A neuroimaging perspective on regulation of emotion, reward, and attention

Emotional symptoms and non-emotional symptoms such as inattention often co-occur. Each of these symptom domains covers symptoms that are distributed along a continuum across the population; from non-clinical levels to clinically significant psychiatric symptoms. In this PhD project, we have focused on emotional symptoms related to emotional instability, i.e. rapidly fluctuating emotional responses and behaviors. Emotional instability is common in psychiatric diagnoses such as conduct disorder (CD) in children and emotionally unstable personality disorder (EUPD) in adults. Similarly, non-emotional symptoms such as inattention, are common in attention-deficit hyperactivity disorder (ADHD). Since emotional instability symptoms and non-emotional symptoms often co-occur, so do many psychiatric diagnoses associated with them.

The overarching aim of this PhD project was to try to disentangle concurrent emotional and non-emotional neural processes, behaviors, and symptoms. We aimed to correlate emotional and non-emotional symptoms to neural and behavioral measurements, while adjusting for the other symptom domain, in order to tease out the unique contributions of each symptom domain and related neural correlates. The four studies included in the project address this overarching aim from slightly different angles, for example by including adolescents and adults, non-clinical and clinical populations, and structural and functional neuroimaging techniques. Our hypothesis was that emotional instability and non-emotional ADHD/inattention symptoms–and behavioral and neural correlates–could be disentangled to some degree.

Some neural regions were of particular importance to this PhD project. Lateral orbitofrontal cortex (lOFC), rostral anterior cingulate cortex (rACC), and ventral striatum (VS)/nucleus accumbens (NAcc) served as primarily “emotional” cortical and subcortical regions of interest (ROIs), and their structure and function were hypothesized to relate to emotional instability symptoms. Similarly, dorsolateral/dorsomedial prefrontal cortex (dl/dmPFC) and caudal anterior cingulate cortex (cACC) were chosen as primarily “non-emotional” ROIs, of which structure and function was hypothesized to be associated to non-emotional ADHD/inattention symptoms.

Study I investigated how structural brain measures in a large community sample of 14-year-olds correlated with emotional instability and non-emotional ADHD symptoms. We found that surface area (SA) of dl/dmPFC and cACC correlated negatively with non-emotional ADHD symptoms, when adjusting for emotional instability symptoms. Grey matter volume (GMV) of rACC correlated negatively with emotional instability symptoms, when adjusting for non-emotional ADHD symptoms. Study II followed up on Study I by correlating structural cortical and subcortical brain measurements of adults with and without ADHD with emotional instability and non-emotional inattention symptoms. We observed a negative correlation between GMV of NAcc (and the caudate) and emotional instability symptoms, adjusting for non-emotional inattention symptoms. In contrast to Study I, we could not show any correlations between cortical brain measurements and emotional instability or non-emotional inattention symptoms in this adult cohort. Study III employed functional magnetic resonance imaging (fMRI) to investigate how neural activation (as estimated by the blood-oxygen-level-dependent (BOLD) response) during anticipation and outcome of reward related to emotional instability and non-emotional inattention symptoms in non-clinical adults. There were no correlations between VS activation during reward anticipation, or ACC and insula activation during reward outcome, and emotional instability or non-emotional inattention symptoms in the sample as a whole. However, in a subsample of females only, VS activation during reward anticipation correlated negatively with emotional instability symptoms, when adjusting for non-emotional inattention symptoms. Finally, Study IV also used fMRI to investigate neural activation during emotional and non-emotional conflict processing, and how that activation related to emotional instability and non-emotional inattention symptoms, in a sample of non-clinical adults. Emotional instability symptoms correlated positively with rACC activation during emotional conflict adjustment (contrasted against non-emotional conflict adjustment), when correcting for non-emotional inattention symptoms. Activation in cACC/dmPFC during exposure to cognitive conflict, or dlPFC activation during non-emotional conflict adjustment, did not correlate with non-emotional inattention symptoms.

Taken together, we found partial support for our overarching hypothesis that emotional instability and non-emotional ADHD/inattention symptoms–and behavioral and neural correlates–may be disentangled to some degree. The findings from Study I through IV, in combination with new literature that has emerged since the start of this PhD project, led to a discussion on future possible separation of emotional and non-emotional symptoms and underlying neural mechanisms Understanding these mechanisms will hopefully help develop a deeper understanding of related psychiatric diagnoses, and help pave the way for new, more individualized, treatments.

List of scientific papers

I. Frida Bayard*, Charlotte Nymberg Thunell*, Christoph Abé, Rita Almeida, Tobias Banaschewski, Gareth Barker, Arun L.W. Bokde, Uli Bromberg, Christian Büchel; Erin Burke Quinlan, Sylvane Desrivières, Herta Flor, Vincent Frouin, Hugh Garavan, Penny Gowland, Andreas Heinz, Bernd Ittermann, Jean-Luc Martinot, Marie-Laure Paillère Martinot, Frauke Nees, Dimitri Papadopoulos Orfanos, Tomáš Paus, Luise Poustka, Patricia Conrod, Argyris Stringaris, Maren Struve, Jani Penttilä, Viola Kappel, Yvonne Grimmer, Tahmine Fadai, Betteke van Noort, Michael N. Smolka, Nora C. Vetter, Henrik Walter, Robert Whelan, Gunter Schumann, Predrag Petrovic, the IMAGEN Consortium. Distinct brain structure and behavior related to ADHD and conduct disorder traits. Molecular Psychiatry. 2020 Nov; 25(11):3020-3033. *Co-first authors.
https://doi.org/10.1038/s41380-018-0202-6

II. Frida Bayard, Christoph Abé, Eva Henje, Orestis Floros, Timea Sparding, Martin Ingvar, Mikael Landén*, Predrag Petrovic*. Smaller nucleus accumbens in ADHD patients and healthy individuals relates to emotional instability but not inattention. *Co-senior authors. [Submitted]

III. Frida Bayard, Christoph Abé, Nathalie Wrobel, Martin Ingvar, Eva Henje, Predrag Petrovic. Emotional instability relates to ventral striatum activity during reward anticipation in females. Frontiers of Behavioral Neuroscience. 2020, volume 14, article 76.
https://doi.org/10.3389/fnbeh.2020.00076

IV. Frida Bayard*, Orestis Floros*, Christoph Abé, Eva Henje, Martin Ingvar, Predrag Petrovic. Neural activation during emotional and non-emotional conflict processing and its relationship with symptoms of emotional instability and inattention. *Co-first authors. [Manuscript]