A Longitudinal Study of Resting-State Connectivity and Response to Psychostimulant Treatment in ADHD

Abstract

Objective: Psychostimulants are first-line pharmacological treatments for attention deficit hyperactivity disorder (ADHD), although symptom reduction varies widely between patients and these individual differences in treatment response are poorly understood. The authors sought to examine whether the resting-state functional connectivity within and between cingulo-opercular, striato-thalamic, and default mode networks was associated with treatment response to psychostimulant medication, and whether this relationship changed with development.

Methods: Patients with ADHD (N=110; 196 observations; mean age at first observation, 10.83 years, SD=2.2) and typically developing control subjects (N=142; 330 observations; mean age at first observation, 10.49 years, SD=2.81) underwent functional neuroimaging on up to five occasions during development (age range, 6-17 years). For patients, symptoms were assessed on and off psychostimulant medication (methylphenidate-based treatments: N=132 observations, 67%; amphetamine-based treatments: N=64 observations, 33%) using the Diagnostic Interview for Children and Adolescents for parents. Linear mixed-effects models examined whether resting-state connectivity was associated with treatment response and its interaction with age. Comparisons with typically developing control subjects were performed to contextualize any significant associations.

Results: Resting-state connectivity within the cingulo-opercular network was associated with a significant interaction between treatment response and age. Specifically, worse responses to treatment compared with better responses to treatment among patients and compared with typically developing control subjects were associated with an atypical increase in cingulo-opercular connectivity with increasing age from childhood to adolescence.

Conclusions: This work delineates how resting-state connectivity may be associated over development with response to psychostimulants in ADHD. Functioning and development within the cingulo-opercular network may warrant further investigation as a contributor to differential response to psychostimulants.

Keywords: Attention Deficit Hyperactivity Disorder (ADHD); Cingulo-Opercular Network; Cognitive Neuroscience; Neurodevelopmental Disorders; Psychostimulants; Resting-State Connectivity.

Figure 1.. Shows the significant interaction between age and treatment response on cingulo-opercular connectivity.

(A). The graph shows the predicted estimates derived from the linear mixed-effects model for the effect of the interaction of age and treatment response group (worse responders, better responders and typically developing controls) on cingulo-opercular connectivity (F(2, 266)= 4.86, p=0.008). The y-axis represents the predicted mean of the Fisher-z transformed correlation coefficients for the cingulo-opercular network based on model estimates, and separate lines indicate group. Error-bars represent 95% confidence intervals. (B). Shows sagittal (left) and axial (right) views of the cingulo-opercular network. Spheres represent nodes (regions of interest) for each of the cingulo-opercular regions. Lines represent cingulo-opercular edges (connections between nodes) that were significant at a nominal p<0.05 uncorrected threshold in the follow-up edgewise analysis.