Different hemodynamic response patterns in the prefrontal cortical sub-regions according to the clinical stages of psychosis

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Abstract

Background

Symptomatic and functional outcomes in schizophrenia are associated with the duration of untreated psychosis. However, no candidate biomarkers have been adopted in clinical settings. Multichannel near-infrared spectroscopy (NIRS), which can easily and noninvasively measure hemodynamics over the prefrontal cortex, is a candidate instrument for clinical use.

Aims

We intended to explore prefrontal dysfunction among individuals at different clinical stages, including ultra-high-risk (UHR), first-episode psychosis (FEP), and chronic schizophrenia (ChSZ), compared to healthy subjects.

Method

Twenty-two UHR subjects, 27 patients with FEP, 38 patients with ChSZ, and 30 healthy subjects participated. We measured hemodynamic changes during a block-designed letter fluency task using multichannel NIRS instruments.

Results

We found that the activations of the bilateral ventrolateral prefrontal cortex, and the fronto-polar and anterior parts of the temporal cortical regions in the UHR group were lower than those of the controls, but similar to those of the FEP and ChSZ groups. However, the activations in the bilateral dorsolateral prefrontal cortex regions decrease with advancing clinical stage.

Conclusions

To the best of our knowledge, this is the first study directly comparing differences in hemodynamic changes with respect to the 3 clinical stages of psychosis. Furthermore, this study also demonstrates different patterns of impairment according to the progression of clinical stages using NIRS instruments. NIRS measurements for UHR and FEP individuals may be candidate biomarkers for the early detection of the clinical stages of psychosis.

Introduction

Retrospective studies suggest that patients with schizophrenia have prodromal symptoms before psychotic symptoms such as depression, anxiety, attenuated psychotic symptoms, and functional decline fully emerge (Yung et al., 1998, Hafner, 2000, Klosterkotter et al., 2001). A recent review suggests that patients with short durations of untreated psychosis (DUP) have better symptomatic and functional outcomes throughout their lives (Perkins et al., 2005). Therefore, supportive services and programs have been developed toward early detection and intervention for people exhibiting prodromal symptoms to reduce DUP and prevent the transition to psychosis (French et al., 2007, Yung and McGorry, 2007, Joa et al., 2008). To screen for high-risk individuals before developing psychosis, called ultra-high-risk (UHR) individuals, various clinical diagnostic tools have been developed in the last 20 years (Yung et al., 1998, Miller et al., 1999, Klosterkotter et al., 2001, Yung et al., 2004, Yung and McGorry, 2007, Cannon et al., 2008). The rate of transition to psychosis is about 20–30% per year for help seekers who meet the UHR criteria according to these assessment tools (Yung et al., 2004, Cannon et al., 2008). These clinical assessments are helpful but insufficient for early detection and intervention; therefore, more objective tools for detection are needed to help high-risk individuals. Several possible biomarkers for improving the predictive value for developing psychosis are reported in structural MRI studies (Fornito et al., 2008, Koutsouleris et al., 2009); however, no candidate biomarkers have been adopted in clinical settings. MRI instruments have an advantage in spatial resolution; this advantage has substantially contributed to the anatomical and functional clarification of psychiatric disorders. However, routine and repetitive MRI use for patients with psychiatric disorders presents difficulties due to increased costs, greater noise, and the restricted position required during testing.

Near-infrared spectroscopy (NIRS), which can easily and noninvasively measure hemodynamics over the surface of the prefrontal cortex, is a candidate instrument for clinical use. NIRS instruments are also small and convenient such that they can be easily moved almost everywhere, including schools and care units. Our previous NIRS studies suggest that patients with chronic schizophrenia (ChSZ) have impaired activity and characteristic waveform patterns over the prefrontal cortical regions during a letter fluency task (LFT) (Suto et al., 2004, Takizawa et al., 2008). On the basis of these results, the Health, Labour, and Welfare Ministry in Japan approved the NIRS instrument as a diagnostic support system for patients with schizophrenia, major depression, and bipolar disorder. However, little is known about how the NIRS signals of pre- and postpsychotic individuals change; thus, we assumed that the activities in the prefrontal cortex might be different at each clinical stage. If we identify these differences, the NIRS system may be a potential candidate biomarker for objectively detecting and evaluating young people experiencing various symptoms and impaired functions.

