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The Topography of Striatal Dopamine and Symptoms in Psychosis: An Integrative Positron Emission Tomography and Magnetic Resonance Imaging Study.

ABSTRACT: BACKGROUND:Striatal dopamine dysfunction is thought to underlie symptoms in psychosis, yet it remains unclear how a single neurotransmitter could cause the diverse presentations that are observed clinically. One hypothesis is that the consequences of aberrant dopamine signaling vary depending on where within the striatum the dysfunction occurs. Positron emission tomography allows for the quantification of dopamine function across the striatum. In the current study, we used a novel method to investigate the relationship between spatial variability in dopamine synthesis capacity and psychotic symptoms. METHODS:We used a multimodal imaging approach combining 18F-DOPA positron emission tomography and resting-state magnetic resonance imaging in 29 patients with first-episode psychosis and 21 healthy control subjects. In each participant, resting-state functional connectivity maps were used to quantify the functional connectivity of each striatal voxel to well-established cortical networks. Network-specific striatal dopamine synthesis capacity (Kicer) was then calculated for the resulting connectivity-defined parcellations. RESULTS:The connectivity-defined parcellations generated Kicer values with equivalent reliability, and significantly greater orthogonality compared with standard anatomical parcellation methods. As a result, dopamine-symptom associations were significantly different from one another for different subdivisions, whereas no unique subdivision relationships were found when using an anatomical parcellation. In particular, dopamine function within striatal areas connected to the default mode network was strongly associated with negative symptoms (p < .001). CONCLUSIONS:These findings suggest that individual differences in the topography of dopamine dysfunction within the striatum contribute to shaping psychotic symptomatology. Further validation of the novel approach in future studies is necessary.

SUBMITTER: McCutcheon RA

PROVIDER: S-EPMC7645803 | biostudies-literature | 2020 Nov

REPOSITORIES: biostudies-literature

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The Topography of Striatal Dopamine and Symptoms in Psychosis: An Integrative Positron Emission Tomography and Magnetic Resonance Imaging Study.

McCutcheon Robert A RA Jauhar Sameer S Pepper Fiona F Nour Matthew M MM Rogdaki Maria M Veronese Mattia M Turkheimer Federico E FE Egerton Alice A McGuire Philip P Mehta Mitul M MM Howes Oliver D OD

Biological psychiatry. Cognitive neuroscience and neuroimaging 20200423 11

<h4>Background</h4>Striatal dopamine dysfunction is thought to underlie symptoms in psychosis, yet it remains unclear how a single neurotransmitter could cause the diverse presentations that are observed clinically. One hypothesis is that the consequences of aberrant dopamine signaling vary depending on where within the striatum the dysfunction occurs. Positron emission tomography allows for the quantification of dopamine function across the striatum. In the current study, we used a novel method ...[more]

PMID: 32653578

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Project description:ImportanceMajor depressive disorder (MDD) might involve dopamine (DA) reductions. The DA transporter (DAT) regulates DA clearance and neurotransmission and is sensitive to DA levels, with preclinical studies (including those involving inescapable stressors) showing that DAT density decreases when DA signaling is reduced. Despite preclinical data, evidence of reduced DAT in MDD is inconclusive.ObjectiveUsing a highly selective DAT positron emission tomography (PET) tracer ([11C] altropane), DAT availability was probed in individuals with MDD who were not taking medication. Levels of DAT expression were also evaluated in postmortem tissues from donors with MDD who died by suicide.Design, setting, and participantsThis cross-sectional PET study was conducted at McLean Hospital (Belmont, Massachusetts) and Massachusetts General Hospital (Boston) and enrolled consecutive individuals with MDD who were not taking medication and demographically matched healthy controls between January 2012 and March 2014. Brain tissues were obtained from the Douglas-Bell Canada Brain Bank. For the PET component, 25 individuals with current MDD who were not taking medication and 23 healthy controls recruited from McLean Hospital were included (all provided usable data). For the postmortem component, 15 individuals with depression and 14 healthy controls were considered.InterventionPET scan.Main outcomes and measuresStriatal and midbrain DAT binding potential was assessed. For the postmortem component, tyrosine hydroxylase and DAT levels were evaluated using Western blots.ResultsCompared with 23 healthy controls (13 women [56.5%]; mean [SD] age, 26.49 [7.26] years), 25 individuals with MDD (19 women [76.0%]; mean [SD] age, 26.52 [5.92] years) showed significantly lower in vivo DAT availability in the bilateral putamen and ventral tegmental area (Cohen d range, -0.62 to -0.71), and both reductions were exacerbated with increasing numbers of depressive episodes. Unlike healthy controls, the MDD group failed to show an age-associated reduction in striatal DAT availability, with young individuals with MDD being indistinguishable from older healthy controls. Moreover, DAT availability in the ventral tegmental area was lowest in individuals with MDD who reported feeling trapped in stressful circumstances. Lower DAT levels (and tyrosine hydroxylase) in the putamen of MDD compared with healthy controls were replicated in postmortem analyses (Cohen d range, -0.92 to -1.15).Conclusions and relevanceMajor depressive disorder, particularly with recurring episodes, is characterized by decreased striatal DAT expression, which might reflect a compensatory downregulation due to low DA signaling within mesolimbic pathways.

Dataset Information

The Topography of Striatal Dopamine and Symptoms in Psychosis: An Integrative Positron Emission Tomography and Magnetic Resonance Imaging Study.

Publications

The Topography of Striatal Dopamine and Symptoms in Psychosis: An Integrative Positron Emission Tomography and Magnetic Resonance Imaging Study.

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