Longitudinal bidirectional relationships between maternal depressive/anxious symptoms and children’s tic frequency in early adolescence

26 Background: Previous studies have revealed an association between maternal depressive/anxious 27 symptoms and children’s tics. However, the longitudinal relationships between these symptoms 28 remain unclear. We examined the longitudinal relationships between maternal depressive/anxious 29 symptoms and children’s tic frequency in early adolescence with a population-based sample. 30 Maternal Depression And Children’s Tic 2 Methods: The participants consisted of 3,171 children and their mothers from the Tokyo Teen Cohort 31 (TTC) study, a population-representative longitudinal study that was launched in Tokyo in 2012. 32 Maternal depressive/anxious symptoms and children’s tics were examined using self-report 33 questionnaires at the ages of 10 (time 1, T1) and 12 (time 2, T2). A cross-lagged model was used to 34 explore the relationships between maternal depressive/anxious symptoms and children’s tic 35 frequency. 36 Results: Higher levels of maternal depressive/anxious symptoms at T1 were related to an increased 37 children’s tic frequency at T2 (β = .06, p < .001). Furthermore, more frequent children’s tics at T1 38 were positively related to maternal depressive/anxious symptoms at T2 (β = .06, p < .001). 39 Conclusions: These findings suggest a longitudinal bidirectional relationship between maternal 40 depressive/anxious symptoms and children’s tic frequency in early adolescence that may exacerbate 41 each other over time and possibly create a vicious cycle. When an early adolescent has tics, it might 42 be important to identify and treat related maternal depressive/anxious symptoms. 43


Introduction 45
Tics are sudden, rapid, recurrent, and nonrhythmic motor movements or vocalizations. The Diagnostic 46 and Statistical Manual of Mental Disorders, 5th edition (DSM-5) includes three tic disorders (1). 47 Tourette syndrome (TS) is defined by the presence of at least two motor tic behaviors and one vocal 48 tic behavior for a minimum period of a year, manifesting before the age of 18. Chronic tic disorder 49 (CT) is defined by the presence of either motor or vocal tics for at least 1 year, while provisional tic 50 disorder is defined as tics that have been present for less than a year. Recent population-based studies 51 have demonstrated that tics are more common than previously recognized (2-5). According to the 52 International Classification of Diseases 10th Revision (ICD-10), which is an international diagnostic 53 classification developed by the World Health Organization (WHO), one in five to ten children has 54 experienced tics (6). Tic disorders impose a psychosocial burden on children and their families because 55 tics are characterized by the visibility of symptoms, which can cause stigma and prejudice (7-10). 56 Attention-deficit/hyperactivity disorder (ADHD) and obsessive-compulsive disorder (OCD) are 57 common comorbidities of tic disorders (7, 11, 12). Tic disorders tend to be remitted with age through 58 adolescence (7, 13, 14). The overall similarity in these patterns of comorbidity and natural history 59 among tic disorders suggests that tic disorders have etiological continuity (15-17), and a recent 60 diagnosis of "tic spectrum disorders" has been suggested (18). Many clinical studies and experimental 61 studies historically use tic frequency on measures to assess severity at outcome (19-24). 62 Tic disorders consist of a complex involvement of both multiple genes and environmental 63 factors (25,26). Little is known about the exact brain mechanisms associated with tic development and 64 expression (27, 28), although preliminary evidence from neurochemical and neuroimaging 65 investigations suggests a primary role for dysfunction of the dopaminergic pathways within the cortico-66 striato-cortico-frontal circuitry (29-31). Environmental factors for tics include infection and 67 autoimmune dysfunction, maternal environment during pregnancy, and psychosocial stress (11, 28). It 68 has been suggested that psychosocial factors such as trauma and intense daily psychological stress may 69 be risk factors in individuals with genetic vulnerabilities to TS (11, 32). 70 The identification of parental psychopathology could be informative in the evaluation of risk 71 factors for the development of tic disorders in children (33). Previous research has shown that there is 72 an association between maternal psychiatric symptoms and children's tic disorders. Chronic maternal anxious symptoms and prenatal maternal depressive symptoms have been associated with increased 74 odds of children having TS/CT at age 13 (34 We evaluated tic frequency at T1 and T2. The participants' primary parents answered a questionnaire 139 about the children's tics; this questionnaire has been used in a previous study (5). The questionnaire 140 includes a section with the following five questions about specific motor and vocal tics in the past year: 141 "Q1: Has your child had any repeated movements of parts of the face and head (e.g., eye blinking, 142 grimacing, sticking tongue out, licking lips, spitting)?"; "Q2: Has your child had repeated movements 143 of the neck, shoulder or trunk (e.g., twisting around, shoulder shrugging, bending over, nodding)?"; 144 "Q3: Has your child had repeated movements of the arms, hands, legs, or feet?"; "Q4: Has your child 145 had repeated noises and sounds (e.g., coughing, clearing throat, grunting, gurgling, hissing)?"; and 146 "Q5: "Has your child had repeated words or phrases?" Each question is answered as either "definitely", 147 "probably" or "not at all" present. Furthermore, we asked the following question about the frequency 148 of these repetitive behaviors: "Q6: About how often does/did this happen in the last year?" This 149 question was answered on the following 5-point Likert scale: "1: less than once a month, 2: 1-3 times 150 a month, 3: about once a week, 4: more than once a week, 5: every day." We defined the participants 151 who responded "definitely" or "probably" to any of Q1, Q2, and Q4 as having tics. The participants 152 who only endorsed repeated movements of the arms, hands, legs or feet (Q3) or repeated words or 153 phrases (Q5) in the absence of a positive response to the other questions about the types of tics (Q1, 154 Q2, Q4) were excluded from a case definition to remove nontic movements such as stereotypy or 155 isolated echolalia. We defined as tics all responses of "definitely" or "probably" to questions 156 concerning motor and/or vocal tics regardless of their frequency because there is no condition of 157 frequency in the diagnostic criteria of tic disorders (1) and because we aimed to exhaustively find tics 158 in the general population. For those without tics, the frequency of tics was regarded as 0, and for those 159 with tics, the frequency of tics was evaluated on a 5-point scale from the answer in Q6. 160 161

