Scientific Papers

Cytokine levels reflect tic symptoms more prominently during mild phases | BMC Neuroscience

Our study strived to investigate the cytokine networks of tic disorder patients. The established literature recognizes the influence of psychotropic medication, particularly antipsychotics, on cytokine levels. We introduced a washout period to minimize such effects. The main regimens used to treat tic disorders in Korea are aripiprazole and risperidone. Aripiprazole has an elimination half-life of 75 h (94 h for its active metabolite), and risperidone has an elimination half-life of 22 h [24, 25]. Based on this information and past studies we considered three weeks to be sufficient for a washout period [26, 27]. Fortunately, only one patient with above moderate tics was taking 15 mg of aripiprazole prior to participation, which was stopped three weeks before assessments.

This study revealed that tic disorder patients and healthy controls show different cytokine profiles. Particularly, patients with mild tic symptoms showed lower IL-1β levels than those of controls. The exact pathway by which IL-1β may affect in tic disorder is also not well known, and past literature on the association between tic disorder and IL-1β show mixed results [15, 16]. However, some studies suggest that inflammatory cytokines including IL-1β may modulate tryptophan metabolism, leading to over-production of toxic metabolites, further leading to abnormal responsiveness to stress [28, 29]. Our study also showed that the YGTSS scores of mild tic patients correlated with the levels of various cytokines: GM-CSF, IL-4, IL-8, IL-12 p40, and TNF-α levels exhibited positive correlations, whereas IL-12 p70 and IL-17a levels exhibited negative correlations. Previous studies have investigated the relationship between tic disorders and cytokines to identify the cytokines that play key roles. A recent research by Tao et al. compared tic disorder patients with controls, determining that patients had higher levels of IL-6 while levels of IL-2, IL-4, IL10, TNF-α, and IFN-γ were lower than controls [18]. Leckman et al. also compared tic disorder patients and healthy controls, showing that the patients had elevated IL-12 and TNF-α levels [30]. A recent meta-analysis summarizing 25 studies also identified small-to-large effect sizes for increased IL-6 levels and a large effect size for increased TNF-α levels in tic disorder patients [31]. Additionally, although not directly about tic disorders, some studies found that OCD patients, which is comorbid with tic disorder, have increased monocytes compared to healthy controls, which in turn release more cytokines including GM-CSF, IL-1β, IL-6, IL-8, and TNF-α [10, 32]. Parker-Athill showed that TNF-α levels were associated with tic symptom exacerbation [17]. A Chinese study on 1724 tic disorder patients also showed that TNF-α among other cytokines increased in levels as symptoms get more severe, although statistical significance was not reached [18].

The above-mentioned studies as well as ours suggest that TNF-α plays a significant role in the etiology of tic disorder. The results of previous studies vary widely. In fact, a recent meta-analysis failed to identify specific cytokines that are significantly associated with Tourette disorder [4]. More comprehensive research on large datasets is necessary to eliminate possible confounding factors and to identify reliable neuroinflammatory biomarkers for tic disorders.

The fact that only patients with mild tic symptoms showed significant results is probably the most important finding of this study. This is not the first study to demonstrate that patient subgroups with different symptom severities exhibit different cytokine profiles. A previous study by Parker-Athill observed patients during the symptom exacerbation and remission phases [17]. Higher TNF-α levels were associated with antipsychotic use during exacerbation phases while increased IL-4 levels were associated with antipsychotic and antibiotic use during remission phases. Another recent study also divided tic disorder patients into minimal, mild, and moderate-to-severe symptom groups, where only the mild symptom group showed increased TNF-α levels [33]. Tao et al. also pointed out that patients with mild symptoms (YGTSS scores below 10) IL-4, IL-10, and IFN-γ levels were significantly lower in medicated patients than in unmedicated patients whereas moderate and severe symptomatic patients did not show differences [18].

These results raise the following fundamental question: Do cytokine levels change with the progression of tic disorders? Tic disorders typically wax and wane in symptom severity over time. Researchers have suggested that severe symptoms are associated with increased neuroinflammatory reactions. Our results suggest that this phenomenon might not be simple, as correlations between cytokine levels and symptom severity were more relevant during the mild or remission phases. Neuro-inflammatory reactions could have “brewed up” during remission phases and quickly reach a stable state as symptoms still developed, thus resulting in no significant correlations during the exacerbation phase. In addition, it is imperative to note that the mild and above moderate tic groups not only significantly differ in the severity of symptoms but also in age and the duration until visit. The fact that the mild tic group is younger, and that the above moderate group has persisted a longer period without treatment might also elucidate the disparities in their cytokine profiles. Future studies on the early exacerbation phases of tic disorders could shed light on possible neuroinflammatory biomarkers of the disease.

Investigating the neuroinflammatory perspective of tic disorders, it was postulated that the temporal duration of experienced inflammation without medical interventions might be of significance. This length of time could have influenced attributes like reactivity of cytokine profiles, thereby potentially modulating the manifestation and progression of the disorder. Unfortunately, despite our investigation, our study did not yield evidence to substantiate this hypothesis.

Our study had a few limitations. First, only 66 participants were included. A larger sample size would have provided more reliable results. Second, we attempted to gather information about the initial onset of tic symptoms to calculate the duration of tic disorder; however, most patients and guardians could not remember the exact time and provided only approximate answers on the year the symptoms emerged. This is probably because most tic symptoms start in a subtle manner, and patients are usually too young to remember the exact moment. We used this information for our analysis, but the results were limited and inaccurate. More precise data on the initial onset and recent aggravation of the disease are necessary in future studies to identify the exact exacerbation and remission phases. Third, our samples were taken throughout the course of tic disorder, but it remains ambiguous whether the observed changes are a precursor or a result of the disorder’s manifestation. Future cohort studies regarding the onset of the disorder would potentially provide further insight to this issue. Fourth, we chose to analyze cytokines that repeatedly demonstrated significant results in previous studies and selected a kit that could investigate as many of these as possible, but it is undeniable that financial constraints were presents during this decision-making process. We hope that future research will allow to analyze a broader array of cytokines, thereby yielding more comprehensive results than those obtained in the present study.

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