TBI and the Neuroendocrine System

Trauma to the hypothalamus frequently occurs in severe head injuries (Crompton 1971; Rudy 1980). The hypothalamus can be injured as a result of direct or indirect damage, small hemorrhages, or ischemia (cf. Lighthall, Gochgarian, and Pinderski 1990). Sudden head movement can shear blood vessels supplying this part of the brain (Mitchell, Steffenson, and Davenport 1997). Regulation of the neuroendocrine systems involves numerous pathways and centers, including afferent neural pathways, the brainstem, the cortex, corticohypothalamic pathways, hypothalamic integrative centers, the pituitary gland, and efferent autonomic pathways. TBI may disturb any part of this complex system, depending on the severity and the location of primary and secondary injuries (Yuan and Wade 1991). Patterns of neuroendocrine abnormalities will vary according to the site of the injury and the extent of injury-transmitted hypothalamic-pituitary damage. For example, damage just above the base of the brain in a distinct region of the hypothalamus called the suprachiasmatic nucleus (SCN) will affect the primary circadian pacemaker that resides there. Three major neural pathways relay information to the SCN that may all be affected after TBI (see Fig. 17.1).

Tbi And Sleep

Figure 17.1. Three major neural pathways bring information to the suprachiasmatic nucleus (SCN), which can be compromised after TBI: (1) a direct pathway from the retinal ganglion cells; (2) a pathway from a region in the thalamus called the intergeniculate leaflet (IGL); (3) a pathway from the neurons of the raphe nuclei of the midbrain, important in the regulation of mood, arousal, sleep and other behavioral aspects. This pathway is connected to the SCN and the IGL. The SCN interacts with and contains a number of chemicals important in cellular communication, such gamma-aminobutyric acid (GABA), other neuropeptides (NP) like NPY, glutamate (GLU), and serotonin (5-HT).

Figure 17.1. Three major neural pathways bring information to the suprachiasmatic nucleus (SCN), which can be compromised after TBI: (1) a direct pathway from the retinal ganglion cells; (2) a pathway from a region in the thalamus called the intergeniculate leaflet (IGL); (3) a pathway from the neurons of the raphe nuclei of the midbrain, important in the regulation of mood, arousal, sleep and other behavioral aspects. This pathway is connected to the SCN and the IGL. The SCN interacts with and contains a number of chemicals important in cellular communication, such gamma-aminobutyric acid (GABA), other neuropeptides (NP) like NPY, glutamate (GLU), and serotonin (5-HT).

Endocrine dysfunction after TBI affecting all hypothalamic-pituitary axes (i.e., corticotropin, growth hormone, gonadotropin, thyrotropin, prolactin, and vasopressin) has been described in clinical studies (Yuan and Wade 1991; Childers, Rupright, Jones, and Merveille 1998; Kelly, Gaw Gonzalo, Cohan, Berman, Swerdloff, and Wang 2000; Benvenga, Campenni, Ruggeri, and Trimarchi 2000; Lieberman, Oberoi, Gilkison, Masel, and Urban 2001; Agha, Phillips, Kelly, Tormey, and Thompson 2005). Indeed, hypopituitarism has been identified in up to half of the long-term survivors (6 to 36 months) of moderate to severe head injury (Kelly et al. 2000; Lieberman et al. 2001; Agha et al. 2005). Specifically, with respect to the HPA axis, a high incidence of ACTH and adrenal insufficiencies has been reported (Benvenga et al. 2000; Cohan et al. 2005). These abnormalities, which occur soon after TBI, are transient in some patients, while the majority shows recovery at 6 months (Agha et al. 2005). Additionally, the extent of neuroendocrine impairment has been found to correlate with the severity of the neurological insult as assessed by the Glasgow Coma Scale (GCS) (Cernak, Savic, Lazarov, Joksimovic, and Markovic 1999). For example, plasma cortisol levels increase during the early post-TBI period, but only in patients with minor to moderate injuries. In contrast, patients with severe trauma exhibit a significant decline in cortisol (Cernak et al. 1999). TBI-induced alterations in circadian rhythmicity of HPA axis function may also contribute to the high incidence of sleep disturbances in patients with TBI, including insomnia, excessive daytime somnolence and alteration of the sleep-wake schedule (Frieboes, Muller, Murch, von Cramon, Holsboer, and Steiger 1999; Mahmood, Rapport, Hanks, and Fichtenberg 2004; Rao and Rollings 2002).

Experimental studies have demonstrated that corticotrophin-releasing hormone (CRH) mRNA is up-regulated at 2 and 4 h after fluid percussion injury (FPI) (Roe, McGowan, and Rothwell 1998; Grundy, Harbuz, Jessop, Lightman, and Sharp les 2001) and ACTH and cortisol are increased up to 6 h after cortical contusion injury (CCI) (McCullers, Sullivan, Scheff, and Herman 2002). However, in experimental models, beyond the acute activation of the HPA axis after the surgical intervention, the effects of TBI on neuroendocrine function at later time-points remain unknown. Furthermore, the longer-term clinical studies have defined alterations in baseline, but not stress-induced neuroendocrine function.

Our recent data indicate that CCI produces dysregulation of the stress-induced HPA response at 4 weeks postinjury in male rats. Moreover, the direction of the dysregulation differs depending upon the location of the CCI (Taylor et al. submitted).

Given that pituitary insufficiency may have serious consequences and may aggravate the physical and neuropsychiatric morbidity observed after TBI (Agha et al. 2005), frequent assessment of the subject's endocrine status is essential. Moreover, with the more elevated and prolonged risk for psychiatric illness, including depression, posttraumatic stress disorder, anxiety and sleep/wakefulness, that are persistent symptoms of TBI (Fann, Burington, Leonetti, Jaffe, Katon, and Thompson 2004; Dikmen, Bobmardier, Machamer, Fann, and Temkin 2004; Ryan and Warden 2003) and the evidence that the neuroendocrine stress system and depression share common neural pathways and hormonal mediators (Gold and Chrousos 2002), measurement of the allostatic HPA stress response should prove to be a relevant biomarker in TBI.

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