Prior MDMA (Ecstasy) use is associated with increased basal ganglia-thalamocortical circuit activation during motor task performance in humans: an fMRI study

Abstract

MDMA (3,4-methylenedioxymethamphetamine; Ecstasy) is a popular recreational drug that produces long-lasting serotonin (5-HT) neurotoxicity consisting of reductions in markers for 5-HT axons. 5-HT innervates cortical and subcortical brain regions mediating motor function, predicting that MDMA users will have altered motor system neurophysiology. We used functional magnetic resonance imaging (fMRI) to assay motor task performance-associated brain activation changes in MDMA and non-MDMA users. 24 subjects (14 MDMA users and 10 controls) performed an event-related motor tapping task (1, 2 or 4 taps) during fMRI at 3 T. Motor regions of interest were used to measure percent signal change (PSC) and percent activated voxels (PAV) in bilateral motor cortex, sensory cortex, supplementary motor area (SMA), caudate, putamen, pallidum and thalamus. We used SPM5 to measure brain activation via three methods: T-maps, PSC and PAV. There was no statistically significant difference in reaction time between the two groups. For the Tap 4 condition, MDMA users had more activation than controls in the right SMA for T-score (p=0.02), PSC (p=0.04) and PAV (p=0.03). Lifetime episodes of MDMA use were positively correlated with PSC for the Tap 4 condition on the right for putamen and pallidum; with PAV in the right motor and sensory cortex and bilateral thalamus. In conclusion, we found a group difference in the right SMA and positive dose-response association between lifetime exposure to MDMA and signal magnitude and extent in several brain regions. This evidence is consistent with MDMA-induced alterations in basal ganglia-thalamocortical circuit neurophysiology and is potentially secondary to neurotoxic effects on 5-HT signaling. Further studies examining behavioral correlates and the specific neurophysiological basis of the observed findings are warranted.

Fig. 1

Task design demonstrating visual stimuli and stimulus onset times. Not to scale. Scan time 266 s.

Fig. 2

Global task activation (Tap 1 + Tap 2 + Tap 4) versus baseline showing activation and T-score intensities in anatomically selected motor regions.

Fig. 3

Reaction time (ms) grouped according to MDMA user status and stimulus.

Fig. 4

Group differences (MDMA users – non-MDMA users) for Tap 4. Cluster-level significance (p = 0.024, cluster size 38 voxels) in the right supplementary motor area (SMA), (MNI coordinates: 6, 12, 57) with a maximum T-score of 5.18.

Fig. 5

Simplified basal ganglia–thalamocortical circuit. Motor circuit paths begin with input arriving to the putamen from the supplementary motor area (SMA), and primary motor cortex (MC). Output from the putamen (and parallel flow from cortex as well) then continues via direct or indirect paths (not shown). The direct path consists of an inhibitory gamma-amino-butyric-acid (GABA) projection from the putamen to the globus pallidus internal segment (GPi) and substantia nigra pars reticulata (SNr). GPi and SNr send inhibitory GABAergic projections to the ventrolateral (VL) nucleus of the thalamus. VL thalamic projections to neocortex are glutamatergic and project to MC, including the hand region in primates (Holsapple et al., 1991). The simplified result of stimulation of the direct path in the basal ganglia–thalamocortical loop is excitatory input to the cortex. The indirect path of the basal ganglia–thalamocortical loop involves GABA inputs from the putamen to the globus pallidus external segment (GPe) which in turn provides a GABAergic projection to the subthalamic nucleus (STN). The STN receives direct input from cortex as well (Alexander et al. 1990) and projects to the GPi and SNr via excitatory glutamate axons. GPI/SNr innervate the VL via GABAergic axons. The simplified result of cortical input to the indirect pathway is inhibition of excitatory thalamic input to the cortex.