Elsevier

Schizophrenia Research

Volume 228, February 2021, Pages 7-18
Schizophrenia Research

Alterations of neurometabolism in the dorsolateral prefrontal cortex and thalamus in transition to psychosis patients change under treatment as usual – A two years follow-up 1H/31P-MR-spectroscopy study

https://doi.org/10.1016/j.schres.2020.11.063Get rights and content

Abstract

Background

The ultra-high risk (UHR) paradigm allows early contact with patients developing acute psychosis and the study of treatment effects on the underlying pathology.

Methods

29 patients with first acute psychosis according to CAARMS criteria (transition patients, TP) (T0) and thereof 22 patients after two-year follow-up (mean 788 d) (T1) underwent 1H-/31P-MR spectroscopy of the prefrontal (DLPFC) and anterior midcingulate (aMCC) cortices and the thalamus. N-acetylaspartate (NAA), glutamate (Glu, Glx), energy (PCr, ATP) and phospholipid metabolites (PME, PDE) were compared to 27 healthy controls by ANCOVA and correlated with patients' symptom ratings (BPRS-E, SCL-90R). For longitudinal analysis, linear mixed model (LMM) and ANCOVA for repeated measures were used.

Results

DLPFC: In patients, NAA and PME were decreased bilaterally and Glu on the left side at T0. Left-sided Glu and NAA (trend) and bilateral Glx increased during follow-up. Thalamus: In TP, bilateral NAA, left-sided Glu and right-sided Glx were decreased at T0; bilateral NAA and left-sided Glx increased during follow-up. aMCC: In TP, bilateral NAA, right-sided Glu, and bilateral PME and PDE were decreased, while left-sided PCr was increased at T0. No changes were observed during follow-up.

Conclusion

Regardless of the long-term diagnosis, the psychotic state of illness includes disturbed neuronal function in the DLPFC, thalamus and aMCC. Treatment-as-usual (TAU), including antipsychotic/antidepressant medication and supportive psychotherapy, had an effect on the thalamo-frontal area but not or less pronounced on the neurometabolic deficits of the aMCC.

Introduction

With a life-time risk of 4.5% (Jacobi et al., 2004), psychosis is one of the most frequent, one of the most serious regarding suicidal risk and one of the most debilitating mental disorders, which we are just beginning to understand through systematic examination of the ultra-high risk (UHR) and the transition to acute psychosis (TP) stage condition.

The experimental method of magnetic resonance spectroscopy (MRS) applied in this study is sensitive to the potentially underlying cell-metabolic mechanisms and allows assessment of metabolites associated with concurrent structural alterations. Proton (1H)-MRS, for example, provides information about neurotransmitters such as glutamate and glutamine (Glu, Gln, sum Glx) or markers of neuronal integrity such as N-Acetyl-aspartate (NAA). In recent 1H-MRS research, several lines of evidence were identified. (i) In a meta-analysis, glutamate was found to be reduced in the medial frontal cortex while glutamine was increased (Marsman et al., 2013), suggesting that frontal glutamatergic activity is disturbed in the early untreated phase of psychosis. Impaired synaptic activity, altered glutamate receptor function, deregulated glutamine-glutamate cycling or impaired glutamate transport was also discussed as possibly related processes. (ii) 1H-MRS examinations of the thalamus and the anterior midcingulate cortex (aMCC, nomenclature according to (Vogt, 2016), in previous literature usually referred to as the anterior cingulate cortex, ACC) showed lower glutamate levels in the thalamus of UHR individuals associated with lower grey matter volume (Stone et al., 2009). Furthermore, lower thalamic glutamate and higher aMCC glutamate indicated unfavourable outcome in terms of transition to psychosis, symptomatology, and social functioning (Egerton et al., 2012; Egerton et al., 2014).

