Neuroimaging of Toxic Encephalopathy Ecstasy Sandy CY Chen, MD Tri-Service General Hospital, Taiwan SNR 2010 Bolongna

Toxic Encephalopathy Pathomechanisms Etiology Imaging approach By etiologies: drugs By history Substance abuse: imaging patterns Occupational & environmental Suicidal attempts

Toxic Encephalopathy -Pathomechanisms Leukoencephalopathy: demyelination, ischemia and astrogliosis Excitotoxicity Vasculopathy Cellular energy failure

Glutamate Excitotoxicity Cellular edema Apoptosis or necrotic cell death Moritani et al. AJNR 2005

Hyperammonemia induce low grade brain edema by impairing glutamate-nitric oxide-cGMP pathway

Hyperammonemia In Hepatic encephalopathy Impair glutamate-nitric oxide-cGMP pathway Disrupt osmolar balance: glutamine mI & Choline NAA Cr GLX mI Cho Chronic relapsing hepatic encephalopathy

Excitotoxicity in Wernicke’s encephalopathy Acetyl CoA Krebs cycle Glutamate α-Ketoglutarate α-KGDH Succinyl CoA Succinate

NMDA –mediated excitotoxicity In Wernicke Encephalopathy Thiamine-dependent enzyme α-ketoglutarate dehydrogenase .

Serotonergic pathway Serotonergic : Memory, mood, cognitive and motor NEJM 2005

Ecstasy encephalopathy High density of 5HT Receptors in globus pallidus Oxidative stress, excitotoxicity, and mitochondrial dysfunction

← - - - - - + + Disinhibition Basal ganglia-thalamocortical circuit MDMA effect ( ) - ( ) + ( ) - ( ) - ( ) + ( ) - ( ) - Disinhibition

Study purpose To investigate the effects of MDMA abuse on the alterations of brain metabolites and anatomical connectivity related to the function of the basal ganglia-thalamocortical circuit using 1H-MRS and DTI 12

Materials and Methods 31 MDMA (24 male, 7 female, aged 18 - 34) abusers with positive hair and urine tests were enrolled as MDMA group, and 33 normal healthy non-abusers (17 male, 16 female, aged 21 - 32) were also included as controls. MR images were acquired at a 3.0 T MR system (Philips, Achieva, Best, Netherlands).

LCModel analysis for MRS Single voxel proton MRS LCModel analysis for MRS 3T scanner Double spin-echo, point resolved spectroscopy (PRESS) TR/TE 2000/40 ms, NEX=128 14

Diffusion tensor imaging DTI analysis Diffusion tensor imaging Diffusion tensor imaging were acquired with 6 non-collinear directions with b =1000s/mm2. -- TR/TE=5890/57ms, matrix size=128x128, slice thickness=3 mm without gap, NEX=6, number of slice=40. The FA difference was statistically compared on a voxel-by-voxel basis between normal and MDMA groups using Student’s t-test. 15

Whole brain FA images: normalized to an ICBM-MNI-FA template using affine registration followed by diffeomorphic demons registration DTI ( MDMA group ) ( control group ) #1 #9 #10 #28 #1 #9 #10 #28 … … … … Average brain Average brain 16

Results : MRS in frontal lobe ml Cho NAA Cr Glx MDMA 5.013± 0.977 1.377 ± 0.287 7.507 ± 1.237 5.990 ± 0.994 12.170 ±2.636 control 5.207 ± 1.519 1.463 ± 0.235 7.302 ± 1.054 6.095 ± 0.768 13.120 ± 0.768 P-value 0.578 0.230 0.603 0.664 0.192 17

Results : MRS in basal ganglia * ml Cho NAA Cr Glx MDMA 4.498 ± 1.543 1.721 ± 0.346 8.122 ± 1.351 7.069 ± 1.128 12.855 ± 3.242 control 3.308 ±1.149 1.638 ±0.220 8.018 ±0.688 7.223 ±0.717 13.444 ±2.608 P-value <0.001 0.11 0.382 0.362 0.265 18

Results voxel-wise P < 0.05 cluster > 50 voxels MDMA > control MDMA < control voxel-wise P < 0.05 cluster > 50 voxels MDMA < control MDMA > control

Discussion The increased mI in the basal ganglia raise the possibility that MDMA-induced deficits on the basal ganglia would reduce inhibitory effects on the thalamus, and therefore increase the thalamocortical activities

Discussion The observed ADC reduction in the corticospinal tracts and thalamus in the present study would likely reflect the increased neuronal activity in the thalamorcortical fibers

Discussion Study limitations 1) many MDMA users have also exposed to other recreational drugs. 2) the causative relationships between MDMA use and the alternations in the basal-thalamocortical circuit can be challenged because we did not conduct standard motor function assessments in MDMA subjects

← - - - - - Conclusion mI + + MDMA effect ( ) ( ) ( ) ( ) ( ) ( ) - ( ) + ( ) - ( ) - ( ) + ( ) - ( ) - Disinhibition Basal ganglia-thalamocortical circuit

Contributions： Professor Hsiao-Wen Chung Ming-Chung Chou Ph.D. Nei-Yu Chuo Hua-Shan Liu Chao-In Wang M.D. Hueng-Wen Gao Chun-Jung Juan Chun-Jen Hsueh *National Taiwan University *National Defense Medical Center *Tri-Service General Hospital