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. Such excessive weight of prior expectations, in turn, could stem from a gain-control process controlled by neuromodulators such as dopamine. To test for such a dopamine-dependent gain-control mechanism of hallucinations, we studied unmedicated patients with schizophrenia with varying degrees of hallucination severity and healthy individuals using molecular imaging with a pharmacological manipulation of dopamine, structural imaging, and a novel task designed to measure illusory changes in the perceived duration of auditory stimuli under different levels of uncertainty. Hallucinations correlated with a perceptual bias, reflecting disproportional gain on expectations under uncertainty. This bias could be pharmacologically induced by amphetamine, strongly correlated with striatal dopamine release, and related to cortical volume of the dorsal anterior cingulate, a brain region involved in tracking environmental uncertainty. These findings outline a novel dopamine-dependent mechanism for perceptual modulation in physiological conditions and further suggest that this mechanism may confer vulnerability to hallucinations in hyper-dopaminergic states underlying psychosis.
•Auditory hallucinations are linked to a perceptual bias toward uncertain expectations•Elevated striatal dopamine function relates to the same pattern of perceptual bias•Volume of dorsal anterior cingulate relates to the same pattern of perceptual bias
Cassidy et al. induced auditory illusions to test a dopamine-dependent cognitive mechanism for hallucinations. Unmedicated schizophrenia patients with auditory hallucinations perceived tone durations in a way similar to what was expected, even when expectations were imprecise, and this perceptual bias related to excess dopamine function.
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 non-neurodegenerative 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. We then validated a voxelwise NM-MRI approach with sufficient anatomical sensitivity to resolve SN subregions. Using this approach and a multimodal dataset of molecular PET and fMRI data, we further showed the NM-MRI signal was related to both dopamine release in the dorsal striatum and resting blood flow within the SN. These results suggest that NM-MRI signal in the SN is a proxy for function of dopamine neurons in the nigrostriatal pathway. As a proof of concept for its clinical utility, we show that the NM-MRI signal correlated to severity of psychosis in schizophrenia and individuals at risk for schizophrenia, consistent with the well-established dysfunction of the nigrostriatal pathway in psychosis. Our results indicate that noninvasive NM-MRI is a promising tool that could have diverse research and clinical applications to investigate in vivo the role of dopamine in neuropsychiatric illness.
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. The systematic search identified 10 relevant articles, primarily focusing on the substantia nigra. An early-stage meta-analysis (n = 6) revealed varied observations ranging from standardized mean differences of −3.55 to +0.62, with a pooled estimate of −0.44 (95 % CI = −1.52, 0.65), but there was insufficient power to detect differences in neuromelanin content among individuals with substance use disorders. Our gap analysis highlights the lack of sufficient replication studies, with existing studies lacking the power to detect a true difference, and a complete lack of neuromelanin studies on certain substances of clinical interest. We provide recommendations for future studies of dopaminergic neurobiology in addictions and related psychiatric comorbidities.
•Ten studies were found that measure dopaminergic changes associated with SUD by employing neuromelanin signal from postmortem tissue and magnetic resonance imaging in vivo data.•In the same fashion as markers of liver injury indicate the severity of alcohol use disorder, neuromelanin may have a potential to be a 'criterion marker' for SUD.•Neuromelanin imaging is a promising approach to further study dopamine neurobiology in SUD.
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. In secondary analyses, we also assessed the ability of NM-MRI to predict L-DOPA treatment response in a subset of these patients (N = 15) who received 3 weeks of L-DOPA. We scanned a further subset of these patients (N = 6) with NM-MRI at baseline and after treatment to preliminarily evaluate the effects of L-DOPA treatment on the NM-MRI signal. We found that lower baseline NM-MRI correlated with slower baseline gait speed (346 of 1807 substantia nigra-ventral tegmental area (SN-VTA) voxels, P
= 0.038), particularly in the more medial, anterior, and dorsal SN-VTA. Secondary analyses failed to show an association between baseline NM-MRI and treatment-related changes in gait speed, processing speed, or depression severity (all P
> 0.361); we however found preliminary evidence of increases in the NM-MRI signal 3 weeks post-treatment with L-DOPA compared to baseline (200 of 1807 SN-VTA voxels; P
= 0.046), although the small sample size of these preliminary analyses warrants caution in their interpretation and future replications. Overall, our findings indicate that NM-MRI is sensitive to variability in gait speed in patients with LLD, suggesting this non-invasive MRI measure may provide a promising marker for dopamine-related psychomotor slowing in geriatric neuropsychiatry.
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.
NM-MRI and T
-weighted images were acquired from 20 participants with cocaine use disorder and 35 control subjects. Diagnostic group effects in NM-MRI signal were determined using a voxelwise analysis within the substantia nigra. A subset of 20 cocaine users and 17 control subjects also underwent functional MRI imaging using the monetary incentive delay task, in order to investigate whether NM-MRI signal was associated with alterations in reward processing.
