Fiona Pepper - Academia.edu (original) (raw)
Papers by Fiona Pepper
Psychopharmacology, 2021
Rationale Ketamine may model aspects of schizophrenia arising through NMDA receptor activity defi... more Rationale Ketamine may model aspects of schizophrenia arising through NMDA receptor activity deficits. Although acute ketamine can induce effects resembling both positive and negative psychotic symptoms, chronic use may be a closer model of idiopathic psychosis. Objectives We tested the hypotheses that ketamine users had lower brain volumes, as measured using MRI, and greater sub-threshold psychotic symptoms relative to a poly-drug user control group. Methods Ketamine users (n = 17) and poly-drug using controls (n = 19) were included in the study. All underwent volumetric MRI imaging and measurement of sub-threshold psychotic symptoms using the Comprehensive Assessment of At-Risk Mental State (CAARMS). Freesurfer was used to analyse differences in regional brain volume, cortical surface area and thickness between ketamine users and controls. The relationship between CAARMS ratings and brain volume was also investigated in ketamine users. Results Ketamine users were found to have sig...
Schizophrenia Bulletin, 2020
Background Striatal dopamine dysfunction is proposed to underlie symptoms in psychosis, yet it is... more Background Striatal dopamine dysfunction is proposed to underlie symptoms in psychosis, yet it is not known how changes in a single neurotransmitter could underlie the heterogenous presentations that are seen clinically. One hypothesis is that the symptomatic consequences of aberrant dopamine signalling may depend on where within the striatum dysfunction occurs. Positron emission tomography (PET) allows for the measurement of dopamine function across the striatum. However, when using typical atlas-based parcellation methods, the collinearity between measures of dopamine function within each striatal subdivision precludes investigation of this hypothesis. Methods We use a novel and data-driven parcellation method to address the above, and investigate relationships between spatial variability in dopamine synthesis capacity and psychotic symptoms. We employ a multimodal imaging approach combining 18F-DOPA PET and resting state MRI in 29 unmedicated and minimally-treated patients with f...
Schizophrenia Bulletin, 2020
Background Cortical dysconnectivity and dysfunctional glutamatergic signalling are both implicate... more Background Cortical dysconnectivity and dysfunctional glutamatergic signalling are both implicated in the pathophysiology of psychotic illness. The relationship between these two systems, and the relevance to psychotic disorders remains unknown. Methods 50 individuals with a psychotic disorder and 54 healthy controls received baseline imaging using 1H-MRS to measure anterior cingulate glutamate concentrations, and resting state MRI to characterise functional brain networks. These measures were subsequently repeated following 3 days treatment with either the glutamatergic regulator riluzole (N=36), or a dopamine antagonist (N=14). The network-based statistic was used to examine relationships between glutamate concentrations and connectivity of the salience and default mode networks in patients and controls, and to investigate how this changed following pharmacological manipulation. Results In healthy controls higher baseline anterior cingulate glutamate concentrations were associated...
Schizophrenia Bulletin, 2020
Background Abnormal Cerebral Blood Flow (CBF) has been found in patients with chronic schizophren... more Background Abnormal Cerebral Blood Flow (CBF) has been found in patients with chronic schizophrenia (SCZ), first-episode psychosis patients (FEP) and individuals at clinical high-risk (CHR). In particular, previous studies using Arterial Spin Labelling (ASL) found that SCZ have a global reduction of CBF in the cortex and increased CBF in the basal ganglia, the hippocampus, and the amygdala as compared with controls. To date, only one study investigated CBF using ASL in a small cohort of medicated FEP reporting increased CBF in the striatum and reduced frontal CBF as compared with controls. However, it is still not clear whether these abnormalities are related to antipsychotic treatment or rather they reflect a disease state independent from medication. Critically, clinical and pre-clinical evidence suggests that antipsychotics increase CBF, especially in the basal ganglia through dopamine D2 receptors blockade. Here, we assessed CBF differences between FEP and controls in a larger c...
Biological Psychiatry: Cognitive Neuroscience and Neuroimaging, 2020
This is a PDF file of an article that has undergone enhancements after acceptance, such as the ad... more This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Biological Psychiatry, 2018
Background: Schizophrenia has been associated with thalamic hyperconnectivity with sensory region... more Background: Schizophrenia has been associated with thalamic hyperconnectivity with sensory regions and hypoconnectivity with cerebellar and prefrontal regions. While this pattern has been consistently replicated in chronic schizophrenia samples, less is known about when these abnormalities emerge in the illness course and if they are present prior to illness onset. Methods: Resting-state fMRI data were collected from clinical high-risk youth (n ¼ 45; CHR), early illness schizophrenia (n ¼ 74; ESZ) patients, and healthy controls (n ¼ 85; HC). Age-adjusted whole-brain functional connectivity, seeded from the thalamus, was compared among the three groups. Main effects of group (FDR-corrected, p < .01) were followed up with pairwise comparisons (Tukey-corrected, p < .05). Results: Main effects of group were observed in left and right middle and superior temporal regions, left cerebellum, and bilateral thalamus. ESZ demonstrated greater thalamic connectivity with all middle and superior temporal regions, and reduced connectivity with cerebellar and thalamic regions. Compared to HCs, CHR demonstrated greater thalamic connectivity with one left and one right middle temporal region, and reduced connectivity with cerebellar and thalamic regions. Compared to CHR, ESZ displayed significantly greater connectivity in all but one middle/superior temporal region, but not cerebellar and thalamic regions. Conclusions: Like chronic patients, ESZ demonstrate hyperconnectivity between the thalamus and sensory regions, and hypoconnectivity with the cerebellum. Further, CHR demonstrate intermediate levels of dysconnectivity, with mean values falling between ESZ and HC. These findings suggest that thalamic dysconnectivity occurs prior to illness onset, but is more pronounced in the early stages of schizophrenia.
