Causal effects of psychostimulants on neural connectivity: a mechanistic, randomized clinical trial

Abstract

Background: Psychostimulants are frequently used to treat attention-deficit/hyperactivity disorder (ADHD), but side effects are common leading to many patients discontinuing treatment. Identifying neural mechanisms by which psychostimulants attenuate symptoms may guide the development of more refined and tolerable therapeutics.

Methods: We conducted a 12-week, randomized, placebo-controlled trial (RCT) of a long-acting amphetamine, lisdexamfetamine (LDEX), in patients with ADHD, ages 6-25 years old. Of the 58 participants who participated in the RCT, 49 completed pre- and post-RCT magnetic resonance imaging scanning with adequate data quality. Healthy controls (HCs; n = 46) were included for comparison. Treatment effects on striatal and thalamic functional connectivity (FC) were identified using static (time-averaged) and dynamic (time-varying) measures and then correlated with symptom improvement. Analyses were repeated in independent samples from the Adolescent Brain Cognitive Development study (n = 103) and the ADHD-200 Consortium (n = 213).

Results: In 49 participants (25 LDEX; 24 Placebo), LDEX increased static and decreased dynamic FC (DFC). However, only DFC was associated with the therapeutic effects of LDEX. Additionally, at baseline, DFC was elevated in unmedicated-ADHD participants relative to HCs. Independent samples yielded similar findings - ADHD was associated with increased DFC, and psychostimulants with reduced DFC. Static FC findings were inconsistent across samples.

Conclusions: Changes in dynamic, but not static, FC were associated with the therapeutic effects of psychostimulants. While prior research has focused on static FC, DFC may offer a more reliable target for new ADHD interventions aimed at stabilizing network dynamics, though this needs confirmation with subsequent investigations.

Trial registration: ClinicalTrials.gov NCT01415440.

Keywords: ADHD; Dynamic Functional MRI (fMRI); Lisdexamfetamine; Striatum; Structural Equation Modeling; Thalamus.

Conflict of interest statement

Conflict of interest statement: See Acknowledgements for full disclosures.

© 2022 Association for Child and Adolescent Mental Health.

Figures

Figure 1

Neuroimaging analytical overview. (A) Striatal (red) and thalamic (cyan) seed regions. (B) Clusters presenting treatment-related changes in seed-based (red, striatal; cyan, thalamic) static and dynamic functional connectivity. (C) Exploratory factor analysis of clusters and latent factors. SFC = static functional connectivity; DFC = dynamic functional connectivity; LSFC-Striatum = latent factor of striatal static functional connectivity; LSFC-Thalamus = latent factor of thalamic static functional connectivity; LDFC = latent factor of combined striatal and thalamic dynamic functional connectivity

Figure 2

Latent changes in striatal (panel A) and thalamic (panel B) static functional connectivity and dynamic functional connectivity (panel C) before (T1, red) and after treatment (T2, sapphire). FC = functional connectivity; LDEX = lisdexamfetamine

Figure 3

Path analysis to investigate associations between treatment, functional connectivity and ADHD symptoms. The first model (panel A) used two latent static FCs as parallel mediators (top, striatum; bottom, thalamus) and the second model using dynamic FC as the latent mediator. Estimated indirect effects and significance test were also present (****p < .0001; ***p < .001; **p < .01; *p < .05). ADHD = attention deficit/hyperactivity disorder; MDFC = latent change score of striatal and thalamic dynamic functional connectivity; MSFC-Striatum. = latent change score of striatal static functional connectivity; MSFC-Thalamus = latent change score of thalamic static functional connectivity

Figure 4

Replicable differences in dynamic functional connectivity between unmedicated ADHD participants and healthy controls from the ADHD-200 NYU study (panel C). Replicable differences were not detected based on static connectivity (panels A and B). NYSPI = New York State Psychiatric Institute; FC = functional connectivity; ADHD = attention deficit hyperactivity. disorder; HC = healthy control. ***p < .0001; ***p < .001; **p < .01; *p < .05

Figure 5

Replicable differences in dynamic functional connectivity between unmedicated and medicated participants with ADHD based on a subsample of participants from the ABCD study (panel C). Replicable differences were not detected based on static connectivity (panels A and B). NYSPI = New York State Psychiatric Institute; FC = functional connectivity; ADHD = attention deficit/hyperactivity. disorder; HC = healthy control. ***p < .0001; ***p < .001; **p < .01; *p < .05