Abnormal frontoparietal synaptic gain mediating the P300 in patients with psychotic disorder and their unaffected relatives

Abstract

The "dysconnection hypothesis" of psychosis suggests that a disruption of functional integration underlies cognitive deficits and clinical symptoms. Impairments in the P300 potential are well documented in psychosis. Intrinsic (self-)connectivity in a frontoparietal cortical hierarchy during a P300 experiment was investigated. Dynamic Causal Modeling was used to estimate how evoked activity results from the dynamics of coupled neural populations and how neural coupling changes with the experimental factors. Twenty-four patients with psychotic disorder, twenty-four unaffected relatives, and twenty-five controls underwent EEG recordings during an auditory oddball paradigm. Sixteen frontoparietal network models (including primary auditory, superior parietal, and superior frontal sources) were analyzed and an optimal model of neural coupling, explaining diagnosis and genetic risk effects, as well as their interactions with task condition were identified. The winning model included changes in connectivity at all three hierarchical levels. Patients showed decreased self-inhibition-that is, increased cortical excitability-in left superior frontal gyrus across task conditions, compared with unaffected participants. Relatives had similar increases in excitability in left superior frontal and right superior parietal sources, and a reversal of the normal synaptic gain changes in response to targets relative to standard tones. It was confirmed that both subjects with psychotic disorder and their relatives show a context-independent loss of synaptic gain control at the highest hierarchy levels. The relatives also showed abnormal gain modulation responses to task-relevant stimuli. These may be caused by NMDA-receptor and/or GABAergic pathologies that change the excitability of superficial pyramidal cells and may be a potential biological marker for psychosis. Hum Brain Mapp 38:3262-3276, 2017. © 2017 Wiley Periodicals, Inc.

Keywords: DCM; GABA; NMDA; P300; cortical excitability; dynamic causal modeling; effective connectivity; genetic risk; intrinsic connectivity; psychosis; schizophrenia; self-inhibition; synaptic gain; unaffected relatives.

Figure 1

EEG signal to standard and oddball tones for each group (grand‐averages across subjects), at channel PZ. [Color figure can be viewed at http://wileyonlinelibrary.com]

Figure 2

Selected dipoles composing the DCM spatial model. Top‐left: studied regions over a MRI head model template; left (−59, −10, 13) and right (61, −13, 11) primary auditory cortices (l‐/r‐A1), left (−37 −48 68) and right (28 −56 63) superior parietal lobules (l‐/r‐SP), and left (−29 55 22) and right (27 60 20) superior frontal gyri (l‐/r‐SF). Coordinates reported in the Montreal Neurological Institute (MNI) system. Top right: structural model presenting the studied extrinsic (black pointed arrows) and intrinsic (black oval arrows) connections. Bottom: source reconstruction of the evoked activity for standard and target conditions, 0–600 ms time window, including all participants.

Figure 3

Preliminary DCM study for studying task condition. Top: eight studied models including bilateral intrinsic (black oval arrows) and/or forward extrinsic (black pointed arrows) modulation. These models included four combinations of extrinsic connectivity: null (n; no extrinsic), forward (f), backward (b) and forward‐backward (fb); and two intrinsic combinations: with and without intrinsic (i) modulation at all levels in the cortical hierarchy. Bottom: relative log‐evidences and posterior probabilities for each model. The winning model “f” included forward extrinsic modulation at the three hierarchy levels. l‐/r‐A1: left/right primary auditory cortices; l‐/r‐SP: left/right superior parietal lobules; l‐/r‐SF: left/right superior frontal gyri.

Figure 4

DCM study for studying diagnosis and genetic risk. Top: sixteen studied models including bilateral intrinsic (black oval arrows) and/or forward extrinsic (black pointed arrows) modulation. These models included eight bilateral combinations of intrinsic connectivity (i) and two extrinsic combinations: with and without forward (f) modulation. Bottom: relative log‐evidences and posterior probabilities for each model. The winning model “i8” included intrinsic modulation at the three hierarchy levels. l‐/r‐A1: left/right primary auditory cortices; l‐/r‐SP: left/right superior parietal lobules; l‐/r‐SF: left/right superior frontal gyri.

Figure 5

Posterior estimates of the intrinsic connections under the winning model for each source and experimental effect. Posterior probabilities are presented in the top for each posterior estimate bar. Bars lying outside the grey area show relevant changes of greater than 20%. l‐/r‐A1: left/right primary auditory cortices; l‐/r‐SP: left/right superior parietal lobules; l‐/r‐SF: left/right superior frontal gyri.

Figure 6

Intrinsic connectivity strengths under the winning model per source, group and task condition. l‐/r‐A1: left/right primary auditory cortices; l‐/r‐SP: left/right superior parietal lobules; l‐/r‐SF: left/right superior frontal gyri; St: standard; Tg: target.