0
We're unable to sign you in at this time. Please try again in a few minutes.
Retry
We were able to sign you in, but your subscription(s) could not be found. Please try again in a few minutes.
Retry
There may be a problem with your account. Please contact the AMA Service Center to resolve this issue.
Contact the AMA Service Center:
Telephone: 1 (800) 262-2350 or 1 (312) 670-7827  *   Email: subscriptions@jamanetwork.com
Error Message ......
Original Investigation |

Dopamine-Related Disruption of Functional Topography of Striatal Connections in Unmedicated Patients With Schizophrenia

Guillermo Horga, MD, PhD1,2; Clifford M. Cassidy, PhD1,2; Xiaoyan Xu, PhD1,2; Holly Moore, PhD1,3; Mark Slifstein, PhD1,2; Jared X. Van Snellenberg, PhD1,2; Anissa Abi-Dargham, MD1,2
[+] Author Affiliations
1Department of Psychiatry, Columbia University College of Physicians and Surgeons, New York, New York
2Division of Translational Imaging, New York State Psychiatric Institute, New York
3Division of Integrative Neuroscience, New York State Psychiatric Institute, New York
JAMA Psychiatry. 2016;73(8):862-870. doi:10.1001/jamapsychiatry.2016.0178.
Text Size: A A A
Published online

Importance  Despite the well-established role of striatal dopamine in psychosis, current views generally agree that cortical dysfunction is likely necessary for the emergence of psychotic symptoms. The topographic organization of striatal-cortical connections is central to gating and integration of higher-order information, so a disruption of such topography via dysregulated dopamine could lead to cortical dysfunction in schizophrenia. However, this hypothesis remains to be tested using multivariate methods ascertaining the global pattern of striatal connectivity and without the confounding effects of antidopaminergic medication.

Objectives  To examine whether the pattern of brain connectivity across striatal subregions is abnormal in unmedicated patients with schizophrenia and whether this abnormality relates to psychotic symptoms and extrastriatal dopaminergic transmission.

Design, Setting, and Participants  In this multimodal, case-control study, we obtained resting-state functional magnetic resonance imaging data from 18 unmedicated patients with schizophrenia and 24 matched healthy controls from the New York State Psychiatric Institute. A subset of these (12 and 17, respectively) underwent positron emission tomography with the dopamine D2 receptor radiotracer carbon 11–labeled FLB457 before and after amphetamine administration. Data were acquired between June 16, 2011, and February 25, 2014. Data analysis was performed from September 1, 2014, to January 11, 2016.

Main Outcomes and Measures  Group differences in the striatal connectivity pattern (assessed via multivariable logistic regression) across striatal subregions, the association between the multivariate striatal connectivity pattern and extrastriatal baseline D2 receptor binding potential and its change after amphetamine administration, and the association between the multivariate connectivity pattern and the severity of positive symptoms evaluated with the Positive and Negative Syndrome Scale.

Results  Of the patients with schizophrenia (mean [SEM] age, 35.6 [11.8] years), 9 (50%) were male and 9 (50%) were female. Of the controls (mean [SEM] age, 33.7 [8.8] years), 10 (42%) were male and 14 (58%) were female. Patients had an abnormal pattern of striatal connectivity, which included abnormal caudate connections with a distributed set of associative cortex regions (χ229 = 53.55, P = .004). In patients, more deviation from the multivariate pattern of striatal connectivity found in controls correlated specifically with more severe positive symptoms (ρ = −0.77, P = .002). Striatal connectivity also correlated with baseline binding potential across cortical and extrastriatal subcortical regions (t25 = 3.01, P = .01, Bonferroni corrected) but not with its change after amphetamine administration.

Conclusions and Relevance  Using a multimodal, circuit-level interrogation of striatal-cortical connections, it was demonstrated that the functional topography of these connections is globally disrupted in unmedicated patients with schizophrenia. These findings suggest that striatal-cortical dysconnectivity may underlie the effects of dopamine dysregulation on the pathophysiologic mechanism of psychotic symptoms.

Figures in this Article

Sign in

Purchase Options

• Buy this article
• Subscribe to the journal
• Rent this article ?

