Altered functional connectivity of the thalamus induced by modified electroconvulsive therapy for schizophrenia
Introduction
Schizophrenia (SZ) is a common devastating psychotic disorder with onset usually in late adolescence or early adulthood, which has dramatic disability rate, morbidity and financial consequences (Lewis and Sweet, 2009; Owen et al., 2016). Some researchers considered it to be a state of ‘fractured mind’, with many researchers refining this definition in terms of pathological alterations in brain connectivity (Chen et al., 2017; Dong et al., 2017; Garrity et al., 2007; Jiang et al., 2017; Skudlarski et al., 2010).
The mainstay of treatment for SZ has been antipsychotic medication, but for one third of individuals this treatment is insufficient and they must be labeled as ‘treatment refractory’. Physical stimulation treatments provide an alternative and compensatory approach to antipsychotic therapy. Electroconvulsive therapy (ECT) was initially developed as a treatment for SZ (Takebayashi, 2013), and has exhibited significant efficacy and safety for patients with severe mental illness including SZ and major depression disorder (MDD). In eastern nations such as India, China, parts of Africa, and other developing countries, ECT is often viewed as a first-line treatment of severe psychosis when symptoms require hospitalization, even following the introduction of first- and second-generation antipsychotics (Rosenquist et al., 2014), due to its rapidly reducing clinical symptoms. Despite the utility of ECT, there remain a number of individuals who do not show a clinical response to the treatment. Therefore, it is necessary to clarify the underlying mechanisms of the action of ECT to help identify patients who may respond best to ECT and better guide clinical practice.
The thalamus plays an important role in the processing and integration of information (Edward, 2007). The thalamus has recently received renewed interest in systems-neuroscience and SZ research because of emerging evidence highlighting its key role in coordinating functional interactions in cortical-subcortical circuits (Duan et al., 2015; Pratt et al., 2017). Converging neuroimaging investigations have revealed considerable thalamic abnormalities in SZ, decreased grey matter volume (Glahn et al., 2008a; McCarley et al., 1999; Okada et al., 2016; Shenton et al., 2001), disordered activity during cognition (Minzenberg et al., 2009), and diminished expression of biochemical markers of neuronal integrity such as N-acetyl aspartate (NAA) (Kraguljac et al., 2012) are included. In addition, several research groups have sequentially reported abnormal thalamic functional connectivity in SZ (Atluri et al., 2015; Klingner et al., 2014; Lerman-Sinkoff and Barch, 2016; Tu et al., 2015; Wang et al., 2015). Diminished prefrontal cortex (PFC)-thalamic connectivity and increased somatomotor-thalamic connectivity have been relatively consistent findings (Giraldo-Chica and Woodward, 2017). Disturbed thalamic functional connectivity in SZ could supply a core pathophysiological mechanism for cognitive deficits and certain symptoms (Anticevic et al., 2014; Ferrarelli et al., 2012; Lisman, 2012; Pinault, 2011; Pratt et al., 2017). Some studies have demonstrated correlations of thalamic functional activity to clinical psychopathology. Anticevic et al. found that mean over-connectivity of sensory-motor regions to the thalamus correlated positively with PANSS total score (Anticevic et al., 2014), while Cheng et al. observed frontal-thalamic hypoconnectivity related to negative symptoms in SZ (Cheng et al., 2015).
Neuroimaging has long been utilized to provide a measure of the effects of ECT on brain structure and function as well as to better understand its mechanisms of action (Nobler et al., 2000). Recent emerging rodent and non-human primate studies have linked brain plasticity to the action of electroconvulsive stimulation (ECS), an analogue of ECT in animal models. Human studies with ECT have found similar results although the human data are based on relatively few patient groups. Brain structural and functional connectivity relating to the frontal cortex (Madsen et al., 2005) and the medial temporal lobe (Hellsten et al., 2004; Newton et al., 2003; Perera et al., 2007) has been the most reported brain regions involved in the brain plasticity in populations with SZ treated with ECT. In a recent publication, based on the same presented dataset, we observed an increased global functional connectivity density in the default mode network (DMN) including the dosal medial prefrontal cortex (dMPFC), ventral medial prefrontal cortex (vMPFC) and left precuneus for SZ patients after 4-week ECT in conjunction with antipsychotics, a pattern which was not identified in the patients taking antipsychotics alone.
