Abstract
The mismatch negativity (MMN) evoked potential, a preattentive brain response to a discriminable change in auditory stimulation, is significantly reduced in psychosis. Glutamatergic theories of psychosis propose that hypofunction of NMDA receptors (on pyramidal cells and inhibitory interneurons) causes a loss of synaptic gain control. We measured changes in neuronal effective connectivity underlying the MMN using dynamic causal modeling (DCM), where the gain (excitability) of superficial pyramidal cells is explicitly parameterised. EEG data were obtained during a MMN task—for 24 patients with psychosis, 25 of their first‐degree unaffected relatives, and 35 controls—and DCM was used to estimate the excitability (modeled as self‐inhibition) of (source‐specific) superficial pyramidal populations. The MMN sources, based on previous research, included primary and secondary auditory cortices, and the right inferior frontal gyrus. Both patients with psychosis and unaffected relatives (to a lesser degree) showed increased excitability in right inferior frontal gyrus across task conditions, compared to controls. Furthermore, in the same region, both patients and their relatives showed a reversal of the normal response to deviant stimuli; that is, a decrease in excitability in comparison to standard conditions. Our results suggest that psychosis and genetic risk for the illness are associated with both context‐dependent (condition‐specific) and context‐independent abnormalities of the excitability of superficial pyramidal cell populations in the MMN paradigm. These abnormalities could relate to NMDA receptor hypofunction on both pyramidal cells and inhibitory interneurons, and appear to be linked to the genetic aetiology of the illness, thereby constituting potential endophenotypes for psychosis. Hum Brain Mapp 37:351–365, 2016. © 2015 The Authors Human Brain Mapping Published by Wiley Periodicals, Inc.
Highlights
Psychotic disorders are among the most severe and enduring mental illnesses, characterised by a distorted sense of reality; an inability to distinguish subjective experiences from the objective world
Our results suggest that psychosis and genetic risk for the illness are associated with both context-dependent and context-independent abnormalities of the excitability of superficial pyramidal cell populations in the mismatch negativity (MMN) paradigm
Our main findings were that; (i) the largest differences in cortical responses between controls and the other groups were expressed at the top of the cortical hierarchy in the right inferior frontal gyrus, rather than in primary sensory areas (A1); (ii) in rIFG, both groups with an increased genetic risk for psychosis demonstrated an increase in cortical excitability across task conditions; and (iii) the two groups with a genetic risk for psychosis showed a reversal of the normal pattern of increased excitability to deviant tones in rIFG
Summary
Psychotic disorders are among the most severe and enduring mental illnesses, characterised by a distorted sense of reality; an inability to distinguish subjective experiences from the objective world. The MMN is abnormal in clinical risk groups as well as in patients, and is a promising biomarker for psychosis prediction [Bodatsch et al, 2014; Nagai et al, 2013]. The MMN has been proposed as a potential endophenotype or a biological marker of genetic risk for psychosis, because it is heritable [Hall et al, 2006, 2009; Hong et al, 2012], and abnormal in first degree relatives of patients, who have an increased genetic risk for psychosis [Jessen et al, 2001; Michie et al, 2002]. Not all studies in unaffected relatives have found MMN abnormalities [Bramon et al, 2004; Hong et al, 2012; Kim et al, 2014]
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