1. Top of page
  2. Abstract
  3. Method
  4. Results
  5. Discussion
  6. Acknowledgements
  7. References


To determine whether post-injury depressive symptoms, and pre-injury major life stressors and genetic factors (HTR1A C(-1019)G alleles; rs6295) are more common in children with mild traumatic brain injury (mTBI) who develop postconcussion syndrome (PCS) symptoms compared with children with asymptomatic mTBI.


This was a cross-sectional study of 47 symptomatic children (32 males, 15 females; mean age 14y [SD 3y 3mo]) who experienced post-concussive symptoms for 7 or more days and 42 asymptomatic children (26 males 16 females; mean age 13y 6mo [SD 3y 1mo]) after mTBI. Outcome measures were the Postconcussion Symptoms Inventory (PCSI), the Children's Depression Inventory (CDI), standard questionnaire of previous life events, and buccal DNA analysis to determine genotype and allele frequencies for the HTR1A C(-1019)G polymorphism.


Depressive symptoms were uncommon. CDI scores did not differ between groups. Allelic and genotypic frequencies for HTR1A C(-1019)G were similar in both groups. Symptomatic children continued to have elevated PCS scores compared with asymptomatic children 1.72 (SD 0.69) years later and had experienced significantly more life stressors (Wald (1)=8.51, p=0.004).


HTR1A polymorphisms do not differ in children with PCS. Children who have experienced more significant life stresses are more likely to develop PCS symptoms after mTBI.


Children's Depression Inventory


Life Events Scale for Children


Mild traumatic brain injury


Postconcussion syndrome


Postconcussion Symptoms Inventory


Stressful Life Events Questionnaire

Traumatic brain injury (TBI) is the most common cause of neurological morbidity, occurring more frequently in childhood and adolescence than at any other time of life.[1, 2] By the age of 16, as many as one in five children will experience a mild traumatic brain injury (mTBI), and in the USA, an estimated 799 out of 100 000 children under 14 years visit the Emergency Department with mTBI every year.[1, 2] The current literature suggests that significant morbidity is associated with mTBI in children due to postconcussion syndrome (PCS).[3-5] Persistent PCS symptoms (>3mo) occur in 11% of children and include physical (i.e. headaches, nausea, dizziness, double vision), cognitive (i.e. difficulties with attention, concentration, thinking speed, and memory), and mood (i.e. irritability, sadness, nervousness, sleep difficulties) changes.[4-6]

Although the complex pathophysiology of mTBI is well described,[7, 8] there is considerably less pathophysiological evidence to explain prolonged PCS.[6] Preinjury factors including substance abuse, psychiatric problems, and life stresses have been associated with persistent PCS.[3, 4, 9-11] The lack of biological explanations for PCS together with the non-specific nature of PCS symptoms has led many researchers to question its validity, and to highlight the potential for misdiagnosis, especially where depression is present.[9]

Depression is common after TBI. One study found that 35% of adults were depressed after mTBI.[12] When present, depression is associated with more severe PCS symptoms and with poorer outcomes.[13] Similarly, children also have an increased prevalence of psychiatric disorders after TBI, with attention deficit and depressive disorders occurring most frequently.[2, 14-18] A family history of psychiatric problems is a risk factor for depression after pediatric TBI, although specific genetic determinants have not been identified.[16]

Further, previous negative childhood experiences are a risk factor for a major depressive disorder after exposure to a stressful event such as mTBI.[19]

A disturbance in the serotonin neurotransmitter system is a potential neuropathological substrate involved in depressive symptoms. Serotonin (5-HT) is a neurotransmitter associated with the regulation of mood, emotion, and stress. The frontal lobes are a major area of projection for the serotonergic system and injury to the left anterior frontal lobe is associated with depression after TBI.[20] A single nucleotide polymorphism (rs6295; NC_000005.9:g.63258565C>G) in the promoter region of the serotonin HTR1A gene results in two different alleles, C(-1019) and G(-1019). The G-allele has been associated with major depression and suicide.[21]

We sought to investigate the relationship between a specific genetic (HTR1A G(-1019) allele) factor, depression, childhood life stressors, and PCS after pediatric mTBI. We hypothesized that as TBI is associated with an increased incidence of depression, and that depression may be misdiagnosed as PCS, that children who have PCS after sustaining a mild TBI are more likely to carry the HTR1A G(-1019) allele, and to report more preinjury life stressors.


