Long-term mortality is increased after mild traumatic brain injury (mTBI). Central cardiovascular–autonomic
dysregulation resulting from subtle, trauma-induced brain lesions might contribute to cardiovascular events and fatalities. We investigated whether there is cardiovascular–autonomic dysregulation after mTBI. In 20 mTBI patients (37 – 13 years, 5–43 months post-injury) and 20 healthy persons (26 – 9 years), we monitored respiration, RR intervals (RRI), blood pressures (BP), while supine and upon standing. We calculated the root mean square successive RRI differences (RMSSD) reflecting cardiovagal modulation, the ratio of maximal and minimal RRIs around the 30th and 15th RRI upon standing (30:15 ratio) reflecting baroreflex sensitivity (BRS), spectral powers of parasympathetic high-frequency (HF: 0.15–0.5 Hz) RRI oscillations, of mainly sympathetic low-frequency (LF: 0.04–0.15 Hz) RRI oscillations, of sympathetic LF-BP oscillations, RRI-LF/HF-ratios reflecting sympathovagal balance, and the gain between BP and RRI oscillations as additional BRS index (BRSgain). We compared supine and standing parameters of patients and controls (repeated measures analysis of variance; significance: p < 0.05). While supine, patients had lower RRIs (874.2 – 157.8 vs. 1024.3 – 165.4 ms), RMSSDs (30.1 – 23.6 vs. 56.3 – 31.4 ms), RRI- HF powers (298.1 – 309.8 vs. 1507.2 – 1591.4 ms2), and BRSgain (8.1 – 4.4 vs. 12.5 – 8.1 ms$mmHg- 1), but higher RRI-LF/HF-ratios (3.0 – 1.9 vs. 1.2 – 0.7) than controls. Upon standing, RMSSDs and RRI-HF-powers decreased significantly in controls, but not in patients; patients had lower RRI-30:15-ratios (1.3 – 0.3 vs. 1.6 – 0.3) and RRI- LF-powers (2450.0 – 2110.3 vs. 4805.9 – 3453.5 ms2) than controls. While supine, mTBI patients had reduced car-diovagal modulation and BRS. Upon standing, their BRS was still reduced, and patients did not withdraw parasympathetic or augment sympathetic modulation adequately. Impaired autonomic modulation probably contributes to cardiovascular irregularities post-mTBI.

Key words: autonomic dysfunction; baroreflex; cardiovascular modulation; head trauma; TBI

Introduction

Traumatic brain injury (TBI) annually affects *1.4 million Americans. Approximately 75% of injuries are
mild TBIs (Centers for Disease Control and Prevention, 2003). Even after mild TBI (mTBI), patients frequently have medical, psychological, and social problems (National Institute of Neurological Disorders and Stroke, 2002), and an unex- plained, long-term increase in mortality rates (Black and Graham, 2002; Brown et al., 2004; Flaada et al., 2007; McMillan and Teasdale, 2007).

In 1448 TBI patients, Brown and associates observed significantly reduced long-term survival, particularly after moderate or severe, but also after mild TBI (Brown et al 2004). After > 6 months post-injury, risk of mortality no longer differed with TBI severity (Brown et al., 2004). However, the authors found no pathophysiology relating fatalities after mTBI to the initial trauma (Brown et al., 2004). In a 7 year follow-up study including 767 TBI patients, McMillan and Teasdale found seven times higher mortality rates in the TBI patients than in the average Scottish population (McMillan and Teasdale, 2007). Again, mortality did not

 depend upon TBI severity after > 1 year post-trauma (McMillan and Teasdale, 2007). Fatalities were mostly the result of unexplained circulatory and respiratory causes but there was no obvious relation between the mTBI and death (McMillan and Teasdale, 2007).
In a recent 13-year follow-up of their TBI cohort, McMillan and co-workers confirmed the significantly increased mor- tality rates, independent of trauma severity beyond the first year after injury (McMillan et al., 2011). Mortality rates were particularly high in younger TBI patients, with death rates more than six times higher in patients aged 15–54 years than in community controls matched for age, gender, and
deprivation; and more than twice as high as in a second control group matched for duration of hospital admission caused by an injury unrelated to the TBI (McMillan et al., 2011). According to the authors, the pathomechanisms for the increased mortality rates remain unclear and require further study (McMillan et al., 2011). As yet, mechanisms of increased mortality after mTBI are unclear. From their unremarkable autopsies of patients with a history of mTBI, Black and Graham concluded that central autonomic dysfunction might have accounted for the enig- matic fatalities (Black and Graham, 2002).

