scholarly journals M7. LOWER THALAMIC DOPAMINE D2-RECEPTOR BINDING IN DRUG-NAIVE PATIENTS WITH PSYCHOSIS – A REPLICATION STUDY USING POSITRON EMISSION TOMOGRAPHY

2020 ◽  
Vol 46 (Supplement_1) ◽  
pp. S135-S136
Author(s):  
Pauliina Victorsson ◽  
Pontus Plavén-Sigray ◽  
Granville Matheson ◽  
Alexander Santillo ◽  
Maria Lee ◽  
...  
Keyword(s):  
High Resolution ◽  
Bayes Factor ◽  
Dopamine D2 Receptor ◽  
D2 Receptor ◽  
First Episode Psychosis ◽  
First Episode ◽  
Cohen’S D ◽  
Positron Emission ◽  
Episode Psychosis ◽  
Cohen's D

Abstract Background The dopamine system is a central focus of research on the pathophysiology and treatment of schizophrenia. With regard to the dopamine D2-receptor (D2-R), Positron Emission Tomography (PET) studies have shown a small increase in striatal receptor availability. In contrast, a more recent line of research has demonstrated lower levels of D2-R (Cohen’s D = -0.32) in the thalamus, a region of key interest for the pathophysiology of schizophrenia. However, some studies included patients previously on antipsychotic medication, or were performed using radioligands with suboptimal affinity for the much lower D2-R density in thalamus compared to striatum. In addition, the resolution of previous PET systems has not allowed for a more detailed analysis of functional thalamic subregions. Here we examined a fully antipsychotic-naïve sample of first-episode psychosis patients using the high-affinity D2-R radioligand [11C]FLB457 and high-resolution PET. The aim was to a) replicate previous findings of lower D2-R in thalamus in patients and b) specifically examine patient-control differences in thalamic subregions based on their cortical connectivity. Methods Nineteen antipsychotic-naïve first episode psychosis patients (mean age = 29.3; sd = 6.3, 11 males) and 19 age- and sex matched healthy comparison subjects were included in the analysis. PET measurements were obtained using a High Resolution Research Tomograph (HRRT). A ROI for whole thalamus was defined using the FSL Harvard Oxford Subcortical Atlas, whereas ROIs for thalamic subregions were based on the Oxford Thalamic Connectivity Atlas. Binding potential (BPND) was calculated using the Logan graphical analysis with cerebellum as reference region. The statistical analyses, which were all pre-registered, were performed using frequentist and Bayesian paired-samples t-tests. Results The frequentist paired t-test showed that patients had significantly lower binding than control subjects in whole thalamus (Cohen’s D = -0.479, p = 0.026). Bayes factor from the Bayesian paired t-test indicated that there was approximately 5 times more support for the hypothesis of lower BPND in patients, compared to the null hypothesis of no difference. Among subregions, the ROI corresponding to prefrontal thalamic connectivity showed the largest effect (Cohen’s D = -0.527, p = 0.017), and Bayes factor indicated that there was 6 times more support for lower BPND in patients compared to no difference. Discussion Using high resolution PET and a high affinity D2-R radioligand in antipsychotic-naïve first-episode psychosis patients, this study replicates the previously reported meta-analytical effect size of lower thalamic receptor availability in patients. The strongest effect was observed in the subregion dominated by connections to prefrontal cortex. The findings may reflect a dysregulation of the thalamic dopamine system in schizophrenia, which in turn could underlie aberrant functional connectivity in key fronto-thalamic circuits.

scholarly journals No association between cortical dopamine D2 receptor availability and cognition in antipsychotic-naive first-episode psychosis

2021 ◽  
Vol 7 (1) ◽  
Author(s):  
Maria Lee ◽  
Helena Fatouros-Bergman ◽  
Pontus Plavén-Sigray ◽  
Pauliina Ikonen Victorsson ◽  
Carl M. Sellgren ◽  
...  
Keyword(s):  
Dopamine D2 Receptor ◽  
D2 Receptor ◽  
Brain Regions ◽  
First Episode Psychosis ◽  
First Episode ◽  
Dopamine D2 ◽  
Clinical Observations ◽  
Positron Emission ◽  
Episode Psychosis ◽  
Dorsolateral Prefrontal

