BACKGROUND:Obstructive sleep apnoea (OSA) is a common disease that leads to daytime sleepiness and cognitive impairment. Attempts to investigate changes in brain morphology that may underlie these impairments have led to conflicting conclusions. This study was undertaken to aim to resolve this confusion, and determine whether OSA is associated with changes in brain morphology in a large group of patients with OSA, using improved voxel-based morphometry analysis, an automated unbiased method of detecting local changes in brain structure.METHODS:60 patients with OSA (mean apnoea hypopnoea index 55 (95% CI 48 to 62) events/h, 3 women) and 60 non-apnoeic controls (mean apnoea hypopnoea index 4 (95% CI 3 to 5) events/h, 5 women) were studied. Subjects were imaged using T1-weighted 3-D structural MRI (69 subjects at 1.5 T, 51 subjects at 3 T). Differences in grey matter were investigated in the two groups, controlling for age, sex, site and intracranial volume. Dedicated cerebellar analysis was performed on a subset of 108 scans using a spatially unbiased infratentorial template.RESULTS:Patients with OSA had a reduction in grey matter volume in the right middle temporal gyrus compared with non-apnoeic controls (p<0.05, corrected for topological false discovery rate across the entire brain). A reduction in grey matter was also seen within the cerebellum, maximal in the left lobe VIIIb close to XI, extending across the midline into the right lobe.CONCLUSION:These data show that OSA is associated with focal loss of grey matter that could contribute to cognitive decline. Specifically, lesions in the cerebellum may result in both motor dysfunction and working memory deficits, with downstream negative consequences on tasks such as driving.

Dyspnoea, usually defined as an uncomfortable awareness of breathing, is one of the most frequent and distressing symptoms experienced by patients with lung disease. Idiopathic hyperventilation (IHV) has unknown aetiology and little is known about the mechanisms that cause the characteristic sustained hypocapnia and chronic dyspnoea. We have shown in IHV and other chronic respiratory disorders that air hunger is the dominant sensation during exercise, while resting breathlessness is characterised by an affective component. The increased drive to breathe in IHV, and indeed dyspnoea in all chronic respiratory disorders, might be better understood if the central mechanisms of dyspnoea were known. The aim of the present study was to characterise the cortical processing of respiratory-related sensory inputs in patients with IHV. Four patients with IHV were studied with ethical approval. Respiratory stimulation was produced using transient occlusion of inspiration (TIO) during spontaneous breathing (delivered in early inspiration with duration c. 300 ms; this is well tolerated) while BOLD fMRI was performed on a 3 Tesla Siemens Trio. TIO was associated with significant activation in sensorimotor and pre-motor cortical areas and the cerebellum, notably the anterior insula, an area previously associated with breathlessness in healthy volunteers. These preliminary observations on the pattern of brain activity in response to respiratory stimulation support the hypothesis that breathlessness in IHV may reflect inappropriate cortical processing of respiratory-related sensory inputs.

Objective: Obstructive sleep apnea (OSA) causes hypoxemia and fragmented sleep, which lead to neurocognitive deficits. We hypothesised that focal loss of cortical gray matter generally within areas associated with memory processing and learning and specifically within the hippocampus would occur in OSA. Methods: Voxel-based morphometry, an automated processing technique for magnetic resonance images, was used to characterise structural changes in gray matter in seven right handed, male patients with newly diagnosed OSA and seven non-apneic, male controls matched for handedness and age. Results: The analysis revealed a significantly lower gray matter concentration within the left hippocampus (p=0.004) in the apneic patients. No further significant focal gray matter differences were seen in the right hippocampus and in other brain regions. There was no difference in total gray matter volume between apneics and controls. Conclusion: This preliminary report indicates changes in brain morphology in OSA, in the hippocampus, a key area for cognitive processing.

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The diaphragm is the main inspiratory muscle during REM sleep. It was hypothesized that patients with isolated bilateral diaphragm paralysis (BDP) might not be able to sustain REM sleep. Polysomnography with EMG recordings was undertaken from accessory respiratory muscles in patients with BDP and normal subjects. Patients with BDP had a normal quantity of REM sleep (mean +/- SD, 18.6 +/- 7.5% of total sleep time) achieved by inspiratory recruitment of extradiaphragmatic muscles in both tonic and phasic REM, suggesting brainstem reorganization.

