Introduction

Schizophrenia is a neurodevelopmental disorder impacting multiple brain system. The thalamus has been of prime interest as a site of pathology in this illness as it constitutes of major relay station via cortical and sub-cortical connections and is known to play a major role in higher order cognition and emotional processing (Andreasen, 1997; Cronenwett & Csernansky, 2010; Dorph-Petersen & Lewis, 2017; Ferri et al., 2018; Pergola, Selvaggi, Trizio, Bertolino, & Blasi, 2015; Sherman, 2004; Wagner et al., 2015).

While thalamic alterations have been reported in schizophrenia patients, the degree to which these are treatment and disease related remains uncertain. In this study, we evaluated volumes different thalamic nuclei in antipsychotic naïve and antipsychotic treated long-term ill schizophrenia patients respectively and compared them with age and sex matched healthy controls.

Methods

This study included 58 schizophrenia patients and 30 healthy comparison subjects from West China Hospital of Sichuan University. For patient group, inclusion required presentation of psychosis for 5 years or more, and a diagnosis of psychotic disorder according to DSM-IV criteria. For untreated group, inclusion required never exposure to antipsychotic medication, and for treated group, inclusion required previous exposure with antipsychotics for ≥5 years.
MRI examinations were performed on a 3-T GE Signa EXCITE scanner (General Electric, Milwaukee, Wis.) with an eight-channel phase array head coil. We used FreeSurfer based (http://surfer.nmr.mgh.harvard.edu) probabilistic atlas for the parcellation of the thalamus into different nuclei, using a probabilistic atlas built with histological data (Iglesias et al., 2018). For each hemisphere we performed statistical analyses on the nuclei in the template that were more than 20 mm3 in volume to enhance conviction regarding reliability and validity of findings.
All statistical analyses were performed using SPSS software (http://www.spss.com), version 22.0. Demographic variables (e.g., age, gender, education) and clinical characteristics (i.e., medications and PANSS scores) were compared among groups via one-way analysis of variance (ANOVA), two-sample t tests or chi square tests.

Results

Analyses of volumes of individual nuclei revealed group differences in volumes in intralaminar (left central medial) F(2,88) = 6.501, p = 0.021, η2 = 0.134, and (left parafascicular) F(2,88) = 7.729, p = 0.016, η2 = 0.155, and posterior (left pulvinar lateral) F(2,88) = 6.175, p = 0.021, η2 = 0.128 nuclei. Post hoc tests showed significantly larger volumes of left central medial, left pulvinar lateral and left parafascicular in AT-CHR when compared with both AN-CHR and controls [figure1]. No alterations were identified in the never treated group relative to healthy controls.
Whole volume of right (F=.988, p =.376) and left (F=.114, p =.892) thalamus did not differ significantly between AN-LTS, AT-LTS and control group.
No correlation was observed between volume measures and current symptoms severity as reflected in PANSS scores, duration of illness or medication dose in both antipsychotic naïve and treated schizophrenia patients
The treated chronically-ill schizophrenia patients had a significant association between greater age and less volume in the left central medial nucleus, but no significant relationship with age was found in left pulvinar lateral and left parafascicular nuclei.

Discussion

The results from current study provides critical evidence about the thalamic structural integrity, and how this important sub-cortical structure responsible for various sensory and emotional processing along with regulation of motor functions is shaped during long-term illness and its response to antipsychotic use for long period in schizophrenia patients. Although previous studies have suggested thalamic abnormalities during the early stages of illness (Coscia et al., 2009; Gilbert et al., 2001), our result suggests no changes of thalamic volumes in patients with long standing illness. The possibility is that, thalamic nuclei might undergo volumetric recovery if it persists for longer period. As no changes in thalamic volumes were observed in antipsychotic naïve patients, it could thus be reckoned that thalamic nuclei might undergo self-remodeling if the illness persists for longer duration via compensatory structural changes to counterbalance likely functional deficits in the overall thalamic networks during the early course of the illness (Crespo-Facorro et al., 2007).
Another important finding form this study on long term ill schizophrenia patients is the observation of increased thalamic volumes in treated schizophrenia patients. Increases in volumes were mainly observed in intralaminar group and posterior thalamic nuclei on the left side of the thalamus, which consisted of left central medial, left parafascicular and left pulvinar lateral nuclei.
Although it is still not ascertained what these increases in thalamic volumes could confer on functional outcomes in schizophrenia patients, it however suggests that long term antipsychotic treatment could reverse the thalamic changes observed during the early stages of the illness.

Conclusion

By studying a rare group of chronically ill antipsychotic naïve along with duration and age matched treated schizophrenia patients; we were able to provide evidence on structural integrity of the thalamic nuclei where we demonstrated that never treated long term ill patients were devoid of thalamic changes, whereas long term antipsychotic treatment was associated with increases in left central medial, left pulvinar and left parafascicular nuclei volumes. The findings provide a conceptual understanding on thalamic nuclei architecture in chronically ill schizophrenia patients without the confounding effects of antipsychotics along with their long-term consequences, which could be instrumental in stage-specific diagnosis and treatment outcomes.

Acknowledgements

This study was supported by National Natural Science Foundation of China (Grant Nos. 81671664, 81621003). Dr Lui would also like to acknowledge the support from Chang Jiang Scholars (Award No. Q2015154) of China and National Program for Support of Top-notch Young Professionals (National Program for Special Support of Eminent Professionals, Organization Department of the Communist Party of China Central Committee, Award No. W02070140).

References

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