AbstractCognitive impairment is an important predictor of disability in schizophrenia. Dopamine neurotransmission in cortical brain regions has been suggested to be of importance for higher-order cognitive processes. The aim of this study was to examine the relationship between extrastriatal dopamine D2-R availability and cognitive function, using positron emission tomography and the high-affinity D2-R radioligand [11C]FLB 457, in an antipsychotic-naive sample of 18 first-episode psychosis patients and 16 control subjects. We observed no significant associations between D2-R binding in the dorsolateral prefrontal cortex or hippocampus (β = 0.013–0.074, partial r = −0.037–0.273, p = 0.131–0.841). Instead, using Bayesian statistics, we found moderate support for the null hypothesis of no relationship (BFH0:H1 = 3.3–8.2). Theoretically, our findings may suggest a lack of detrimental effects of D2-R antagonist drugs on cognition in schizophrenia patients, in line with clinical observations.

scholarly journals Thalamic dopamine D2-receptor availability in schizophrenia: a study on antipsychotic-naive patients with first-episode psychosis and a meta-analysis

2021 ◽  
Author(s):  
Pontus Plavén-Sigray ◽  
Pauliina Ikonen Victorsson ◽  
Alexander Santillo ◽  
Granville J. Matheson ◽  
Maria Lee ◽  
...  
Keyword(s):  
Diffusion Tensor ◽  
Dopamine D2 Receptor ◽  
Meta Analysis ◽  
D2 Receptor ◽  
First Episode Psychosis ◽  
Binding Potential ◽  
First Episode ◽  
Healthy Controls ◽  
Dopamine D2 ◽  
Episode Psychosis

AbstractPharmacological and genetic evidence support a role for an involvement of the dopamine D2-receptor (D2-R) in the pathophysiology of schizophrenia. Previous molecular imaging studies have suggested lower levels of D2-R in thalamus, but results are inconclusive. The objective of the present study was to use improved methodology to compare D2-R density in whole thalamus and thalamic subregions between first-episode psychosis patients and healthy controls. Differences in thalamocortical connectivity was explored based on the D2-R results. 19 antipsychotic-naive first-episode psychosis patients and 19 age- and sex-matched healthy controls were examined using high-resolution Positron Emission Tomography (PET) and the high-affinity D2-R radioligand [11C]FLB457. The main outcome was D2-R binding potential (BPND) in thalamus, and it was predicted that patients would have lower binding. Diffusion tensor imaging (DTI) was performed in a subgroup of 11 patients and 15 controls. D2-R binding in whole thalamus was lower in patients compared with controls (Cohen’s dz = −0.479, p = 0.026, Bayes Factor (BF) > 4). Among subregions, lower BPND was observed in the ROI representing thalamic connectivity to the frontal cortex (Cohen’s dz = −0.527, p = 0.017, BF > 6). A meta-analysis, including the sample of this study, confirmed significantly lower thalamic D2-R availability in patients. Exploratory analyses suggested that patients had lower fractional anisotropy values compared with controls (Cohen’s d = −0.692, p = 0.036) in the inferior thalamic radiation. The findings support the hypothesis of a dysregulation of thalamic dopaminergic neurotransmission in schizophrenia, and it is hypothesized that this could underlie a disturbance of thalamocortical connectivity.

scholarly journals Acute conceptual disorganization in untreated first-episode psychosis: A combined magnetic resonance spectroscopy and diffusion imaging study of the cingulum

2020 ◽  
Author(s):  
Pan Yunzhi ◽  
Kara Dempster ◽  
Peter Jeon ◽  
Jean Théberge ◽  
Ali Khan ◽  
...  
Keyword(s):  
White Matter ◽  
Magnetic Resonance ◽  
Magnetic Resonance Spectroscopy ◽  
First Episode Psychosis ◽  
Anterior Cingulate ◽  
First Episode ◽  
Resonance Spectroscopy ◽  
Cohen’S D ◽  
Episode Psychosis ◽  
Cohen's D