Compared with control subjects, cocaine users showed significantly increased NM-MRI signal in ventrolateral regions of the substantia nigra (area under the receiver operating characteristic curve=0.83). Exploratory analyses did not find a significant correlation of NM-MRI signal to activation of the ventral striatum during anticipation of monetary reward.
Given that previous imaging studies show decreased dopamine signaling in the striatum, the finding of increased NM-MRI signal in the substantia nigra provides additional insight into the pathophysiology of cocaine use disorder. One interpretation is that cocaine use disorder is associated with a redistribution of dopamine between cytosolic and vesicular pools, leading to increased accumulation of neuromelanin. The study findings thus suggest that NM-MRI can serve as a practical imaging tool for interrogating the dopamine system in addiction.
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. OBJECTIVES: To examine whether the pattern of brain connectivity across striatal subregions is abnormal in unmedicated patients with schizophrenia and whether this abnormality relates to psychotic symptoms and extrastriatal dopaminergic transmission. DESIGN, SETTING, AND PARTICIPANTS: In this multimodal, case-control study, we obtained resting-state functional magnetic resonance imaging data from 18 unmedicated patients with schizophrenia and 24 matched healthy controls from the New York State Psychiatric Institute. A subset of these (12 and 17, respectively) underwent positron emission tomography with the dopamine D2 receptor radiotracer carbon 11–labeled FLB457 before and after amphetamine administration. Data were acquired between June 16, 2011, and February 25, 2014. Data analysis was performed from September 1, 2014, to January 11, 2016. MAIN OUTCOMES AND MEASURES: Group differences in the striatal connectivity pattern (assessed via multivariable logistic regression) across striatal subregions, the association between the multivariate striatal connectivity pattern and extrastriatal baseline D2 receptor binding potential and its change after amphetamine administration, and the association between the multivariate connectivity pattern and the severity of positive symptoms evaluated with the Positive and Negative Syndrome Scale. RESULTS: Of the patients with schizophrenia (mean SEM age, 35.6 11.8 years), 9 (50%) were male and 9 (50%) were female. Of the controls (mean SEM age, 33.7 8.8 years), 10 (42%) were male and 14 (58%) were female. Patients had an abnormal pattern of striatal connectivity, which included abnormal caudate connections with a distributed set of associative cortex regions (χ229 = 53.55, P = .004). In patients, more deviation from the multivariate pattern of striatal connectivity found in controls correlated specifically with more severe positive symptoms (ρ = −0.77, P = .002). Striatal connectivity also correlated with baseline binding potential across cortical and extrastriatal subcortical regions (t25 = 3.01, P = .01, Bonferroni corrected) but not with its change after amphetamine administration. CONCLUSIONS AND RELEVANCE: Using a multimodal, circuit-level interrogation of striatal-cortical connections, it was demonstrated that the functional topography of these connections is globally disrupted in unmedicated patients with schizophrenia. These findings suggest that striatal-cortical dysconnectivity may underlie the effects of dopamine dysregulation on the pathophysiologic mechanism of psychotic symptoms.
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
FMK6240 and
FAZD4694, respectively). Integrity of the LC-norepinephrine system was assessed based on contrast-to-noise ratio of the LC on NM-MRI images. Braak stage of AD was derived from regional binding of
FMK6240. NPS were assessed with the Mild Behavioral Impairment Checklist (MBI-C). LC signal contrast was decreased in tau-positive participants (t
= -4.00, p = 0.0001) and negatively correlated to Braak stage (Spearman ρ = -0.31, p = 0.00006). In tau-positive participants (n = 51), higher LC signal predicted NPS severity (ρ = 0.35, p = 0.019) independently of tau burden, amyloid-β burden, and cortical gray matter volume. This relationship appeared to be driven by the impulse dyscontrol domain of NPS, which was highly correlated to LC signal (ρ = 0.44, p = 0.0027). NM-MRI reveals loss of LC integrity that correlates to severity of AD. However, LC preservation in AD may also have negative consequences by conferring risk for impulse control symptoms. NM-MRI shows promise as a practical biomarker that could have utility in predicting the risk of NPS or guiding their treatment in AD.
•Neuromelanin is thought to serve as a biomarker for midbrain dopamine function.•Neuromelanin can be detected by an NM-MRI non-invasively and cost-effectively.•Schizophrenia showed higher NM-MRI ...signals in the substantia nigra than controls.•Further studies will validate the clinical utility of NM-MRI for stratifying schizophrenia.
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. This study included 7 articles in total. Five studies employed NM-sensitive MRI (NM-MRI) and two were postmortem brain studies. The patient group (n = 163) showed higher NM levels in the substantia nigra (SN) than HCs (n = 228) in both the analysis of the seven studies and the subgroup analysis of the 5 NM-MRI studies. This analysis suggest increased NM levels in the SN may be a potential biomarker for stratifying schizophrenia, warranting further research that accounts for the heterogeneity of this disorder.
PDF