Biological Psychiatry, 2018
Methods: A highly efficient and novel balanced steady-state free precession 7Li-MRI technique was... more Methods: A highly efficient and novel balanced steady-state free precession 7Li-MRI technique was developed on a clinical 3T scanner (scan duration 8 minutes), and evaluated in test objects and patients. Euthymic lithium-treated and lithiumnaïve BD patients also underwent diffusion weighted imaging. A voxel-wise estimation of generalised fractional anisotropy (gFA) was performed and values within WM regions of interest (ROI) compared between treatment groups. The relationship between 7Li-MRI signal intensity and gFA differences was explored. Results: 7Li-MRI signal intensity was uniform across uniform test objects and closely correlated with concentration (Pearson coefficient 0.98). In lithium-treated patients, brain lithium distribution was heterogeneous (coefficient of variation 27.9±3.6%; scan evaluation subgroup n¼8) and greater in WM compared to grey matter (6.10±0.89 versus 5.22±0.47; arbitrary units, p¼0.03). Comparing patient groups, those taking lithium (n¼10) had higher gFA in 41 of the 48 WM ROI than lithium-naïve patients (n¼16). 7Li-MRI signal intensity correlated positively with gFA effect size (r¼0.45; p¼0.001). Conclusions: Brain lithium distribution can be swiftly measured using 7Li-MRI. Regional lithium concentration correlated with localised tissue-level effects, strengthening the assertion that lithium improves WM integrity.
Molecular Psychiatry, 2019
If citing, it is advised that you check and use the publisher's definitive version for pagination... more If citing, it is advised that you check and use the publisher's definitive version for pagination, volume/issue, and date of publication details. And where the final published version is provided on the Research Portal, if citing you are again advised to check the publisher's website for any subsequent corrections.
Schizophrenia Bulletin, 2018
at risk of autism), showing that there are common dopaminergic alterations linked to psychosis ac... more at risk of autism), showing that there are common dopaminergic alterations linked to psychosis across disorders, as well as showing that structural and neurochemical brain heterogeneity is increased in most brain regions, but also identifying key cortical and sub-cortical regions with increased homogeneity. Dr. Clementz, USA, will present new EEG and cognitive data from over 400 patients with schizophrenia, and bipolar disorder. This shows differences in intrinsic neural activity that cuts across diagnoses, identifying subtypes that were linked to differences in cognitive functioning. Dr. Wichers, Netherlands, will present new data from a longitudinal study of adolescents using in-depth real-time phenotyping using experience sampling to investigate the relationship between the coherence of responses and the subsequent development of psychotic and other symptom domains one year later. Her novel application of complex systems theory identifies suspiciousness as a common predictor of the later development of a number of symptoms, but also that other responses, such as low mood, determine the specificity of later outcomes to psychosis. Overall this symposium will bring together researchers using different, complementary approaches to provide a comprehensive and multidisciplinary analysis. By bringing researchers from different disciplines together it will enable common mechanisms to be considered, and new insights to be developed. Finally, Dr. DeLisi's wide-reaching experience means she is well placed to lead the discussion of the implications of these findings for understanding the neurobiology of schizophrenia, and for biomarker development as well as considering their implications for the developing new treatments. The symposium includes gender diversity in presenters and chairs, speakers from multiple institutions across continents, and diversity in career levels with speakers from early, mid and established positions.
npj Schizophrenia, 2019
Neuroimaging studies in schizophrenia have linked elevated glutamate metabolite levels to non-rem... more Neuroimaging studies in schizophrenia have linked elevated glutamate metabolite levels to non-remission following antipsychotic treatment, and also indicate that antipsychotics can reduce glutamate metabolite levels. However, the relationship between symptomatic reduction and change in glutamate during initial antipsychotic treatment is unclear. Here we report proton magnetic resonance spectroscopy (1H-MRS) measurements of Glx and glutamate in the anterior cingulate cortex (ACC) and thalamus in patients with first episode psychosis (n = 23) at clinical presentation, and after 6 weeks and 9 months of treatment with antipsychotic medication. At 9 months, patients were classified into Remission (n = 12) and Non-Remission (n = 11) subgroups. Healthy volunteers (n = 15) were scanned at the same three time-points. In the thalamus, Glx varied over time according to remission status (P = 0.020). This reflected an increase in Glx between 6 weeks and 9 months in the Non-Remission subgroup tha...
