From lab to daily life: determining the acute neurochemical effects of intrusive thinking in pathological and non-pathological worriers

Background: Intrusive thinking (IT) is a transdiagnostic psychiatric symptom that causes clinically significant distress and impairments in important areas of functioning. Alterations in glutamate and GABA metabolism are posited to be implicated in the pathophysiology of many neuropsychiatric disorders, such as depression and generalized anxiety disorder[1,2]. However, in humans, levels of such metabolites are quantified ex vivo or in circulating plasma. Moreover, comparisons between pathological and healthy individuals are primarily at rest[3] and not during specific disease states, making it difficult to understand the psychobiological processes underpinning IT. The present study had two Aims: i) investigating the acute effects of an experimental induction of IT on levels of glutamate and GABA in pathological and non-pathological worriers; ii) testing daily-life validity of the results by ecological momentary assessment (EMA) of IT on the same participants. Methods: 3T-proton magnetic resonance spectroscopy (MRS) was applied in the bilateral Anterior Cingulate Cortex (ACC) and regional levels of Glx (Glutamate+Glutamine) and GABA were in vivo quantified before and after a well-replicated experimental induction of IT[4]. ACC was selected since it regulates the central autonomic network and it is involved in the clinical maintenance of IT[5]. After completed a psychiatric and clinical screening, both pathological (n = 16; 7 males) and control individuals (n = 17; 8 males) were asked to recall and describe an episode/image that had been recently intruding in their mind over and over without them wanting this to happen. Visual analog scales were administered at four time points to assess manipulation effects on self-reported momentary mood and levels of thoughts intrusiveness, repetitiveness and stuckness. Heart rate and respiration were recorded throughout MRS sessions to assess the physiological concomitants of IT[4]. Laboratory session was followed-up by a two-day EMA aimed at measuring daily-life emergence of IT. Repeated measures ANOVA and random effect regression models were used as methods of analysis. Results: The two groups did not differ in any of the examined socio-demographic and baseline variables. The induction strongly engendered levels of thoughts intrusiveness, repetitiveness and stuckness in both groups. Results showed a trend toward an increase in regional levels of GABA from pre- to post-induction in both pathological and healthy individuals, though they were not statistically significant. Notably, an opposite pattern emerged for Glx where a statistically significant Time x Goup interaction emerged (for Glx/Water: p = .04, ηp2= .18; for Glx/Cre: p=.03, ηp2= .17), with a pre- to post-induction increase in controls (ps < .05) and a decrease in pathological worriers (ps < .05). Resting levels of GABA and Glx in ACC predicted subjective responses to the induction (ps < .05) as well as daily life levels of thoughts intrusiveness and repetitiveness (ps < .05). Conclusion: Current findings suggest that dysfunctions in glutamatergic neurometabolism within ACC may contribute to the maintenance of IT in pathological individuals, and they are in line with a dimensional view of psychopathology, showing that IT has the effect of making healthy individuals neurally-like disordered ones. If replicated, present results may inform personally-tailored treatments in the framework of precision psychiatry. References [1] Brambilla P, Perez J, Barale F, Schettini G, Soares JC. GABAergic dysfunction in mood disorders. Mol Psychiatry. 2003;8(8):721-737. [2] Lener MS, Niciu MJ, Ballard ED, et al. Glutamate and Gamma-Aminobutyric Acid Systems in the Pathophysiology of Major Depression and Antidepressant Response to Ketamine. Biological Psychiatry. 2017;81(10):886-897. [3] Moriguchi S, Takamiya A, Noda Y, et al. Glutamatergic neurometabolite levels in major depressive disorder: a systematic review and meta-analysis of proton magnetic resonance spectroscopy studies. Mol Psychiatry. 2019;24(7):952-964. [4] Ottaviani C, Thayer JF, Verkuil B, et al. Physiological concomitants of perseverative cognition: A systematic review and meta-analysis. Psychological Bulletin. 2016;2016;142(3):231-25959. [5] Makovac E, Fagioli S, Rae CL, Critchley HD, Ottaviani C. Can’t get it off my brain: Meta-analysis of neuroimaging studies on perseverative cognition. Psychiatry Research: Neuroimaging. 2020;295:111020.