Rationale
Anterior cingulate cortex (ACC) glutamatergic abnormalities are reported in treatment-resistant schizophrenia (TRS) and implicated in functional dysconnectivity and psychopathology. ...Preclinical evidence indicates riluzole reduces synaptic glutamate. However, it is unknown whether riluzole can modulate glutamate metabolite levels and associated functional connectivity in TRS.
Objectives
To examine the relationship between glutamatergic function and cortical connectivity and determine if riluzole can modulate glutamate metabolite levels and cortical functional connectivity in TRS.
Methods
Nineteen TRS patients and 18 healthy volunteers (HV) underwent magnetic resonance imaging consisting of MR spectroscopy measuring ACC glutamate plus glutamine (Glx), fMRI measuring resting ACC-functional connectivity, and arterial spin labelling measuring regional cerebral blood flow (rCBF), and clinical measures. They then received 50 mg riluzole twice daily for 2 days when imaging was repeated.
Results
Baseline (pre-riluzole) Glx levels were correlated directly with negative symptom severity (
r
= 0.49;
p
= 0.03) and inversely with verbal learning in TRS (
r
= − 0.63;
p
= 0.002), but not HV (
r
= − 0.24;
p
= 0.41). Connectivity between the ACC and anterior prefrontal cortex (aPFC) was correlated with verbal learning in TRS (
r
= 0.49;
p
= 0.04), but not HV (
r
= 0.28;
p
= 0.33). There was a significant group × time interaction effect on Glx levels (
p
< 0.05) and on ACC connectivity to the aPFC (
p
< 0.05, FWE-corrected). Riluzole decreased Glx and increased ACC-aPFC connectivity in TRS relative to HV. Change in Glx correlated inversely with change in ACC-aPFC connectivity in TRS (
r
= − 0.52;
p
= 0.02) but not HV (
r
= 0.01;
p
= 0.98). Riluzole did not alter rCBF (
p
> 0.05), indicating absence of a non-specific blood flow effect.
Conclusion
Results indicate glutamatergic function and cortical connectivity are linked to symptoms and cognitive measures and that it is possible to pharmacologically modulate them in TRS.
Elevated striatal dopamine synthesis capacity has been implicated in the etiology and antipsychotic response in psychotic illness. The effects of antipsychotic medication on dopamine synthesis ...capacity are poorly understood, and no prospective studies have examined this question in a solely first-episode psychosis sample. Furthermore, it is unknown whether antipsychotic efficacy is linked to reductions in dopamine synthesis capacity. We conducted a prospective 18F-dihydroxyphenyl-L-alanine positron emission tomography study in antipsychotic naïve/free people with first-episode psychosis commencing antipsychotic treatment.
Dopamine synthesis capacity (indexed as influx rate constant) and clinical symptoms (measured using Positive and Negative Syndrome Scale) were measured before and after at least 5 weeks of antipsychotic treatment in people with first-episode psychosis. Data from a prior study indicated that a sample size of 13 would have >80% power to detect a statistically significant change in dopamine synthesis capacity at alpha = .05 (two tailed).
A total of 20 people took part in the study, 17 of whom were concordant with antipsychotic medication at therapeutic doses. There was no significant effect of treatment on dopamine synthesis capacity in the whole striatum (p = .47), thalamus, or midbrain, nor was there any significant relationship between change in dopamine synthesis capacity and change in positive (ρ = .35, p = .13), negative, or total psychotic symptoms.
Dopamine synthesis capacity is unaltered by antipsychotic treatment, and therapeutic effects are not mediated by changes in this aspect of dopaminergic function.
Introduction Glutamatergic dysfunction is implicated in the pathophysiology of schizophrenia. It is unclear whether glutamatergic dysfunction predicts response to treatment or if antipsychotic ...treatment influences glutamate levels. We investigated the effect of antipsychotic treatment on glutamatergic levels in the anterior cingulate cortex (ACC), and whether there is a relationship between baseline glutamatergic levels and clinical response after antipsychotic treatment in people with first episode psychosis (FEP). Materials and methods The sample comprised 25 FEP patients; 22 completed magnetic resonance spectroscopy scans at both timepoints. Symptoms were assessed using the Positive and Negative Syndrome Scale (PANSS). Results There was no significant change in glutamate baseline 13.23 ± 2.33; follow-up 13.89 ± 1.74; t(21) = −1.158, p = 0.260, or Glx levels baseline 19.64 ± 3.26; follow-up 19.66 ± 2.65; t(21) = −0.034, p = 0.973. There was no significant association between glutamate or Glx levels at baseline and the change in PANSS positive (Glu r = 0.061, p = 0.777, Glx r = −0.152, p = 0.477), negative (Glu r = 0.144, p = 0.502, Glx r = 0.052, p = 0.811), general (Glu r = 0.110, p = 0.607, Glx r = −0.212, p = 0.320), or total scores (Glu r = 0.078, p = 0.719 Glx r = −0.155, p = 0.470). Conclusion These findings indicate that treatment response is unlikely to be associated with baseline glutamatergic metabolites prior to antipsychotic treatment, and there is no major effect of antipsychotic treatment on glutamatergic metabolites in the ACC.
