It Takes Your Breath Away

Dr. Oppenheimer has indicated no financial conflicts of interest. The insula lies beneath the fronto-parietal operculum, and the superior temporal plane and is the area of cortex that over-lies the claustrum.1 Using stimulation techniques in the cat, monkey, and dog insulae, Kaada elicited progressive shallowness of respiratory movements, finally ceasing altogether in expiration.2 Apnea persisted for 25-30 seconds while insular stimulation continued and then normal respiratory activity resumed. In the monkey this effect was noted even when the insula was surgically isolated, indicating that it was unlikely to be due to stimulation of fibers of passage; a cortical origin was also suggested as this response was abolished by anesthetizing the insula with procainamide. More recently much interest has focused on the role of the insula in cardiovascular regulation particularly regarding cardiac rhythm and contractility. Prolonged stimulation of the insula in rats results in cardiac structural changes and lethal cardiac arrhythmias.3 There is recent evidence that left insular damage may contribute to the increased cardiac morbidity and mortality seen in patients on long-term follow-up after stroke.4 Insular regions involved in cardiovascular regulation are lateralized with parasympathetic and baroreceptor regulatory control focused more in the left caudal insula in the rat, or left anterior insula in the human, and sympathetic cardiovascular mechanisms more concentrated in the right insula.5,6 However the functional separation is not absolute, and there are insulo-insular reciprocal connections linking both cardiovascular zones.7 Convergence of nociceptive and baroreceptor inputs onto insular cells in the monkey and rat indicate further an integrative action for the insula.8,9 This is heightened by a consideration of anatomical connectivity, showing that the insula receives reciprocal connections from other brain areas involved in memory, cognitive, sensorimotor, and emotional functions.10,11 Emerging from these studies is the concept that the insular cortex functions with other brain areas including the anterior cingulate and pre-frontal cortices to integrate interoceptive and exteroceptive perception, with cognitive, memory, and emotional engrams adapting autonomic patterning to produce a response appropriate to the environmental circumstance. This is a complex role, and it is hardly surprising that these paired structures show compartmentalized lateralization of function and that the nature of this may vary temporally as well as spatially according to the nature of the eliciting stimuli.12 In this issue of SLEEP, Yadav and colleagues report on changes in the insular cortex in patients recently diagnosed with obstructive sleep apnea.13 Previously, in a series of elegant studies, this group had shown specific loss of neurons in the right anterior and left posterior insulae of patients with heart failure compared with normal controls.14,15 This was associated with significant changes in heart rate response to a cold pressor challenge applied to the forehead compared to those of normal controls, and it was thought to indicate a loss of inhibition of insular regulation of cardiac sympathetic tone, which resulted in the observed augmented heart rate response to the challenge. The cause of this neuronal loss was unclear but possibilities included chronic cerebral ischemia/ hypoxia secondary to a low cardiac output state and/ or sleep apneic episodes to which patients with heart failure are often subject. These findings have now been expanded in the study by Yadav et al. Using proton magnetic resonance spectroscopy (MRS), a method of interrogating the cellular content and metabolism of specific brain regions, Yadav and colleagues found that MRS markers indicated neuronal loss in both right and left anterior insulae together with increased glial activity in the left anterior insula. These correlated significantly with hypoxic and apneic events as well as depression and anxiety scoring. The authors suggest that these insular changes are secondary to hypoxia, and that the left insular gliosis is a possible indicator of an ongoing cerebral inflammatory response to this circumstance.13 The functional consequences may be the disordered cardiac autonomic tone and affective abnormalities seen in obstructive sleep apnea patients, the former possibly contributing to the increased incidence of arrhythmias and sudden death associated with this condition. But what if it were the other way round? Could there be a primary insular pathology that initiates or compounds obstructive sleep apnea? Patients with Foix-Chavany-Marie syndrome may have a variety of bucco-pharyngeal complications, and although the primary pathology is focused on the operculum, there is evidence of insular involvement in this condition.16 Could some apneic cases, or perhaps vulnerability to developing apnea, relate to a more restricted syndrome with primary insular pathology? Further investigation of lactate levels might help indicate chronic insular ischemia in these patients. Although this study used normal controls for comparison, investigation of other cortical areas would indicate whether or not the findings were specific or just an indication of a generalized change seen in the brains of such patients. However, this would not really explain the lateralized findings noted by Yadav et al.13 and their earlier studies.14,15 One possibility is a selective vulnerability of neuronal cells in the insula according to laterality; another may relate to the difference in size between the two insulae (i.e., the left being the larger in the human)—differences in blood supply to the two insulae may offer a further explanation. The report by Yadav adds considerably to our understanding of the role of the insula. Coupled with earlier studies from this group and data from others regarding the autonomic, nociceptive, somesthetic, and affective functions of the insula, it indicates a key integrative role whereby perception of the external world is merged with autonomic, memory, and emotional constructs. Working normally, a smooth integration of the organism into the environment is attained; but when deranged, inappropriate autonomic, emotional, and behavioral responses may occur that are damaging and possibly catastrophic when leading to uncontrolled autonomic responses including, hypoventilation, hypoperfusion, cardiac arrhythmias, and sudden death.