Scientific Reports, 2019
Converging lines of evidence suggest that glutamatergic dysfunction may contribute to the pathoph... more Converging lines of evidence suggest that glutamatergic dysfunction may contribute to the pathophysiology of first episode psychosis. We investigated whether first episode psychosis patients free from all pharmacological treatments and illicit substances show cortical glutamatergic alterations. One-hundred and eleven volunteers including 65 healthy volunteers and 46 first episode psychosis patients free from all pharmacological treatments (28 drug naïve) underwent a proton magnetic resonance spectroscopy scan measuring glutamate levels in the bilateral anterior cingulate cortex. Symptom severity was measured using the Positive and Negative Syndrome Scale (PANSS) and cognition was measured using the Wechsler Adult Intelligence Scale (WAIS) digit symbol test. There were no differences in glutamate levels between patients and controls. These findings remained unchanged when adjusting for the effects of age, sex and ethnicity or when restricting the analyses to patients who were both me...
Schizophrenia Bulletin, 2019
Poster Session III S339 of these metabolites differ across individuals affected by psychotic illn... more Poster Session III S339 of these metabolites differ across individuals affected by psychotic illness, those carrying genetic liability for such disorders, and non-psychiatric control participants.
Schizophrenia Bulletin, 2019
In contrast, early psychosis patients with low memory performance showed the opposite pattern; be... more In contrast, early psychosis patients with low memory performance showed the opposite pattern; better memory was associated with a more sustained response in the anterior hippocampus (r = 0.46, p = 0.02). Discussion: We find that hippocampal habituation is disrupted in the early stage of psychosis and is associated with relational memory impairments. Habituation deficits and brain/behavior relationships were specific to the anterior hippocampus, with habituation differences in the posterior hippocampus. These results suggest neural habituation may provide a novel target for early cognitive interventions in psychosis.
Schizophrenia Bulletin, 2019
Background: Neuroimaging studies in schizophrenia have linked elevated glutamate metabolite level... more Background: Neuroimaging studies in schizophrenia have linked elevated glutamate metabolite levels to non-remission following antipsychotic treatment and have also indicated that antipsychotics can reduce glutamate metabolite levels. However, the relationship between symptomatic reduction and change in glutamate during initial antipsychotic treatment is unclear. Methods: Proton magnetic resonance spectroscopy (1H-MRS) measured Glx and glutamate in the anterior cingulate cortex (ACC) and thalamus in patients with first episode psychosis (n=23) at clinical presentation, and after 6 weeks and 9 months of treatment with antipsychotic medication. At 9 months, patients were classified into Remission (n=12) and Non-Remission (n=11) subgroups. Healthy volunteers (n=15) were scanned at the same three time-points. Results: Glx levels in the thalamus increased over time in Non-Remitters (P=0.008), such that after 9 months Glx levels were higher in patients who were not in remission than in those who were (P=0.033). No change in thalamic Glx levels over time were evident in the Remission subgroup. In addition, the change in Glx in the thalamus over the 9 months of treatment was positively correlated with the change in the severity of PANSS positive, total and general symptoms (P<0.05). There were no significant effects of group or time on glutamate metabolites in the ACC, and no differences between either patient subgroup and healthy volunteers. Discussion: These data suggest that the nature of the response to antipsychotic medication may be related to the pattern of changes in glutamatergic metabolite levels over the course of treatment. The findings add to existing evidence linking the response to treatment in schizophrenia to alterations in central glutamate function.
The Lancet Psychiatry, 2018
Background The pathophysiology of psychosis is incompletely understood. Disruption in cortical gl... more Background The pathophysiology of psychosis is incompletely understood. Disruption in cortical glutamatergic signalling causing aberrant striatal dopamine synthesis capacity is a proposed model for psychosis, but has not been tested in vivo. We therefore aimed to test the relationship between cortical glutamate concentrations and striatal dopamine synthesis capacity, and psychotic symptoms. Methods In this cross-sectional multimodal imaging study, 28 individuals with first-episode psychosis and 20 healthy controls underwent ¹⁸F-DOPA PET (measuring striatal dopamine synthesis capacity), and proton magnetic resonance spectroscopy (measuring anterior cingulate cortex glutamate concentrations). Participants were recruited from firstepisode psychosis services in London, UK and were required to be in the first episode of a psychotic illness, with no previous illness or treatment episodes. Exclusion criteria for all participants were: history of substantial head trauma, dependence on illicit substances, medical comorbidity (other than minor illnesses), and contraindications to scanning (such as pregnancy). Symptoms were measured using the Positive and Negative Syndrome Scale. The primary endpoint was the relationship between anterior cingulate cortex glutamate concentrations and striatal dopamine synthesis capacity in individuals with their first episode of psychosis as shown by imaging, examined by linear regression. Linear regression was used to examine relationships between measures. Findings Glutamate concentrations showed a significant inverse relationship with striatal dopamine synthesis capacity in patients with psychosis (R²=0•16, p=0•03, β −1•71 × 10-⁴, SE 0•76 × 10-⁴). This relationship remained significant after the addition of age, gender, ethnicity, and medication status to the model (p=0•015). In healthy controls, there was no significant relationship between dopamine and glutamate measures (R²=0•04, p=0•39). Positive and Negative Syndrome Scale positive psychotic symptoms were positively associated with striatal dopamine synthesis capacity (R²=0•14, p=0•046, β 2546, SE 1217) and showed an inverse relationship with anterior cingulate glutamate concentrations (R²=0•16, p=0•03, β −1•71 × 10 − ⁴, SE 7•63 × 10 − ⁵). No relationships were seen with negative symptoms (positive symptoms, mean [SD] −18•4 (6•6) negative symptoms, mean [SD] −15•4 [6•1]). Interpretation These observations are consistent with the hypothesis that cortical glutamate dysfunction is related to subcortical dopamine synthesis capacity and psychosis. Although the precise mechanistic relationship between cortical glutamate and dopamine in vivo remains unclear, our findings support further studies to test the effect of modulating cortical glutamate in the treatment of psychosis.
