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Targeting emotional dysregulation in adult attention-deficit hyperactivity disorder
Antonia Kaiser1,2,3, Liesbeth Reneman1,2, Paul J. Lucassen2,3, Taco de Vries4, Anne Marije Kaag2,5,6, and Anouk Schrantee1,2,3,7

1Department of Radiology and Nuclear Medicine, Amsterdam UMC, University of Amsterdam, Amsterdam, Netherlands, 2Amsterdam Neuroscience, Amsterdam, Netherlands, 3Swammerdam Institute for Life Sciences, Center for Neurosciences, University of Amsterdam, Amsterdam, Netherlands, 4Dept. Anatomy and Neuroscience, Neuroscience Campus Amsterdam, Amsterdam UMC, Vrije Universiteit, Amsterdam, Netherlands, 5Addiction Development and Psychopathology (ADAPT) Lab, Department of Psychology, University of Amsterdam, Amsterdam, Netherlands, 6Department of Psychiatry, Amsterdam UMC, University of Amsterdam, Amsterdam, Netherlands, 7Spinoza Centre for Neuroimaging, Royal Netherlands Academy of Arts and Sciences (KNAW), Amsterdam, Netherlands

Synopsis

Emotional dysregulation (ED) is a core symptom of ADHD. Previous studies suggested that taxing WM can reduce amygdala hyper-responsiveness (associated with ED), using traditional emotional interference tasks. However, these tasks make it impossible to disentangle emotional and WM mechanisms. We therefore conducted an fMRI study, in ADHD patients and controls, using a modified, emotional interference task to assess WM-task induced brain activity and its possible interaction with activity induced by emotional stimuli. Our results suggest that taxing WM has no direct effect on improving emotional regulation in ADHD. This stresses the importance of tasks that disentangle emotional and WM mechanisms.

Introduction

One of the core symptoms of Attention-Deficit/Hyperactivity Disorder (ADHD) is emotional dysregulation (ED). It often results in irrelevant emotional stimuli disrupting goal-oriented processes1. Previous studies have demonstrated that ADHD patients exhibit a hyper-responsiveness of the amygdala to negative emotional stimuli2. In healthy controls and other psychiatric populations, it has been shown that activating prefrontal control circuits, e.g. by means of working-memory (WM) tasks, can reduce amygdala hyper-responsiveness by enhancing top-down control3,4. Therefore, WM training has been suggested as an add-on behavioral therapy to reduce ED5. However, in ADHD patients it is unclear if taxing WM can reduce amygdala hyperactivity because ADHD patients might have WM deficits6. Previous studies investigating the influence of taxing WM on emotional processing, have used traditional emotional interference tasks, in which emotional stimuli are presented during executive processes5. However, using these tasks, it is impossible to disentangle the effect of WM processes on emotional processing from the effect of negative emotion induction on WM processes. We therefore conducted an fMRI study, in which both ADHD patients and healthy controls underwent a modified, emotional interference task to assess WM-task induced brain activity and its possible interaction with activity induced by emotional stimuli. We hypothesized that ADHD would be associated with impaired WM and ED. Consequently, we hypothesized that taxing WM would reduce emotional responsiveness in ADHD patients to a smaller extent than in controls.

Methods

We included 30 male AD(H)D patients and 30 matched healthy controls (figure 1). Passive blocks of emotional and neutral stimuli were preceded by active WM blocks with either a low (0-back) or high (2-back) WM load (figure 2). Images were taken from the International Affective Pictures System (IAPS)7.

MRI-scans were conducted on a 3T Philips scanner using a 32-channel head coil. A T1-weighted scan was acquired using a 3D-TFE (resolution=0.8mm³, FOV=240x256x200mm, TR/TE=9.8ms/4.5ms, FA=8°). Functional scans were acquired using a 2D-GE-EPI sequence (resolution=2.5x2.5x2.2mm, FOV=240x240x131.8mm, TR/TE=1500ms/30ms, FA=70°, MB-factor=3, SENSE=1.5).

Data were preprocessed using FMRIPREP, including distortion correction and ICA-AROMA8. Beta coefficients were extracted from regions of interest (ROI) in the left and right amygdala (LAmyg, RAmyg) and the paracingulate-gyrus (PaCG) using FSL (figure 3A+B). WM-related activity was compared by contrasting 0-back to 2-back blocks (figure 3C+D). Emotion-induced activity was assessed by contrasting emotional to neutral images (figure 3E+F). The influence of WM-blocks on emotional blocks and vice versa was assessed by subdividing the blocks depending on the preceding block (figure 2B+C). After the MRI, participants underwent a recognition task, and rated the images on emotional valence. Continuous variables were assessed with (non-)parametric t-tests.