Resting state functional magnetic resonance imaging (rs-fMRI) is increasingly applied for the development of functional biomarkers in brain disorders. Recent studies have revealed spontaneous ...vigilance drifts during the resting state, involving changes in brain activity and connectivity that challenge the validity of uncontrolled rs-fMRI findings. In a combined rs-fMRI/eye tracking study, the pupil size of 32 healthy subjects after 2h of sleep restriction was recorded as an indirect index for activity of the locus coeruleus, the brainstem's noradrenergic arousal center. The spontaneous occurrence of pupil dilations, but not pupil size per se, was associated with increased activity of the salience network, thalamus and frontoparietal regions. In turn, spontaneous constrictions of the pupil were associated with increased activity in visual and sensorimotor regions. These results were largely replicated in a sample of 36 healthy subjects who did not undergo sleep restriction, although in this sample the correlation between thalamus and pupil dilation fell below whole-brain significance. Our data show that spontaneous pupil fluctuations during rest are indeed associated with brain circuitry involved in tonic alertness and vigilance. Pupillometry is an effective method to control for changes in tonic alertness during rs-fMRI.
•Pupil size is not associated with robust brain network activity.•Spontaneous pupil dilations are associated with salience network activation.•Pupil constrictions involve activation of visual and sensorimotor areas.•Pupillometry provides a marker for alertness/vigilance during resting state fMRI.
Glutamatergic dysregulation is one of the leading theories regarding the pathoaetiolopy of schizophrenia. Meta-analysis of magnetic resonance spectroscopy studies in schizophrenia shows increased ...levels of glutamate and glutamine (Glx) in the medial frontal cortex and basal ganglia in clinical high-risk groups for psychosis and increased glutamine levels in the thalamus, but it is unclear if this is also the case in people at genetic high risk for psychosis. The aim of this study was to investigate glutamatergic function in the anterior cingulate cortex, striatum and thalamus in carriers of a genetic variant (22q11.2 deletion) associated with a high risk for psychosis. 53 volunteers (23 22q11.2 deletion carriers and 30 controls) underwent proton magnetic resonance spectroscopy imaging and neuropsychological assessments for prodromal psychotic symptoms, schizotypy, anxiety, depression and FSIQ. We did not find any difference between groups in Glx in the anterior cingulate cortex, striatum or thalamus (Glx: t(50)=-1.26, p = 0.21; U = 251, z = −0.7, p = 0.49; U = 316, z= -0.26, p = 0.79, respectively). No correlation was detected between Glx levels in any region and symptomatology or FSIQ. Our findings indicate that glutamatergic function is not altered in people at genetic high risk of psychosis due to the 22q11.2 deletion, which could suggest that this is not the mechanism underlying psychosis risk in 22q11.2 deletion carriers.
Abstract
Background
Dopaminergic and glutamatergic dysregulation are among the leading hypotheses for schizophrenia. Previous in vivo imaging studies have shown that increased striatal presynaptic ...dopamine synthesis capacity (DSC) predates the onset of psychosis and is associated with symptom severity. Recent meta-analysis in magnetic resonance spectroscopy studies in schizophrenia reported increased levels of glutamate and glutamine (Glx) in basal ganglia and medial frontal cortex in clinical high-risk groups for psychosis. Despite the evidence of alterations in both dopamine and glutamate in schizophrenia, the degree to which these alterations are trait markers linked to genetic risk for psychosis or reflects state changes is not clear from previous studies. Over the last fifteen years, it has been well established that 22q11 deletion is one of the most important genetic risk factors for the development of schizophrenia. Individuals with 22q11 deletion are at increased genetic risk for psychosis, reaching a prevalence 30% for psychotic disorder. The aims of our study were to investigate dopaminergic and glutamatergic function in individuals with 22q11.2 deletion.
