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.

Alterations in Schizophrenia-Associated Genes Can Lead to Increased Power in Delta Oscillations

“…Previous computational studies on the topic have been performed using less detailed biophysical modeling, such as dynamic causal modeling (DCM). In one study, patients with psychosis and healthy controls performed an oddball paradigm task during EEG (Díez et al 2017). The researchers used DCM to construct a neural mass model that predicted a decrease in frontal inhibitory connections in patients with psychosis, which led to local hyperexcitability of superficial pyramidal cells.…”

“…Using similar methods in a mismatch negativity paradigm, an increase in the excitability of superficial pyramidal cells of inferior frontal gyrus was predicted in patients with psychosis in Ranlund et al (2016). However, due to the spatial overlap between deep layer and superficial layer neuron populations, their contributions to the EEG signal can easily be mixed, and thus, we suspect that the predictions obtained for superficial populations in Ranlund et al (2016) and Díez et al (2017) may apply to L5PC populations as well. Network models more detailed than that of Ranlund et al (2016) and Díez et al (2017) (based on the microcircuit model of Bastos et al 2012) could be used to more accurately characterize the source of neural alterations observed in patients with psychosis, which would allow a more detailed comparison of the results of biophysically detailed modeling of L5PCs and DCM-based results.…”

Working Memory Load Modulates Neuronal Coupling

“…It has been validated pharmacologically (Muthukumaraswamy et al 2015), using data from single-gene mutation channelopathy (Gilbert et al 2016) and aging studies (Cooray et al 2014;Moran et al 2014). The model has also explained the manipulation of sensory expectation and attention engaging frontoparietal networks in healthy subjects and patients (Auksztulewicz and Friston 2015;Cooray et al 2014;Díez et al 2017;Phillips et al 2015;Ranlund et al 2016). A very similar model was recently used to explain context-dependent dynamics in hierarchical brain networks (Mejias et al 2016).…”

“…The first 2 datasets included CSD data from trials with 1 contralateral object, from the early (500-900 ms after sample onset) or late (1100-1500 ms after sample onset) delay period. The last 2 datasets included CSD data from trials with (Heinzle et al 2007;Ma et al 2012;Phillips et al 2015;Ranlund et al 2016;Díez et al 2017). We have omitted extrinsic connections between PFC and LIP in the figure and depicted 1 out of 4 possible connection patterns that correspond to results from anatomical studies (Hilgetag et al 2016).…”

Top-Down Disconnectivity in Schizophrenia During P300 Tasks

“…Using approaches that rely on the physiological models, such as Dynamic Causal Modeling (DCM) (Friston et al, 2003 ), the dynamic patterns among multiple specialized areas can be marked out and further adopted to account for the mechanism of brain functions (Brázdil et al, 2007 ; Liu et al, 2016 ), as well as the cognitive deficits in SZs (Dima et al, 2010 ; Wagner et al, 2015 ). For example, in DCM study conducted by Diez et al, the atypical frontoparietal synaptic gain was verified to mediate the generations of P300s in patients with psychtoic disorder when comapred to their unaffected relatives (Diez et al, 2017 ). Previous studies have proved the great importance of coupled top-down flows of the brain in regulating P300s (Li et al, 2015 , 2016 ); meanwhile, the dysfunctions of multiple brain regions, such as dorsolateral PFC (DLPFC) and IPS, have also been claimed to be responsible for the cognitive deficits in SZs (Ohtani et al, 2014 ; Mouchlianitis et al, 2015 ).…”