Background: Disorganized thinking is a core feature of acute psychotic episodes that is linked to social and vocational functioning. Based on the close association between cingulum and disorganized thinking, we examine three candidate mechanistic markers in relation to acute conceptual disorganization (CD) in first episode psychosis: glutamate excess; cortical antioxidant (glutathione) status and the integrity of the cingulum bundle. Methods: We used fractional anisotropy (FA) maps from 7T diffusion-weighted imaging to investigate bilateral cingulum based on a probabilistic white-matter atlas. We compared the high-CD, low-CD and healthy control groups and performed probabilistic fiber tracking from the identified clusters (ROI within cingulum) to the rest of the brain. We quantified glutamate and glutathione with magnetic-resonance-spectroscopy (MRS) in the dorsal anterior cingulate cortex.Results: There was a significant FA reduction (F=9.04; p=0.036) in a cluster in left cingulum in high-CD compared to low-CD (Cohen’s d=1.39; p=0.003) and controls (Cohen’s d=0.86; p=0.009). Glutamate levels did not vary among the groups, but glutathione levels were higher in high-CD compared to the low-CD group. Higher glutathione related to lower FA in the high-CD group in the cingulum cluster.Discussion: Acute CD relates to indicators of oxidative stress as well as reduced white matter integrity of the cingulum but not to MRI-based glutamatergic excess. We propose that both oxidative imbalance and structural dysconnectivity underlie acute disorganization.Limitation: MRS measures of glutamine were highly uncertain and MRs was acquired from a single voxel only.

scholarly journals N-Methyl-D-Aspartate Receptor binding in First-Episode Psychosis: A PET brain imaging study

BJPsych Open ◽  
2021 ◽  
Vol 7 (S1) ◽  
pp. S7-S7
Author(s):  
Katherine Beck ◽  
Atheeshaan Arumuham ◽  
Barbara Santangelo ◽  
Mattia Veronese ◽  
Robert McCutcheon ◽  
...  
Keyword(s):  
Symptom Severity ◽  
First Episode Psychosis ◽  
Anterior Cingulate ◽  
First Episode ◽  
Healthy Controls ◽  
Cohen’S D ◽  
Aspartate Receptor ◽  
Selective Ligand ◽  
Episode Psychosis ◽  
Cohen's D

AimsEvidence from genetics, post mortem and animal studies suggest that N-Methyl-D-Aspartate Receptor (NMDAR) hypofunction has an important role in the pathophysiology of psychosis. However, it is not known if NMDAR activity is altered in the early stages of psychosis or if this links to symptom severity. Our aim was to investigate NMDAR availability in first-episode psychosis (FEP) and determine if it links to symptom severity. The NMDAR hypofunction hypothesis of schizophrenia was initially proposed in the 1990s on the basis of observations that ketamine and phencyclidine (PCP) induced the full range of schizophrenia-like symptoms (positive, negative and cognitive) when given to healthy participants and also that they worsen symptoms in patients with schizophrenia.MethodWe recruited 40 volunteers, including 21 patients with schizophrenia from early intervention services in London (12 antipsychotic-free and 9 receiving antipsychotic medication) and 19 matched healthy controls. The uptake of an NMDAR selective ligand, [18F]GE179, was measured using positron emission tomography (PET) and indexed using the distribution volume ratio (DVR) and volume of distribution (VT, in millilitres per cubic centimetre) of [18F]GE179 in the hippocampus and additional exploratory regions (anterior cingulate cortex (ACC), thalamus, striatum and temporal lobe). Symptom severity was measured using the Positive and Negative Syndrome Scale (PANSS).ResultA total of 37 individuals were included in the analyses (mean [SD] age of controls, 26.7 [4.5] years; mean [SD] age of patients, 25.3 [4.9] years). There was a significant reduction in hippocampal DVR in the patients with schizophrenia relative to healthy controls (p = 0.02, Cohen's d = 0.81). Although the VT of [18F]GE179 was lower in absolute terms in patients, there was no significant effect of group on VT in the hippocampus (p = 0.15, Cohen's d = 0.49) or the exploratory brain regions. There was a negative association between hippocampal DVR and total PANSS symptoms (rho = –0.47, p = 0.04), depressive symptoms (rho = –0.67, p = 0.002), and general PANSS symptoms (rho = –0.74, p = 0.001).ConclusionThese results indicate lower hippocampal NMDAR levels in schizophrenia relative to controls with a large effect size, and that lower NMDAR levels are associated with greater levels of symptom severity. These findings are consistent with the role of NMDAR hypofunction in the pathophysiology of schizophrenia; however, further work is required to test specificity and causal relationships.

