Elsevier

Schizophrenia Research

Volume 220, June 2020, Pages 248-253
Schizophrenia Research

Bridging the associations between dopamine, brain volumetric variation and IQ in drug-naïve schizophrenia

https://doi.org/10.1016/j.schres.2020.03.005Get rights and content

Abstract

Background

Although patients with schizophrenia are well-known to exhibit significant brain volume reduction and cognitive function impairment, it remains unclear as to whether the reduction/impairment is correlated with dopaminergic activity under drug-naïve conditions.

Methods

51 drug-naïve patients with and 128 healthy subjects were recruited in this study. DAT by [99mTc]TRODAT-1 single-photon emission computed tomography (SPECT), regional gray matter volume (GMV) by voxel-based morphometry (VBM) analysis, and cognitive function in terms of IQ were measured in both groups.

Result

A significantly lower DAT availability existed in the drug-naïve group as compared with the healthy subjects (1.67 ± 0.45 vs. 1.98 ± 0.37, P < 0.005). DAT availability was significantly positively correlated with GMV in the left middle frontal lobe (r = 0.58, P < 0.005), the GMV being significantly reduced in the patients with schizophrenia (0.45 ± 0.10 vs. 0.49 ± 0.07, P < 0.005). Furthermore, the GMV in the left middle frontal lobe was significantly and positively correlated with full IQ (r = 0.34, P = 0.02) in the patients with schizophrenia, but not in the controls.

Conclusions

Dysregulated dopaminergic activity may modulate volume variation in specific brain areas, and brain volume might alter IQ in drug-naïve patients with 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 CGIsingle bondS, 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.

References (41)

  • M. Akil et al.

    Lamina-specific alterations in the dopamine innervation of the prefrontal cortex in schizophrenic subjects

    Am. J. Psychiatry

    (1999)
  • N.C. Andreasen

    A unitary model of schizophrenia: Bleuler’s “fragmented phrene” as schizencephaly

    Arch. Gen. Psychiatry

    (1999)
  • W.H. Chang et al.

    Unaltered dopamine transporter availability in drug-naive patients with schizophrenia after 6 months of antipsychotics treatment: a naturalistic study

    J. Clin. Psychopharmacol.

    (2017)
  • K.C. Chen et al.

    Striatal dopamine transporter availability in drug-naive patients with schizophrenia: a case-control SPECT study with [(99m)Tc]-TRODAT-1 and a meta-analysis

    Schizophr. Bull.

    (2013)
  • J. Darcourt et al.

    EANM procedure guidelines for brain neurotransmission SPECT using (123)I-labelled dopamine transporter ligands, version 2

    Eur. J. Nucl. Med. Mol. Imaging

    (2010)
  • D.S. Djang et al.

    SNM practice guideline for dopamine transporter imaging with 123I-ioflupane SPECT 1.0

    J. Nucl. Med.

    (2012)
  • H.R. Friedman et al.

    Coactivation of prefrontal cortex and inferior parietal cortex in working memory tasks revealed by 2DG functional mapping in the rhesus monkey

    J. Neurosci.

    (1994)
  • C.D. Frith

    Functional brain imaging and the neuropathology of schizophrenia

    Schizophr. Bull.

    (1997)
  • W. Guy

    ECDEU Assessment for Psychopharmacology

    (1976)
  • B.C. Ho et al.

    Long-term antipsychotic treatment and brain volumes: a longitudinal study of first-episode schizophrenia

    Arch. Gen. Psychiatry

    (2011)
  • Cited by (7)

    • Autophagy as a gateway for the effects of methamphetamine: From neurotransmitter release and synaptic plasticity to psychiatric and neurodegenerative disorders

      2021, Progress in Neurobiology
      Citation Excerpt :

      METH impairs DAT activity either via direct inhibition or via reverting its direction, which potentiates the accumulation of freely diffusible DA in the extracellular space (Schmidt and Gibb, 1985; Sulzer, 2011; Sulzer and Rayport, 1990; Volz et al., 2007). Similar to what occurs in the animal and human METH-addicted brain, reduced DAT expression was detected in animal models and subjects with psychiatric disorders or PD (Wilson et al., 1996; Miller et al., 1999; Kitamura, 2009; McCann et al., 2008; McFadden et al., 2012; Markota et al., 2014; Purves-Tyson et al., 2017; Volkow and Morales, 2015; Chang et al., 2020). METH-induced impairment and downregulation of DAT lead to unusually high extracellular DA levels, which produces synaptic effects at both short and long-distance through a volume transmission (Fuxe et al., 2010).

    View all citing articles on Scopus
    View full text