Obstructive sleep apnea (OSA) is associated with abnormalities of higher order executive cognitive functions. The precise neuroanatomical localization of these deficits is unknown. The physiological correlates of executive cognitive dysfunction are poorly defined, and recovery following therapy may be incomplete. This project proposes the novel use of a neuroimaging technology, functional magnetic resonance imaging (fMRI), and precise neurobehavioral protocols, to localize the neuroanatomical site of dysfunction. Additional protocols will isolate specific physiological correlates of these neurocognitive abnormalities such as sleep fragmentation, sleep deprivation, and nocturnal oxygen desaturation and will relate them to altered regional cortical function. We will examine the cause of incomplete recovery of executive function while on therapy with nasal positive airway pressure. Working memory is a brain system that provides temporary storage and manipulation of information necessary to execute complex cognitive tasks, and it contributes to several executive functions. The n-back paradigm is an extensively used probe of working memory in MU studies, and is normally associated with activation of dorsolateral prefrontal cortex (DLPFC), anterior cingulate and posterior parietal cortex. We have adapted this task at the 2- back level of difficulty for use in OSA patients. Our preliminary data suggest a reversible (with treatment) reduction of working memory capacity in OSA patients that may be secondary to selective dysfunction in the DLPFC, relative to other nodes in the executive control network. Based on this data we hypothesize that: 1) Patients with OSA have reduced activation of the DLPFC, relative to posterior parietal cortex during tests of working memory. 2) Sleep deprivation or fragmentation but not nocturnal hypoxia disrupts working memory in normal subjects. 3). Post-treatment residual abnormalities are caused by persisting sleep fragmentation, not prior hypoxic exposure. The P.I. has training in general medicine, neurology, sleep disorders and functional neuroimaging. The proposed projects will be performed under the direct guidance of experts in sleep disorders, cognitive neuroscience, and fMRI within the Harvard system. The relevant research environment is particularly rich at the participating institutions-basic and applied neurobiology of sleep, clinical sleep disorders, behavioral neurology, and fMRI. The career development plan will include training in MRI physics, applied MRI, statistics and research methodology, ethics, planning of clinical research, and cognitive neuroscience. The immediate career goal is to acquire the necessary skills for applied clinical fMRI and determine the functional neurocircuitry of the localization, etiology and recovery of reduced working memory capacity in patients with OSA using the 2-back task paradigm. The longterm career goal is to develop a model of the function of sleep by demonstrating the functional consequences of sleep disruption in conditions such as depression, age-related memory dysfunction, and attention deficit hyperactivity disorder.
| Weiss, Matthew D; Tamisier, Renaud; Boucher, Judith et al. (2009) A pilot study of sleep, cognition, and respiration under 4 weeks of intermittent nocturnal hypoxia in adult humans. Sleep Med 10:739-45 |
| Thomas, Robert Joseph; Tamisier, Renaud; Boucher, Judith et al. (2007) Nocturnal hypoxia exposure with simulated altitude for 14 days does not significantly alter working memory or vigilance in humans. Sleep 30:1195-203 |