Striatal D2 receptor binding as a marker of prognosis and outcome in untreated first-episode psychosis

NeuroImage ◽  
2006 ◽  
Vol 29 (2) ◽  
pp. 662-666 ◽  
Author(s):  
Iluminada Corripio ◽  
Víctor Pérez ◽  
Ana M. Catafau ◽  
Esther Mena ◽  
Ignasi Carrió ◽  
...  
Keyword(s):  
Receptor Binding ◽  
D2 Receptor ◽  
First Episode Psychosis ◽  
First Episode ◽  
Episode Psychosis

Cannabis use and striatal D2 receptor density in untreated first-episode psychosis: An in vivo SPECT study

2011 ◽  
Vol 129 (2-3) ◽  
pp. 169-171 ◽  
Author(s):  
Gemma Safont ◽  
Iluminada Corripio ◽  
María J. Escartí ◽  
Maria J. Portella ◽  
Víctor Pérez ◽  
...  
Keyword(s):  
D2 Receptor ◽  
First Episode Psychosis ◽  
Cannabis Use ◽  
First Episode ◽  
Receptor Density ◽  
Episode Psychosis

scholarly journals Effective Connectivity and Dopaminergic Function of Fronto-Striato-Thalamic Circuitry in First-Episode Psychosis, Established Schizophrenia, and Healthy Controls

2021 ◽  
Author(s):  
Kristina Sabaroedin ◽  
Adeel Razi ◽  
Sidhant Chopra ◽  
Nancy Tran ◽  
Andrii Pozaruk ◽  
...  
Keyword(s):  
Symptom Severity ◽  
Effective Connectivity ◽  
First Episode Psychosis ◽  
Striatal Dopamine ◽  
Positive Symptom ◽  
Dopamine Synthesis ◽  
First Episode ◽  
Positron Emission ◽  
Episode Psychosis ◽  
Patient Groups

Dysfunction of fronto-striato-thalamic (FST) circuits is thought to contribute to dopaminergic dysfunction and symptom onset in psychosis, but it remains unclear whether this dysfunction is driven by aberrant bottom-up subcortical signaling or impaired top-down cortical regulation. Here, we used spectral dynamic causal modelling (DCM) of resting-state functional magnetic resonance imaging (fMRI) to characterize the effective connectivity of dorsal and ventral FST circuits in a sample of 46 antipsychotic-naive first-episode psychosis (FEP) patients and 23 controls and an independent sample of 36 patients with established schizophrenia (SCZ) patients and 100 controls. We found that midbrain and thalamic connectivity were implicated across both patient groups. Dysconnectivity in FEP patients was mainly restricted to the subcortex, with positive symptom severity being associated with midbrain connectivity. Dysconnectivity between the cortex and subcortical systems was only apparent in SCZ patients. In another independent sample of 33 healthy individuals who underwent concurrent fMRI and [18F]DOPA positron emission tomography, we found that striatal dopamine synthesis capacity was associated with the effective connectivity of nigrostriatal and striatothalamic pathways, implicating similar circuits as those associated with psychotic symptom severity in patients. Our findings thus indicate that subcortical dysconnectivity is salient in the early stages of psychosis, that cortical dysfunction may emerge later in the illness, and that nigrostriatal and striatothalamic signaling are closely related to striatal dopamine synthesis capacity, which is a robust risk marker for psychosis.

scholarly journals Hypofrontality in men with first-episode psychosis

2005 ◽  
Vol 186 (3) ◽  
pp. 203-208 ◽  
Author(s):  
V. Molina ◽  
J. Sanz ◽  
S. Reig ◽  
R. Martínez ◽  
F. Sarramea ◽  
...  
Keyword(s):  
Prefrontal Cortex ◽  
First Episode Psychosis ◽  
First Episode ◽  
Psychotic Episode ◽  
Attention Task ◽  
Positron Emission ◽  
Episode Psychosis ◽  
Dorsolateral Prefrontal ◽  
Prefrontal Region ◽  
And Control

BackgroundDecreased metabolic activity in the prefrontal cortex during cognitive activation is a recurrent finding and a likely functional marker of schizophrenia.AimsTo investigate the occurrence of hypofrontality in patients with first-episode psychosis, with or without evolution to schizophrenia.MethodWe used fluorodeoxyglucose positron emission tomography during the performance of an attention task and magnetic resonance imaging to study the dorsolateral prefrontal region in 13 men with a first episode of psychosis. Data from patients who progressed to schizophrenia were compared with those of patients who did not meet criteria for this diagnosis after 2 years.ResultsPatients who developed schizophrenia demonstrated a significant hypofrontality in the dorsolateral prefrontal cortex in comparison with the non-schizophrenia and control groups.ConclusionsOur results suggest that hypofrontality could be a marker of schizophrenia at the time of the first psychotic episode, in agreement with neurodevelopmental theories of schizophrenia.

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