A VBM study demonstrating 'apparent' effects of a single dose  of medication on T1-weighted MRIs.
Voxel-based morphometry (VBM) studies have interpreted longitudinal medication- or behaviorally induced changes observed on T1-weighted magnetic resonance images (MRIs) as changes in neuronal structure. Although neurogenesis or atrophy certainly occurs, the use of T1-weighted scans to identify change in brain structure in vivo in humans has vulnerability: the T1 relaxation time for arterial blood and gray matter are not clearly distinguishable and therefore, apparent reported structural findings might be at least partially related to changes in blood flow or other physiological signals. To examine the hypothesis that apparent structural modifications may reflect changes introduced by additional mechanisms irrespective of potential neuronal growth/atrophy, we acquired a high-resolution T1-weighted structural scan and a 5-min perfusion fMRI scan (a measurement of blood flow), before and after administration of an acute pharmacological manipulation. In a within-subject design, 15 subjects were either un-medicated or were administered a 20 mg dose of baclofen (an FDA-approved anti-spastic) approximately 110 min before acquiring a T1-weighted scan and a pseudo continuous arterial spin labeled perfusion fMRI scan. Using diffeomorphic anatomical registration through exponentiated lie algebra within SPM7, we observed macroscopic, and therefore implausible, baclofen-induced decreases in VBM 'gray matter' signal in the dorsal rostral anterior cingulate (family wise error corrected at p<0.04, T = 6.54, extent: 1,460 voxels) that overlapped with changes in blood flow. Given that gray matter reductions are unlikely following a single dose of medication these findings suggest that changes in blood flow are masquerading as reductions in gray matter on the T1-weighted scan irrespective of the temporal interval between baseline measures and longitudinal manipulations. These results underscore the crucial and immediate need to develop in vivo neuroimaging biomarkers for humans that can uniquely capture changes in neuronal structure dissociable from those related to blood flow or other physiological signals.
Department of Psychiatry, Center for Studies of Addiction, University of Pennsylvania School of Medicine, 3900 Chestnut Street, Philadelphia, PA 19104, USA. franklin_t@mail.trc.upenn.edu
Teresa R
TR
Franklin
Ze
Z
Wang
Joshua
J
Shin
Kanchana
K
Jagannathan
Jesse J
JJ
Suh
John A
JA
Detre
Charles P
CP
O'Brien
Anna Rose
AR
Childress
D000328:Adult; D016477:Artifacts; D001284:Atrophy; D001418:Baclofen / Q000494:pharmacology*; D001931:Brain Mapping / Q000379:methods*; D016022:Case-Control Studies; D002560:Cerebrovascular Circulation / Q000187:drug effects*; D005260:Female; D006179:Gyrus Cinguli / Q000098:blood supply* / Q000187:drug effects* / Q000473:pathology; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D009125:Muscle Relaxants, Central / Q000494:pharmacology*; D055495:Neurogenesis / Q000187:drug effects*; D055420:Perfusion Imaging / Q000379:methods*; D011237:Predictive Value of Tests; D015203:Reproducibility of Results
D009125:Muscle Relaxants, Central; D001418:Baclofen