Biological Psychiatry, 2018
BACKGROUND: A wide range of neuropsychiatric disorders, from schizophrenia to drug addiction, inv... more BACKGROUND: A wide range of neuropsychiatric disorders, from schizophrenia to drug addiction, involve abnormalities in both the mesolimbic dopamine system and the cortical salience network. Both systems play a key role in the detection of behaviorally relevant environmental stimuli. Although anatomical overlap exists, the functional relationship between these systems remains unknown. Preclinical research has suggested that the firing of mesolimbic dopamine neurons may activate nodes of the salience network, but in vivo human research is required given the species-specific nature of this network. METHODS: We employed positron emission tomography to measure both dopamine release capacity (using the D 2/3 receptor ligand 11 C-PHNO, n = 23) and dopamine synthesis capacity (using 18 F-DOPA, n = 21) within the ventral striatum. Resting-state functional magnetic resonance imaging was also undertaken in the same individuals to investigate salience network functional connectivity. A graph theoretical approach was used to characterize the relationship between dopamine measures and network connectivity. RESULTS: Dopamine synthesis capacity was associated with greater salience network connectivity, and this relationship was particularly apparent for brain regions that act as information-processing hubs. In contrast, dopamine release capacity was associated with weaker salience network connectivity. There was no relationship between dopamine measures and visual and sensorimotor networks, indicating specificity of the findings. CONCLUSIONS: Our findings demonstrate a close relationship between the salience network and mesolimbic dopamine system, and they are relevant to neuropsychiatric illnesses in which aberrant functioning of both systems has been observed.
Schizophrenia Bulletin, 2017
Background: Antipsychotic medication remains the primary treatment for symptoms of psychosis. The... more Background: Antipsychotic medication remains the primary treatment for symptoms of psychosis. The dopamine system, in particular, the presynaptic system, has been linked to treatment response, leading to the suggestion that dopaminergic and nondopaminergic forms of schizophrenia exist. This has been examined in vivo, using PET to index presynaptic dopamine (linking elevated dopamine to good treatment response), and Magnetic Resonance Spectroscopy (MRS) to measure glutamatergic function, linking elevated anterior cingulate glutamate to poor antipsychotic response. To date, no study has utilised these measures to examine antipsychotic response prospectively, in first episode patients. We sought to examine both neuroimaging methods in antipsychotic-naïve, first-episode psychosis patients, before and after treatment. Methods: 18F-DOPA PET and 1-H MRS study, in people witfirst episode psychosis, naive of antipsychotic medication, those minimally treated with antipsychotic medication (for less than 2 weeks) and those not taking antipsychotic medication. Baseline and follow-up whole striatum Kicer, anterior cingulate glutamate and baseline and follow-up PANSS after antipsychotic treatment Results: There was a significant positive correlation between baseline Kicer and subsequent improvement in PANSS positive (rho =0.64, P < .01), negative (rho=0.48, P = .03), total symptoms (rho=0.56, P = .01) and GAF score (rho=0.54,. There was no relationship between glutamate levels and any clinical measure. There was a significant effect of group on Kicer (F(2,25)=5.73, P < .01). Kicer was significantly higher in responders than both non-responders (P = .03) and healthy volunteers (P < .01). Cohen's d effect size for the elevation in the responders relative to nonresponders was 1.28. No difference in dopamine synthesis capacity was found after treatment for at least 4 weeks of antipsychotic medication, t (20) = 0.73, P = 0.49. A positive correlation was found between change in dopamine synthesis capacity and change in PANSS positive symptoms (Pearson's r = .47, P = .04), though not PANSS negative (r = .4, P = .1) or total symptoms (r = .42, P = .08). Conclusion: Dopamine, and not glutamate function, predicts the response to antipsychotic treatment. Change in dopamine synthesis capacity is related to positive symptom change. Variability exists in the effects of antipsychotic medication on presynaptic dopamine function.
