>Magister Scientiae - MSc / INTRODUCTION: Sustained attention is known to be dysfunctional in psychotic disorders. Sustained attention is the ability to remain focused on a specific time-locked stimulus within a task. We aimed to determine whether there are specific group differences between CON and three psychotic disorders: SCZ, MPD and BPD, then to determine differences between these psychotic disorders. This included differences in behavioural performance and prominent electrophysiological event-related potential (ERP) wave components during cueing and target processing of a visual sustained attention task. Further we aimed to characterize ERP waveform component relationships across and within these groups for demographics, substance use, behavioural performance, and clinical variables, the last limited to the psychotic groups. Lastly, we investigated the effects of prescribed medications on ERP wave components within the psychotic groups. METHODOLOGY: 103 participants (29 schizophrenia (SCZ), 28 bipolar disorder with a history of psychosis (BPD), 21 methamphetamine-induced psychotic disorder (MPD), and 30 controls (CON)) underwent electroencephalography (EEG) record while completing a visual continuous performance task. Participants were presented with 60 trials with three consecutive S’s, the presentation of the third S required a behavioural response. Prominent ERP waveform components were extracted from cues and target stimulus. Group differences were determined by ANOVA with Bonferroni post-hoc correction or multivariate Kruskal-Wallis test dependent on data distribution. Relationships between ERP wave components were determined appropriate with Spearman’s Rank order correlation analyses. RESULTS: (1) MPD reported higher use of substances compared to CON, SCZ and BPD. SCZ behavioural performance was poorer compared to CON which was shown by their longer response times, reduced accuracy and increased errors of omission. Clinically, MPD was found to have a shorter duration of illness compared to SCZ. Then SCZ was found to have more positive symptoms compared to BPD whereas BPD had more negative symptoms compared to SCZ. For the first cue, wave component differences were found only over the left hemisphere, for P100 amplitude over the frontal cortex, P300 amplitude over the central cortex, and N170 amplitude over the parietal cortex. For the presentation of the second cue, differences noted for all groups were localised to the frontal and central brain regions, for P100 and N170 ERP waveforms. For the target stimulus wave component differences were found over the prefrontal, frontal and parietal brain regions, within CON, SCZ, BPD and MPD. (2) For the first cue, education positively correlated with the N170 left parietal amplitude in CON and P300 right parietal amplitude in MPD. During the second cue, the left parietal N170 latency in SCZ correlated positively with education and the left central P300 latency correlated negatively with education in MPD. The age on the day of testing correlated positively with the target left frontal P300 latency in MPD. For the first cue, substance use positively correlated with the left and right parietal P300 latency and negatively for the right parietal P100 amplitude in SCZ. In MPD, a negative correlation was noted across left and right prefrontal N170 and P300 amplitudes, and positive correlation for the left prefrontal P300 latency in MPD. For the target stimulus, correlations were evident for the left and right parietal N70, N170 amplitudes, P300 latency, the right parietal P100 amplitude and left central P300 latency in SCZ. For the first cue, in SCZ PANSS total score correlated positively with left and right central P300 amplitudes and the left parietal P300 amplitude. For the second cue; in MPD, the PANSS negative symptom score, positively correlated with the P100 and N170 left parietal amplitude, left and right parietal P150 amplitude, left central and right parietal P300 amplitude. For the target, the Hamilton depression rating scale correlated positively with the left and right frontal P300 amplitude in MPD and then negatively with the right parietal P300 amplitude in SCZ. Behavioural performance in CON, positively correlated with the left parietal N70, P100, P150 and N170 amplitude the number of correct responses, and left central N170 amplitude. While the number of impulsive responses correlated negatively with the left parietal N70, P100, P150 and N170 and the left central N170 amplitude of CON. For the second cue, behavioural performance was related to the fronto-parietal relationship across all groups. For the target stimulus, impulsive responses positively correlated with the left parietal N70 latency in SCZ. Overall response time negatively correlated with the right parietal P300 latency for SCZ. (3) Medication was found to affect ERP wave components during the sustained visual attention task. For the first cue FGA’s increased the left central P100 amplitude in both SCZ and BPD and decreased the left parietal P100 amplitude in SCZ only. The use of antipsychotics increased the right parietal N70 and left central P100 amplitudes in BPD, specifically the right prefrontal N170 amplitude was increased with the use of SGA’s. Then clozapine use increased the left frontal P100 amplitude in SCZ. For the second cue, SGA’s decreased the right parietal P150 amplitude in SCZ but in MPD the right parietal P150 amplitude was increased with haloperidol use, and FGA. SGA’s increased the left parietal P300 latency in BPD and sodium valproate decreased the left prefrontal P300 latency. For the target stimulus, SGA’s decreased the right parietal P100, P150 and left parietal P150 amplitudes and increased the left central P300 latency in BPD. CONCLUSION: (1) sustained attentional performance is poorer in SCZ. Our study adds to previous studies showing attention processing deficits in SCZ, are evident during cueing of a sustained attention tasks; (2) substance use was found to slow cognitive processing, education improved executive function and information processing, and symptom severity was associated with dysfunction of prefrontal and frontal cortices; (3) antipsychotic medication was related to improved processing of salient information. These data support the current literature and provide novel insights to the attentional processing deficits during cueing in the psychotic disorders.

Genome-wide association studies (GWASs) have reported numerous associations between risk variants and major psychiatric disorders (MPDs) including schizophrenia (SCZ), bipolar disorder (BPD), major depressive disorder (MDD) and others. We reviewed all of the published GWASs, and extracted the genome-wide significant (p<10) and replicated associations between risk SNPs and MPDs. We found the associations of 6 variants located in 6 genes, including L type voltage-gated calcium channel (LTCCs) subunit alpha1 C gene (), that were genome-wide significant ( ) and replicated at single-point level across at least two GWASs. Among them, the associations between MPDs and rs1006737 within are most robust. Thus, as a next step, the expression of the replicated risk genes in human hippocampus was analyzed. We found had significant mRNA expression in human hippocampus in two independent cohorts. Finally, we tried to elucidate the roles of venlafaxine and ω-3 PUFAs in the mRNA expression regulation of the replicated risk genes in hippocampus. We used cDNA chip-based microarray profiling to explore the transcriptome-wide mRNA expression regulation by ω-3 PUFAs (0.72/kg/d) and venlafaxine (0.25/kg/d) treatment in chronic mild stress (CMS) rats. ω-3 PUFAs and venlafaxine treatment elicited significant up-regulation. We concluded that might confer the genetic vulnerability to the shared depressive symptoms across MPDs and CACNA1C might be the therapeutic target for depressive endophenotype as well.