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Review
. 2022 Sep 20:13:925476.
doi: 10.3389/fpsyt.2022.925476. eCollection 2022.

Magnetic resonance imaging of the dopamine system in schizophrenia - A scoping review

Julia Schulz  1   2 , Juliana Zimmermann  1   2 , Christian Sorg  1   2   3 , Aurore Menegaux  1   2 , Felix Brandl  1   2   3
Affiliations
Review

Magnetic resonance imaging of the dopamine system in schizophrenia - A scoping review

Julia Schulz et al. Front Psychiatry. .

Abstract

For decades, aberrant dopamine transmission has been proposed to play a central role in schizophrenia pathophysiology. These theories are supported by human in vivo molecular imaging studies of dopamine transmission, particularly positron emission tomography. However, there are several downsides to such approaches, for example limited spatial resolution or restriction of the measurement to synaptic processes of dopaminergic neurons. To overcome these limitations and to measure complementary aspects of dopamine transmission, magnetic resonance imaging (MRI)-based approaches investigating the macrostructure, metabolism, and connectivity of dopaminergic nuclei, i.e., substantia nigra pars compacta and ventral tegmental area, can be employed. In this scoping review, we focus on four dopamine MRI methods that have been employed in patients with schizophrenia so far: neuromelanin MRI, which is thought to measure long-term dopamine function in dopaminergic nuclei; morphometric MRI, which is assumed to measure the volume of dopaminergic nuclei; diffusion MRI, which is assumed to measure fiber-based structural connectivity of dopaminergic nuclei; and resting-state blood-oxygenation-level-dependent functional MRI, which is thought to measure functional connectivity of dopaminergic nuclei based on correlated blood oxygenation fluctuations. For each method, we describe the underlying signal, outcome measures, and downsides. We present the current state of research in schizophrenia and compare it to other disorders with either similar (psychotic) symptoms, i.e., bipolar disorder and major depressive disorder, or dopaminergic abnormalities, i.e., substance use disorder and Parkinson's disease. Finally, we discuss overarching issues and outline future research questions.

Keywords: dopamine; magnetic resonance imaging; schizophrenia; substantia nigra; ventral tegmental area.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