UCL logo UCL Discovery. ...
Psychopharmacology, 2021
Rationale Ketamine may model aspects of schizophrenia arising through NMDA receptor activity defi... more Rationale Ketamine may model aspects of schizophrenia arising through NMDA receptor activity deficits. Although acute ketamine can induce effects resembling both positive and negative psychotic symptoms, chronic use may be a closer model of idiopathic psychosis. Objectives We tested the hypotheses that ketamine users had lower brain volumes, as measured using MRI, and greater sub-threshold psychotic symptoms relative to a poly-drug user control group. Methods Ketamine users (n = 17) and poly-drug using controls (n = 19) were included in the study. All underwent volumetric MRI imaging and measurement of sub-threshold psychotic symptoms using the Comprehensive Assessment of At-Risk Mental State (CAARMS). Freesurfer was used to analyse differences in regional brain volume, cortical surface area and thickness between ketamine users and controls. The relationship between CAARMS ratings and brain volume was also investigated in ketamine users. Results Ketamine users were found to have sig...
Schizophrenia Bulletin, 2020
Background Striatal dopamine dysfunction is proposed to underlie symptoms in psychosis, yet it is... more Background Striatal dopamine dysfunction is proposed to underlie symptoms in psychosis, yet it is not known how changes in a single neurotransmitter could underlie the heterogenous presentations that are seen clinically. One hypothesis is that the symptomatic consequences of aberrant dopamine signalling may depend on where within the striatum dysfunction occurs. Positron emission tomography (PET) allows for the measurement of dopamine function across the striatum. However, when using typical atlas-based parcellation methods, the collinearity between measures of dopamine function within each striatal subdivision precludes investigation of this hypothesis. Methods We use a novel and data-driven parcellation method to address the above, and investigate relationships between spatial variability in dopamine synthesis capacity and psychotic symptoms. We employ a multimodal imaging approach combining 18F-DOPA PET and resting state MRI in 29 unmedicated and minimally-treated patients with f...
Schizophrenia Bulletin, 2020
Background Cortical dysconnectivity and dysfunctional glutamatergic signalling are both implicate... more Background Cortical dysconnectivity and dysfunctional glutamatergic signalling are both implicated in the pathophysiology of psychotic illness. The relationship between these two systems, and the relevance to psychotic disorders remains unknown. Methods 50 individuals with a psychotic disorder and 54 healthy controls received baseline imaging using 1H-MRS to measure anterior cingulate glutamate concentrations, and resting state MRI to characterise functional brain networks. These measures were subsequently repeated following 3 days treatment with either the glutamatergic regulator riluzole (N=36), or a dopamine antagonist (N=14). The network-based statistic was used to examine relationships between glutamate concentrations and connectivity of the salience and default mode networks in patients and controls, and to investigate how this changed following pharmacological manipulation. Results In healthy controls higher baseline anterior cingulate glutamate concentrations were associated...
Schizophrenia Bulletin, 2020
Background Abnormal Cerebral Blood Flow (CBF) has been found in patients with chronic schizophren... more Background Abnormal Cerebral Blood Flow (CBF) has been found in patients with chronic schizophrenia (SCZ), first-episode psychosis patients (FEP) and individuals at clinical high-risk (CHR). In particular, previous studies using Arterial Spin Labelling (ASL) found that SCZ have a global reduction of CBF in the cortex and increased CBF in the basal ganglia, the hippocampus, and the amygdala as compared with controls. To date, only one study investigated CBF using ASL in a small cohort of medicated FEP reporting increased CBF in the striatum and reduced frontal CBF as compared with controls. However, it is still not clear whether these abnormalities are related to antipsychotic treatment or rather they reflect a disease state independent from medication. Critically, clinical and pre-clinical evidence suggests that antipsychotics increase CBF, especially in the basal ganglia through dopamine D2 receptors blockade. Here, we assessed CBF differences between FEP and controls in a larger c...
Biological Psychiatry: Cognitive Neuroscience and Neuroimaging, 2020
This is a PDF file of an article that has undergone enhancements after acceptance, such as the ad... more This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Biological Psychiatry, 2018
Background: Schizophrenia has been associated with thalamic hyperconnectivity with sensory region... more Background: Schizophrenia has been associated with thalamic hyperconnectivity with sensory regions and hypoconnectivity with cerebellar and prefrontal regions. While this pattern has been consistently replicated in chronic schizophrenia samples, less is known about when these abnormalities emerge in the illness course and if they are present prior to illness onset. Methods: Resting-state fMRI data were collected from clinical high-risk youth (n ¼ 45; CHR), early illness schizophrenia (n ¼ 74; ESZ) patients, and healthy controls (n ¼ 85; HC). Age-adjusted whole-brain functional connectivity, seeded from the thalamus, was compared among the three groups. Main effects of group (FDR-corrected, p < .01) were followed up with pairwise comparisons (Tukey-corrected, p < .05). Results: Main effects of group were observed in left and right middle and superior temporal regions, left cerebellum, and bilateral thalamus. ESZ demonstrated greater thalamic connectivity with all middle and superior temporal regions, and reduced connectivity with cerebellar and thalamic regions. Compared to HCs, CHR demonstrated greater thalamic connectivity with one left and one right middle temporal region, and reduced connectivity with cerebellar and thalamic regions. Compared to CHR, ESZ displayed significantly greater connectivity in all but one middle/superior temporal region, but not cerebellar and thalamic regions. Conclusions: Like chronic patients, ESZ demonstrate hyperconnectivity between the thalamus and sensory regions, and hypoconnectivity with the cerebellum. Further, CHR demonstrate intermediate levels of dysconnectivity, with mean values falling between ESZ and HC. These findings suggest that thalamic dysconnectivity occurs prior to illness onset, but is more pronounced in the early stages of schizophrenia.
