMS (ANOVA; F = 8.16, P = 0.01). Interactions between the inferior frontal gyrus and the anterior part of the hippocampus did not differ across the three groups. Perturbed hippocampal-prefrontal interactions are evident in individuals at high risk of developing psychosis and in patients who have just developed schizophrenia. This suggests that it may be a correlate of increased vulnerability to psychosis and that it is not attributable to an effect of chronic illness or its treatment.

Schizophrenia susceptibility pathway neuregulin 1–ErbB4 suppresses Src upregulation of NMDA receptors

“…To investigate whether NRG1β affects Src-induced enhancement of synaptic NMDARs in another brain region implicated in the pathogenesis of schizophrenia, we studied the prefrontal cortex 43,49,50 . In acute slices from the medial prefrontal cortex, we evoked NMDAR EPSCs in layer V pyramidal neurons by stimulating the corticocortical neurons and afferents in layers II and III while pharmacologically blocking AMPA and GABA receptors.…”

“…As NRG1β blocks NMDAR-dependent long-term potentiation (LTP) at hip-pocampal Schaffer collateral-CA1 synapses [32][33][34][35][36][37] , a form of LTP also dependent on Src activity 5,38,39 , we determined the effect of NRG1β-ErbB4 signaling on Src-mediated enhancement of NMDAR function, tyrosine phosphorylation of NMDARs and the resultant potentiation of synaptic transmission. We examined neuronal responses not only in the hippocampus but also in the prefrontal cortex (PFC); both of these brain regions are crucial in the pathobiology of cognitive dysfunction in schizophrenia 21,[40][41][42][43] .…”

Brain-Wide Analysis of Functional Connectivity in First-Episode and Chronic Stages of Schizophrenia

“…The pathophysiology of schizophrenia involves distributed functional dysconnectivity involving a number of brain regions, 1,2 including the frontal lobe, [3][4][5][6][7][8][9][10] and its language-related areas in the inferior frontal gyrus, 11,12 sensory-motor areas, 13 the temporal lobe, 14 limbic structures, 15,16 and thalamus. [17][18][19][20][21][22][23][24] Despite numerous leads, the reported findings are somewhat inconsistent and the core regions associated with the pathogenesis of schizophrenia still remain controversial.…”

“…2 There are additional studies that have focused on the early changes in schizophrenia, including. 6,12,15,[29][30][31][32] Another important factor in the heterogeneity of the findings may be that many studies have focused on functional connectivity between regions specified a priori, rather than adopting a whole-brain analysis. Consequently the reported findings are influenced by choice of the regions of interest, and may not cover the most significantly different areas that may reflect the core pathological changes in schizophrenia.…”

Subanesthetic Ketamine Treatment Promotes Abnormal Interactions between Neural Subsystems and Alters the Properties of Functional Brain Networks

“…The disorder involves dysfunction in a number of brain regions including the prefrontal and temporal cortices, the hippocampus (HP), and thalamic regions. Recent data from functional brain imaging studies in schizophrenia have advanced our understanding of how functional interactions between distinct neural subsystems, such as the prefrontal cortex (PFC) and HP (Meyer-Lindenberg et al, 2005;Benetti et al, 2009), and between other discrete cortical regions (Kim et al, 2005) are disrupted in the disorder. However, given that these studies often involve a priori selection of the functional interaction of interest, the data may overemphasize the relative importance of these particular interactions while missing others that are biologically important.…”