Results

Behaviorally, no group difference in WM performance was found (0-back: p=0.71; 2-back: p=0.07) (figure 4A). Images preceded by a 2-back block were recognized significantly less accurate than images preceded by a 0-back block, regardless of emotional content (main effect: p<0.01) (figure 4C). Emotional images were rated as more negative than the neutral images (p<0.01) (figure 4B).

Despite a main effect of emotional blocks (LAmyg: p<0.01; RAmyg: p<0.01; PaCG p=0.31) and WM (LAmyg p<0.01; RAmyg p<0.01; PaCG p<0.01) (figure 5A+D), fMRI results did not show significant interactions between WM and emotional blocks (LAmyg: p=0.76; RAmyg: p=0.68; PaCG: p=0.48). Moreover, there were no significant differences found between groups. However, exploratory analyses showed significant higher PaCG activity in controls compared to ADHD patients during emotional images preceded by 2-back vs. 0-back blocks (p=0.02) (figure 5B). Additionally, we found significantly lower LAmyg activity during 2-back blocks preceded by emotional vs. neutral stimuli in ADHD patients compared to controls (p=0.04) (figure 5E).

Discussion and Conclusion

Contrary to our hypothesis we did not detect amygdala hyperactivity to emotional stimuli in ADHD patients. Additionally, we did not find evidence supporting impaired WM mechanisms in ADHD patients. No group differences were found in the effect of WM on emotional processing and vice versa. However, amygdala activity during a high-load WM block was reduced when being preceded by negative emotional stimuli in ADHD patient. In addition, the PaCG responsiveness during a negative emotions block was increased when being preceded by a high-load WM block, in controls.

This suggests that inducing a negative emotional state reduces emotional arousal during WM processes in ADHD, whereas taxing WM improves cognitive control during processing of negative emotional stimuli in controls only. Summarizing, the results of this study suggest that taxing WM has no direct effect on improving emotional responsiveness in ADHD. Moreover, this stresses the importance of using tasks that disentangle emotional and WM mechanisms, to be able to fully understand the potential of using WM training as an add-on therapy for ADHD.

Acknowledgements

We would like to thank Juliette van Seventer and Simon Poortman for their contribution to this project.

References

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Figures

FIGURE 1. | Demographics: Participants were matched on age, education, smoking, alcohol and substance use. The ADHD-RS was used to measure ADHD severity in the ADHD group and to exclude controls with ADHD symptoms (cut-off score = 4)10. ADHD patients show slightly, but significantly more motion compared to controls. AUDIT = Alcohol Use Disorders Identification Test; CUDIT= Cannabis Use Disorders Identification Test; DUDIT = Drug Use Disorders Identification Test; ADHD-RS = ADHD Rating Scale; FD = frame-wise displacement.

FIGURE 2. | Study design: A) Interleaved active n-back blocks and passive emotional stimuli blocks. B) The effect of WM blocks preceding emotional stimuli was assessed by subdividing the emotional stimuli into four conditions: emotional-after-0-back (0E), emotional-after-2-back (2E), neutral-after-0-back (0N), neutral-after-2-back (2N). C) Conversely, the effect of emotional stimuli preceding WM blocks was assessed with the following conditions: 0-back-after-emotional (E0), 2-back-after-emotional (E2), 0-back-after-neutral (N0), 2-back-after-neutral (N2).

FIGURE 3. | ROIs and voxel-based main effects: A) The amygdala was defined as a ROI to assess the response to negative emotional stimuli11. B) The PaCG mask was selected to assess the effect of the WM task11. C+D) Main effect of negative emotional vs. neutral stimuli in ADHD patients (C) and controls (D). E+F) Main effect of 2-back vs. 0-back blocks in ADHD patients (E) and controls (F).

FIGURE 4. | Behavioral results: A) Task performance was significantly lower for 2-back than 0-back. B) ADHD patients, as well as controls, rated the emotional images as more negative than the neutral images (lower values are more negative). C) Images, regardless of emotions, were recognized less correctly (white) when they were preceded by a 2-back block. * p<0.05; ** p<0.01.

FIGURE 5. | fMRI results: A) Main effect of the emotional vs. the neutral blocks. B+C) During emotional images (B), but not neutral images (C) preceded by 2-back vs. 0-back PaCG activity of controls was found to be higher than in ADHD patients. D) Main effect of the 2-back vs. 0-back blocks. E+F) ADHD patients show a lower left amygdala activity during the 2-back (E), but not 0-back task (F) when preceded by emotional images. * p<0.05

Proc. Intl. Soc. Mag. Reson. Med. 27 (2019)
0715