Phosphorous (31P)-MRS allows the investigation of structure maintaining phospholipid metabolites (PME, PDE) and mitochondrial high-energy phosphates (ATP, PCr). So far, only isolated studies on genetic risk populations have been published, indicating disturbed membrane synthesis (decreased phosphomonoester, PME) and increased membrane breakdown (increased phosphodiester, PDE) in prefrontal cortical regions (Keshavan et al., 2003; Klemm et al., 2001). With respect to manifest schizophrenia, 31P-MRS studies revealed alterations in the phospholipid metabolism in the prefrontal cortex, but also in the aMCC, thalamus, insular cortex, caudate nucleus and anterior cerebellum (Gangadhar et al., 2004; Jayakumar et al., 2003; Jensen et al., 2004; Smesny et al., 2007; Volz et al., 2000; Yuksel et al., 2015). In neuroleptic-naïve first-episode patients, the most consistent findings were observed in the prefrontal cortex, including decrease of phospholipid precursors (PME) and/or increase in phospholipid breakdown metabolites (PDE) as well as decrease in adenosine triphosphate (ATP) and/or increase in phosphocreatine (PCr) (Keshavan et al., 2000). These findings were interpreted as an expression of focally increased neuronal/synaptic membrane damage accompanied by deficits in maintaining or re-establishing physiological membrane texture and energy supply (Smesny et al., 2007).

In this current study, both 1H- and 31P-MRS were applied in patients admitted to service as UHR individuals who had their first acute psychotic episode according to the criteria of the Comprehensive Assessment of At-Risk Mental States (CAARMS) (Yung et al., 2005), developed at the Personal Assessment and Crisis Evaluation (PACE) Clinic in Melbourne in 1994 (Yung et al., 2007) (see inclusion criteria below). Investigations were performed at the time of established diagnosis of transition to acute psychosis. This group of patients was compared with a group of healthy individuals and, in a first step, the particular patterns of neurometabolic aberrations in this patient population, which has never been medicated (neuroleptic-naïve) and whose long-term diagnosis is still unknown, were examined. After detecting state-related neurometabolic abnormalities, the study also focused on changes in these abnormalities during the first two years of treatment in a typical in- and outpatient psychiatric setting (TAU). For this reason, patients and controls were examined a second time after a two-year follow-up interval (mean 788 d). Therefore, our study relates to metabolic abnormalities in the psychotic state of developing schizophrenic and non-schizophrenic disorders and their response to TAU.

We formulated hypotheses that (i) a prefrontal glutamatergic disturbance (Glu, Glx and NAA decrease), (ii) functional deficits in the thalamus (decreased Glu, Glx), and (iii) in aMCC (increased Glu or Glx) will normalize within the two-year interval of treatment as usual (TAU) by antipsychotic and/or antidepressant medication and supportive psychotherapy.

Section snippets

Subjects

Out of a population of 168 UHR patients for psychosis, who were screened using the CAARMS semi-structured interviews (Yung et al., 2005) in an outpatient psychosis prevention and early intervention service, we included 29 patients (transition rate 17.3%) at the time of transition to acute psychosis (transition patient, TP) according to the Personal Assessment and Crisis Evaluation (PACE) criteria (Yung et al., 2007) (see Table 1 for inclusion criteria and Table 2 for demographic details). Since

Demographics and psychopathology

As expected, the use of cannabis and alcohol in TP was significantly higher. While at T0 none of the TP (and HC) fulfilled ICD-10 criteria of a dependency, at T1 one patient was diagnosed with alcohol dependence and two patients with abuse of alcohol and THC (tetrahydrocannabinol). In fact, cannabis use had decreased at T1. For details of substance use, see Table 2.