Biological Psychiatry, 2018
Methods: A highly efficient and novel balanced steady-state free precession 7Li-MRI technique was... more Methods: A highly efficient and novel balanced steady-state free precession 7Li-MRI technique was developed on a clinical 3T scanner (scan duration 8 minutes), and evaluated in test objects and patients. Euthymic lithium-treated and lithiumnaïve BD patients also underwent diffusion weighted imaging. A voxel-wise estimation of generalised fractional anisotropy (gFA) was performed and values within WM regions of interest (ROI) compared between treatment groups. The relationship between 7Li-MRI signal intensity and gFA differences was explored. Results: 7Li-MRI signal intensity was uniform across uniform test objects and closely correlated with concentration (Pearson coefficient 0.98). In lithium-treated patients, brain lithium distribution was heterogeneous (coefficient of variation 27.9±3.6%; scan evaluation subgroup n¼8) and greater in WM compared to grey matter (6.10±0.89 versus 5.22±0.47; arbitrary units, p¼0.03). Comparing patient groups, those taking lithium (n¼10) had higher gFA in 41 of the 48 WM ROI than lithium-naïve patients (n¼16). 7Li-MRI signal intensity correlated positively with gFA effect size (r¼0.45; p¼0.001). Conclusions: Brain lithium distribution can be swiftly measured using 7Li-MRI. Regional lithium concentration correlated with localised tissue-level effects, strengthening the assertion that lithium improves WM integrity.
Molecular Psychiatry, 2019
If citing, it is advised that you check and use the publisher's definitive version for pagination... more If citing, it is advised that you check and use the publisher's definitive version for pagination, volume/issue, and date of publication details. And where the final published version is provided on the Research Portal, if citing you are again advised to check the publisher's website for any subsequent corrections.
Schizophrenia Bulletin, 2018
at risk of autism), showing that there are common dopaminergic alterations linked to psychosis ac... more at risk of autism), showing that there are common dopaminergic alterations linked to psychosis across disorders, as well as showing that structural and neurochemical brain heterogeneity is increased in most brain regions, but also identifying key cortical and sub-cortical regions with increased homogeneity. Dr. Clementz, USA, will present new EEG and cognitive data from over 400 patients with schizophrenia, and bipolar disorder. This shows differences in intrinsic neural activity that cuts across diagnoses, identifying subtypes that were linked to differences in cognitive functioning. Dr. Wichers, Netherlands, will present new data from a longitudinal study of adolescents using in-depth real-time phenotyping using experience sampling to investigate the relationship between the coherence of responses and the subsequent development of psychotic and other symptom domains one year later. Her novel application of complex systems theory identifies suspiciousness as a common predictor of the later development of a number of symptoms, but also that other responses, such as low mood, determine the specificity of later outcomes to psychosis. Overall this symposium will bring together researchers using different, complementary approaches to provide a comprehensive and multidisciplinary analysis. By bringing researchers from different disciplines together it will enable common mechanisms to be considered, and new insights to be developed. Finally, Dr. DeLisi's wide-reaching experience means she is well placed to lead the discussion of the implications of these findings for understanding the neurobiology of schizophrenia, and for biomarker development as well as considering their implications for the developing new treatments. The symposium includes gender diversity in presenters and chairs, speakers from multiple institutions across continents, and diversity in career levels with speakers from early, mid and established positions.
npj Schizophrenia, 2019
Neuroimaging studies in schizophrenia have linked elevated glutamate metabolite levels to non-rem... more Neuroimaging studies in schizophrenia have linked elevated glutamate metabolite levels to non-remission following antipsychotic treatment, and also indicate that antipsychotics can reduce glutamate metabolite levels. However, the relationship between symptomatic reduction and change in glutamate during initial antipsychotic treatment is unclear. Here we report proton magnetic resonance spectroscopy (1H-MRS) measurements of Glx and glutamate in the anterior cingulate cortex (ACC) and thalamus in patients with first episode psychosis (n = 23) at clinical presentation, and after 6 weeks and 9 months of treatment with antipsychotic medication. At 9 months, patients were classified into Remission (n = 12) and Non-Remission (n = 11) subgroups. Healthy volunteers (n = 15) were scanned at the same three time-points. In the thalamus, Glx varied over time according to remission status (P = 0.020). This reflected an increase in Glx between 6 weeks and 9 months in the Non-Remission subgroup tha...
