Using Neuromelanin-Sensitive MRI to Examine Catecholaminergic Disorders Over Time

“One of the most promising aspects of [neuromelanin-sensitive MRI (NM-MRI)] is its noninvasive nature without radiation exposure, making it suitable for longitudinal studies and for early diagnosis and monitoring,” said investigators of a recent study examining this imaging technique in relation to psychiatric disorders.¹ The paper noted that NM-MRI has shown promise specifically for disorders involving catecholaminergic dysfunction, like schizophrenia, substance use disorder, and major depressive disorder.^2,3

Across studies examined, NM-MRI offers a neurobiological lens and potential contributions to biomarker research for psychiatric disorders. Researcher Marieke van der Pluijm shared more on this project with Psychiatric Times.

Psychiatric Times: Clinicians may be familiar with imaging techniques like PET and functional MRI, but how does NM-MRI provide a different measure?

Marieke van der Pluijm, PhD: Neuromelanin is a byproduct of dopamine and noradrenaline metabolism. It forms through a process of oxidation and polymerization, producing iron-neuromelanin complexes that gradually accumulate over the course of a lifetime, primarily in the dopamine-producing neurons of the substantia nigra and ventral tegmental area, along with the noradrenaline-producing neurons of the locus coeruleus. Neuromelanin complexes show up as a bright signal on neuromelanin-sensitive MRI sequences, allowing measurement of both the intensity and the spatial extent of the signal in their specific brain regions. It is important to note, however, that NM-MRI does not provide a direct measure of dopamine or noradrenaline levels. What it offers is a reflection of neuromelanin accumulation and potentially broader tissue characteristics in these brain regions, giving indirect insights into the long-term state of the dopaminergic and noradrenergic systems.

PT: What background and context inspired investigation into NM-MRI for psychiatric disorders in particular?

van der Pluijm: Despite advances in neuroimaging, the neurobiological mechanisms driving these conditions remain poorly understood. Structural and functional MRI have revealed shared alterations across disorders such as schizophrenia, depression, and bipolar disorder, but these findings lack specificity and typically emerge only at the group level. Instead, these broad alterations may reflect downstream consequences of more fundamental disruptions in neurotransmitter functioning. Neurotransmitters are central to how we think, feel, and behave, and their dysregulation has been linked to a wide range of psychiatric conditions. Notably, they are also primary targets of most psychiatric medications.

The main tools for studying these systems in the living brain, PET and single-photon emission computed tomography (SPECT) scans, involve radiation exposure and are costly, making them unsuitable for routine or pediatric use. This created a clear need for a noninvasive, scalable alternative.

NM-MRI emerged as a promising solution, offering a way to assess the brain regions responsible for producing 2 key neurotransmitters: dopamine, which plays a central role in motivation and salience, and noradrenaline, which is closely tied to our stress response.

It can be performed on a standard MRI scanner with no radiation required, and that combination of accessibility, safety, and specificity is what makes it such a promising tool for psychiatric research.

PT: Can NM-MRI provide unique information that other forms of imaging cannot provide, perhaps in areas of temporal or spatial resolution?

van der Pluijm: Yes, NM-MRI can provide meaningful additional information. PET and SPECT quantify various aspects of neurotransmitter functioning, but they involve ionizing radiation, have limited spatial resolution, and are costly, ruling them out for routine or pediatric use. Structural MRI can identify changes in brain size and shape but cannot target specific neurotransmitter systems. Functional MRI tracks neural activity indirectly through blood flow but does not link directly to the underlying neurochemistry.

NM-MRI occupies a distinct niche: it is non-invasive, requires no radioactive tracer, and specifically targets the neurons that produce dopamine and noradrenaline. Crucially, it operates on a fundamentally different timescale to functional MRI or PET, rather than capturing real-time signaling or moment-to-moment neurotransmitter fluctuations, it reflects the cumulative, long-term biological state of these neurons. Depending on the question being asked, that is both a limitation and a unique strength.

