Neuromelanin-Sensitive Magnetic Resonance Imaging in Schizophrenia: A Meta-Analysis of Case-Control Studies

Abstract

Background: Psychiatry is in urgent need of reliable biomarkers. Novel neuromelanin-sensitive magnetic resonance imaging (NM-MRI) sequences provide a time-efficient and non-invasive way to investigate the human brain in-vivo. This gives insight into the metabolites of dopaminergic signaling and may provide further evidence for potential dopaminergic alterations in patients with schizophrenia (SCZ). The present systematic review provides a meta-analysis of case-control studies using neuromelanin-sensitive sequences in SCZ vs. healthy controls (HC).Methods: According to predefined search terms and inclusion criteria studies were extracted on PubMed. Meta-analyses with a fixed and random-effects model with inverse variance method, DerSimonian-Laird estimator for τ2, and Cohen's d were calculated. Bias was assessed using funnel plots. The primary study outcome was contrast-to-noise ratio (CNR) in the substantia nigra compared between HC and SCZ.Results: The total sample of k = 6 studies included n = 183 cases and n = 162 controls. Across all studies we found a significant elevation of CNR in the substantia nigra (d = 0.42 [0.187; 0.655], z = 3.521, p < 0.001) in cases compared to controls. We found no significant difference in the control region of locus coeruleus (d = −0.07 [−0.446; 0.302], z = −0.192, p = 0.847), with CNR for the latter only reported in k = 3 studies.Conclusion: CNR in the substantia nigra were significantly elevated in cases compared to controls. Our results support neuromelanin as a candidate biomarker for dopaminergic dysfunction in schizophrenia. Further studies need to assess this candidate marker in large, longitudinal cohorts and address potential effects of disease state, medication and correlations with symptoms.

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

“…(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 ).…”

“…A typical outcome measure of neuromelanin MRI analysis is the contrast-to-noise ratio (CNR), which describes the ratio between the signal in a presumably neuromelanin-rich region, for example substantia nigra, and the signal of a reference region that presumably contains no neuromelanin, for example crus cerebri ( Figure 2B ) ( 39 , 40 ). While neuromelanin MRI has been used to quantify dopaminergic neuron loss in neurodegenerative conditions for some time ( 39 , 41 , 42 ), it has recently also been validated to measure dopamine function in vivo in subjects without neurodegeneration: Cassidy et al showed a relationship between substantia nigra CNR and both post-mortem neuromelanin concentration in the substantia nigra and amphetamine-induced striatal dopamine release measured by PET ( 43 ).…”

“…Third, more work is needed to understand the temporal dynamics of neuromelanin accumulation, e.g., how fast one can expect signal changes when conditions (for example, psychotic symptoms) change. Fourth, the neuromelanin MRI signal could be confounded by many other non-structural factors, e.g., medication, about which reliable data are not yet available ( 40 ).…”

Suboptimal foraging decisions and involvement of the ventral tegmental area in human opioid addiction

“…While prior work indicates NM-MRI serves as a reliable proxy measure of the function of catecholamines (38) and shows promise as a clinical marker of disorders of these systems even in the absence of neurodegeneration, including depression and psychosis (64)(65)(66), the precise relationship to tonic (vs. phasic) dopamine remains unclear. Studies show chronic L-DOPA, which is thought to increase both phasic and tonic dopamine, increases neuromelanin concentration in both humans and rodents (66,67), providing some assurance that NM-MRI could serve as a reasonable proxy of these neurobiological processes.…”

Normative values of neuromelanin-sensitive MRI signal in older adults obtained using a standard protocol for acquisition and analysis

“…[19][20][21]27 Therefore, age is a critical factor that should be adjusted for when using NM-MRI. 19,28 With these challenges in mind, future NM-MRI work using standard methods of acquisition and analysis and stratifying a large sample of participants by age would be well positioned to determine the normative range of SN and LC contrast ratios and volumes in healthy people of all ages. In the context of its potential use as a biomarker, access to a standardized, age-adjusted normative range of NM-MRI metrics is essential to identify patients on the extreme ends of the range, presumably those who may require clinical intervention.…”