Neuromelanin-sensitive MRI for mechanistic research and biomarker development in psychiatry.

Neuromelanin-sensitive MRI is a burgeoning non-invasive neuroimaging method with an increasing number of applications in psychiatric research. This MRI modality is sensitive to the concentration of neuromelanin, which is synthesized from intracellular catecholamines and accumulates in catecholaminergic nuclei including the dopaminergic substantia nigra and the noradrenergic locus coeruleus. Emerging data suggest the utility of neuromelanin-sensitive MRI as a proxy measure for variability in catecholamine metabolism and function, even in the absence of catecholaminergic cell loss.

Neuromelanin levels in individuals with substance use disorders: A systematic review and meta-analysis.

Dopamine's role in addiction has been extensively studied, revealing disruptions in its functioning throughout all addiction stages. Neuromelanin in the substantia nigra (SN) may reflect dopamine auto-oxidation, and can be quantified using neuromelaninsensitive magnetic resonance imaging (neuromelanin-MRI) in a non-invasive manner.In this pre-registered systematic review, we assess the current body of evidence related to neuromelanin levels in substance use disorders, using both post-mortem and MRI examinations.

Neuromelanin-Sensitive MRI as Candidate Marker for Treatment Resistance in First-Episode Schizophrenia.

Objective: Markers for treatment resistance in schizophrenia are needed to reduce delays in effective treatment. Nigrostriatal hyperdopaminergic function plays a critical role in the pathology of schizophrenia, yet antipsychotic nonresponders do not show increased dopamine function. Neuromelanin-sensitive MRI (NM-MRI), which indirectly measures dopamine function in the substantia nigra, has potential as a noninvasive marker for nonresponders.

Evidence for Locus Coeruleus-Norepinephrine System Abnormality in Military Posttraumatic Stress Disorder Revealed by Neuromelanin-Sensitive Magnetic Resonance Imaging.

Background: The complex neurobiology of posttraumatic stress disorder (PTSD) calls for the characterization of specific disruptions in brain functions that require targeted treatment. One such alteration could be an overactive locus coeruleus (LC)-norepinephrine system, which may be linked to hyperarousal symptoms, a characteristic and burdensome aspect of the disorder.

Methods: Study participants were Canadian Armed Forces veterans with PTSD related to deployment to combat zones (n = 34) and age- and sex-matched healthy control participants (n = 32).

Characterization of an automated method to segment the human locus coeruleus.

Following the development of magnetic resonance imaging (MRI) methods to assay the integrity of catecholamine nuclei, including the locus coeruleus (LC), there has been an effort to develop automated methods that can accurately segment this small structure in an automated manner to promote its widespread use and overcome limitations of manual segmentation. Here we characterize an automated LC segmentation approach (referred to as the funnel-tip [FT] method) in healthy individuals and individuals with LC degeneration in the context of Alzheimer's disease (AD, confirmed with tau-PET imaging using [18F]MK6240). The first sample included n = 190 individuals across the AD spectrum from cognitively normal to moderate AD.

Normative Values of Neuromelanin-Sensitive MRI Signal in Older Adults Obtained Using a Turbo Spin Echo Sequence.

Background: The integrity and function of catecholamine neurotransmitter systems can be assessed using neuromelanin-sensitive MRI (NM-MRI). The relevance of this method to neurodegenerative and psychiatric disorders is becoming increasingly evident, and it has potential as a clinical biomarker.

Purpose: To support future application of NM-MRI as a clinical biomarker by defining the normative range of NM-MRI signal and volume metrics in cognitively normal older adults.

Associations between locus coeruleus integrity and diagnosis, age, and cognitive performance in older adults with and without late-life depression: An exploratory study.

Late-life depression (LLD) is a risk factor for age-dependent cognitive deterioration. Norepinephrine-related degeneration in the locus coeruleus (LC) may explain this link. To examine the LC norepinephrine system in vivo, we acquired neuromelanin-sensitive MRI (NM-MRI) in a sample of 48 participants, including 25 with LLD (18 women, age 68.

