0
Original Investigation |

Effects of Methylphenidate on Resting-State Functional Connectivity of the Mesocorticolimbic Dopamine Pathways in Cocaine Addiction

Anna B. Konova, MA1,2; Scott J. Moeller, PhD1; Dardo Tomasi, PhD3; Nora D. Volkow, MD3,4; Rita Z. Goldstein, PhD1
[+] Author Affiliations
1Departments of Psychiatry and Neuroscience, Icahn School of Medicine at Mount Sinai, New York, New York
2Department of Psychology, Stony Brook University, Stony Brook, New York
3National Institute on Alcohol Abuse and Alcoholism, Rockville, Maryland
4National Institute on Drug Abuse, Bethesda, Maryland
JAMA Psychiatry. 2013;70(8):857-868. doi:10.1001/jamapsychiatry.2013.1129.
Text Size: A A A
Published online

Importance  Cocaine addiction is associated with altered resting-state functional connectivity among regions of the mesocorticolimbic dopamine pathways. Methylphenidate hydrochloride, an indirect dopamine agonist, normalizes task-related regional brain activity and associated behavior in cocaine users; however, the neural systems–level effects of methylphenidate in this population have not yet been described.

Objective  To use resting-state functional magnetic resonance imaging to examine changes in mesocorticolimbic connectivity with methylphenidate and how connectivity of affected pathways relates to severity of cocaine addiction.

Design  Randomized, placebo-controlled, before-after, crossover study.

Setting  Clinical research center.

Participants  Eighteen nonabstaining individuals with cocaine use disorders.

Interventions  Single doses of oral methylphenidate (20 mg) or placebo were administered at each of 2 study sessions. At each session, resting scans were acquired twice: immediately after drug administration (before the onset of effects [baseline]) and 120 minutes later (within the window of peak effects).

Main Outcomes and Measures  Functional connectivity strength was evaluated using a seed voxel correlation approach. Changes in this measure were examined to characterize the neural systems–level effects of methylphenidate; severity of cocaine addiction was assessed by interview and questionnaire.

Results  Short-term methylphenidate administration reduced an abnormally strong connectivity of the ventral striatum with the dorsal striatum (putamen/globus pallidus), and lower connectivity between these regions during placebo administration uniquely correlated with less severe addiction. In contrast, methylphenidate strengthened several corticolimbic and corticocortical connections.

Conclusions and Relevance  These findings help elucidate the neural systems–level effects of methylphenidate and suggest that short-term methylphenidate can, at least transiently, remodel abnormal circuitry relevant to the pathophysiologic characteristics of cocaine addiction. In particular, the effects of methylphenidate within striatal and cortical pathways constitute a potentially viable mechanism by which methylphenidate could facilitate control of behavior in cocaine addiction.

Figures in this Article

Sign In to Access Full Content

Don't have Access?

Register and get free email Table of Contents alerts, saved searches, PowerPoint downloads, CME quizzes, and more

Subscribe for full-text access to content from 1998 forward and a host of useful features

Activate your current subscription (AMA members and current subscribers)

Purchase Online Access to this article for 24 hours

Figures

Place holder to copy figure label and caption
Figure 1.
Center Coordinates and Locations of the Mesocorticolimbic Seed Regions (Color Boxes)

The listed x, y, z coordinates follow Montreal Neurological Institute convention. ACC indicates anterior cingulate cortex; Amyg, amygdala; BA, Brodmann area; Hipp, hippocampus; MDN Thal, mediodorsal nucleus thalamus; NAcc, nucleus accumbens; and VTA, ventral tegmental area.

