Rebuttal from David Gozal

Abstract

The arguments set forth by Rosenzweig and colleagues (2012) are extremely valuable since they point out (i) the complexity of the effects on CNS as a result of the sleep and gas exchange perturbations accompanying sleep apnoea disease, and (ii) the possibility that the conventional imaging technologies used in the studies published to date may not have specifically investigated unique structural properties of the CNS. Indeed, novel functional and structural connectivity maps have revealed complex interactions between a priori undetectable or very subtle anatomical deficits that impinge upon the functional integrity of the neural systems (Alexander et al. 2011; Fornito et al. 2012; Segall et al. 2012). Therefore to deny that there is CNS injury, simply because some of the symptoms can be putatively attributed to a phenotypic constellation that is not fully associated with specific lesions of the CNS (as defined in the context of conventional brain imaging), is tantamount to surmising that sleep apnoea elicits functional perturbations in a neural network without affecting any of its integral anatomical components. To move the field forward, I would argue for the use of integrative approaches that combine more advanced connectivity-based imaging technologies, and couple them to pertinent functional reporters that integrate pathway analyses with exquisitely sensitive cellular and molecular stimulus-triggered responses (Saygin et al. 2011). The conceptual framework of the cerebellum (Rosenzweig et al. 2012) as one of the putative targets and central sites of vulnerability is, however, important. Indeed, outputs from the cerebellum have been identified in non-motor areas in the prefrontal and posterior parietal cortex, and the spectrum of tasks associated with cerebellar activation encompasses tasks designed to assess attention, executive control, language, working memory, learning and emotion (Strick et al. 2009). All of these functions are potentially affected by sleep apnoea. In fact, evidence for the cerebellum as a neural site that is uniquely vulnerable to intermittent hypoxia has been previously identified (Pae et al. 2005; Ramanathan et al. 2005). Similarly, the analogy of CNS perturbations with those of thalamo-cortical dysrhythmia may not fully capture the complexity of neuronal cellular losses imposed by the presence of sleep apnoea, along with the compensatory cellular processes recruited over time to preserve higher level functioning (Goghari et al. 2010; Schulman et al. 2011). Thus, the cumulative animal and human evidence supports the underlying concepts of initial cellular losses in the context of sleep apnoea as the major underlying driver for potential alterations in higher level brain functioning.