Substance Abuse in Emerging Adults: The Role of Neuromelanin and Ventral Striatal Response to Social and Monetary Rewards.

Perturbations in dopamine system function may increase risk of substance use disorder (SUD). We recently demonstrated that neuromelanin (NM) MRI signal in the substantia nigra, a non-invasive index of dopamine system function, is elevated in long term cocaine users (Cassidy et al., 2020).

Association of locus coeruleus integrity with Braak stage and neuropsychiatric symptom severity in Alzheimer's disease.

The clinical and pathophysiological correlates of locus coeruleus (LC) degeneration in Alzheimer's disease (AD) could be clarified using a method to index LC integrity in vivo, neuromelanin-sensitive MRI (NM-MRI). We examined whether integrity of the LC-norepinephrine system, assessed with NM-MRI, is associated with stage of AD and with neuropsychiatric symptoms (NPS), independent of cortical pathophysiology (amyloid-β and tau burden). Cognitively normal older adults (n = 118), and individuals with mild cognitive impairment (MCI, n = 44), and AD (n = 28) underwent MR imaging and tau and amyloid-β positron emission tomography (with [F]MK6240 and [F]AZD4694, respectively).

Neuromelanin accumulation in patients with schizophrenia: A systematic review and meta-analysis.

Although schizophrenia is associated with increased presynaptic dopamine function in the striatum, it remains unclear if neuromelanin levels, which are thought to serve as a biomarker for midbrain dopamine neuron function, are increased in patients with schizophrenia. We conducted a systematic review and meta-analysis of magnetic resonance imaging (MRI) and postmortem studies comparing neuromelanin (NM) levels between patients with schizophrenia and healthy controls (HCs). Standard mean differences were calculated to assess group differences in NM accumulation levels between patients with schizophrenia and HCs.

Neural Abnormalities in Fear Generalization in Schizophrenia and Associations With Negative Symptoms.

Background: Associative learning and memory processes, including the generalization of previously learned associations, may be altered in schizophrenia. Deficits in schizophrenia in stimulus generalization, one of the simplest forms of memory, could interfere with the ability to efficiently categorize related, similar information, potentially leading to impairments in daily functioning.

Methods: To measure generalization in schizophrenia, 37 individuals with a nonaffective psychotic disorder and 32 demographically matched healthy control subjects underwent a Pavlovian fear conditioning and generalization procedure, which accounted for variation in perceptual ability across participants, while undergoing functional magnetic resonance imaging.

Association between neuromelanin-sensitive MRI signal and psychomotor slowing in late-life depression.

Late-life depression (LLD) is a prevalent and disabling condition in older adults that is often accompanied by slowed processing and gait speed. These symptoms are related to impaired dopamine function and sometimes remedied by levodopa (L-DOPA). In this study, we recruited 33 older adults with LLD to determine the association between a proxy measure of dopamine function-neuromelanin-sensitive magnetic resonance imaging (NM-MRI)-and baseline slowing measured by the Digit Symbol test and a gait speed paradigm.

Evidence for Dopamine Abnormalities in the Substantia Nigra in Cocaine Addiction Revealed by Neuromelanin-Sensitive MRI.

Objective: Recent evidence supports the use of neuromelanin-sensitive MRI (NM-MRI) as a novel tool to investigate dopamine function in the human brain. The authors investigated the NM-MRI signal in individuals with cocaine use disorder, compared with age- and sex-matched control subjects, based on previous imaging studies showing that this disorder is associated with blunted presynaptic striatal dopamine.

Methods: NM-MRI and T-weighted images were acquired from 20 participants with cocaine use disorder and 35 control subjects.

Neuromelanin-sensitive MRI as a noninvasive proxy measure of dopamine function in the human brain.

Neuromelanin-sensitive MRI (NM-MRI) purports to detect the content of neuromelanin (NM), a product of dopamine metabolism that accumulates with age in dopamine neurons of the substantia nigra (SN). Interindividual variability in dopamine function may result in varying levels of NM accumulation in the SN; however, the ability of NM-MRI to measure dopamine function in nonneurodegenerative conditions has not been established. Here, we validated that NM-MRI signal intensity in postmortem midbrain specimens correlated with regional NM concentration even in the absence of neurodegeneration, a prerequisite for its use as a proxy for dopamine function.