Scientific Reports, 2019
Converging lines of evidence suggest that glutamatergic dysfunction may contribute to the pathoph... more Converging lines of evidence suggest that glutamatergic dysfunction may contribute to the pathophysiology of first episode psychosis. We investigated whether first episode psychosis patients free from all pharmacological treatments and illicit substances show cortical glutamatergic alterations. One-hundred and eleven volunteers including 65 healthy volunteers and 46 first episode psychosis patients free from all pharmacological treatments (28 drug naïve) underwent a proton magnetic resonance spectroscopy scan measuring glutamate levels in the bilateral anterior cingulate cortex. Symptom severity was measured using the Positive and Negative Syndrome Scale (PANSS) and cognition was measured using the Wechsler Adult Intelligence Scale (WAIS) digit symbol test. There were no differences in glutamate levels between patients and controls. These findings remained unchanged when adjusting for the effects of age, sex and ethnicity or when restricting the analyses to patients who were both me...
Schizophrenia Bulletin, 2019
Poster Session III S339 of these metabolites differ across individuals affected by psychotic illn... more Poster Session III S339 of these metabolites differ across individuals affected by psychotic illness, those carrying genetic liability for such disorders, and non-psychiatric control participants.
Schizophrenia Bulletin, 2019
In contrast, early psychosis patients with low memory performance showed the opposite pattern; be... more In contrast, early psychosis patients with low memory performance showed the opposite pattern; better memory was associated with a more sustained response in the anterior hippocampus (r = 0.46, p = 0.02). Discussion: We find that hippocampal habituation is disrupted in the early stage of psychosis and is associated with relational memory impairments. Habituation deficits and brain/behavior relationships were specific to the anterior hippocampus, with habituation differences in the posterior hippocampus. These results suggest neural habituation may provide a novel target for early cognitive interventions in psychosis.
Schizophrenia Bulletin, 2019
Background: Neuroimaging studies in schizophrenia have linked elevated glutamate metabolite level... more Background: Neuroimaging studies in schizophrenia have linked elevated glutamate metabolite levels to non-remission following antipsychotic treatment and have also indicated that antipsychotics can reduce glutamate metabolite levels. However, the relationship between symptomatic reduction and change in glutamate during initial antipsychotic treatment is unclear. Methods: Proton magnetic resonance spectroscopy (1H-MRS) measured Glx and glutamate in the anterior cingulate cortex (ACC) and thalamus in patients with first episode psychosis (n=23) at clinical presentation, and after 6 weeks and 9 months of treatment with antipsychotic medication. At 9 months, patients were classified into Remission (n=12) and Non-Remission (n=11) subgroups. Healthy volunteers (n=15) were scanned at the same three time-points. Results: Glx levels in the thalamus increased over time in Non-Remitters (P=0.008), such that after 9 months Glx levels were higher in patients who were not in remission than in those who were (P=0.033). No change in thalamic Glx levels over time were evident in the Remission subgroup. In addition, the change in Glx in the thalamus over the 9 months of treatment was positively correlated with the change in the severity of PANSS positive, total and general symptoms (P<0.05). There were no significant effects of group or time on glutamate metabolites in the ACC, and no differences between either patient subgroup and healthy volunteers. Discussion: These data suggest that the nature of the response to antipsychotic medication may be related to the pattern of changes in glutamatergic metabolite levels over the course of treatment. The findings add to existing evidence linking the response to treatment in schizophrenia to alterations in central glutamate function.
The Lancet Psychiatry, 2018
Background The pathophysiology of psychosis is incompletely understood. Disruption in cortical gl... more Background The pathophysiology of psychosis is incompletely understood. Disruption in cortical glutamatergic signalling causing aberrant striatal dopamine synthesis capacity is a proposed model for psychosis, but has not been tested in vivo. We therefore aimed to test the relationship between cortical glutamate concentrations and striatal dopamine synthesis capacity, and psychotic symptoms. Methods In this cross-sectional multimodal imaging study, 28 individuals with first-episode psychosis and 20 healthy controls underwent ¹⁸F-DOPA PET (measuring striatal dopamine synthesis capacity), and proton magnetic resonance spectroscopy (measuring anterior cingulate cortex glutamate concentrations). Participants were recruited from firstepisode psychosis services in London, UK and were required to be in the first episode of a psychotic illness, with no previous illness or treatment episodes. Exclusion criteria for all participants were: history of substantial head trauma, dependence on illicit substances, medical comorbidity (other than minor illnesses), and contraindications to scanning (such as pregnancy). Symptoms were measured using the Positive and Negative Syndrome Scale. The primary endpoint was the relationship between anterior cingulate cortex glutamate concentrations and striatal dopamine synthesis capacity in individuals with their first episode of psychosis as shown by imaging, examined by linear regression. Linear regression was used to examine relationships between measures. Findings Glutamate concentrations showed a significant inverse relationship with striatal dopamine synthesis capacity in patients with psychosis (R²=0•16, p=0•03, β −1•71 × 10-⁴, SE 0•76 × 10-⁴). This relationship remained significant after the addition of age, gender, ethnicity, and medication status to the model (p=0•015). In healthy controls, there was no significant relationship between dopamine and glutamate measures (R²=0•04, p=0•39). Positive and Negative Syndrome Scale positive psychotic symptoms were positively associated with striatal dopamine synthesis capacity (R²=0•14, p=0•046, β 2546, SE 1217) and showed an inverse relationship with anterior cingulate glutamate concentrations (R²=0•16, p=0•03, β −1•71 × 10 − ⁴, SE 7•63 × 10 − ⁵). No relationships were seen with negative symptoms (positive symptoms, mean [SD] −18•4 (6•6) negative symptoms, mean [SD] −15•4 [6•1]). Interpretation These observations are consistent with the hypothesis that cortical glutamate dysfunction is related to subcortical dopamine synthesis capacity and psychosis. Although the precise mechanistic relationship between cortical glutamate and dopamine in vivo remains unclear, our findings support further studies to test the effect of modulating cortical glutamate in the treatment of psychosis.
