Drug and disease effects on the human brain studied by functional MRI

Background: With the advent of magnetic resonance imaging (MRI) technology, various functional MRI (fMRI) techniques have become available for non-invasive neuroscientific studies and clinical diagnostics, which have led to a better understanding of the human brain function in normal and diseased subjects. In order to interpret the fMRI results correctly and design optimal research studies it is important to understand both the potentials and limitations associated with each fMRI technique. In this thesis we used two fMRI techniques: arterial spin labeling (ASL) and resting-sate BOLD (blood-oxygen-level dependent) fMRI to study the effects of a CNS-active (central nervous system) drug and neurologic disorder on the human brain function.

Purpose: The main research purposes of this thesis are the following: 1) We assess the reproducibility and reliability of rCBF (regional cerebral blood flow) measurements conducted at 3T with pCASL (pseudo continuous ASL) technique; 2) We study the pharmacokinetics of a CNS active drug in normal volunteers by conducting rCBF measurements as a function of time after intake of a single dose of 20 mg d-amphetamine with the pCASL technique; 3) We investigate the possible neurological abnormalities of mild traumatic brain injury (mTBI) patients with chronic fatigue by performing rCBF and resting-sate functional connectivity measurements before, during and after a 20 minute continuous psychomotor vigilance task (PVT).

Conclusion: The results from these studies show that the pCASL technique is a relatively robust method for quantitative measurements of rCBF in both normal volunteers and patient subjects. Repeated rCBF measurements with the pCASL method is a non-invasive and sufficiently sensitive approach to assess pharmacokinetic response to CNS active chemicals and should be useful for studying the neurophysiological characteristics in vivo of potential CNS drugs. The results from the mTBI subjects demonstrate that the repeated measurements of rCBF and functional connectivity metrics before, during and after a PVT provide sensitive diagnostic imaging methods to assess neurological abnormality of mTBI patients without apparent neuroanatomical damage. In addition to the clinical diagnostic value, these studies also contribute to important knowledge for the design and analysis of brain functional imaging studies of drugs and neurological diseases.

List of scientific papers

I. Inter- and intra-subject variability of brain perfusion measurements using pseudo continuous arterial spin labeling (pCASL) technique at 3T Tie-Qiang Li, Love Engström Nordin. [Manuscript]

II. Cortical responses to amphetamine exposure studied by pCASL and pharmacokinetic/pharmacodynamic dose modeling Love Engström Nordin, Tie-Qiang Li, Jakob Brogren, Patrik Johansson, Niclas Sjögren, Kristin Hannesdottir, Charlotta Björk, Märta Segerdahl, Danny J.J. Wang, Per Julin NeuroImage 2013;68:75-82.
https://doi.org/10.1016/j.neuroimage.2012.11.035

III. Post mTBI fatigue is associated with abnormal brain functional connectivity Love Engström Nordin, Marika C. Möller, Per Julin, Aniko Bartfai, Farouk Hashim, Tie-Qiang Li Scientific Reports 6, Article number: 21183 (2016).
https://doi.org/10.1038/srep21183

IV. Neural activity during vigilance test performance– relation to cognitive fatigability in mild TBI Marika C. Möller, Love Engström Nordin, TieQiang Li, Aniko Bartfai, Per Julin. [Manuscript]