  1. Top of page
  2. Abstract
  3. Method
  4. Results
  5. Discussion
  6. Acknowledgements
  7. References


This was a cross-sectional, controlled cohort study. Participants were recruited between July 2005 and June 2007 from a prospective database consisting of 670 children (aged 0–18y) with mTBI without extracranial injury. mTBI was defined as a Glasgow Coma Score (GCS) of 13 to 15, loss of consciousness (LOC) or altered mental state lasting less than 20 minutes, absence of focal neurological deficits, and posttraumatic amnesia less than 24 hours. The database included 155 children with PCS who showed an objective increase in post-concussive symptoms 7 to 10 days after injury compared with preinjury symptoms, using the Postconcussion Symptoms Inventory (PCSI). Families of all children in the database were contacted by phone and invited to voluntarily participate in the study. Informed parent and child consents were obtained for all participants. The sample consisted of 47 children who had PCS symptoms (symptomatic) and 42 children who had no symptoms (asymptomatic) after mTBI. Participants were older than the database population (10.0 SD 5.1y vs 7.4 SD 5.6y, t(−3.9), p<0.001), but had the same sex distribution (59.5% male, p=1.0). Buccal DNA collection kits and questionnaires were mailed to all participating families between June and September 2008, 1 to 3 years (mean 1.73y) after the TBI. The kit contained a cytology brush and written instructions requiring patients to swab the inside of their mouth three times before depositing the brush in a sealable cryotube.

Outcome measures

Postconcussion symptoms inventory (PCSI)

The PCIS is a standardized questionnaire consisting of 26 symptoms and provides an overall rating of symptomatology based on parent report. It has a high level of internal consistency, alpha = 0.93.[22] Individual scores for each symptom (0–4), a total symptom score (0–104) and a ‘degree of difference from baseline’ score (0–4) were obtained. A change of two or more points in any symptom was considered clinically significant. The PCSI was initially administered to all database participants 7 to 10 days post injury to determine symptomatic versus asymptomatic groups. A second PCSI survey was administered to all study participants with all other questionnaires 1 to 3 years post injury (mean 1.73y).

Children's Depression Inventory (CDI)

The CDI is a self-report measure of depressive symptoms designed for children aged 7 to 17 years. The CDI is a validated, reliable measure that has been standardized on typical and clinical pediatric populations. Children of 7 years of age or older completed the surveys. Sum total scores were calculated. As a result of parental concern, one question about suicidal ideation was removed from all surveys. This has been done before, including in one of the major studies used to establish the validity and reliability of the test.[23]

Stressful Life Events Questionnaire (SLEQ)

The Stressful Life Events Questionnaire (SLEQ) was developed specifically for this population. This parent-report survey contained 10 questions about familial and personal stressors experienced in the child's lifetime. The content overlaps considerably with common standardized measures including the Life Events Scale for Children (LES-C), which assesses recent stressors (within 12mo).[24] Answers were scored by category as follows: Previous hospitalizations: none = 0, one = 1, two or more = 2; Life threatening illness: no = 0, yes = 1, details; Major illness: no = 0, yes = 1, details; Major accidents: no = 0, yes = 1, details; Episodes of physical force (physical abuse, physical assault by adult/sibling/peer resulting in significant injury [e.g. stitches, broken bone, severe bruising]): no = 0, yes = 1; Deaths: pet/friend/second-degree relative = 1 each, first-degree relative = 2 each; Life threatening illnesses of someone close: yes = 1 for each person; Break-ups in family: no = 0, yes = 1; Moving homes: no = 0, yes = 1; Changing schools in middle of school year: no = 0, yes = 1. A sum total score was calculated.


Genomic DNA was isolated using standard protocols in the Molecular Diagnostic Laboratory, Alberta Children's Hospital. Genotyping of the HTR1A C(-1019)G polymorphism was performed using a TaqMan assay (Applied Biosystems, Carlsbad, CA, USA), which utilizes two fluorescently, labeled probes to differentiate the two alleles. Allelic discrimination was determined using the Applied Biosystems 7900 Real Time PCR instrument and the manufacturer's Sequence Detection System software.

Statistical analysis

Normative distribution was determined using the Kolomogorov Smirnov test (age, time since injury, length of PCS, CDI, PCSI, and SLEQ total scores). For normally distributed data, the symptomatic and asymptomatic groups were compared using independent sample Student's t-test with two-tailed p values. A χ2 test and Fisher's exact test where appropriate, with two-sided p values, were used to analyze sex differences between the two groups. Logistic regression analysis was used for stressful life event data, correcting for age. Data were analyzed by using spss 17.0 (IBM Corporation, New York, USA). The level of significance was set at p value <0.05.