Graphic Jump Location
Place holder to copy figure label and caption
Figure 2.
Changes in Hippocampal (Hipp) Connectivity With Methylphenidate

Increased left (L) postcentral gyrus (Brodmann areas [BAs] 4, 6) functional connectivity with the right (R) (A and C) and L (B and D) Hipp seeds (shown in red) following a single dose of oral methylphenidate hydrochloride, 20 mg. Color maps (A and B) show increased connectivity strength with methylphenidate vs placebo (orange) in a T-score window from ±3.0 to ±7.0. Bar plots (C and D) show the Fisher Z values for placebo peak effects (light gray) and methylphenidate peak effects (dark gray) plotted from values of healthy control participants scanned during placebo conditions. Error bars represent SEM. *P < .005. †P < .05.

Graphic Jump Location
Place holder to copy figure label and caption
Figure 3.
Changes in Rostral Anterior Cingulate Connectivity With Methylphenidate

Increased left (L) rostral anterior cingulate cortex (ACC) (Brodmann area [BA] 24) (seed shown in green) with right (R) parahippocampal gyrus connectivity and decreased L rostral anterior cingulate with inferior parietal cortex connectivity following a single dose of oral methylphenidate hydrochloride, 20 mg. Color map (A) shows increased (orange) or decreased (cyan) connectivity strength with methylphenidate vs placebo in a T-score window from ±3.0 to ±7.0. Bar plots (B and C) show the Fisher Z values for placebo peak effects (light gray) and methylphenidate peak effects (dark gray) plotted from values of healthy control participants scanned during placebo conditions. Error bars represent SEM. IPL indicates inferior parietal lobule. *P < .05.

Graphic Jump Location
Place holder to copy figure label and caption
Figure 4.
Changes in Nucleus Accumbens (NAcc) Connectivity With Methylphenidate and Relationship to Addiction Severity

Increased right (R) NAcc (A) (seed shown in white) with R superior temporal gyrus (STG) extending to the postcentral gyrus and rolandic operculum connectivity (C) and decreased R NAcc with left (L) putamen/globus pallidus (GP) connectivity (D) following a single dose of oral methylphenidate hydrochloride, 20 mg. Color map (A) shows increased (orange) or decreased (cyan) connectivity strength with methylphenidate vs placebo in a T-score window from ±3.0 to ±7.0. Bar plots (C and D) show the Fisher Z values for placebo peak effects (light gray) and methylphenidate peak effects (dark gray) plotted from values of healthy control participants scanned during placebo conditions. Error bars represent SEM. The connectivity strength between the R NAcc and L putamen/GP during placebo (C) was uniquely positively correlated with the severity of cocaine addiction composite scores (B). *P < .005. †P < .05.

Graphic Jump Location

Tables

References

Correspondence

CME
Meets CME requirements for:
Browse CME for all U.S. States
Accreditation Information
The American Medical Association is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians. The AMA designates this journal-based CME activity for a maximum of 1 AMA PRA Category 1 CreditTM per course. Physicians should claim only the credit commensurate with the extent of their participation in the activity. Physicians who complete the CME course and score at least 80% correct on the quiz are eligible for AMA PRA Category 1 CreditTM.
Note: You must get at least of the answers correct to pass this quiz.
You have not filled in all the answers to complete this quiz
The following questions were not answered:
Sorry, you have unsuccessfully completed this CME quiz with a score of
The following questions were not answered correctly:
Commitment to Change (optional):
Indicate what change(s) you will implement in your practice, if any, based on this CME course.
Your quiz results:
The filled radio buttons indicate your responses. The preferred responses are highlighted
For CME Course: A Proposed Model for Initial Assessment and Management of Acute Heart Failure Syndromes
Indicate what changes(s) you will implement in your practice, if any, based on this CME course.
NOTE:
Citing articles are presented as examples only. In non-demo SCM6 implementation, integration with CrossRef’s "Cited By" API will populate this tab (http://www.crossref.org/citedby.html).
Submit a Comment

Multimedia

Some tools below are only available to our subscribers or users with an online account.

Web of Science® Times Cited: 2

Sign In to Access Full Content

Related Content

Customize your page view by dragging & repositioning the boxes below.

Articles Related By Topic
Related Topics
PubMed Articles
Jobs
brightcove.createExperiences();