No man is an island: the role of social defeat and cognition in excitation/inhibition balance in first episode psychosis

Rationale
Social defeat (SD) and cognition have been positioned as features of those at high-risk of developing psychosis (McCleery and Nuechterlein, 2019; Selten and Cantor-Graae, 2005). SD, in particular, has been hypothesised to be a mediating factor between demographic factors and increased risk of psychosis (Schalbroeck, 2023; Van Nierop et al., 2014). Moreover, the balance between excitatory and inhibitory (E/I) activity has been shown to be vital in the functioning of the brain and how information gets transferred (Gao and Penzes, 2015). The balance between E/I is largely maintained through glutamatergic and GABAergic activity, and has been hypothesised to be an intermediate phenotype for psychosis (Grent-’t Jong et al., 2018). Social defeat, cognition and E/I balance have all been understood as mechanisms in psychosis, and could provide significant insight into potential risk factors, E/I markers and novel targets for interventions (Lee et al., 2022).

Objectives
This thesis aims to investigate the relationship between social defeat, cognition, and potential E/I markers in first-episode psychosis. Additionally, this thesis anticipates to explore the interaction between the three different potential E/I markers: mismatch negativity, relative spectral band power and E/I related metabolite levels.

Methods
The data for this thesis was collected during two separate experimental study session: electroencephalography (EEG) and magnetic resonance spectroscopy (MRS). The EEG study included the use of mismatch negativity (MMN) and relative spectral band power for delta, theta, alpha, beta and gamma bands. Both the MMN and spectral band power were assessed for the FCz (fronto-central) electrode, with the MMN being measured during a visual task and the spectral band power measured during resting state. The EEG session included a SD manipulation with false feedback to induce feelings of social defeat in participants. Spectral band power was compared before and after the SD manipulation to assess the potential role of SD on frontal neural activity. A total of 21 healthy controls (HC) and 22 patients with first-episode psychosis (FEP) were recruited for the EEG sessions. Proton MRS data was acquired from the anterior cingulate cortex (ACC) and dorso-lateral prefrontal cortex (DLPFC) using a 7-tesla Siemens scanner with 32 channel head coils. A total of 20 healthy controls and 20 patients with FEP were recruited for the MRS study.
Social defeat was measured using the social defeat scale (SDS) and the social comparison rating scale (SCRS). In the EEG study session cognitive performance was measured using an adapted continuous random dot motion visual task. In the MRS study session cognitive performance was measured using the Brief Assessment of Cognition in Schizophrenia (BACS), N-Back and Stroop Colour test. There were several clinical questionnaires to assess symptoms of psychosis and other categories including: the Positive and Negative Symptom Scale, Hamilton Depression Rating Scale and Young Mania Rating Scale.

Results
In this thesis SD was seen to be consistently significantly increased in the FEP group compared to HC (p = 0.038). Moreover, SD was seen to be correlated with both positive (p = 0.036) and general (p < 0.001) symptoms of psychosis but not negative symptoms. There were several significant correlations between SD and performance across several cognitive tasks for the FEP group, but none for the HC group.
SD was associated with MMN amplitudes in the HC group (p = 0.045) but not in the FEP group. SD was not correlated with any relative frontal spectral band power in either group. Further, SD was not correlated with neither ACC nor DLPFC E/I metabolite levels in the FEP nor HC group.
The FEP group performed significantly worse than controls on the BACS, N-back and Stroop Colour test but not on the CRDM. Relative spectral power and ACC and DLPFC E/I metabolite levels were associated with performance on these cognitive tasks, whereas MMN was not.
Though not significant the FEP group had reduced MMN amplitudes and longer latency compared to controls. The relative spectral band power in the non-SD condition was slightly but non-significantly increased across all power bands aside from alpha in the FEP group compared to HC. Similarly, in the SD-induced condition there were slightly but non-significant increases in delta, theta and gamma in the FEP group compared to controls. E/I metabolite levels in the ACC were all non-significantly increased in the FEP group compared to HC. Whereas, the GABA and glutamate levels in the DLPFC were non-significantly increased and the glutamine and combined glutamate and glutamine were non-significantly decreased in the FEP group compared to HC. Moreover, spectral band power was not significantly different in the non-SD and SD condition for either controls or FEP. However, these potential E/I markers had several significant correlations between MMN, relative frontal spectral power and MRS E/I metabolite levels in both the HC and FEP.

Conclusion
There were several trend level, but non-significant findings relating to E/I metabolic differences between FEP and HC groups, and the involvement of SD and cognition. Social defeat is a consistent feature of first-episode psychosis. The lack of significant associations between potential E/I markers and SD in the FEP group could suggest that the association occurs prior to symptom onset or that SD does not directly impact glutamate and GABA. This is supported by SD’s correlation with positive and general symptoms, suggesting its involvement in the glutamate-dopamine pathway posited for these specific symptom sub-types. The non-significant differences between the control and FEP group in the MMN, spectral band power and E/I metabolite levels could suggest that glutamatergic disturbances occur in a prodromal stage prior to psychosis onset. This may also account for the lack of significant association between SD and E/I markers. The findings of an association between spectral band power and E/I metabolite levels with cognition implicates E/I balance in cognitive impairment in FEP. Despite the sample size and other limitations, this thesis established some novel links between E/I markers and SD and cognitive outcomes which could provide significant insights into disease pathology or mechanisms of psychosis.

Keywords: social defeat
mismatch negativity
MRS
GABA
glutamate
first episode psychosis
spectral analysis
psychosis
E/I balance
Advisor: Weber, L
Godlewska, B
Lennox, B