Figures

Place holder to copy figure label and caption
Figure 1.
Differences in Multivariate Patterns of Striatal Connections Between Unmedicated Patients With Schizophrenia and Healthy Controls

Top, Coronal views of striatal subregion seeds; voxels identified as part of each subregion in at least half of the study participants are overlaid on a group-averaged T1-weighted image. Middle, Patterns of striatal connectivity are shown in controls (top) and patients (bottom) as bar plots of connectivity strength (group mean [SEM] β) by striatal subregion (using the same color scheme as in the top panel) and target region on the x-axis (from left to right, cortical Brodmann areas [BAs] followed by hippocampus, globus pallidus, and thalamic nuclei). Bottom, β weights (log odds ratio [OR]) corresponding to each of the predictor variables or regressors included in the final logistic regression model predicting group membership (1 indicates controls and 0 indicates patients); this final (most parsimonious) model included only striatal-target pairs related to the anterior caudate and posterior caudate (eMethods in the Supplement). P values indicate logistic regression β estimates significantly different than zero (post hoc tests of individual β estimates adjusted their degrees of freedom based on the total number of predictor variables, thus controlling for multiple comparisons). GP indicates globus pallidus; MD, mediodorsal; VA, ventral anterior; VL, ventrolateral; VPL, ventral posterior lateral nucleus; VPM, ventral posterior medial.

aP < .01.

bP < .05.

Graphic Jump Location
Place holder to copy figure label and caption
Figure 2.
Correlations of Striatal Connectivity Pattern With Symptom Severity and D2 Receptor Density Measured With Carbon 11–Labeled FLB457 Positron Emission Tomography (PET)

Scatterplots show associations between connectivity pattern (log odds of belonging to the healthy group based on the multivariate pattern of striatal connectivity) and severity of positive symptoms based on the Positive and Negative Syndrome Scale positive total (PANSS-PT) scores, severity of negative symptoms based on the Positive and Negative Syndrome Scale negative total (PANSS-NT) scores, and baseline binding potential (BPND) (corresponding to the first principal component score), adjusted by group and functional magnetic resonance imaging data quality score across all participants (note that group adjustment shifts the group means such that the connectivity pattern appears to overlap between the groups along the x-axis). For positive and negative symptoms, values are ranked across subjects given that the appropriate corresponding tests are nonparametric. [11C] indicates radiotracer carbon 11–labeled.

Graphic Jump Location
Place holder to copy figure label and caption
Figure 3.
Voxelwise Connectivity of Striatal Subregions in Patients and Healthy Controls

Top, Regions showing significant connectivity with each of the 5 striatal subregions (each in a different color) are depicted in controls (left) and patients (right) and overlaid onto an inflated brain surface (using the PALS-B12 atlas in Caret software, version 5.65). Connectivity maps show effects corresponding to P < .05 (false discovery rate corrected). Bottom, t maps show regions with significantly stronger connectivity to the anterior caudate than to the other 4 striatal subregions in warm colors in controls (left) and patients (right).

Graphic Jump Location
Place holder to copy figure label and caption
Figure 4.
Global Brain Connectivity of Striatal Subregions in Patients and Healthy Controls

Mean (SEM) absolute β values across all extrastriatal brain voxels are plotted by striatal subregion and group.

Graphic Jump Location

Tables

References

Correspondence

CME
Also 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.
Please click the checkbox indicating that you have read the full article in order to submit your answers.
Your answers have been saved for later.
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.

Multimedia

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

1,138 Views
0 Citations
×

Sign in

Purchase Options

• Buy this article
• Subscribe to the journal
• Rent this article ?

Related Content

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

See Also...
Articles Related By Topic
Related Collections
PubMed Articles
Jobs
JAMAevidence.com

Users' Guides to the Medical Literature: A Manual for Evidence-Based Clinical Practice, 3rd ed
Clarifying Your Question

Users' Guides to the Medical Literature: A Manual for Evidence-Based Clinical Practice, 3rd ed
Three Examples of Question Clarification

brightcove.createExperiences();