The pill and the will : pharmacological and psychological modulation of cognitive and affective processes

Background: Impairments in cognition are components of practically all psychiatric disorders and in that sense transdiagnostic factors. In both clinical and non-clinical populations, ‘hot’ and ‘cold’ cognitive control, i.e., in emotional context and non-emotional context, is strongly associated with daily functioning and physical and mental well-being. The paradigm shift that the National Institute of Mental Health (NIMH) Research Domain Criteria initiative (RDoC) has introduced, signifies that targeting the underlying biological and behavioural endophenotypes that determine mental health and illness might be more fruitful than simply focusing on symptom based diagnostic categories. Yet, little is known on how pharmacological interventions such as selective serotonin reuptake inhibitors (SSRI) and psychostimulants (CS), that are routinely used in everyday clinical praxis, affect cognitive and emotional processes beyond the symptoms they are supposed to treat.

Aim: The aim of this thesis was to compare induction and regulation of fear and disgust in healthy subjects, and to investigate how SSRI affect these processes. This basic design was expanded to also include the effect of stimulant medication on the induction and regulation of negative emotions in healthy controls and patients with ADHD. A parallel aim was to compare pharmacological emotion regulation (SSRI and CS) with psychological emotion regulation (reappraisal) and emotion regulation with skills training/ exposure (task repetition).

Methods: A multimodal approach was used to explore (i) subjective rating of emotion intensity and objective measures of performance at the behavioural level, (ii) neural underpinnings in the CNS with functional near-infrared spectroscopy (fNIRS), functional magnetic resonance imaging (fMRI) and voxel-based morphometry (VBM) and (iii) physiological components of the sympathetic nervous system (electrodermal activity), which were all evaluated in the absence and presence of pharmacological and psychological interventions, during emotion induction, emotion regulation, cognitive Stroop and emotional Stroop paradigms.

Results: Study I and IV demonstrated that emotion regulation with reappraisal is an effective strategy with robust effects on subjective emotional experience and electrodermal activity. Study II and III showed that task repetition improved performance during both cognitive and emotional Stroop tasks, and reduced electrodermal activity during cognitive Stroop, without significantly modifying emotion induction or emotion regulation.

Study II and III showed significant effects of single dose escitalopram in reducing subjective emotional experience, improving task performance during affective interference of an ongoing cognitive process, altering prefrontal activity in a task-specific manner, and blurring the differences in the electrodermal activity between fear and disgust seen at baseline. Study IV showed that single dose CS reduced emotion induction, and that emotion regulation with reappraisal was significantly more effective in reducing subjective emotional experience compared to pharmacological emotion regulation with CS.

Lastly, Study IV revealed aberrant emotion processing in patients with ADHD both at the behavioural and CNS levels, with patients reporting lower emotion induction and regulation scores, accompanied by less activation of dorsolateral prefrontal cortex, less deactivation of the default mode network and instead greater deactivation of the dorsal attention network, during emotion regulation compared to healthy controls. Structurally (VBM), less gray matter volume was found in limbic and paralimbic areas in patients with ADHD compared to healthy controls.

Conclusions and implications: Dimensional approach using behavioural endophenotypes is a fruitful framework for studying normal physiology and diagnostic and treatment aspects of psychiatric disorders. In this thesis, it is demonstrated that emotional and non-emotional cognitive processes, although part of a continuum, likely respond differentially to psychological and pharmacological interventions and skills training with task repetition. Ultimately, improved knowledge in this field will help formulate hypothesisdriven and science-informed frameworks that will guide diagnosis and treatment plans, and usher a shift in psychiatric praxis.

List of scientific papers

I. Myrto Sklivanioti Greenfield, Yanlu Wang, Mussie Msghina. Similarities and differences in the induction and regulation of the negative emotions fear and disgust: A functional near infrared spectroscopy study. Scandinavian Journal of Psychology. (2022).
https://doi.org/10.1111/sjop.12836

II. Myrto Sklivanioti Greenfield, Yanlu Wang, Mussie Msghina. Behavioural, cortical and autonomic effects of single-dose escitalopram on the induction and regulation of fear and disgust: Comparison with single-session psychological emotion regulation with reappraisal. Frontiers in psychiatry. (2023).
https://doi.org/10.3389/fpsyt.2022.988893

III. Myrto Sklivanioti Greenfield, Yanlu Wang, Lina Martinsson, Tie-Qiang Li, Mussie Msghina. Behavioural intervention with task repetition compared to pharmacological intervention with SSRI for enhancement of cognitive control in emotional and non-emotional settings. [Submitted]

IV. Myrto Sklivanioti Greenfield, Yanlu Wang, Per Thunberg, Mussie Msghina. Emotion dysregulation in adult ADHD not reversed by stimulant medication. [Manuscript]