L-dopa modulates functional connectivity in striatal cognitive and motor networks: a double-blind placebo-controlled study

Abstract

Functional connectivity (FC) analyses of resting-state fMRI data allow for the mapping of large-scale functional networks, and provide a novel means of examining the impact of dopaminergic challenge. Here, using a double-blind, placebo-controlled design, we examined the effect of L-dopa, a dopamine precursor, on striatal resting-state FC in 19 healthy young adults. We examined the FC of 6 striatal regions of interest (ROIs) previously shown to elicit networks known to be associated with motivational, cognitive and motor subdivisions of the caudate and putamen (Di Martino et al., 2008). In addition to replicating the previously demonstrated patterns of striatal FC, we observed robust effects of L-dopa. Specifically, L-dopa increased FC in motor pathways connecting the putamen ROIs with the cerebellum and brainstem. Although L-dopa also increased FC between the inferior ventral striatum and ventrolateral prefrontal cortex, it disrupted ventral striatal and dorsal caudate FC with the default mode network. These alterations in FC are consistent with studies that have demonstrated dopaminergic modulation of cognitive and motor striatal networks in healthy participants. Recent studies have demonstrated altered resting state FC in several conditions believed to be characterized by abnormal dopaminergic neurotransmission. Our findings suggest that the application of similar experimental pharmacological manipulations in such populations may further our understanding of the role of dopaminergic neurotransmission in those conditions.

Figure 1.

Left hemisphere putamen functional connectivity. Thresholded Z-score maps (min Z >2.3; cluster significance: p < 0.05, corrected) of positive functional connectivity for each condition, and significant l-dopa-related increases and decreases in functional connectivity. Images are displayed according to radiological convention (left is right).

Figure 2.

Right hemisphere putamen functional connectivity. Thresholded Z-score maps (min Z >2.3; cluster significance: p < 0.05, corrected) of positive functional connectivity for each condition, and significant l-dopa-related increases and decreases in functional connectivity. Images are displayed according to radiological convention (left is right).

Figure 3.

Left hemisphere caudate functional connectivity. Thresholded Z-score maps of positive functional connectivity for each condition, and significant l-dopa-related increases and decreases in functional connectivity. Images are displayed according to radiological convention (left is right).

Figure 4.

Right hemisphere caudate functional connectivity. Thresholded Z-score maps of positive functional connectivity for each condition, and significant l-dopa-related increases and decreases in functional connectivity. Images are displayed according to radiological convention (left is right).

Figure 5.

A–D, l-Dopa-related increase in VSi-vlPFC connectivity is inversely related to the l-dopa-related decrease in connectivity with PCC. We observed a significant inverse correlation between the l-dopa-related changes in connectivity: the greater the l-dopa-related increase in connectivity between VSs and PFC, the greater the l-dopa-related decrease in connectivity between the VSs and PCC for the same participant. Across participants, there were significant inverse correlations between the l-dopa-related changes in connectivity: the greater the l-dopa-related increase in FC between VSi and vlPFC, the greater the l-dopa-related decrease in FC for the same participant between left VSi and PCC (A), between right DC and PCC (B), between right VSs and PCC (C), and between left VSs and PCC (D).

Figure 6.

Left hemisphere probability-weighted functional connectivity. Thresholded Z-score maps of positive functional connectivity for each condition, and significant l-dopa-related increases and decreases in functional connectivity, for each of the three probability-weighted ROIs. Images are displayed according to radiological convention (left is right).

Figure 7.

Right hemisphere probability-weighted functional connectivity. Thresholded Z-score maps of positive functional connectivity for each condition, and significant l-dopa-related increases and decreases in functional connectivity, for each of the three probability-weighted ROIs. Images are displayed according to radiological convention (left is right).

Figure 8.

l-Dopa reduces functional connectivity within the default mode network. The iterative connectivity analysis, which examined the FC of the PCC region that demonstrated reduced connectivity with the right hemisphere probability-weighted caudate ROI (seed location shown on left of figure). The figure displays the thresholded Z-score maps of positive functional connectivity for each condition, and significant l-dopa-related increases and decreases in functional connectivity for this PCC seed ROI. A significant reduction in the connectivity of the default mode network in the l-dopa condition, relative to placebo, was observed. Images are displayed according to radiological convention (left is right).