Ethical approval for this study was obtained from the University of Calgary conjoint health research ethics board.


  1. Top of page
  2. Abstract
  3. Method
  4. Results
  5. Discussion
  6. Acknowledgements
  7. References

Participants in this study included 47 symptomatic children (32 males, 15 females; mean age 14y [SD 3y 3mo]) who experienced post-concussive symptoms for 7 or more days and 42 asymptomatic children (26 males 16 females; mean age 13y 6mo [SD 3y 1mo]) after mTBI. Age, Ethnicity, and other clinical details of the participants is shown in Table 1. Five of 42 of children in the symptomatic group and none of the asymptomatic group were hospitalized (p<0.001). The symptomatic group experienced PCS symptoms for 110.7 (SD 85.6) days. The asymptomatic group had no increase in symptoms compared with baseline when telephoned at 11.2 (SD 4.2) days post injury. Outcome measures were collected at 1.72 (SD 0.69) years post injury, with similar timing between groups (p=0.19).

Table 1. Demographic characteristics and survey results of asymptomatic and symptomatic groups
 Asymptomatic n=42Symptomatic n=47 p
  1. aStatistically significant. bFor children from 7 to 17 years. PCSI, Postconcussion Symptoms Inventory; mTBI, mild traumatic brain injury.

Mean age in years (SD)13.6 (3.1)14.0 (3.3)0.26
Caucasian ethnicity (%)40 (95)46 (98)0.60
Time in years since injury (SD)1.62 (0.60)1.83 (0.77)0.19
Initial PCSI after mTBI (SD)10.52 (8.5)21.63 (15.2)<0.001a
Current PCSI (SD)8.9 (7.3)20.9 (15.01)<0.001a
Children's Depression Inventoryb (SD)

5.92 (7.64)


7.16 (6.83)


Life events score (range)1 (0–6)3 (0–7)0.004a

Children in the symptomatic group had higher PCSI scores (mean 20.9, SD 15.01) compared with the asymptomatic group (mean 8.9, SD 7.3, t(76)=4.56, p<0.001). The most common persistent symptoms reported included ‘irritability’ (18 out of 42), ‘acting more emotional’ (18 out of 42), and ‘headache’ (18 out of 42). The CDI instrument is validated for ages 7 to 17 years, thus was only administered to participants within this age range. The mean total CDI score (children aged 7–17y) for the symptomatic cohort (n=37) was 7.16 (SD 6.83) and 5.92 (SD 7.64) for the asymptomatic group (n=24). The CDI scores in the symptomatic and asymptomatic groups did not differ (t(45)=0.648, p=0.520). One participant in each group, 3% overall, had clinically significant depression symptoms (a score of ≥19). One participant in the symptomatic group had been diagnosed with depression before her mTBI.

The symptomatic group reported more stressful life events (median score 3, range 0–7) compared with the asymptomatic group (median score 1, range 0–6). Multiple logistic regression analysis examining age and stressful life events score showed a significant difference between groups (χ2 (1)=9.71, p=0.002). After controlling for the effects of age, the SLEQ score was a significant predictor of being symptomatic after mTBI (Wald (1)=8.51, p=0.004).

Of the 89 DNA collection kits returned (two DNA samples were not returned with surveys because of parental reservations regarding DNA collection: one symptomatic and one asymptomatic), 90.8% of the samples were successfully analyzed. Table 2 shows the relative frequencies of the alleles and genotypes for both groups. The asymptomatic (n=38) and symptomatic (n=41) groups did not differ significantly in allelic frequency from each other), or from known frequencies of a reported control population from Ontario.[21]

Table 2. Frequency of the HTR1A C(-1019) and G(-1019) genotypes and alleles
  1. a

    Ontario population obtained from Lemonde et al. (2003).[21]

Symptomatic (n=41)0.220O.5370.2440.4880.512
Asymptomatic (n=38)0.2630.4740.2630.5000.500
Ontario (n=134)a0.3730.5070.1190.6270.373


  1. Top of page
  2. Abstract
  3. Method
  4. Results
  5. Discussion
  6. Acknowledgements
  7. References

We report a low prevalence of depression (3%) in children after mTBI. Our results are in contrast to previous studies that report an increased prevalence of depressive disorders in children after TBI, ranging from 11 to 36%.[16-18] Most of the previous studies, however, had small sample sizes,[16-18] and they report depression in children with a wide range of TBI severity, including subsets of hospitalized mTBI patients. Although transient depressive symptoms in the first 6 months after injury could have been missed,[17] the low prevalence in mTBI we report is in keeping with earlier observations that mood disorders increase in prevalence with increasing severity of injury.[18]

