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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

Background Recent studies have established a clear topographical and functional organization of projections to and from complex subdivisions of the striatum. Manual segmentation of these functional subdivisions is labor-intensive and time-consuming, and automated methods are not as reliable as manual segmentation. Purpose To utilize multitask learning (MTL) as a method to segment subregions of the striatum consisting of pre-commissural putamen (prePU), pre-commissural caudate (preCA), post-commissural putamen (postPU), post-commissural caudate (postCA), and ventral striatum (VST). Study type Retrospective. Population Eighty-seven total data sets from patients with schizophrenia and matched controls. Field strength/sequence 1.5 T and 3.0 T, T1 -weighted (SPGR SENSE, 3D BRAVO). Assessment MTL-generated segmentations were compared to the Imperial College London Clinical Imaging Center (CIC) atlas. Dice similarity coefficient (DSC) was used to compare the automated methods to manual segmentations. Positron emission tomography (PET) imaging: 60 minutes of emission data were acquired using [11 C]raclopride. Data were reconstructed by filtered back projection (FBP) with computed tomography (CT) used for attenuation correction. Binding potential values, BPND , and region of interest (ROI) time series and whole-brain connectivity using functional magnetic resonance imaging (fMRI) images were compared between manual and both automated segmentations. Statistical tests Pearson correlation and paired t-test. Results MTL-generated segmentations showed excellent spatial agreement with manual (DSC ≥0.72 across all striatal subregions). BPND values from MTL-generated segmentations were shown to correlate well with manual segmentations with R2 ≥ 0.91 in all caudate and putamen subregions, and R2 = 0.69 in VST. Mean Pearson correlation coefficients of the fMRI data between MTL-generated and manual segmentations were also high in time series (≥0.86) and whole-brain connectivity (≥0.89) across all subregions. Data conclusion Across both PET and fMRI task-based assessments, results from MTL-generated segmentations more closely corresponded to results from manually drawn ROIs than CIC-generated segmentations did. Therefore, the proposed MTL approach is a fast and reliable method for three-dimensional striatal subregion segmentation with results comparable to manually segmented ROIs. Level of evidence 2 TECHNICAL EFFICACY STAGE: 1.

BACKGROUND: Recent studies have established a clear topographical and functional organization of projections to and from complex subdivisions of the striatum. Manual segmentation of these functional subdivisions is labor-intensive and time-consuming, and automated methods are not as reliable as manual segmentation. PURPOSE: To utilize Multi-Task Learning (MTL) as a method to segment subregions of the striatum consisting of pre-commissural putamen (prePU), pre-commissural caudate (preCA), post-commissural putamen (postPU), post-commissural caudate (postCA), and ventral striatum (VST). STUDY TYPE: Retrospective POPULATION: 87 total data sets from patients with schizophrenia and matched controls. FIELD STRENGTH/SEQUENCE: 1.5T and 3.0T, T(1)-weighted (SPGR SENSE, 3D BRAVO) ASSESSMENT: MTL-generated segmentations were compared to the Imperial College London Clinical Imaging Center (CIC) atlas. Dice similarity coefficient (DSC) was used to compare the automated methods to manual segmentations. PET imaging: 60min of emission data were acquired using [11C]raclopride. Data were reconstructed by filtered back projection (FBP) with computed tomography (CT) used for attenuation correction. Binding potential values, BP(ND), and ROI time-series and whole-brain connectivity using fMRI images were compared between manual and both automated segmentations STATISTICAL TESTS: Pearson correlation and paired t-test. RESULTS: MTL-generated segmentations showed excellent spatial agreement with manual (DSC ≥ 0.72 across all striatal subregions). BP(ND) values from MTL-generated segmentations were shown to correlate well with manual segmentations with R(2) ≥ 0.91 in all caudate and putamen subregions, and R(2)=0.69 in VST. Mean Pearson correlation coefficients of the fMRI data between MTL-generated and manual segmentations were also high in time-series (≥0.86) and whole-brain connectivity (≥0.89) across all subregions. DATA CONCLUSION: Across both PET and fMRI task-based assessment, results from MTL-generated segmentations more closely corresponded to results from manually drawn ROIs than CIC-generated segmentations did. Therefore, the proposed MTL approach is a fast and reliable method for 3D striatal subregion segmentation with results comparable to manually segmented ROIs.

Cognitive behavioral therapy (CBT) including exposure and response prevention is a well-established treatment for obsessive-compulsive disorder (OCD) and is based on the principles of fear extinction. Fear extinction is linked to structural and functional variability in the ventromedial prefrontal cortex (vmPFC) and has been consistently associated with glutamate neurotransmission. The relationship between vmPFC glutamate and fear extinction and its effects on CBT outcome have not yet been explored in adults with OCD. We assessed glutamate levels in the vmPFC using 3T magnetic resonance spectroscopy, and fear extinction (learning and recall) using skin conductance responses during a 2-day experimental paradigm in OCD patients (n = 17) and in healthy controls (HC; n = 13). Obsessive-compulsive patients (n = 12) then received manualized CBT. Glutamate in the vmPFC was negatively associated with fear extinction recall and positively associated with CBT outcome (with higher glutamate levels predicting a better outcome) in OCD patients. Glutamate levels in the vmPFC in OCD patients were not significantly different from those in HC, and were not associated with OCD severity. Our results suggest that glutamate in the vmPFC is associated with fear extinction recall and CBT outcome in adult OCD patients.

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.