PT: Why is NM-MRI’s ability to see change over longer periods of time important?

van der Pluijm: Because neuromelanin accumulates gradually over years, the NM-MRI signal functions as a kind of biological record of long-term dopaminergic and noradrenergic activity. This is particularly relevant in psychiatry, where many conditions involve chronic, sustained neurochemical dysregulation rather than short-lived disruptions. It means NM-MRI could be sensitive to illness progression, the cumulative effects of stress or substance use on these neurons, or the long-term biological impact of treatment. It is also less susceptible to short-term fluctuations, such as day-to-day mood or symptom changes and current drug or medication use, which adds to its stability as a measure.

That said, most existing NM-MRI findings in psychiatry come from cross-sectional studies, meaning patients were scanned only once. This limits what can currently be concluded about how the signal changes over time. More longitudinal studies are therefore a critical step to determine whether NM-MRI measures can genuinely track change over time in clinically meaningful ways.

PT: How and why has NM-MRI been used to investigate schizophrenia specifically?

van der Pluijm: Schizophrenia has been one of the primary targets for NM-MRI research because disruptions in the dopamine system are central to its neurobiology. The dopamine hypothesis of psychosis has been supported by decades of PET evidence showing elevated dopamine synthesis and release in the striatum. NM-MRI offers a way to investigate the upstream source of this dysregulation: the substantia nigra and ventral tegmental area, where the dopaminergic neurons that project to the striatum originate.

Studies have used NM-MRI to examine whether neuromelanin concentration or volume in these regions differs between individuals with schizophrenia and healthy controls, and whether any differences relate to symptom severity or response to antipsychotic medication. It has also been applied to individuals at clinical high risk for psychosis, to explore whether dopaminergic changes are detectable before the illness fully develops, and whether dopaminergic changes predict transition to psychosis.

PT: What have the major findings of NM-MRI in schizophrenia been in the field?

van der Pluijm: Schizophrenia is currently one of the psychiatric conditions with the most consistent NM-MRI evidence. Across studies, there is converging support for an elevated NM-MRI signal in the substantia nigra in people with schizophrenia compared to healthy individuals. This is interpreted as reflecting increased dopaminergic neuronal activity, consistent with the dopamine hypothesis of psychosis. Importantly, these findings align with the broader body of PET literature and provide complementary, noninvasive corroboration of dopaminergic dysregulation.

PT: What do you hope NM-MRI will be used for in the future? Do you see it being useful for a particular disorder or a function like diagnosis?

van der Pluijm: Rather than positioning NM-MRI as a diagnostic tool in itself, I think its most meaningful near-term contributions will be in risk stratification, treatment monitoring, and biomarker development. Diagnosing a mental health condition involves far more than a single brain scan, and the science still needs to mature before any clinical application is possible.

Given that current findings are largely cross-sectional and derived from heterogeneous protocols, the current priority is standardization, harmonizing acquisition, and analysis approaches to make findings comparable across sites and studies. Beyond that, longitudinal studies and cross-diagnostic comparisons are needed to determine whether NM-MRI can track meaningful neurobiological change over time. In the longer term, if validated, it could help identify patients whose difficulties are driven by dopamine or noradrenaline dysfunction, potentially guiding more personalized treatment decisions, or serve as an early marker of neurobiological risk. The potential is real, though significant validation work still lies ahead.

Dr van der Pluijm is a postdoctoral researcher in psychiatry at Amsterdam UMC in the Netherlands.

References

1. Neutelings E, van de Giessen E, de Haan L, et al. The potential of neuromelanin-sensitive MRI in psychiatric disorders. Neurosci Appl. 2026;5:106994.

2. Mallet J, Meloni R, Laurent C. Catecholamine metabolism and psychiatric or behavioral disorders. Curr Opin Genet Dev. 1994;4(3):419-26.

3. Suker S, Mihov Y, Wolf A, et al. Behavioral response to catecholamine depletion in individuals with schizophrenia and healthy volunteers. Schiz Bull Open. 2023;4(1).