Several studies have reported functional connectivity change of some brain network involving mediodorsal thalamus after ECT in MDD (Leaver et al., 2016). Despite the rise of studies implicating the thalamus in both SZ and efficacious treatment, few studies have detailed the change of functional connectivity within the thalamus induced by ECT in SZ populations. It was worth noting that recent research has proposed that modified ECT (mECT) may significantly raise NAA concentration, an indicator of neural structural and/or functional integrity, in the left PFC and left thalamus among individuals with ECT-treated SZ in contrast to those treated solely with antipsychotics (Gan et al., 2017). Accordingly, we hypothesized that ECT could enhance the functional connectivity of thalamus with subcortical structure or reduce the functional connectivity of thalamus with cortical structure that might be relative to the effect on clinical symptomology. In this study, we designed a parallel contrast cohort including two SZ groups with one group only taking antipsychotic and another receiving mECT in combination with antipsychotics to determine the underlying mechanism of mECT.
Section snippets
Subjects
In this nonrandom observational study, 42 inpatients with SZ were divided into two groups according to their treatment strategy. In this current study, patients are considered to be medication-refractory if they do not respond to two or more adequate antipsychotic trials in the past five years (Kane et al., 1988; Wimberley et al., 2016). Those patients were prescribed mECT therapy if they were diagnosed as drug-refractory and elected for the course of treatment. Thus, one patient group received
Demographic and clinical data
The detailed demographic and clinical data of all subjects are shown in Table 1. The two patient groups show no significant difference in terms of age, gender, years of the education, duration of illness, or daily antipsychotic medication dosage during this study. Additionally, the MSZ and DSZ groups did not show any significant group differences in mean framewise displacement (FD) values or PANSS scores at baseline and after 4-week treatment.
Functional connectivity analysis: differences between two patient groups at baseline
At baseline, there was no significant difference
Discussion
The advantage of this study is that including a patient control group taking only antipsychotics contrasting to a patient group receiving mECT combined with antipsychotics, which is important to further clarify the mechanism underlying the ECT for SZ. This is also the first study using ROI approach targeting the thalamus, specifically sub-regions of thalamus to investigate the change of functional connectivity induced by ECT in SZ populations. Contrasting to decreased functional connectivity of
Limitation
There are several limitations in our study. Firstly, the usage of antipsychotics medicine might be a confounding factor due to substantial heterogeneity in pharmacological treatments employed in both patients groups. Variations in antipsychotic usage may also introduce variability in terms of the interaction between mECT and specific drugs, further confounding an already diverse disease. Changes here ascribed to mECT, may therefore in part embody these interactions instead. Secondly, the
Conclusions
Significantly enhanced thalamic-putamen functional connectivity and reduced thalamic-sensory cortex connectivity were observed in SZ patients treated with mECT in combination with antipsychotics compared to those undergoing antipsychotic therapy alone. These findings indicate that changes to the functional connectivity of the thalamus might be relevant to mechanisms underlying the effect of mECT.
Authors' contributions
Junjie Wang who was the first author contributed to the data acquisition and writing of the first draft manuscript.
Yuchao Jiang who was the co-first author contributed to the data analysis and manuscript writing.
Yingying Tang who was the co-corresponding author contributed to the experimental design, data acquisition and interpretation of the results.
MengQing Xia, Jin Li, Jianhua Sheng, Tianhong Zhang,Li Hui,Hongliang Zhu all contributed to the recruitments of and clinical assessments.
Chunbo
Role of funding source
This research was supported by Ministry of Science and Technology of China, National Key Research and Development Program of China (2016YFC1306800); National Nature Science Foundation of China (81361120403, 81671332, 81671329, and 81871050); Shanghai Science and Technology Committee, China (16JC1420200 and 17411953100); Clinical Research Center at Shanghai Mental Health Center (CRC2018ZD01, CRC2018ZD04, CRC2018YB01 and CRC2019ZD02); and Natural Science Foundation of Shanghai, China (17ZR1424700
Declaration of competing interest
The authors report no conflicts of interests.
Acknowledgments
The authors would like to thank all the patients and healthy subjects for participation in this study.
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