Human Ecstasy use is associated with increased cortical excitability: an fMRI study

Abstract

The serotonergic neurotoxin, 3,4-methylenedioxymethamphetamine (MDMA/Ecstasy), is a highly popular recreational drug. Human recreational MDMA users have neurocognitive and neuropsychiatric impairments, and human neuroimaging data are consistent with animal reports of serotonin neurotoxicity. However, functional neuroimaging studies have not found consistent effects of MDMA on brain neurophysiology in human users. Several lines of evidence suggest that studying MDMA effects in visual system might reveal the general cortical and subcortical neurophysiological consequences of MDMA use. We used 3 T functional magnetic resonance imaging during visual stimulation to compare visual system lateral geniculate nucleus (LGN) and Brodmann Area (BA) 17 and BA 18 activation in 20 long abstinent (479.95±580.65 days) MDMA users and 20 non-MDMA user controls. Lifetime quantity of MDMA use was strongly positively correlated with blood oxygenation level-dependent (BOLD) signal intensity in bilateral LGN (r(s)=0.59; p=0.007), BA 17 (r(s)=0.50; p=0.027), and BA 18 (r(s)=0.48; p=0.031), and with the spatial extent of activation in BA 17 (r(s)=0.059; p=0.007) and BA 18 (r(s)=0.55; p=0.013). There were no between-group differences in brain activation in any region, but the heaviest MDMA users showed a significantly greater spatial extent of activation than controls in BA 17 (p=0.031) and BA 18 (p=0.049). These results suggest that human recreational MDMA use may be associated with a long-lasting increase in cortical excitability, possibly through loss of serotonin input to cortical and subcortical regions. When considered in the context of previous results, cortical hyper-excitability may be a biomarker for MDMA-induced serotonin neurotoxicity.

Figure 1

Blood oxygen level-dependent (BOLD) signal intensity in lateral geniculate nucleus (LGN), Brodmann Area (BA) 17, and BA 18 in 3,4-methylenedioxymethamphetamine (MDMA) users and controls. BOLD signal intensity increased in all regions and in both groups with increasing visual stimulus intensity. Circles on box plot indicate outliers extending 1.5 times the box height; asterisks indicate extreme outliers extending three times the box height). Legend equals visual stimulus intensity: , low; , medium; and , high.

Figure 2

Activation to high-intensity visual stimulus. This figure depicts (left to right) coronal, axial, and parasagittal activation maps from all subjects (3,4-methylenedioxymethamphetamine (MDMA) and control) during high-intensity stimulation (combined red and blue light) overlayed on canonical brain T1 template from SPM5. Representative sections depict lateral geniculate nucleus (LGN) and Brodmann Areas (BA) 17 and 18. For display purposes, threshold is set at p<0.05 (t=1.65) uncorrected without a cluster extent threshold (one-sample t-test). This threshold was chosen for display because LGN activation was not detectable using the corrected cluster extent (a voxel level threshold of p=0.05 combined with a cluster extent of 90 voxels produced a family-wise error corrected p=0.05 for the total volume included in bilateral LGN, BA 17, and BA 18). Color bar indicates t-scores.

Figure 3

Relationship of lifetime 3,4-methylenedioxymethamphetamine (MDMA) use to signal intensity in lateral geniculate nucleus (LGN), Brodmann Area (BA) 17, and BA 18. Y axis is the rank of signal intensity for the ROI (calculated as mean percent BOLD signal increase for high-intensity stimuli in right and left hemisphere). X axis is the rank of self-reported lifetime MDMA use in mg. Data shown for MDMA users only, N=20.

Figure 4

Signal intensity by brain region and group. Plot of individual signal intensity values by group shows the degree of overlap between the control and 3,4-methylenedioxymethamphetamine (MDMA) groups. As shown in Table 2, mean signal intensity did not differ by group. BA, Brodmann Area; LGN, lateral geniculate nucleus.

Figure 5

Spatial extent of activation by brain region and group. Plot of individual spatial extent of activation by group shows the degree of overlap between the Control and 3,4-methylenedioxymethamphetamine (MDMA) groups. As shown in Table 2, mean spatial extent of activation did not differ by group. Corrected threshold for activated voxels was p<0.05, cluster extent 90 voxels (one-sample t-test). Because there were no activated voxels in lateral geniculate nucleus (LGN) using corrected thresholds, spatial extent data is shown only for Brodmann Area (BA) 17 and BA 18.

Figure 6

3,4-Methylenedioxymethamphetamine (MDMA)-induced reduction in visual pathway serotonin (5-HT) signaling may produce shifts in cortical excitability. Figure depicts simplified visual pathway circuit in pre-MDMA and post-MDMA conditions. 5-HT is shown in brown; glutamatergic neurons are shown in red. Plus (+) sign indicates excitatory transmission. (a) Pre-MDMA: the retina contains 5-HT containing cells and glutamatergic retinal ganglion cells that project to lateral geniculate nucleus (LGN). LGN provides feedforward glutamatergic excitatory projects to Brodmann Area (BA) 17 glutamatergic stellate cells (red octagon), which (through additional local processing) leads to feedforward excitation to glutamatergic pyramidal neurons in BA 17 that provide feedforward excitation to BA 18 pyramidal (and other neurons). BA 17 pyramidal cells provide feedback excitatory projection to LGN (which may synapse on inhibitory interneurons). Raphe 5-HT inputs to LGN, BA 17, and BA 18 neurons modulate evoked neuronal activity with mixed inhibitory or excitatory actions depending upon neuron and receptor type. On pyramidal neurons, the dendritically located 5-HT2A receptor is excitatory, whereas the 5-HT1A receptor at the axon hillock is inhibitory (receptors not shown in diagram). (b) Post-MDMA: following MDMA exposure, 5-HT neurotransmission is reduced, either through frank axotomy or reduced 5-HT synthesis. Retinal effects of MDMA on 5-HT are unclear. The net effect of altered 5-HT input to LGN, BA 17, and BA 18 is depicted as increased excitation at each juncture. (Note that if BA 17 feedback to LGN results normally in inhibition of LGN projection neurons through inhibitory interneurons, then increased BA 17 excitatory output might lead to increased feedback inhibition to LGN, and thus reduce feedforward excitation to BA 17. On the basis of the available data, the net effect is depicted as overall increased excitation in the thalamo-cortical pathway.).