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. 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.

In light of the clinical evidence implicating dopamine in schizophrenia, and the prominent hypotheses put forth regarding alterations in dopaminergic transmission in this disease, molecular imaging has been used to examine multiple aspects of the dopaminergic system. Here we review the imaging methods used and compare the findings across the different molecular targets. Findings have converged to suggest early dysregulation in the striatum, especially in the rostral caudate, manifesting as excess synthesis and release. Recent data showed deficit extending to most cortical regions, and even to other extrastriatal subcortical regions not previously considered to be “hypodopaminergic” in schizophrenia. These findings yield a new topography for the dopaminergic dysregulation in schizophrenia. In this review we discuss the dopaminergic innervation within the individual projection fields to provide a topographical map of this dual dysregulation and explore potential cellular and circuit based mechanisms for brain region-dependent alterations in dopaminergic parameters. This refined knowledge is essential to better guide translational studies and efforts in early drug development.

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.

Most drugs of abuse lead to a general blunting of dopamine release in the chronic phase of dependence, which contributes to poor outcome. To test whether cannabis dependence is associated with a similar dopaminergic deficit, we examined striatal and extrastriatal dopamine release in severely cannabis dependent participants (CD), free of any comorbid conditions, including nicotine use. Eleven CD and twelve healthy controls (HC) completed two positron emission tomography scans with [11C]-(+)-PHNO, before and after oral administration of d-amphetamine. CD stayed inpatient for 5–7 days prior to the scans to standardize abstinence. Magnetic Resonance Imaging (MRS) measures of glutamate in the striatum and hippocampus were obtained in the same subjects. Percent change in [11C]-(+)-PHNO binding potential (ΔBPND) was compared between groups and correlations with MRS glutamate, subclinical psychopathological and neurocognitive parameters were examined. CD had significantly lower ΔBPND in the striatum (p=0.002, effect size (ES)=1.48), including the associative striatum (p=0.003, ES=1.39), sensorimotor striatum (p=0.003, ES=1.41), and the pallidus (p=0.012, ES=1.16). Lower dopamine release in the associative striatum correlated with inattention and negative symptoms in CD, and with poorer working memory and probabilistic category learning performance in both CD and HC. No relationships to MRS glutamate and amphetamine-induced subclinical positive symptoms were detected. In conclusion, this study provides evidence that severe cannabis dependence -without the confounds of any comorbidity- is associated with a deficit in striatal dopamine release. This deficit extends to other extrastriatal areas and predicts subclinical psychopathology.

Background The neural correlates of working memory (WM) impairment in schizophrenia remain a key puzzle in understanding the cognitive deficits and dysfunction of dorsolateral prefrontal cortex observed in the disorder. We sought to determine whether patients with schizophrenia exhibit an alteration in the inverted-U relationship between WM load and activation that we recently observed in healthy individuals, and whether this could account for WM deficits in this population. Methods Medicated (N=30) and unmedicated (N=21) patients with schizophrenia and healthy controls (N=45) performed the self-ordered WM task during functional Magnetic Resonance Imaging. We identified regions exhibiting an altered fit to an inverted-U relationship between WM load and activation that were also predictive of WM performance. Results A blunted inverted-U response was observed in left DLPFC in patients and was associated with behavioral deficits in WM capacity. In addition, suppression of medial prefrontal cortex (mPFC) during WM was reduced in patients, and was also associated with poorer WM capacity in patients. Finally, activation of visual cortex in the cuneus was elevated in patients and associated with improved WM capacity. Together, these findings explained 55% of the interindividual variance in WM capacity when combined with diagnostic and medication status, which alone accounted for only 22% of the variance in WM capacity. Conclusions These findings identify a novel biomarker and putative mechanism of WM deficits in patients with schizophrenia, a reduction or flattening of the inverted-U relationship between activation and WM load observed in healthy individuals in left dorsolateral prefrontal cortex.