Maternal depressive/anxious symptoms 162
We employed the Kessler Psychological Distress Scale (K6) (39-41) for T1 and the General Health 163 Questionnaire-28 (GHQ-28) (42, 43) for T2. The K6 and the GHQ-28 are both widely used self-report 164 questionnaires that were developed to evaluate depressive/anxious symptoms. We used different scales 165 between T1 and T2 in the current study because the TTC study also switched the scale used for maternal 166 depressive/anxious symptoms from the K6 to the GHQ-28 starting at T2. The K6 is a short 167 questionnaire consisting of 6 questions about the subjective mental distress of the respondent over the 168 past 30 days that are answered on a 5-point scale, and the scores of the 6 items are added together (0-169 24 points). The GHQ-28 consists of 28 questions about the respondent's subjective physical and mental 170 states over the past few weeks, with a total score being calculated for each item by giving 0 points each 171 for the right two responses and 1 point each for the left two responses (0-28 points income was evaluated on an 11-point scale, which ranged from "0-990,000 yen" to "more than 186 10,000,000 yen." Information on maternal alcohol use during pregnancy was obtained from maternity 187 record books that were provided for almost all mothers by local public organizations in Japan. 188 189

Statistical analysis 190
Longitudinal relationships between maternal depressive/anxious symptoms and children ' We investigated the relationships between maternal depressive/anxious symptoms and children's tic 226 frequency in a cross-lagged model analysis (Figure 2, Table 2). There was a cross-sectional association 227 between maternal depressive/anxious symptoms and child's tic frequency at T1 and T2. Higher levels 228 of maternal depressive/anxious symptoms at T1 significantly increased children's tic frequency at T2 229 (adjusted model: β = .06, p < .001). In contrast, higher frequency of children's tics at T1 was related 230 to higher levels of maternal depressive/anxious symptoms at T2 (adjusted model: β = .06, p < .001). 231 All of these models indicated good model fit to the data (adjusted model: CFI = .950, RMSEA = .046). 232 These results revealed that maternal depressive/anxious symptoms and children's tic frequency had 233 longitudinal, bidirectional relationships with each other. 234 235

