Is balance performance reduced after mild traumatic brain injury?: Interim analysis from chronic effects of neurotrauma consortium (CENC) multi-centre study

<p><b>Objectives</b>: Determine if mild traumatic brain injury (mTBI) history is associated with balance disturbances.</p> <p><b>Setting</b>: Chronic Effects of Neurotrauma Consortium (CENC) centres.</p> <p><b>Participants</b>: The CENC multi-centre study enrols post-9/11 era Service Members and Veterans with combat exposure. This sample (<i>n</i> = 322) consisted of enrolees completing initial evaluation by September 2016 at the three sites conducting computerized dynamic post-urography (CDP) testing.</p> <p><b>Design</b>: Observational study with cross-sectional analyses using structural equation modelling.</p> <p><b>Main Measures</b>: Comprehensive structured interviews were used to diagnose all lifetime mild traumatic brain injuries (mTBIs). The outcome, Sensory Organization Test (SOT), was measured on CDP dual-plate force platform. Other studied variables were measured by structured interviews, record review and questionnaires.</p> <p><b>Results</b>: The overall positive/negative mTBI classification did not have a significant effect on the composite equilibrium score. However, the repetitive mTBI classification showed lower scores for participants with ≥ 3 mTBI versus 1–2 lifetime mTBIs. For repetitive mTBI, pain interference acted as a mediator for the indirect effect, and a direct effect was evident on some sensory condition equilibrium scores.</p> <p><b>Conclusion</b>: These findings show that repeated mTBI, partially mediated by pain, may lead to later balance disturbances among military combatants. Further study of CDP outcomes within this accruing cohort is warranted.</p

Changes in sociosexual investigation at adulthood after pediatric but not adolescent TBI.

<p>Investigative behaviors were quantified at adulthood after addition of a novel female mouse, after injury or sham-operation at p21 or p35. Sham and TBI mice injured at p21 showed similar investigative behaviors overall (a). However, sexual behavior was markedly reduced (b), with TBI mice initiating fewer mounting attempts, and a delayed latency to the first attempt (*p<0.05). After injury at p35 (c), both sham and TBI mice showed similar investigative behaviors towards a novel female mouse. Sexual behavior, quantified as the number of mounting attempts and latency to first attempt, were also comparable in sham and TBI mice after injury at adolescence (d).</p

Reduced social investigation at adulthood after pediatric but not adolescent TBI.

<p>Experimental timelines illustrate the timing of behavioral assessments; Cohort 1 (a) consisted of n = 10/group after TBI or sham-operation at p21; Cohort 2 (b) was n = 7–8/group, also after TBI or sham at p21; Cohort 3 (c) consisted of mice that received TBI or sham-operation at p35 (adolescence; n = 9/group). Investigative and interactive behaviors by sham and TBI mice, at adulthood after p21 or p35 injury, were quantified after addition of a novel male mouse in the resident-intruder (RI) paradigm (d). Brain-injured mice that received TBI at p21 (e) spent less time engaged in social investigative behaviors including ano-genital sniffing and following (**p<0.01, *p<0.05). Antagonistic behaviors (f), quantified as the number of fighting bouts and latency to first fight, were not different between the injury groups. After injury at p35 (g, h), sham and TBI mice also showed similar investigative behaviors towards a novel male mouse.</p

Reduced scent marking indicates impaired sociosexual communication after pediatric TBI.

<p>Scent marking by sham and TBI mice was assessed in an open field arena lined with absorbent paper, in the presence and absence of a cage-enclosed novel female mouse (a). Representative examples from sham mice and after injury at p21 are shown in panels (b) and (c), respectively. All mice produced more scent marks in the presence of a stimulus female compared to an empty arena (d). However, despite comparable production of scent marks at baseline (empty open field), TBI mice deposited significantly fewer scent marks in response to a novel female, compared to sham-operated mice (*p<0.05). This reduction was unlikely due to potential changes in mobility, anxiety or gross bladder dysfunction, as measures of anxiety (e) and bladder capacity (f) were comparable.</p

Loss of social novelty preference at adulthood is unique to TBI at p35.

<p>Independent of injury, all mice spent equal time in the left and right side chambers during habituation (stage 1; a). During stage 2 (b), both sham and TBI mice showed a similar preference for spending more time in the chamber containing the stimulus mouse, compared to the empty chamber (2-way ANOVA overall effect of stimulus, *p<0.05). In stage 3 (c), sham mice showed a strong preference for spending more time with stimulus mouse 2 compared to mouse 1, indicating social recognition or memory of ‘now-familiar’ stimulus 1 (2-way ANOVA post-hoc, ****p<0.0001). In contrast, TBI mice injured at p35 spent equivalent time with both stimulus mice (post-hoc, n.s.), indicating a lack of preference for social novelty.</p

The number and duration of USV calls after injury at p21 are both stimulus and experience-dependent.

<p>USVs were recorded at adulthood after injury at p21, in response to three different stimuli; addition of a novel male mouse, novel female mouse, or bedding from a cage of novel female mice. In Cohort 1, which had previously encountered conspecifics of both genders during the resident-intruder test, TBI mice emitted significantly more total calls (a), particularly in response to a female stimulus mouse (*p<0.05). Histograms of the mean median call frequency revealed a distribution of calls above and below 75 kHz (c; dotted line). Application of a frequency filter to restrict analysis to calls greater than 75 kHz found that TBI mice produced more high frequency calls compared to sham mice in response to both a female mouse kHz found that TBI mice produced more high frequency calls compared to sham mice in response to both a female mouse (***p<0.001) and female bedding (**p<0.01). In contrast, a lack of prior social encounters as experienced by Cohort 2 (b, d, f) resulted in sham and TBI mice emitting a similar number of calls (both total and restricted to >75 kHz kHz). Call duration was not affected by injury in Cohort 1 (g), although in Cohort 2 (h) there was a trend towards TBI mice producing calls of shorter duration compared to sham mice overall (p = 0.069).</p

Burst analyses reveal temporal differences in USV calls after injury at p21.

<p>Call burst patterns were calculated from the distribution of inter-call intervals. In Cohort 1, the mean number of calls per burst was higher in mice after injury at p21 compared to sham mice in response to the female stimulus mouse (*p<0.05). Similarly, bursts of USV calls from TBI mice towards female stimuli were of a longer duration (c; **p<0.01), as well as towards a stimulus male (*p<0.05). In contrast, no such injury-related differences were observed in burst patterns produced in the absence of prior social experience (Cohort 2; b, d).</p