Methods
Participants underwent 18F DOPA PET, MRI, as well as clinical measures.21 individuals with 22q11 deletion (14 females and 7 males, age (mean, SD): 26.1(7.72)) and 26 healthy volunteers (15 females and 11 males, age (mean, SD): 26.12(4.28)) took part in the 18F DOPA PET. Standardised ROIs was defined in the striatum, including limbic, associative and sensorimotor sub-regions, and the reference region, defined according to previous study. The ROI atlas was normalised to each individual PET dynamic image. A Patlak analysis was applied to calculate influx constants (Ki values) for the whole striatal ROI relative to uptake in the cerebellar reference region (Kicer min-1).
In addition, 17 individuals with 22q11 deletion (11 females and 6 males, age (mean, SD): 26.39(7.7)) and 30 healthy controls (17 females and 13 males, age (mean, SD): 27.17(4.8)) had MRI. 1H-MRS voxels were placed on the anterior cingulate cortex and left striatum. Spectra were analyzed using LC Model version 6.3-1L. Poorly fitted metabolite peaks (Cramer–Rao minimum variance bounds >20% as reported by LC Model) were excluded from further analysis.
Results
DSC in the whole striatum was significantly increased in the individuals with 22q11 deletion compared to healthy controls (mean (Kicer min-1 =0.0143; SD=0.001; mean Kicer min-1 = 0.0127; SD=0.001, respectively; effect size (Cohen’s d= 1.47, p< 0.000). In addition, no difference was found between groups in Glx levels in anterior cingulate cortex (individuals with 22q11 deletion; mean=19.85; SD=3.17, healthy controls; mean= 21.04; SD=3.91) and left striatum (individuals with 22q11 deletion; mean=11.45; SD=2.88, healthy controls; mean=11.6;SD=2.74)(t(44) =-1.065; p=0.29, t(42)=-0.172;p=0.86, respectively).Psychopathology scales were not correlated with either dopaminergic or glutamatergic function in the group of 22q11 deletion.
Discussion
Our findings provide evidence that dopamine synthesis capacity has a strong trait component and glutamatergic dysfunction may be most likely associated with disease status. Future studies with longitudinal design are warranted to further investigate the role of dopamine and glutamate in individuals with 22q11 deletion. Moreover, there is a clear need for studies utilizing higher field resonance strength and appropriate radiotracers to investigate glutamatergic function in this population. These will be crucial steps towards the development of new treatments, that can be applied in early stages of illness.
Abstract
Background
Glutamatergic dysfunction is implicated in the pathophysiology of schizophrenia, with studies reporting elevated glutamatergic metabolites across brain regions of patients. There ...is consistent evidence showing a decrease in glutamate metabolites after antipsychotic administration. However, the literature on the relationship between the glutamate levels and clinical response after antipsychotics is inconsistent. In this study, we investigated whether antipsychotics change brain glutamate levels in the anterior cingulate cortex (ACC), and whether there is a relationship between baseline glutamate levels and clinical response in the ACC after taking antipsychotics, in antipsychotic naïve people or minimally treated people with first episode psychosis. We hypothesized that 1) glutamate levels decrease after antipsychotic administration; 2) glutamate levels at baseline are associated with the clinical response at follow up.
Methods
The sample comprised 27 first episode psychosis patients (13 antipsychotic naïve, 7 minimally treated, and 7 were medication-free). Clinical assessment was completed for twenty-three participants at follow up, whereas follow up glutamate data was acquired for twenty patients. Proton magnetic resonance spectroscopy (MRS) was used to measure glutamate levels in the ACC at baseline and follow-up. Patient symptoms were assessed using the Positive and Negative Syndrome Scale (PANSS) at baseline and following antipsychotic treatment for a minimum of 4 weeks. Change in the clinical symptoms was measured by calculating percentage change in the PANSS score, accounting for minimum scores (7 for positive and negative symptoms). Normality of distribution was assessed using Shapiro–Wilkes test. To test the first hypothesis, we conducted a paired sample t-test. To test the second hypothesis, we used Pearson’s correlation coefficients for normally distributed data and Spearman’s correlation coefficients for non-normally distributed data.
Results
There was no significant change found between baseline MRS signal (M = 13.72, SD = 2.14) and follow up MRS signal (M = 13.99, SD = 1.56); t(19)= -0.47, p = 0.643. No significant association was found between baseline MRS signal and PANSS positive scores (r = -0.121, n=23, p=0.584), and between baseline MRS signal and PANSS negative scores (rho = -0.182, n=23, p=0.406).
Discussion
The current study observed no effect of antipsychotics on glutamate levels in the anterior cingulate cortex, and the therapeutic effects were not associated with glutamate levels acquired before antipsychotic administration. This relationship needs to be further investigated using a larger sample size. The association between changes in the glutamate levels in the anterior cingulate of first-episode psychosis patients after antipsychotic administration should be compared with a healthy population.
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