Glutamatergic changes in the medial prefrontal cortex associated with psychosis history in bipolar disorder and their relationship to executive function
C.-Y. Chang1, C.Y. Wu2, S.-Y. Wei2, H.H. Chang3,4, T.-H. Lu2, W.H. Chang2,5, C.-F. Hsu6, R.-Y. Lin7,8, F.-Z. Shaw7,9, Y.K. Yang2,10, P.S. Chen2,10, H.-H. Tseng2,10
1National Taiwan University Hospital, College of Medicine, National Taiwan University, Department of Psychiatry, Taipei, Taiwan, 2National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Department of Psychiatry, Tainan, Taiwan, 3National Cheng Kung University, Institute of Clinical Pharmacy and Pharmaceutical Sciences, Tainan, Taiwan, 4National Cheng Kung University, School of Pharmacy, College of Medicine, Tainan, Taiwan, 5National Cheng Kung University Hospital, Dou-Liou Branch, Department of Psychiatry, Yunlin, Taiwan, 6College of Medicine, National Cheng Kung University, Department of Occupational Therapy, Tainan, Taiwan, 7National Cheng Kung University, Tainan, Taiwan 10Department of Psychology, National Cheng Kung University, Mind Research and Imaging Center, Tainan, Taiwan, 8National Cheng Kung University, Department of Psychology, Tainan, Taiwan, 9National Cheng Kung University, Tainan, Taiwan 11Institute of Behavioral Medicine, College of Medicine, Department of Psychology, Tainan, Taiwan, 10College of Medicine, National Cheng Kung University, Institute of Behavioral Medicine, Tainan, Taiwan
Background: Psychosis affects over half of individuals with bipolar disorder (BD) and has been linked to glutamatergic dysfunction within the default mode network (DMN). Altered glutamate/GABA signaling in the DMN may contribute to cognitive deficits, yet findings remain inconsistent. Differences between BD with (BD-P) and without past psychotic experiences (BD-NP) remain underexplored, underscoring the need for further investigation.
Aims & Objectives: This study aims to examine excitatory and inhibitory neurotransmitter levels, their ratio, and their relationship with executive function in key default mode network (DMN) hubs among BD-P and BD-NP.
Method: We recruited 78 BD patients, comprising 32 BD-P and 46 BD-NP. Proton magnetic resonance spectroscopy (¹H-MRS) was performed in the posterior cingulate cortex (PCC) and medial prefrontal cortex (mPFC) to quantify excitatory glutamate/glutamine (Glx) and inhibitory GABA, yielding an E/I ratio. Cognitive flexibility was assessed using the Wisconsin Card Sorting Test (WCST), and sustained attention with the Continuous Performance Test (CPT).
Results: BD-P exhibited higher mPFC Glx (p = 0.009) and Glu (p < 0.001) compared to BD-NP, while E/I ratios did not differ in either region. In BD-NP, cognitive flexibility, indexed by WCST completed categories, correlated negatively with mPFC E/I ratio (r = -0.35, p = 0.018), and higher E/I ratio predicted poorer cognitive flexibility after controlling for covariates (β = -0.21, p = 0.014).
Discussion & Conclusions: Elevated mPFC Glu and Glx in BD-P suggest that localized glutamatergic hyperactivity may underlie psychotic experience of BD. The negative association between mPFC E/I ratio and cognitive flexibility observed only in BD-NP indicates that glutamatergic regulation of executive function differs by psychosis history, potentially reflecting compensatory mechanisms in BD-NP versus more diffuse network dysregulation in BD-P.
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