Bridging the associations between dopamine, brain volumetric variation and IQ in drug-naïve schizophrenia
Introduction
Schizophrenia is generally regarded as neurodevelopmental impairment of the human brain (Insel, 2010). Possible pathogeneses of schizophrenia, involving neurotransmitter dysregulation, connectivity abnormalities, and even brain structural variation, have been discussed in depth in previous studies (Frith, 1997). Among potential structural impairments, brain volume variation has been studied widely in patients with schizophrenia using the technique of voxel-based morphometry (VBM) (Wright et al., 1995). For example, previous studies have demonstrated that the whole brain and hippocampal volumes were reduced, and the ventricular volume increased, in patients as compared with healthy controls (Steen et al., 2006; Takayanagi et al., 2011). One meta-analysis showed regional reductions in the volumes of the left superior temporal gyrus and the left medial temporal lobe, which are key regions of structural difference in patients with schizophrenia (Honea et al., 2005); while another study of 1588 independent patients with schizophrenia demonstrated a specifically smaller subcortical volume (Wright et al., 2000). Unfortunately, the subjects recruited in most of the studies mentioned above may have included a mixture of medicated and unmedicated patients with schizophrenia. Some studies have focused on patients with first-episode schizophrenia, and showed that the volume of gray matter is mainly reduced in the frontal-temporal-parietal regions (Kubicki et al., 2002). Several potential risk factors might alter the brain volume in patients with schizophrenia; for example, duration of illness (Velakoulis et al., 2002), age (Zhang et al., 2015), and even antipsychotic treatment (Ho et al., 2011). Hence, drug-naïve patients with schizophrenia could avoid medications-related influence in which to examine brain volumetric variation in comparison with healthy controls.
Another important risk factor, mentioned in few studies, is monoamine-related neurotoxicity. The dopamine hypothesis has long been regarded as a durable pathogenesis of schizophrenia, and neurotoxicity triggered by dopaminergic dysregulation, or other more complicated mechanisms, in patients with schizophrenia has been reported (Howes et al., 2012). Furthermore, alteration of dopamine activity in specific brain areas might influence the brain volume in different diseases (Ho et al., 2011). Previous findings demonstrated that drug-naïve patients with schizophrenia had an unaltered dopamine transporter (DAT) availability after antipsychotic treatment (Chang et al., 2017), but the relationships between dopaminergic activity and specific brain volume variations in drug-naïve patients with schizophrenia remain unclear. To conclude, brain volume reduction in schizophrenia might be related to a combination of early neurodevelopmental processes within illness progression and medication use, while the dopaminergic influence could play a very important role.
We speculated that altered dopaminergic tone could be associations between reduced brain volume in certain specific areas among patients with schizophrenia. Also, we are interested in the correlations between brain volume, dopamine activity and cognitive function, although these relationships have been studied in depth (Baare et al., 1999; Kubota et al., 2015). Therefore, the aims of our study were to (A) identify the brain volume variations on the specific region related with dopaminergic tone, asserted with [99mTc]TRODAT-1 of DAT among schizophrenia, and (B) probing the relationship between cognitive function impairment and brain volume variations on the specific region. We used intelligence quotient (IQ) as the measurement tool because it presents the most comprehensive analysis of cognitive function, and for reasons mentioned above (Kubota et al., 2015).
Section snippets
Participants
A total of 51 drug-naïve first-episode patients with schizophrenia and 128 normal healthy subjects were recruited from the psychiatric outpatient clinic of the National Cheng Kung University Hospital from 2005 to 2014, and the inclusion as well as the exclusion criteria for patients with drug-naïve schizophrenia and healthy subjects were listed in our previous studies (Yeh et al., 2012; Chen et al., 2013). Before any procedure was performed, written informed consent was obtained from each of
Demographic data and associated neuroimaging data in the two groups
The results presented in Table 1 show that the DAT availability in the patient group was significantly lower than that in the normal healthy subjects (1.67 ± 0.45 vs. 1.98 ± 0.37, P < 0.005). The scores of the CGIS, GAF, and PANSS, in addition to the duration of illness, are also listed in Table 1.
MRI data: correlations between DAT availability and specific GMVs in the two groups
According to the hypothesis of dopaminergic activity and the potential brain volume variations mentioned in the Introduction, we attempted to ascertain possible interactions in the two groups of DAT
Discussion
In subjects with schizophrenia, reduction in brain volume in specific regions, dopamine dysregulation, and cognitive impairment have been recognized in previous studies, as detailed in the Introduction. Our study provided further information regarding the associations between the brain volumes of specific regions, dopamine activity and cognitive function in terms of IQ.
In this study, a significantly lower DAT availability was noted in the drug-naïve patients with schizophrenia, which was in
Contributors
Yen Kuang Yang designed the study and wrote the protocol. Nan Tsing Chiu helped to design the study. Huai-Hsuan Tseng and Po See Chen contributed to the statistical analyses. Wei Hung Chang wrote the first draft of the manuscript. Kao Chin Chen, I Hui Lee, and Yen Kuang Yang managed the data collection. All authors interpreted the analysis of the results and helped to revise the manuscript.
Role of funding source
This work was supported by grants from the National Science Council of Taiwan (NSC 93-2314-B-006-107, NSC 95-2314-B-006-052, NSC 95-2314-B-006-115-MY2, NSC 97-2314-B-006-006-MY3, NSC 99-2314-B-006-019-MY3, and NSC 101-2314-B-006-065), the Atomic Energy Council of Taiwan (NSC 91-NU-7-006-002), and the Ministry of Science and Technology, R.O.C. (MOST 102-2420-H-006-007-MY2 and MOST 104-2314-B-006-032-MY2).
Declaration of competing interest
The funding institutions had no further role in the study design, the collection, analysis, and interpretation of data, the writing of this paper, or the decision to submit it for publication. The authors report no financial relationships with commercial interests.
Acknowledgements
The authors wish to thank Dr. Shih-Hsien Lin, Ms. Tsai Hua Chang, Mr. Chien Ting Lin, and Professor Yuan-Hwa Chou from Taipei Veterans General Hospital for their support.
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