Introduction Pulmonary nodules often require operative resection to obtain a diagnosis. However, 10–30% of operations result in a benign diagnosis. Our purpose was to determine whether negative thoracic operations are futile by describing the pathological diagnoses, determining new diagnoses and treatment changes initiated based on operative findings, and assessing morbidity, mortality and cost of the procedure. Methods At our academic medical center 278 thoracic operations were performed for known or suspected cancer between January 1, 2005 and April 1, 2009. We collected and summarized data pertaining to pre-operative patient and nodule characteristics, pathologic diagnosis, post-operative treatment changes resulting from surgical resection, peri-operative morbidity and mortality, and hospital charges for patients with benign pathology. Results Twenty-three percent (65/278) of patients who underwent surgical resection for a suspicious nodule had benign pathology. We report granulomatous disease in 57%, benign tumors in 15%, fibrosis in 12%, and autoimmune and vascular diseases in 9%. Definitive diagnosis or treatment changes occurred in 85% of cases. Surgical intervention led to a new diagnosis in 69% and treatment course changes in 68% of benign cases; medication changes in 38%, new consultation in 31%, definitive treatment in 9%, and underlying disease management in 34%. There was no intraoperative, in-hospital, or 30-day mortality. Post-operative in-hospital events occurred in 7 patients. The mean total cost was $25,515 with a mean cost per day of $7,618. Conclusions Patients with a benign diagnosis after surgical resection for a pulmonary nodule received a new diagnosis or had a treatment course change in 85% of the cases.

Recent genetic, molecular and postmortem studies suggest impaired D2R trafficking in patients with schizophrenia (SZ). Imaging and preclinical studies have shown agonist-induced D2R internalization can be imaged with positron emission tomography (PET) using dopamine-D2 receptor (D2R) radiotracers combined with psychostimulant challenge. This is feasible if radiotracer binding is measured when post-challenge dopamine (DA) levels have returned to baseline, following the initial competition phase between DA and radiotracer for binding to D2R. Here we used “late”-phase imaging post-challenge to test the hypothesis that impaired D2R internalization in SZ leads to blunted late phase displacement, or a faster return to baseline, in patients compared to healthy controls (HC). We imaged 10 patients with SZ and 9 HC with PET and [11C]raclopride at baseline and twice (3–5hr and 6–10hr) following 0.5 mg/kg dextro-amphetamine. We measured binding potential relative to non-displaceable compartment (BPND) and derived percent reduction from baseline (ΔBPND) for each post-amphetamine scan. To test the hypothesis that time course of return of striatal BPND to baseline differed between SZ and HC, we implemented a linear model with ΔBPND as dependent variable, time post-amphetamine as repeated measure, and time post-amphetamine and diagnostic group as fixed effects. Neither diagnostic group nor interaction of diagnostic group-by-time post-amphetamine significantly affected striatal ΔBPND (F=1.38, p=0.26; F=0.51, p=0.61). These results show similar pattern of return of BPND to baseline as a function of time in patients with SZ and HC, suggesting striatal D2R internalization as measured by our imaging paradigm is normal in patients with SZ.

Background Neuromelanin‐sensitive magnetic resonance imaging (NM‐MRI) is a validated measure of neuromelanin concentration in the substantia nigra–ventral tegmental area (SN–VTA) complex and is a proxy measure of dopaminergic function with potential as a noninvasive biomarker. The development of generalizable biomarkers requires large‐scale samples necessitating harmonization approaches to combine data collected across sites. Purpose To develop a method to harmonize NM‐MRI across scanners and sites. Study Type Prospective. Population A total of 128 healthy subjects (18–73 years old; 45% female) from three sites and five MRI scanners. Field Strength/Sequence 3.0 T; NM‐MRI two‐dimensional gradient‐recalled echo with magnetization‐transfer pulse and three‐dimensional T1‐weighted images. Assessment NM‐MRI contrast (contrast‐to‐noise ratio [CNR]) maps were calculated and CNR values within the SN–VTA (defined previously by manual tracing on a standardized NM‐MRI template) were determined before harmonization (raw CNR) and after ComBat harmonization (harmonized CNR). Scanner differences were assessed by calculating the classification accuracy of a support vector machine (SVM). To assess the effect of harmonization on biological variability, support vector regression (SVR) was used to predict age and the difference in goodness‐of‐fit (Δr) was calculated as the correlation (between actual and predicted ages) for the harmonized CNR minus the correlation for the raw CNR. Statistical Tests Permutation tests were used to determine if SVM classification accuracy was above chance level and if SVR Δr was significant. A P‐value <0.05 was considered significant. Results In the raw CNR, SVM MRI scanner classification was above chance level (accuracy = 86.5%). In the harmonized CNR, the accuracy of the SVM was at chance level (accuracy = 29.5%; P = 0.8542). There was no significant difference in age prediction using the raw or harmonized CNR (Δr = −0.06; P = 0.7304). Data Conclusion ComBat harmonization removes differences in SN–VTA CNR across scanners while preserving biologically meaningful variability associated with age. Level of Evidence 2 Technical Efficacy 1