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
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.
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