Altered Medial Temporal Activation Related to Local Glutamate Levels in Subjects with Prodromal Signs of Psychosis

doi:10.1016/j.biopsych.2010.08.033

Biological Psychiatry

Volume 69, Issue 1, 1 January 2011, Pages 97-99

https://doi.org/10.1016/j.biopsych.2010.08.033 Get rights and content

Background

Both medial temporal cortical dysfunction and perturbed glutamatergic neurotransmission are regarded as fundamental pathophysiological features of psychosis. However, although animal models of psychosis suggest that these two abnormalities are interrelated, their relationship in humans has yet to be investigated.

Methods

We used a combination of functional magnetic resonance imaging and magnetic resonance spectroscopy to investigate the relationship between medial temporal activation during an episodic memory task and local glutamate levels in 22 individuals with an at-risk mental state for psychosis and 14 healthy volunteers.

Results

We observed a significant between-group difference in the coupling of medial temporal activation with local glutamate levels. In control subjects, medial temporal activation during episodic encoding was positively associated with medial temporal glutamate. However, in the clinical population, medial temporal activation was reduced, and the relationship with glutamate was absent.

Conclusions

In individuals at high risk of psychosis, medial temporal dysfunction seemed related to a loss of the normal relationship with local glutamate levels. This study provides the first evidence that links medial temporal dysfunction with the central glutamate system in humans and is consistent with evidence that drugs that modulate glutamatergic transmission might be useful in the treatment of psychosis.

Section snippets

Methods and Materials

We used a combination of functional magnetic resonance imaging and proton magnetic resonance spectroscopy (¹H-MRS) in the same individuals. The study was approved by the joint South London and Maudsley and the Institute of Psychiatry National Health Service Research Ethics Committee, and all participants gave written informed consent to participate after a complete description of the study.

Results

During verbal encoding the ARMS group showed, consistent with previous studies (8), reduced activation relative to control subjects in the left parahippocampal gyrus (p = .047 family-wise error) (Figure 1), where the degree of activation in the ARMS group was directly correlated with task performance [the number of words correctly recalled during the subsequent recognition condition; r(20) = .497, p = .019]. In control subjects, activation in this cluster during encoding was positively

Discussion

These results suggest that medial temporal dysfunction in people with prodromal symptoms of psychosis is related to a loss of the normal relationship between function in this region and local glutamate levels. Although medial temporal dysfunction and altered glutamate levels have each been described separately in relation to psychosis in humans (2, 4), this is the first time a link between them has been demonstrated in the same subjects. A direct relationship between them provides support to