According to the World Health Organization (WHO) definition of mTBI, conventional neuroimaging methods, using cranial computed tomography (CCT) or magnetic resonance imaging (MRI), show no structural abnormalities in mTBI (Holm et al., 2005). However, novel techniques unveil brain
lesions even after mTBI (Huang et al., 2009; Levine et al., 2008; Niogi et al., 2008; Rutgers et al., 2008). Using voxel-based brain and cerebrospinal fluid volume analysis and high-resolution MRI, Levine and associates found volume loss affecting almost all brain regions, particularly frontal, temporal, and cingulate regions in all their mTBI patients (Levine et al., 2008).
In 10 mTBI patients without visible lesions in conventional CCT and MRI studies, Huang and associates demonstrated slow magnetoencephalography waves and reduced fractional anisotropy (FA) with diffusion tensor weighted MRIs (DTIs) (Huang et al., 2009) in multiple brain regions, and concluded that there is deafferentation of gray-matter areas caused by axonal injuries in white-matter fibers with reduced FA
(Huang et al., 2009).

Several DTI studies confirmed widespread FA alteration indicating white-matter lesions in mTBI patients (Niogi et al., 2008; Rutgers et al., 2008). In 34 mTBI patients, Niogi and associates found microstructural white-matter and tract lesions, e.g., in the anterior corona radiata, uncinate fasciculus, genu of the corpus callosum, inferior longitudinal fasciculus, and cingulum bundle (Niogi et al., 2008). In their 21 mTBI patients, Rutgers and associates saw signs of axonal white matter injury in multiple areas, including subcortical white matter, internal capsules, corpus callosum, fornix, and infra-
tentorial brain stem and cerebellum (Rutgers et al., 2008).

Using fiber tracking techniques, the authors also saw fiber bundle lesions in multiple areas, including supratentorial
projection fiber bundles, corpus callosum fibers, association bundles, and fronto-temporo-occipital fiber bundles (Rutgers et al., 2008).

Diffuse volume loss (Levine et al., 2008), widespread white- matter injuries (Huang et al., 2009; Niogi et al., 2008) and gray matter deafferentation (Huang et al., 2009) may explain dys function of the complex central autonomic nervous system (CAN) (Benarroch, 1997) that comprises many of the above
named areas, such as the ventromedial prefrontal cortex, anterior cingulate gyrus, amygdala, suprachiasmatic hypo-thalamic nucleus, medial preoptic nucleus, magnocellular neurons in the supraoptic nucleus and the paraventricular nucleus, hypothalamus, arcuate nucleus, or the insula cortex
(Benarroch, 1997).

Although patients do not always manifest clinically overt autonomic dysfunction after mTBI, we assume that there is sub-clinical autonomic dysfunction in patients who had cerebral lesions involving CAN structures. Mild autonomic dysfunction can be unveiled by autonomic challenge maneuvers that involve peripheral and brainstem autonomic pathways and supratentorial CAN structures. Baroreflex challenge by active standing up is a readily available test of peripheral and central autonomic function.

Activation or unloading of baroreceptors generates impulses at the level of the nucleus tractus solitarii (NTS) that propa- gate rostrally towards the multiple CAN areas that modulate and adjust the efferent autonomic responses to the heart and arteries (Benarroch, 1997). These CAN areas include, e.g., the beforementioned magnocellular neurons of the supraoptic and paraventricular nuclei, posterior hypothalamus, para-
ventricular and dorsomedial hypothalamic nuclei, preopticanterior hypothalamic region, the periaqueductal gray, the central nucleus of the amygdala, and the insular cortex
(Benarroch, 1997), i.e., areas very likely to be affected by the volume loss and axonal lesions observed in the beforementioned studies (Huang et al., 2009; Levine et al., 2008; Niogi et al., 2008).
Consequently, we hypothesize that patients with a history of mTBI have altered baroreflex responses caused by lesions compromising adjustment and fine-tuning of baroreflex responses within CAN circuitries.

In this study, we therefore tested whether baroreflex challenge unveils abnormal responses of heart rate, blood pressure (BP), and sympathetic and parasympathetic responses to standing in patients with a history of mTBI.

Methods

We studied heart rate, BP, and autonomic responses to active standing up in 20 patients (3 women, 17 men, mean age 37 – 13 years) who had had an mTBI 5–43 months prior to examination [mean post-injury interval 20 months; standard deviation (SD) 11 months; Table 1]. The diagnosis of mTBI was established according to WHO operational criteria including 1) one or more of the following: confusion or disorientation; loss of consciousness for £ 30 min; post-traumatic amnesia for < 24 h; and/or other transient neurological abnormalities such as focal signs, seizure, and intracranial lesion not requiring surgery; 2) Glasgow Coma
Scale (GCS) scores of 13–15 after 30 min post-injury or later upon presentation to health care (Holm et al., 2005). We excluded patients from the study in whom the above man-
ifestations were caused by drugs; alcohol; medications; other injuries or treatment for other injuries, e.g., systemic injuries, facial injuries, or intubation; other problems, e.g., psychological trauma, language barrier, or coexisting medi- cal conditions; or penetrating craniocerebral injury (Holmet al., 2005).