Changes in interleukin-1 beta induced by rTMS are significantly correlated with partial improvement of cognitive dysfunction in treatment-resistant depression: a pilot study

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Highlights

  • Repetitive transcranial magnetic stimulation (rTMS) for the treatment of depression

  • rTMS significantly improved depressive symptom scores

  • rTMS significantly improved some subscales of cognitive dysfunction

  • Changes in cognitive function and changes in IL-1β were significantly correlated

Abstract

The impairment experienced by many individuals with depression is closely related to the cognitive symptoms of the disorder. Repetitive transcranial magnetic stimulation (rTMS) is a noninvasive brain stimulation method that provides a promising technique for improving cognitive symptoms in treatment-resistant depression (TRD). It has recently been demonstrated that TRD is associated with increased inflammatory process. In the present study, we investigated whether a relationship exists between changes in cognitive function and those in inflammatory cytokines before and after rTMS treatment. Eleven patients with TRD were enrolled in a high-frequency (10 Hz) rTMS study. Cognitive function, depressive symptoms and serum concentration of inflammatory cytokines (interleukin (IL)-1β, IL-6 and tumor necrosis factor-α) were measured at baseline and at the endpoint of rTMS treatment. rTMS treatment significantly improved depressive symptom scores and some subscales of cognitive dysfunction. The present study has demonstrated that partial changes in cognitive function and changes in IL-1β were significantly correlated. The partial improvement of cognitive dysfunction by rTMS in the present study might be attributable to the reduction of peripheral IL-1β levels. The present results should be replicated for verification in future studies.

Introduction

The impairment experienced by many individuals with depression is closely related to the cognitive symptoms of the disorder (Culpepper et al., 2017). Cognitive impairment affects several spheres of functioning, including employment, social life, family life, and home responsibilities (Culpepper et al., 2017). A shorter duration of untreated depression is associated with more favorable outcomes including depression-related psychosocial impairment (Ghio et al., 2015). Depression and its associated cognitive impairment may even be linked to enhanced suicide risk. The emotional turmoil of survivors of individuals who commit suicide may last a long time, and in some cases, may end with their own suicide (Pompili et al., 2013). Specific biological factors, such as prolactin and thyroid hormone levels, may be dysregulated and significantly associated with suicide attempts. These biological factors are also involved in a complex compensatory mechanism to correct reduced central serotonin activity (Pompili et al., 2012). Several neuropsychological studies have demonstrated that cognitive deficits are present across a broad range of cognitive domains in depression, including executive function. Executive function deficits associated with frontal lobe dysfunction are reported to be prominent among depressed patients (Fossati et al., 2002). Repetitive transcranial magnetic stimulation (rTMS) is a noninvasive brain stimulation technique that is considered valuable and promising for improving cognitive symptoms in treatment-resistant depression (TRD) (Serafini et al., 2015; Pallanti et al., 2012; Guse et al., 2010).

Patients with major depression have been found to exhibit increased peripheral blood inflammatory biomarkers, including inflammatory cytokines (Miller et al., 2009). The association of inflammation with major depression disorder has been a viable hypothesis for over a decade (Miller et al., 2009). The inflammatory process has also been reported to be involved in the pathophysiology of depression in a recent systematic review and meta-analysis (Horn et al., 2018). It has recently been demonstrated that TRD is associated with an increased inflammatory process (Strawbridge et al., 2019; Haroon et al., 2018). TRD patients had higher levels of numerous inflammatory proteins than controls, and elevated interleukin (IL)-6 and 8, tumor necrosis factor (TNF), c-reactive protein (CRP) and macrophage inflammatory protein-1 were associated with poorer treatment outcomes (Strawbridge et al., 2019). Haroon et al.’s study (2018) demonstrated that a significant relationship was found between the number of failed treatment trials and TNF, soluble TNF receptor 2 (sTNF-R2) and IL-6. Post hoc pairwise comparisons with correction for multiple testing revealed that patients with three or more failed trials in the current episode had significantly higher plasma TNF, sTNF-R2 and IL-6 compared with individuals with 0 or 1 trial (Haroon et al., 2018). High sensitivity CRP was also associated with a greater number of treatment failures, but only in models with the body mass index excluded (Haroon et al., 2018).

Cytokines might impact cognition in various mechanisms. To date, the majority of studies investigating mechanisms by which cytokines contribute to cognitive impairment have focused on the role of IL-1, IL-6 and TNF-α (Misiak et al., 2018). Recent reports indicated that an enhanced inflammatory process leads to attenuation of functional brain connectivity, which is closely related to cognitive dysfunction (Nusslock et al., 2019; Yin et al., 2019; Mehta et al., 2018). To the best of our knowledge, no previous reports have examined the relationship between the therapeutic effect of rTMS on cognitive dysfunction and changes in inflammatory cytokines in depression. We hypothesize that there is a relationship between changes in cognitive function by rTMS and those in inflammatory cytokines in depression. Thus, we examined the correlation between changes in cognitive function and those in inflammatory cytokines before and after treatment with rTMS.

Section snippets

Methods

The present study was an exploratory study of TRD patients without a control group. The present study was approved by Saga University Clinical Research Review Board (Japan Registry of Clinical Trials, jRCTs072180045) and written informed consent was obtained from all the patients.

Participant characteristics

Eleven participants completed the present study, all of whom voluntarily agreed to take part. All patients were naive to rTMS prior to this study. The age range was 28 to 72 years, with an average age of 52.2 years (SD = 15.3 years). The average number of antidepressants used was 3.2 (SD =1.8). The average number of anti-inflammatory drugs used was 0 (SD =0). All participants were Japanese. Participant characteristics by group are reported in Table 1.

Changes in depressive symptoms and cognitive function induced by rTMS

The mean HAM-D score before rTMS was 21.36 ±

Discussion

rTMS treatment significantly improved HAM-D, BDI, the TE of WCST, the category of WFT and part 3 of the CST scores. Although serum IL-1β, IL-6, and TNF-α did not show any significant change, serum IL-1β showed a decreasing tendency. The improvement of part 3 of the CST scores and the decrease of serum IL-1β showed a significant correlation. In rTMS responders (n = 5) or rTMS non-responders (n = 6), rTMS treatment did not significantly improve any cognitive dysfunction. In rTMS responders

Conclusion

The present study has demonstrated that partial changes in cognitive function and changes in IL-1β were significantly correlated. The partial improvement of cognitive dysfunction by rTMS in the present study might be attributable to the reduction of peripheral IL-1β levels. The present results should be replicated for verification in future studies.

Funding

This work was supported by the Japan Society for the Promotion of Science (JSPS KAKENHI Grant Number 17K10307).

Author contributions

Dr. Tateishi and Dr. Monji created the concept and designed and supervised the study. Dr. Maekawa guided Dr. Tateishi in rTMS treatment. Dr. Tateishi acquired, analyzed, and interpreted data. Dr. Kawaguchi performed statistical analysis. Dr. Matsushima acquired the cognitive function data. Dr. Mizoguchi, Mr. Imamura and Ms. Kunitake measured inflammatory cytokines. Dr. Tateishi drafted the manuscript. Dr. Mizoguchi, Dr. Murakawa, Dr. Haraguchi, Dr. Kunitake, Dr. Kato and Dr. Asami reviewed and

Declaration of Competing Interest

The authors declare that they have no conflict of interest to report.

Acknowledgements

The authors are grateful for the assistance given by Clinical Research Center for Saga University Hospital.

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