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We identified three studies in the at risk mental state (ARMS) populations and five in schizophrenia populations reporting associations between glutamate and the BOLD response (3 in chronic medicated patients, one in medicated FEP and one in chronic unmedicated patients). In overlapping ARMS populations compared to controls, Fusar-Poli (Fusar-Poli et al., 2011) reported opposite associations between thalamic glutamate levels and prefrontal, hippocampal and superior temporal activation during verbal fluency, while Valli (Valli et al., 2011) identified opposite pattern of coupling between medial temporal glutamate and medial temporal activation during episodic memory. ARMS patients followed for 18 months after scanning were categorized into those achieving good versus poor functional outcomes; at baseline, those who subsequently achieved poor outcome showed negative associations between thalamic glutamate and prefrontal striatal activation, patterns that were not seen in the subjects achieving good outcome and the controls (Allen et al., 2015).
Epidemiologic, genetic, and neurobiological studies suggest considerable overlap between schizophrenia and mood disorders. Importantly, both disorders are associated with a broad range of cognitive deficits as well as altered glutamatergic and GABAergic neurometabolism. We conducted a systematic review of magnetic resonance spectroscopy (MRS) studies investigating the relationship between glutamatergic and GABAergic neurometabolites and cognition in schizophrenia spectrum disorders and mood disorders. A literature search in Pubmed of studies published before April 15, 2019 was conducted and 37 studies were deemed eligible for systematic review. We found that alterations in glutamatergic and GABAergic neurotransmission have been identified relatively consistently in both schizophrenia and mood disorders. However, because of the vast heterogeneity of published studies in terms of illness stage, medication exposure, MRS acquisition parameters and data post-processing strategies, we still do not understand the relationship between those neurotransmitters and cognitive dysfunction in mental illness, which is a critical initial step for rational drug development. Our findings emphasize the need for coordinated multi-center studies that characterize cognitive function and its biological substrates in large and well-defined clinical populations, using harmonized imaging sequences and analytical methods with the goal to elucidate the underlying pathophysiological mechanisms and to inform future clinical trials.
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Seven studies investigated GABA or GABA + of the mPFC (Da Silva et al., 2019; de la Fuente-Sandoval et al., 2016; Marenco et al., 2016; Menschikov et al., 2016; Modinos et al., 2018b; Wang et al., 2016; Wenneberg et al., 2019;). Eight studies investigated glutamate of the mPFC (Da Silva et al., 2019; Egerton et al., 2014; Lutkenhoff et al., 2010; Modinos et al., 2018a, 2018b; Purdon et al., 2008; Stone et al., 2009; Valli et al., 2011). Seven studies investigated glutamate of the left hippocampus (Bloemen et al., 2011; Howes et al., 2020; Lutkenhoff et al., 2010; Nenadic et al., 2015; Shakory et al., 2018; Stone et al., 2009; Valli et al., 2011).
Accumulating evidence implicates that individuals at high-risk of psychosis have already exhibited pathophysiological changes in brain metabolites including glutamate, gamma-Aminobutyric Acid (GABA), N-Acetylaspartate (NAA), creatine (Cr), myo-inositol (MI) and choline (Cho). These changes may contribute to the development of schizophrenia and associate with psychotic genes. However, specific metabolic changes of brain sub-regions in individuals at risk have still been controversial. Thus, the current study aimed to investigate the brain metabolic changes including glutamate, Glx, GABA, GABA/Glx, NAA, Cr, MI and Cho levels in individuals at risk by conducting a case-control meta-analysis and meta-regression of proton magnetic resonance spectroscopy studies. Primary outcomes revealed that individuals at risk exhibited increased Cr levels at the rostral medial prefrontal cortex (rmPFC), decreased NAA and Cr levels at the thalamus, and increased MI levels at the dorsolateral prefrontal cortex. Sub-group analyses further indicated that individuals with clinical high-risk (CHR) exhibited increased Cr levels at the medial prefrontal cortex (mPFC) and decreased Glx levels at the thalamus, while individuals with genetic risk (siblings of psychiatric patients) exhibited significant increased Glx and MI levels at the mPFC. However, GABA, GABA/Glx and Cho levels showed no significant result. These findings suggest that the dysfunctional metabolites at the mPFC and the thalamus may be an essential neurobiological basis at the early stage of psychosis.
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We found no significant differences between glutamate levels in the ACC or thalamus or GABA levels in the thalamus between UHR individuals and healthy control subjects. This is in accordance with most UHR studies, which reported no difference in glutamate levels in the ACC (32–35), but in contrast to findings of decreased glutamate levels in the thalamus (32–34). Interestingly, studies in the medial prefrontal cortex with more ventrally situated voxels have found increased levels of Glx and GABA in UHR (38) and first-episode psychosis (47,49).
Studies examining glutamate or gamma-aminobutyric acid (GABA) in ultra-high risk for psychosis (UHR) and the association with pathophysiology and cognition have shown conflicting results. We aimed to determine whether perturbed glutamate and GABA levels in the anterior cingulate cortex and glutamate levels in the left thalamus were present in UHR individuals and to investigate associations between metabolite levels and clinical symptoms and cognition.