The aim of this study is to explore the prefrontal dysfunction of UHR help seekers and patients with first-episode psychosis (FEP) compared to controls during a block-designed LFT, using multichannel NIRS instruments. In addition, if we succeed in early detection and intervention for young patients, they would be able to preserve their functions during the chronic phase. Therefore, we compared patients with ChSZ matched for age-at-onset and DUP to patients with FEP.

Section snippets

Participants

A total of 117 Japanese individuals participated in this study: 22 subjects who fulfilled the UHR criteria, 27 patients with FEP, 38 patients with ChSZ, and 30 healthy subjects (HC group) as controls (Table 1). All participants were recruited from the University of Tokyo Hospital and the Tokyo Metropolitan Matsuzawa Hospital. All UHR individuals and most patients with FEP were help seekers registered at the outpatient unit specialized for early intervention in the University of Tokyo Hospital.

Results

Among the UHR, FEP, and ChSZ groups, there were no differences in premorbid IQ, GAF, and PANSS total scores or in PANSS positive, negative, and general subscores (Table 1). Sixteen UHR individuals and 2 patients with FEP were antipsychotics naïve, and 8 UHR individuals and 1 FEP patient were FEP drug naïve at their measurement points. The chlorpromazine, diazepam, and biperiden equivalent doses of the FEP group did not differ from those of the ChSZ group. Letter numbers as task performances

Discussion

Our results show that the task-related hemoglobin changes over the prefrontal cortical surface areas and the anterior part of the temporal cortex regions gradually decrease with advancing clinical stages of psychosis (i.e., UHR, FEP, and ChSZ). The activation in the UHR group was lower than that of the controls but not significantly different when compared to the reduced activations in the bilateral VLPFC, bilateral fronto-polar, and bilateral aTC regions in the FEP and ChSZ groups. On the

Conclusion

In conclusion, we found that hemodynamic changes decrease with advancing clinical stages of psychosis (i.e., at-risk mental state, first-episode psychosis, and chronic stage of schizophrenia) over the prefrontal cortical surface areas and in the bilateral anterior part of the temporal cortex regions using multichannel NIRS instruments. Although this study was cross-sectional, future studies are needed to carry out longitudinal clinical follow-up and NIRS measurements for UHR and FEP individuals

Role of funding sources

This study was supported by grants from the Ministry of Health, Labour, and Welfare (Health and Labour Sciences Research Grants, Research on Psychiatric and Neurological Diseases and Mental Health, H20-kokoro-ippan-001, H20-3, and H22-seishin-ippan-015 to KK; Health and Labour Science Research Grants for Comprehensive Research on Disability Health and Welfare, H23-seishin-ippan-002 to RT), from the JSPS/MEXT (No. 21249064 and Grant-in-Aid for Scientific Research on Innovative Areas

Contributions

SK contributed to project management and wrote the manuscript. RT and YN conducted NIRS measurements and data analysis. Y. Takano contributed to project management, and clinical assessment and management. YN, Y. Takayanagi, HH, and YO contributed to NIRS measurements and assessment of clinical information in the Tokyo Metropolitan Matsuzawa Hospital. MK contributed to NIRS measurements. TA, MF, and KK coordinated the entire research design and took responsibility for the management of this

Conflict of interest

The principal investigators of each site (Masato Fukuda of Gunma University, Yuji Okazaki of Tokyo Metropolitan Matsuzawa Hospital, and Kiyoto Kasai of The University of Tokyo) have potential conflicts of interest. Each site and the Hitachi Group (Advanced Research Laboratory, Hitachi Ltd. and The Research and Developmental Center, Hitachi Medical Corporation) have had official contracts for a collaborative study on the clinical application of near-infrared spectroscopy in psychiatric

Acknowledgments

We thank the members of Integrated Neuroimaging Studies in Schizophrenia Targeted for Early Intervention and Prevention (IN-STEP) research team in the University of Tokyo Hospital for their advice and assistance with this project, especially Yoshihiro Satomura for assistance with NIRS measurements and clinical assessment as well as Norichika Iwashiro, Motomu Suga, and Hideyuki Inoue for their assessment of clinical information. We also thank Shingo Kawasaki for assistance with statistical

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