A Perceptual Inference Mechanism for Hallucinations Linked to Striatal Dopamine.

Hallucinations, a cardinal feature of psychotic disorders such as schizophrenia, are known to depend on excessive striatal dopamine. However, an underlying cognitive mechanism linking dopamine dysregulation and the experience of hallucinatory percepts remains elusive. Bayesian models explain perception as an optimal combination of prior expectations and new sensory evidence, where perceptual distortions such as illusions and hallucinations may occur if prior expectations are afforded excessive weight.

Dopamine-Related Disruption of Functional Topography of Striatal Connections in Unmedicated Patients With Schizophrenia.

Importance: Despite the well-established role of striatal dopamine in psychosis, current views generally agree that cortical dysfunction is likely necessary for the emergence of psychotic symptoms. The topographic organization of striatal-cortical connections is central to gating and integration of higher-order information, so a disruption of such topography via dysregulated dopamine could lead to cortical dysfunction in schizophrenia. However, this hypothesis remains to be tested using multivariate methods ascertaining the global pattern of striatal connectivity and without the confounding effects of antidopaminergic medication.

Dynamic Connectivity between Brain Networks Supports Working Memory: Relationships to Dopamine Release and Schizophrenia.

Unlabelled: Connectivity between brain networks may adapt flexibly to cognitive demand, a process that could underlie adaptive behaviors and cognitive deficits, such as those observed in neuropsychiatric conditions like schizophrenia. Dopamine signaling is critical for working memory but its influence on internetwork connectivity is relatively unknown. We addressed these questions in healthy humans using functional magnetic resonance imaging (during ann-back working-memory task) and positron emission tomography using the radiotracer [(11)C]FLB457 before and after amphetamine to measure the capacity for dopamine release in extrastriatal brain regions.

Do reward-processing deficits in schizophrenia-spectrum disorders promote cannabis use? An investigation of physiological response to natural rewards and drug cues.

Background: Dysfunctional reward processing is present in individuals with schizophrenia-spectrum disorders (SSD) and may confer vulnerability to addiction. Our objective was to identify a deficit in patients with SSD on response to rewarding stimuli and determine whether this deficit predicts cannabis use.

Methods: We divided a group of patients with SSD and nonpsychotic controls into cannabis users and nonusers.

Do motivation deficits in schizophrenia-spectrum disorders promote cannabis use? An investigation of behavioural response to natural rewards and drug cues.

Deficits in incentive motivation are often present in both Schizophrenia Spectrum Disorders (SSD) and substance-use disorders. The current study aims to test whether the presence of such deficits confers vulnerability to cannabis use in individuals with SSD. SSD patients (n=35) and healthy controls (n=35) were each divided into a group with (n=20) and a group without (n=15) current cannabis use disorder.

Case manager- and patient-rated alliance as a predictor of medication adherence in first-episode psychosis.

Objective: The objective of this study was to evaluate the association between adherence to antipsychotic medication and working alliance (WA) ratings as reported separately by case manager (CM) and patient in first-episode psychosis (FEP) and to identify whether other factors previously related to adherence influence this relationship.

Methods: Adherence was evaluated every month in 81 participants who met criteria for a Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, psychotic disorder (affective or nonaffective) and were treated in a specialized early intervention program. Adherence was measured, taking into account information from patient and clinician reports and pill counting.

Cannabis use and anticipatory pleasure as reported by subjects with early psychosis and community controls.

Background: There is evidence of decreased pleasure and deficits in the anticipation of reward in both psychotic illness and drug addiction. Individuals with low anticipatory pleasure may preferentially engage in behaviours associated with immediate reward such as cannabis use.

Method: Ninety-one psychosis patients and 91 controls without history of psychosis were administered the Temporal Experience of Pleasure Scale (TEPS), a self report which measures anticipatory and consummatory pleasure.