We included 122 UHR individuals and 60 healthy control subjects. Participants underwent proton magnetic resonance spectroscopy to estimate glutamate and GABA levels and undertook clinical and cognitive assessments.
We found no differences in metabolite levels between UHR individuals and healthy control subjects. In UHR individuals, we found negative correlations in the anterior cingulate cortex between the composite of glutamate and glutamine (Glx) and the Comprehensive Assessment of At-Risk Mental States composite score (p = .04) and between GABA and alogia (p = .01); positive associations in the anterior cingulate cortex between glutamate (p = .01) and Glx (p = .01) and spatial working memory and between glutamate (p = .04), Glx (p = .04), and GABA (p = .02) and set-shifting; and a positive association in the thalamus between glutamate and attention (p = .04). No associations between metabolites and clinical or cognitive scores were found in the healthy control subjects.
An association between glutamate and GABA levels and clinical symptoms and cognition found only in UHR individuals suggests a loss of the normal relationship between metabolite levels and cognitive function. Longitudinal studies with investigation of clinical and cognitive outcome and the association with baseline levels of glutamate and GABA could illuminate whether glutamatergic and GABAergic dysfunction predicts clinical outcome.
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Cannabis use is associated with increased risk of psychotic symptoms and in a small number of cases it can lead to psychoses. This review examines the neurobiological mechanisms that mediate the link between cannabis use and psychosis risk. We use an established preclinical model of psychosis, the methylazoxymethanol acetate (MAM) rodent model, as a framework to examine if psychosis risk in some cannabis users is mediated by the effects of cannabis on the hippocampus, and this region’s role in the regulation of mesolimbic dopamine. We also examine how cannabis affects excitatory neurotransmission known to regulate hippocampal neural activity and output. Whilst there is clear evidence that cannabis/cannabinoids can affect hippocampal and medial temporal lobe function and structure, the evidence that cannabis/cannabinoids increase striatal dopamine function is less robust. There is limited evidence that cannabis use affects cortical and striatal glutamate levels, but there are currently too few studies to draw firm conclusions. Future work is needed to test the MAM model in relation to cannabis using multimodal neuroimaging approaches.
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Although clinical intervention at the clinical high risk stage has the potential to prevent the onset of psychosis, there are still no licensed pharmacological treatments for this purpose. The development of preventative treatments is informed by models of psychosis onset, especially those that reflect the time course and symptomatology of the disorder. This chapter describes four different preclinical models of psychosis onset, involving a neonatal hippocampal lesion, prenatal immune activation, and administration of PCP (phencyclidine) or methylazoxymethanol acetate (MAM), respectively. While all these models are useful, the neonatal hippocampal model lacks construct validity, the evidence linking prenatal immune activation with psychosis is limited, and the chronic PCP model does not have a neurodevelopmental component. The MAM model reproduces a neurodevelopmental trajectory of neural and behavioral changes that resemble those evident in human studies of psychosis onset. Collectively, these models have advanced knowledge of the mechanisms underlying the onset of psychotic disorders and have provided a rationale for novel preventative interventions.
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Over the last three decades there has been an accumulation of Magnetic Resonance Imaging (MRI) studies reporting that aberrant functional networks may underlie cognitive deficits and other symptoms across a range of psychiatric diagnoses. The use of pharmacological MRI and ¹H-Magnetic Resonance Spectroscopy (¹H-MRS) has allowed researchers to investigate how changes in network dynamics are related to perturbed excitatory and inhibitory neurotransmission in individuals with psychiatric conditions. More recently, changes in functional network dynamics and excitatory/inhibitory (E/I) neurotransmission have been linked to early childhood trauma, a major antecedents for psychiatric illness in adulthood. Here we review studies investigating whether perturbed network dynamics seen across psychiatric conditions are related to changes in E/I neurotransmission, and whether such changes could be linked to childhood trauma. Whilst there is currently a paucity of studies relating early traumatic experiences to altered E/I balance and network function, the research discussed here lead towards a plausible mechanistic hypothesis, linking early traumatic experiences to cognitive dysfunction and symptoms mediated by E/I neurotransmitter imbalances.

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Brief ReportAltered Medial Temporal Activation Related to Local Glutamate Levels in Subjects with Prodromal Signs of Psychosis

Background

Methods

Results

Conclusions

Section snippets

Methods and Materials

Results

Discussion

Schizophr Res

Brain Res Rev

Neuropsychopharmacology

Trends Neurosci

Biol Psychiatry

Lancet

Trends Neurosci

Glutamate and glutamine measured with 4.0 T proton MRS in never-treated patients with schizophrenia and healthy volunteers

Am J Psychiatry

First in vivo evidence of an NMDA receptor deficit in medication-free schizophrenic patients

Mol Psychiatry

Ionotropic glutamate receptors and expression of N-methyl-D-aspartate receptor subunits in subregions of human hippocampus: effects of schizophrenia

Am J Psychiatry

Brief Report
Altered Medial Temporal Activation Related to Local Glutamate Levels in Subjects with Prodromal Signs of Psychosis