According to the GSI values of the SCL-90R, at T0 TP suffered from clear psychiatric impairment, defined as a GSI-score of ≥63 (TP

Discussion

Regarding our initial hypotheses, we found (i) correlates of a bilateral prefrontal neuronal disturbance expressed by decreased Glu and NAA in the left and decreased NAA in the right DLPFC. Such an abnormality was not found in the Glx data of the DLPFC. These findings were accompanied by a disturbed structure maintaining metabolism, expressed by bilaterally decreased membrane phospholipid precursors (PME). During follow-up, a change of the neuronal disturbance was observed as bilateral increase

Conclusion

In a population of transition to psychosis patients we were able to show a deficit in mitochondrial and glutamate metabolism in the DLPFC, thalamus and aMCC, which is accompanied by abnormalities of energy metabolism in the left aMCC and deregulated structure maintaining phospholipid metabolism in the bilateral DLPFC and aMCC. According to our findings, this pathology is associated with the exacerbation of the acute psychotic state of illness rather than with the long-term diagnosis of

CRediT authorship contribution statement

StS, AG, and JRR conceived the work. StS created a first outline. StS, DB, AG, and MW had full access to all the data in the study and take responsibility for data integrity and the accuracy of the data analysis. DB, AG, NS, KL and MW performed the measurements and analysed the data. All authors contributed to the writing of the paper and approved the final version.

Role of the funding source

The sponsor of the study had no role in study design, data collection, data analysis, data interpretation, or writing of the report.

Declaration of competing interest

We declare that we have no conflict of interest.

Acknowledgements

StS was supported by the German Research Foundation (DFG) (Sm 68/3-1). JRR and AG acknowledge support from the DFG (RE 1123/11-1). AG additionally acknowledges support from the DFG (GU 1108/3-1).

We would like to thank the staff of the MRI research facility for their support in acquiring and processing spectroscopic data. We also thank all participants of the study and their families.

References (83)

  • J.L. Gan et al.

    Atypical antipsychotic drug treatment for 6 months restores N-acetylaspartate in left prefrontal cortex and left thalamus of first-episode patients with early onset schizophrenia: a magnetic resonance spectroscopy study

    Psychiatry Res.

    (2014)
  • K.E.M. Godfrey et al.

    Differences in excitatory and inhibitory neurotransmitter levels between depressed patients and healthy controls: a systematic review and meta-analysis

    J. Psychiatr. Res.

    (2018)
  • P.N. Jayakumar et al.

    Membrane phospholipid abnormalities of basal ganglia in never-treated schizophrenia: a 31P magnetic resonance spectroscopy study

    Biol. Psychiatry

    (2003)
  • M.S. Keshavan et al.

    Magnetic resonance spectroscopy in schizophrenia: methodological issues and findings—part II

    Biol. Psychiatry

    (2000)
  • A. Marsman et al.

    GABA and glutamate in schizophrenia: a 7 T (1)H-MRS study

    NeuroImage Clin.

    (2014)
  • J.R. Moffett et al.

    N-Acetylaspartate in the CNS: from neurodiagnostics to neurobiology

    Prog. Neurobiol.

    (2007)
  • P. Ohrmann et al.

    Cognitive impairment and in vivo metabolites in first-episode neuroleptic-naive and chronic medicated schizophrenic patients: a proton magnetic resonance spectroscopy study

    J. Psychiatr. Res.

    (2007)
  • R.C. Oldfield

    The assessment and analysis of handedness: the Edinburgh inventory

    Neuropsychologia

    (1971)
  • G. Paslakis et al.

    N-acetyl-aspartate (NAA) as a correlate of pharmacological treatment in psychiatric disorders: a systematic review

    Eur. Neuropsychopharmacol.

    (2014)
  • S. Smesny et al.

    Metabolic mapping using 2D 31P-MR spectroscopy reveals frontal and thalamic metabolic abnormalities in schizophrenia

    Neuroimage

    (2007)
  • S. Smesny et al.

    Prefrontal glutamatergic emotion regulation is disturbed in cluster B and C personality disorders - a combined (1)H/(31)P-MR spectroscopic study

    J. Affect. Disord.

    (2018)
  • J.A. Stanley et al.