Biological Psychiatry, 2018
BACKGROUND: A wide range of neuropsychiatric disorders, from schizophrenia to drug addiction, inv... more BACKGROUND: A wide range of neuropsychiatric disorders, from schizophrenia to drug addiction, involve abnormalities in both the mesolimbic dopamine system and the cortical salience network. Both systems play a key role in the detection of behaviorally relevant environmental stimuli. Although anatomical overlap exists, the functional relationship between these systems remains unknown. Preclinical research has suggested that the firing of mesolimbic dopamine neurons may activate nodes of the salience network, but in vivo human research is required given the species-specific nature of this network. METHODS: We employed positron emission tomography to measure both dopamine release capacity (using the D 2/3 receptor ligand 11 C-PHNO, n = 23) and dopamine synthesis capacity (using 18 F-DOPA, n = 21) within the ventral striatum. Resting-state functional magnetic resonance imaging was also undertaken in the same individuals to investigate salience network functional connectivity. A graph theoretical approach was used to characterize the relationship between dopamine measures and network connectivity. RESULTS: Dopamine synthesis capacity was associated with greater salience network connectivity, and this relationship was particularly apparent for brain regions that act as information-processing hubs. In contrast, dopamine release capacity was associated with weaker salience network connectivity. There was no relationship between dopamine measures and visual and sensorimotor networks, indicating specificity of the findings. CONCLUSIONS: Our findings demonstrate a close relationship between the salience network and mesolimbic dopamine system, and they are relevant to neuropsychiatric illnesses in which aberrant functioning of both systems has been observed.
Schizophrenia Bulletin, 2017
Background: Antipsychotic medication remains the primary treatment for symptoms of psychosis. The... more Background: Antipsychotic medication remains the primary treatment for symptoms of psychosis. The dopamine system, in particular, the presynaptic system, has been linked to treatment response, leading to the suggestion that dopaminergic and nondopaminergic forms of schizophrenia exist. This has been examined in vivo, using PET to index presynaptic dopamine (linking elevated dopamine to good treatment response), and Magnetic Resonance Spectroscopy (MRS) to measure glutamatergic function, linking elevated anterior cingulate glutamate to poor antipsychotic response. To date, no study has utilised these measures to examine antipsychotic response prospectively, in first episode patients. We sought to examine both neuroimaging methods in antipsychotic-naïve, first-episode psychosis patients, before and after treatment. Methods: 18F-DOPA PET and 1-H MRS study, in people witfirst episode psychosis, naive of antipsychotic medication, those minimally treated with antipsychotic medication (for less than 2 weeks) and those not taking antipsychotic medication. Baseline and follow-up whole striatum Kicer, anterior cingulate glutamate and baseline and follow-up PANSS after antipsychotic treatment Results: There was a significant positive correlation between baseline Kicer and subsequent improvement in PANSS positive (rho =0.64, P < .01), negative (rho=0.48, P = .03), total symptoms (rho=0.56, P = .01) and GAF score (rho=0.54,. There was no relationship between glutamate levels and any clinical measure. There was a significant effect of group on Kicer (F(2,25)=5.73, P < .01). Kicer was significantly higher in responders than both non-responders (P = .03) and healthy volunteers (P < .01). Cohen's d effect size for the elevation in the responders relative to nonresponders was 1.28. No difference in dopamine synthesis capacity was found after treatment for at least 4 weeks of antipsychotic medication, t (20) = 0.73, P = 0.49. A positive correlation was found between change in dopamine synthesis capacity and change in PANSS positive symptoms (Pearson's r = .47, P = .04), though not PANSS negative (r = .4, P = .1) or total symptoms (r = .42, P = .08). Conclusion: Dopamine, and not glutamate function, predicts the response to antipsychotic treatment. Change in dopamine synthesis capacity is related to positive symptom change. Variability exists in the effects of antipsychotic medication on presynaptic dopamine function.
UCL logo UCL Discovery. ...