Loss of hypocretin (orexin) neurons with traumatic brain injury

Abstract

Chronic, daytime sleepiness is a major, disabling symptom for many patients with traumatic brain injury (TBI), but thus far, its etiology is not well understood. Extensive loss of the hypothalamic neurons that produce the wake-promoting neuropeptide hypocretin (orexin) causes the severe sleepiness of narcolepsy, and partial loss of these cells may contribute to the sleepiness of Parkinson disease and other disorders. We have found that the number of hypocretin neurons is significantly reduced in patients with severe TBI. This observation highlights the often overlooked hypothalamic injury in TBI and provides new insights into the causes of chronic sleepiness in patients with TBI.

Figure 1

Overview of hypocretin and MCH cell counts. Patients with traumatic brain injury (TBI) have fewer hypocretin neurons. On average, TBI patients have a total of 23,655 hypocretin neurons, whereas controls have 32,318 neurons (p = 0.001). The numbers of hypocretin neurons on the left and right sides of the hypothalamus differ more in TBI patients, probably reflecting asymmetry of the trauma. TBI patients also have fewer MCH neurons than controls (39,540 in total vs. 57,176, p = 0.06).

Figure 2

TBI patients and controls have similar caudal-rostral distributions of hypocretin neurons. The graphs show the average number of hypocretin neurons per section (mean values across all cases). Overall, TBI patients have fewer neurons, especially in the center of the hypocretin field. Level a: fornix touches the dorsal edge of the mammillary bodies; level b: fornix next to the paraventricular nucleus.

Figure 3

TBI patients have dense perivascular hypocretin immunoreactivity within the hypothalamic hypocretin field (A, B), but not in adjacent areas (C).