There was no relationship between the HTR1A C(-1019)G allele and the development of PCS after mTBI in children. The genotype and allele frequencies in our sample are consistent with those seen in a population from Ontario (Table 2), and therefore are representative of predominantly Caucasian English-speaking individuals in Canada. Although there are no previous studies examining the HTR1A (C-1019)G allelic polymorphisms in TBI, this result is in keeping with recent genetic studies examining the role of serotonin transporter gene-linked polymorphisms (5-HTTLPR) in depression after TBI.[25]

Previous life stressors do appear to be associated with PCS symptoms after mTBI. We found that children who were symptomatic after mTBI had an increased number of stressful life events before their injury compared with those children who recovered quickly after mTBI. Our findings are consistent with previous literature linking premorbid stressors and low socio-economic status to persistent PCS symptoms and cognitive and behavioral problems after mTBI in children.[11] One explanation for this could be that stress from the injury may summate with the premorbid stress and overwhelm psychological coping mechanisms, resulting in increased perception of PCS symptoms. Alternatively, we hypothesize that significant preinjury life stresses at a young age can precondition or sensitize a child to become susceptible to the development of persistent PCS symptoms after a TBI. Post's behavior sensitization model of mood disorders suggests repeated stress leads to underlying neuropathological changes in the brain;[12] that is, premorbid stress may prime the brain by creating a neurobiological substrate for the subsequent development of PCS symptoms after the trigger of an mTBI. Indeed the relative absence of PCS symptoms in orthopedic control groups suggests that the brain injury itself is vital to the development of symptoms.[3, 6] Although our finding needs to be replicated in other studies with larger sample sizes, identifying preinjury life stressors as a potential risk factor for the development of PCS has important implications for future management of mTBI. Early interventions including stress counseling may benefit patients with mTBI who have a history of significant premorbid stress burden and early PCS symptoms.

This study has several limitations, including a small sample size. Given that there are no previous studies examining the HTR1A C(-1019)G allelic polymorphisms in TBI on which to base the sample size estimation, the results should be interpreted somewhat cautiously. Although the CDI has been shown to discriminate between controls and depressed children, and is able to assess symptom severity,[26] a clinical interview is needed to diagnose depression. The prevalence of the depression may have been underestimated, as a clinical interview was not performed at the time of the survey. The SLEQ represents another limitation. Self-report checklists are the most widely used method for assessing life stressors; however, currently there are no standardized measures of stressors in children.[27] The SLEQ used in this study has not been validated although it is similar to other such questionnaires, for example LES-C, and has good face validity. Developing our own questionnaire enabled us to include events occurring over the lifetime of the child, that is, it allowed for summation of events and did not assume a linear relationship between severity or number of events (potentially inflating the effect of stressful events) and probability of depression. The stressful life event survey does not assess the temporal impact of events. For example, does a grandparent's death have the same impact on an infant as on an older child? Stressor checklists cannot distinguish between independent stressors versus those dependent on subsequent behavior and symptom expression;[27] prospective studies are needed to investigate the relationship between life stressors and development of PCS symptoms over time. Retrospective self-reporting of the SLEQ does introduce the possibility of attribution bias; however, this risk was minimized by the inclusion of predominantly external objective SLEQ items reflecting environmental conditions rather than subjective assessment of the stressors. Both the CDI and SLEQ were co-administered 1 to 3 years post injury. No evidence of reporting bias was found in the CDI results, which were not significantly different in patients with persistent PCS compared with those without.

In summary, although the results of this pilot study must be interpreted cautiously given the sample size, they are suggestive that depressive symptoms and HTR1A polymorphisms may not play a role in the expression and persistence of PCS symptoms after mTBI in children. This is in contrast to preinjury life stressors which have been associated with the development of PCS. Larger prospective studies are needed to confirm and validate these preliminary findings. It is likely that prolonged PCS may be the result of a combination of preinjury factors, i.e. stressful life events and postinjury neuropathological and psycho-social factors,[12] although specific genetic determinants have not yet been identified.[3, 4, 11] Screening pediatric patients with mTBI for a history of previous stressful life events may help to identify patients at risk of developing PCS.


  1. Top of page
  2. Abstract
  3. Method
  4. Results
  5. Discussion
  6. Acknowledgements
  7. References

This study was funded by a research grant provided by the Alberta Children's Hospital Foundation.


  1. Top of page
  2. Abstract
  3. Method
  4. Results
  5. Discussion
  6. Acknowledgements
  7. References
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