Discussion 236
This was the first study to examine the longitudinal relationships between maternal depressive/anxious symptoms and children's tic frequency in a population-based early adolescent sample. which can lead to family conflicts, poor parent-child relationships and increased frustrations in 284 parenting (7, 9, 10, 69, 70). Parenting stress in parents of children with tics could also occur due to 285 children's comorbidities, such as ADHD, OCD, and behavioral problems (67, 68). In a previous 286 population-based study, 21.2% of children had tics, and children with tics were more affected by 287 psychopathologies, including ADHD and OCD, than were children without tics (12). In addition to 288 these environmental factors, both genetic factors and genetic/environmental interactions might have an 289 effect of children's tics on maternal depressive/anxious symptoms. 290 The implications of this study were that the longitudinal bidirectional relationships between 291 maternal depressive/anxious symptoms and children's tic frequency may suggest a vicious cycle in 292 which maternal depressive/anxious symptoms make tic frequency increased, and children's tic 293 frequency make maternal depressive/anxious symptoms worse. This study also suggested that not only 294 intervention in children's tics but also intervention in maternal depressive/anxious symptoms might be 295 important for the treatment of tics. However, the present study was unable to separate genetic and 296 environmental factors in the association between children's tic frequency and maternal 297 depressive/anxious symptoms; therefore, further research is needed to determine the effect of 298 intervention on maternal anxiety/depressive symptoms. While there has been a consensus on the 299 importance of family psychoeducation in the treatment of tics (7, 27), it is not known whether maternal 300 psychiatric problems influence the course of children's tics. This study provides new insights for future 301 research and practice. 302 The strength of this study was that, for the first time, it was shown that higher levels of 303 maternal depressive/anxious symptoms are related to an increased children's tic frequency two years 304 later and that there are longitudinal relationships between maternal depressive/anxious symptoms and 305 children's tic frequency. Other strengths were the large sample size, the high follow-up rate of the 306 study, and the inclusion of nonclinical tics. In contrast, this study also had several limitations. First, we 307 used different measures of maternal depressive/anxious symptoms for T1 and T2. We found that the 308 distributions of the K6 and the GHQ-28 were similar by graphing the cumulative distribution of the Z 309 scores of the K6 and the GHQ-28 (Supplementary Figure 1). Additionally, this limitation did not 310 influence the course from maternal depressive/anxious symptoms to children's tic frequency. Second, 311 in this study, children's tics were evaluated not by direct clinical assessments but by questionnaires to 312 caregivers. However, we deliberately chose rigorous tic definitions and sought to exclude participants 313 with nontic movement disorders (e.g., stereotypies associated with autism or an intellectual disability, 314 repetitive arm/leg movements that could be better explained by tremor or motor restlessness) (5). In 315 this study, the prevalence of tics was 23.3% at age 10 and 23.5% at age 12. These prevalence rates 316 could be considered reasonable based on the following evidence. Point prevalence depends strongly 317 on age; the highest rate is estimated to be approximately 20% at age 5-10, and the lifetime prevalence 318 is much higher (3). In previous studies that have directly observed children, tics were found in 29.2% 319 of fourth-grade children in an elementary school in Washington D.C.
(2) and in 21.2% of children aged 320 9-17 years old (mean 13.1 years old) in Monroe County, Rochester, New York (4). The prevalence 321 rates of tics in the present study were consistent with those found in these previous studies. Third, the 322 data analysis in this study could not adjust for ADHD and OCD, which are frequently comorbid with 323 tics. That may be because of the strong association of tics with ADHD and OCD. Future studies are 324 needed to examine the effects of ADHD and OCD on the bidirectional relationships between maternal 325 depressive/anxious symptoms and children's tic frequency. The fourth limitation was that the research 326 interval in this longitudinal study was relatively short. Typically, tics improve gradually during 327 adolescence, with repeated periods of remission and exacerbation. Thus, it might be difficult to capture 328 change in the short research period of two years. Longer-term follow-up periods are needed in the 329 future. The fifth limitation was that we did not collect information about the maternal history of tics. 330 Given the low rate of medical consultation for tics (5, 12, 65) and the clinical outcome that tics often 331 improve or disappear after adolescence (7, 13, 14), it is probably not possible to obtain accurate 332 information on the maternal history of tics. Finally, there were also some limitations inherent to the 333 cross-lagged model (71); i.e., there is a possibility that there are multiple potential additional factors 334 (not included in the model) that influence the bidirectional relationship over time. 335 The following two studies would be helpful in testing the viability of the relationships 336 between maternal depressive/anxious symptoms and children's tic frequency and in advancing research 337 and practice.    Abbreviations: T1, 10 years of age; T2, 12 years of age; β, standardized coefficient; B, coefficient; SE, standard error; CI, confidence interval; CFI, comparative fit index; RMSEA, root mean square error of approximation.  Table 2.  567 Paths from covariates are omitted from the figure. Abbreviations: e, error variable; T1, 10 years of 568 age; T2, 12 years of age. *** p < .001 569   Cross-lagged model of relationships between maternal depressive/anxious symptoms and children's tic frequency. Note: This gure shows the results of the adjusted model in Table 2. Paths from covariates are omitted from the gure. Abbreviations: e, error variable; T1, 10 years of age; T2, 12 years of age. ***p < .001

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