The human striatum is a collection of subcortical nuclei that serves as a critical node in an information processing network. Recent studies have established a clear topographical and functional organization of projections to and from striatal regions that involves detailed and complex subdivisions of the striatum. Manual segmentation of these functional subdivisions is labor-intensive and time-consuming, yet automated methods have also been a challenging computational problem. Recently, deep learning has emerged as a powerful tool for various tasks, including semantic segmentation. Multi-Task Learning (MTL) is a machine learning technique that allows latent representations between related tasks to be shared during model prediction of multiple tasks with better accuracy. We utilized MTL to segment subregions of the striatum consisting of pre-commissural putamen (prePU), pre-commissural caudate (preCA), post-commissural putamen (postPU), post-commissural caudate (postCA), and ventral striatum (VST). Dice similarity coefficients (DSC) demonstrate excellent spatial agreement between manual and MTL-generated segmentations (≥ 0.72 across all striatal subregions). Further quantitative task-based analysis was also conducted. Binding potential values, BPND, of [11C]raclopride PET, and ROI time-series and whole-brain connectivity using fMRI images were compared between results generated from manual segmentations and MTL-generated segmentations. BPND values from MTL-generated segmentations were shown to correlate well with manual segmentations with R2 ≥ 0.91 in all caudate and putamen subregions, and R2=0.69 in VST. Mean Pearson correlation coefficients of the fMRI data between MTL-generated and manual segmentations were also high in time-series (≥0.86) and whole-brain connectivity (≥0.89) across all subregions. We conclude that the MTL approach is a fast, robust and reliable method for 3D striatal subregion segmentation with results comparable to manually segmented ROIs.

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.

Recent genetic, molecular and post-mortem studies suggest impaired dopamine (DA)-D2 receptor (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 D2R radiotracers combined with psychostimulant challenge. This is feasible if radiotracer binding is measured when postchallenge 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 after 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 with healthy controls (HCs). We imaged 10 patients with SZ and 9 HCs with PET and [11C]raclopride at baseline and two times (3–5 and 6–10 h) following 0.5 mg kg−1 dextroamphetamine. We measured binding potential relative to non-displaceable compartment (BPND) and derived percent reduction from baseline (ΔBPND) for each postamphetamine scan. To test the hypothesis that time course of return of striatal BPND to baseline differed between SZ and HCs, we implemented a linear model with ΔBPND as dependent variable, time after amphetamine as repeated measure and time after amphetamine and diagnostic group as fixed effects. Neither diagnostic group nor interaction of diagnostic group-by-time after 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 that striatal D2R internalization as measured by our imaging paradigm is normal in patients with SZ.

Correction to: Molecular Psychiatry advance online publication, 16 May 2017; doi: 10.1038/mp.2017.107 The authors’ affiliations were presented incorrectly. The correct affiliations appear below: JJ Weinstein1,2, E van de Giessen3, RJ Rosengard4, X Xu4, N Ojeil4, G Brucato2,4, RB Gil1, LS Kegeles2,4,M Laruelle2, M Slifstein1, A Abi-Dargham1

Background: Converging evidence suggests concomitant abnormalities in NMDA-dependent processes in schizophrenia in addition to dopaminergic disturbances. These include the robust and replicable deficits in mismatch negativity (MMN), an NMDA-dependent event-related potential to unexpected auditory events, and MR spectroscopy findings showing increased glutamate in untreated SCZ in several cortical and subcortical regions (thalamus, striatum, hippocampus, and medial prefrontal cortex). Studies of medicated patients have shown a glutamate- or glutamine-lowering effect of antipsychotic medications. We also recently measured a deficit in cortical dopamine release using PET and the amphetamine challenge. Taken together these findings suggest that dopamine and glutamate may be both affected in the cortex and raise a special therapeutic challenge. Furthermore, in the striatum glutamate and dopamine have both been found to be abnormal.

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 12 healthy controls (HC) completed two positron emission tomography scans with [(11)C]-(+)-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 spectroscopy (MRS) measures of glutamate in the striatum and hippocampus were obtained in the same subjects. Percent change in [(11)C]-(+)-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 this 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 control subjects ( 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 dorsolateral prefrontal cortex in patients and was associated with behavioral deficits in WM capacity. In addition, suppression of medial prefrontal cortex during WM was reduced in patients and was 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.

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.

Depression remains a great societal burden and a major treatment challenge. Most antidepressant medications target serotonergic raphé nuclei. Acute tryptophan depletion (ATD) modulates serotonin function. To better understand the raphé's role in mood networks, we studied raphé functional connectivity in depression. Fifteen depressed patients were treated with sertraline for 12 weeks and scanned during ATD and sham conditions. Based on our previous findings in a separate cohort, resting state MRI functional connectivity between raphé and other depression-related regions (ROIs) was analyzed in narrow frequency bands. ATD decreased raphé functional connectivity with the bilateral thalamus within 0.025–0.05 Hz, and also decreased raphé functional connectivity with the right pregenual anterior cingulate cortex within 0.05–0.1 Hz. Using the control broadband filtlter 0.01–0.1 Hz, no significant differences in raphé-ROI functional connectivity were observed. Post-hoc analysis by remission status suggested increased raphé functional connectivity with left pregenual anterior cingulate cortex in remitters (n = 10) and decreased raphé functional connectivity with left thalamus in non-remitters (n = 5), both within 0.025–0.05 Hz. Reducing serotonin function appears to alter coordination of these mood-related networks in specific, low frequency ranges. For examination of effects of reduced serotonin function on mood-related networks, specific low frequency BOLD fMRI signals can identify regions implicated in neural circuitry and may enable clinically-relevant interpretation of functional connectivity measures. The biological significance of these low frequency signals detected in the raphé merits further study.

Introduction Pulmonary nodules often require operative resection to obtain a diagnosis. However, 10 to 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 preoperative patient and nodule characteristics, pathologic diagnosis, postoperative treatment changes resulting from surgical resection, perioperative 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%, 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. Postoperative in-hospital events occurred in seven patients. The mean total cost was $25,515 with a mean cost per day of $7618. 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.