Abstract 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.
•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.
Despite longstanding interest in the central cholinergic system in schizophrenia (SCZ), cholinergic imaging studies with patients have been limited to receptors. Here, we conducted a proof-of-concept ...positron emission tomography study using 18F-VAT, a new radiotracer that targets the vesicular acetylcholine transporter as a proxy measure of acetylcholine transmission capacity, in patients with SCZ and explored relationships of vesicular acetylcholine transporter with clinical symptoms and cognition.
A total of 18 adult patients with SCZ or schizoaffective disorder (the SCZ group) and 14 healthy control participants underwent a positron emission tomography scan with 18F-VAT. Distribution volume (VT) for 18F-VAT was derived for each region of interest, and group differences in VT were assessed with 2-sample t tests. Functional significance was explored through correlations between VT and scores on the Positive and Negative Syndrome Scale and a computerized neurocognitive battery (PennCNB).
No group differences in 18F-VAT VT were observed. However, within the SCZ group, psychosis symptom severity was positively associated with VT in multiple regions of interest, with the strongest effects in the hippocampus, thalamus, midbrain, cerebellum, and cortex. In addition, in the SCZ group, working memory performance was negatively associated with VT in the substantia innominata and several cortical regions of interest including the dorsolateral prefrontal cortex.
In this initial study, the severity of 2 important features of SCZ—psychosis and working memory deficit—was strongly associated with 18F-VAT VT in several cortical and subcortical regions. These correlations provide preliminary evidence of cholinergic activity involvement in SCZ and, if replicated in larger samples, could lead to a more complete mechanistic understanding of psychosis and cognitive deficits in SCZ and the development of therapeutic targets.
Abstract 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.
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
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 11Craclopride. 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
Patients with schizophrenia have a high prevalence of cigarette smoking and respond poorly to conventional treatments, highlighting the need for new therapies. We conducted a mechanistic, ...proof-of-concept study using bilateral deep repetitive transcranial magnetic stimulation (dTMS) of insular and prefrontal cortices at high frequency, using the specialized H4 coil. Feasibility of dTMS was tested for disruption of tobacco self-administration, insula target engagement, and insula circuit modulation, all of which were a priori outcomes of interest. Twenty patients completed the study, consisting of weekday dTMS sessions (randomization to active dTMS or sham; double-blind; 10 patients per group), a laboratory tobacco self-administration paradigm (pre/post assessments), and multimodal imaging (three MRI total sessions). Results showed that participants assigned to active dTMS were slower to initiate smoking their first cigarette compared with sham, consistent with smoking disruption. The imaging analyses did not reveal significant Time × Group interactions, but effects were in the anticipated directions. In arterial spin labeling analyses testing for target engagement, an overall decrease in insula blood flow, measured during a post-treatment MRI versus baseline, was numerically more pronounced in the active dTMS group than sham. In fMRI analyses, resting-state connectivity between the insula and default mode network showed a numerically greater change from baseline in the active dTMS group than sham, consistent with a functional change to insula circuits. Exploratory analyses further suggested a therapeutic effect of dTMS on symptoms of psychosis. These initial observations pave the way for future confirmatory studies of dTMS in smoking patients with schizophrenia.
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