    Reduced N-acetyl-aspartate levels in schizophrenia patients with a younger onset age: a single-voxel 1H spectroscopy study

    Schizophr. Res.

    (2007)
  • J.M. Stone et al.

    Glutamate dysfunction in people with prodromal symptoms of psychosis: relationship to gray matter volume

    Biol. Psychiatry

    (2009)
  • J. Theberge et al.

    Duration of untreated psychosis vs. N-acetylaspartate and choline in first episode schizophrenia: a 1H magnetic resonance spectroscopy study at 4.0 Tesla

    Psychiatry Res.

    (2004)
  • J. Theberge et al.

    Regarding “increased prefrontal and hippocampal glutamate concentration in schizophrenia: evidence from a magnetic resonance spectroscopy study”

    Biol. Psychiatry

    (2007)
  • G. Tsai et al.

    N-acetylaspartate in neuropsychiatric disorders

    Prog. Neurobiol.

    (1995)
  • L. Vanhamme et al.

    Improved method for accurate and efficient quantification of MRS data with use of prior knowledge

    Magn. Reson.

    (1997)
  • B.A. Vogt

    Midcingulate cortex: structure, connections, homologies, functions and diseases

    J. Chem. Neuroanat.

    (2016)
  • H.R. Volz et al.

    Reduced phosphodiesters and high-energy phosphates in the frontal lobe of schizophrenic patients: a (31)P chemical shift spectroscopic-imaging study

    Biol. Psychiatry

    (2000)
  • S.J. Wood et al.

    A 1H-MRS investigation of the medial temporal lobe in antipsychotic-naive and early-treated first episode psychosis

    Schizophr. Res.

    (2008)
  • C. Yuksel et al.

    Phosphorus magnetic resonance spectroscopy studies in schizophrenia

    J. Psychiatr. Res.

    (2015)
  • A. Zabala et al.

    Findings of proton magnetic resonance spectometry in the dorsolateral prefrontal cortex in adolescents with first episodes of psychosis

    Psychiatry Res.

    (2007)
  • N. Aoyama et al.

    Grey matter and social functioning correlates of glutamatergic metabolite loss in schizophrenia

    Br. J. Psychiatry

    (2011)
  • R. Bartha et al.

    Measurement of glutamate and glutamine in the medial prefrontal cortex of never-treated schizophrenic patients and healthy controls by proton magnetic resonance spectroscopy

    Arch. Gen. Psychiatry

    (1997)
  • C. Basoglu et al.

    Comparison of right thalamus and temporal cortex metabolite levels of drug-naive first-episode psychotic and chronic schizophrenia in patients

    Turk psikiyatri dergisi Turk. J. Psychiatry

    (2006)
  • T.E. Bates et al.

    Inhibition of N-acetylaspartate production: implications for 1H MRS studies in vivo

    Neuroreport

    (1996)
  • D.F. Braus et al.

    Favorable effect on neuronal viability in the anterior cingulate gyrus due to long-term treatment with atypical antipsychotics: an MRSI study

    Pharmacopsychiatry

    (2001)
  • J.R. Bustillo et al.

    Proton magnetic resonance spectroscopy during initial treatment with antipsychotic medication in schizophrenia

    Neuropsychopharmacology

    (2008)
  • J.R. Bustillo et al.

    1H-MRS at 4 Tesla in minimally treated early schizophrenia

    Mol. Psychiatry

    (2010)
  • K.M. Cecil et al.

    Proton magnetic resonance spectroscopy of the frontal lobe and cerebellar vermis in children with a mood disorder and a familial risk for bipolar disorders

    J. Child Adolesc. Psychopharmacol.

    (2003)
  • J.B. Clark

    N-acetyl aspartate: a marker for neuronal loss or mitochondrial dysfunction

    Dev. Neurosci.

    (1998)
  • Cited by (0)

    View full text