FIGURE 1
FIGURE 1
Overview of the human dopamine system. (A) The dopamine system in humans. Schematic depiction of the human brain’s dopamine system, captured by the distribution of both dopamine cell bodies in the midbrain, i.e., in substantia nigra pars compacta (SNc) and ventral tegmental area (VTA), and dopamine D1 and D2 receptors mainly in striatum and frontal cortices (adapted with permission from 12). Note the topographic arrangement of dopamine projections, indicated by the same colors at different levels of the dopamine system. (B) Dopaminergic cells and nuclei. Top: Dopaminergic cells in the midbrain (Tyrosine hydroxylase immunostaining) [adapted with permission from (168)]. Bottom: Boundaries between the red nucleus (RN), parabrachial pigmented nucleus (PBP), substantia nigra (SNc and SNr), and subthalamic nucleus, overlaid on a T1w template of midbrain MRIs with isotropic voxel size of 700 μm [adapted from (158), open-access]. (C) Dopamine synapses and axon arborization in mice. Top left: Scheme of the modulatory nature of dopamine synapses [adapted with permission from (13)]. Bottom left: Lattice-like, volume-focused distribution of dopamine synapses in the striatum of mice [adapted with permission from (14)]. Right: Dopamine axon arborization in the striatum of mice [adapted from (169), open-access]. (D) Dopamine connections of VTA. Diffusion-weighted MRI-based tractography of human VTA into the cortex [adapted with permission from (168)].
FIGURE 2
FIGURE 2
Neuromelanin MRI in schizophrenia. (A) Neuromelanin MRI signal. Schematic depiction of the metabolization of dopamine into neuromelanin-containing organelles and how neuromelanin influences the magnetic resonance imaging (MRI) signal. On the right, an exemplary preprocessed neuromelanin MRI image of one healthy subject is shown, with focus on the mesencephalon. (B) ROIs for neuromelanin MRI analysis. Typical regions of interest (ROIs) (43) used for contrast-to-noise-ratio analysis, which calculates the ratio between the MRI signals of substantia nigra and a reference region, e.g., crus cerebri. (C) Neuromelanin MRI changes in schizophrenia. Schematic depiction of the consistent elevation of substantia nigra contrast-to-noise-ratio in patients with schizophrenia (SCZ) compared to healthy controls (HC), based on meta-analytic evidence (40, 47).
FIGURE 3
FIGURE 3
MRI-based morphometric analysis of dopaminergic nuclei in schizophrenia. (A) T1- and T2-weighted relaxation curves. The figure shows the recovery of the longitudinal magnetization (T1 relaxation). Tissues with a short T1 relaxation time such as fat and white matter (WM) recover faster and produce a stronger signal. The T2 relaxation reflects the decay of transverse magnetization. Tissue with a short T2 relaxation decays more quickly and produces a weaker signal. (B) Anatomy of SN and VTA. Axial view of the SN (blue) and VTA (red) derived from a probabilistic atlas shown on the MNI anatomical template (158). (C) T1- and T2-weighted images showing SN and VTA. Axial T1w (left) and T2w (right) structural imaging of the brainstem. The arrows point to the area of SN and VTA. (D) Unclear morphometric changes of dopaminergic nuclei in schizophrenia. Due to the low number of studies and methodological challenges, no clear trends have emerged so far.
FIGURE 4
FIGURE 4
Structural connectivity of dopaminergic nuclei in schizophrenia based on diffusion-weighted MRI. (A) Principles of diffusion-weighted imaging (DWI). Water molecules are free to diffuse in all directions in free water while their diffusion is restricted in biological tissue such as axonal fiber bundles and will follow their main orientation. It can be quantified using a mathematical model called a tensor which can be represented as an ellipsoid with its main axis representing the principal direction of diffusion. In the case of free water there is no principal direction of diffusion thus the ellipsoid takes the shape of a sphere. (B) Structural connectivity outcome measures. Example of a DWI volume. All DWI volumes are used to perform tractography between two regions of interest. In deterministic tractography, each reconstructed streamline follows the main direction of diffusion per voxel or while in probabilistic tractography as represented here, a distribution of possible orientations is modeled and each streamline is reconstructed from each possible orientation. In the reconstructed path, the value in each voxel represents how many streamlines passed through it. The higher number of streamlines per voxel, the higher the probability for that voxel to be part of a fiber bundle. (C) VTA and SN structural connectivity in healthy controls (HC). Example of probabilistic tractography from VTA and SN showing their connectivity to the rest of the brain [adapted with permission from (107)]. (D) Mixed structural connectivity findings in schizophrenia. Structural connectivity can be estimated by a variety of different outcome measures, making comparisons across studies difficult; so far, no clear trends have emerged.
FIGURE 5
FIGURE 5
Blood oxygenation MRI of dopaminergic nuclei and their BOLD resting-state functional connectivity in schizophrenia. (A) BOLD fMRI principles. The figure shows the proposed relationship between neurophysiological underpinnings of BOLD signal fluctuation along time, i.e., synaptic activity, neurotransmitter recycling and metabolic demand (above), and the physical underpinning of the T2*-weighted imaging-based effect of deoxyhemoglobin on the MRI signal (below) [adapted with permission from (121)]. (B) Analysis flow chart and outcome measure of seed-based FC analysis. To investigate the functional architecture of the dopaminergic system during resting state, a region of interest is selected as a seed, for example the VTA. The delineation of the seed can be done via manual segmentation, created based on a specific MNI coordinate or based on a mask derived from an atlas, e.g., as in this example (170). Next, a correlation coefficient (e.g., Pearson’s) is calculated between the seed’s time course and every other voxel in the rest of the brain, creating individual seed-wise FC maps as outcome (125, 126). (C) VTA and SNc BOLD FC in healthy adults. Positive whole-brain resting state FC analysis of the VTA and SNc. All comparisons were thresholded at an FWE-corrected voxel-level significance of p < 0.05 and at an FDR-corrected cluster-level significance of p < 0.05. pACC, perigenual anterior cingulate cortex; dACC, dorsal anterior cingulate cortex; PCC, posterior cingulate cortex; VMPFC, ventromedial prefrontal cortex; NAc, nucleus accumbens; THAL, thalamus; Cereb, cerebellum; DM, dorsal medulla [adapted with permission from (171)]. (D) BOLD FC reduction in schizophrenia. Regions showing VTA/midbrain connectivity in controls (n = 21) compared to pre-treatment unmedicated patients with schizophrenia (n = 21); two tailed two sample t-test corrected with a false discovery rate (FDR) at p < 0.05 [adapted with permission from (145)].
FIGURE 6
FIGURE 6
Exemplary concepts for multimodal analyses involving several dopamine MRI methods or combining MRI and dopamine PET. (A) MRI-based multimodal analysis. A combination of neuromelanin MRI data, which have a high contrast for dopaminergic midbrain nuclei, and regions-of-interest from atlases, which for example were constructed based on structural MRI data, might improve the delineation of dopaminergic nuclei. The regions-of-interest derived from such a delineation procedure could then, in a second step, be used for morphometric analyses or as seed regions for structural and functional connectivity analyses. Plots adapted with permission from (171) and (107). (B) Multimodal combination of MRI and dopamine PET data. Two examples from the literature are shown, displaying correlation analyses between MRI measures and dopamine PET measures. Plots adapted under Creative Commons license or re-use of own work in line with journal guidelines from (43) and (172). ASM, auditory-sensorimotor network; HC, healthy controls; iFC, intrinsic functional connectivity; NM-MRI CNR, neuromelanin MRI contrast-to-noise-ratio; SCZ, patients with schizophrenia; SMST-DSC, sensorimotor striatum dopamine synthesis capacity.
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