Nocturnal hypoxia is a major pathological factor associated with cardiorespiratory disease. During wakefulness, a decrease in arterial O-2 tension results in a decrease in cerebral vascular tone and a consequent increase in cerebral blood flow; however, the cerebral vascular response to hypoxia during sleep is unknown, In the present study, we determined the cerebral vascular reactivity to isocapnic hypoxia during wakefulness and during stage 3/4 non-rapid eye movement (NREM) sleep. In 13 healthy individuals, left middle cerebral artery velocity (MCAV) was measured with the use of transcranial Doppler ultrasound as an index of cerebral blood flow. During wakefulness, in response to isocapnic hypoxia (arterial O-2 saturation -10%), the mean (+/-SE) MCAV increased by 12.9+/-2.2% (P<0.001); during NREM sleep, isocapnic hypoxia was associated with a -7.4 +/- 1.6% reduction in MCAV (P<0.001). Mean arterial blood pressure was unaffected by isocapnic hypoxia (P>0.05); R-R interval decreased similarly in response to isocapnic hypoxia during wakefulness (-21.9+/-10.4%; P<0.001) and sleep (-20.5 +/- 8.5%; P<0.001). The failure of the cerebral vasculature to react to hypoxia during sleep Suggests a major state-dependent vulnerability associated with the control of the cerebral circulation and may contribute to the pathophysiologies of stroke and sleep apnea.

During wakefulness, increases in the partial pressure of arterial CO(2) result in marked rises in cortical blood flow. However, during stage III-IV, non-rapid eye movement (NREM) sleep, and despite a relative state of hypercapnia, cortical blood flow is reduced compared with wakefulness. In the present study, we tested the hypothesis that, in normal subjects, hypercapnic cerebral vascular reactivity is decreased during stage III-IV NREM sleep compared with wakefulness. A 2-MHz pulsed Doppler ultrasound system was used to measure the left middle cerebral artery velocity (MCAV; cm/s) in 12 healthy individuals while awake and during stage III-IV NREM sleep. The end-tidal Pco(2) (Pet(CO(2))) was elevated during the awake and sleep states by regulating the inspired CO(2) load. The cerebral vascular reactivity to CO(2) was calculated from the relationship between Pet(CO(2)) and MCAV by using linear regression. From wakefulness to sleep, the Pet(CO(2)) increased by 3.4 Torr (P < 0.001) and the MCAV fell by 11.7% (P < 0.001). A marked decrease in cerebral vascular reactivity was noted in all subjects, with an average fall of 70.1% (P = 0.001). This decrease in hypercapnic cerebral vascular reactivity may, at least in part, explain the stage III-IV NREM sleep-related reduction in cortical blood flow.

Increases in cerebral blood flow produced by vasoactive agents will increase blood oxygen level-dependent (BOLD) MRI signal intensity. The effects of such vasodilation on activation-related signal changes are incompletely characterized. The two signal changes may be simply additive or there may be more a complex interaction. To investigate this, BOLD MRI was performed in four normal male subjects using T2*-weighted echo planar imaging; brain volumes were acquired every 6.2 s, using a Siemens VISION scanner operating at 2 Tesla; each volume consisted of 64 sequential transverse slices (64 × 64 pixels per slice, 3 × 3 × 3 mm). Sixteen periods of visual stimulation were produced using a flickering checkerboard (8 Hz, 31 s On/31 s Off); this was coupled with five periods of hypercapnia (4% inspired CO2, 62 s On/124 s Off). Data were analyzed using SPM96. Mean signal intensity, calculated globally for the whole brain, closely mirrored changes in the partial pressure of end-tidal CO2 (PCO2), and hypercapnia was associated with widespread significant signal increases (P < 0.001), predominantly within grey matter. As expected, the visual stimulation produced significant signal changes within the occipital cortex (P < 0.001). Within the occipital cortex, no significant interactions (P > 0.001) between the effects of the visual stimulation and PCO2 were present. The increases in PCO2 imposed dynamically in the present study would increase cerebral blood flow by between 25 and 40%, an increase within the physiological range and comparable to that induced by neural activation. With this flow change the effects of vasodilation, on an activation-related signal change, are simply additive.

We have used voluntary tongue contraction to test whether we can image activation of the hypoglossal nuclei within the human brain stem by using functional magnetic resonance imaging (fMRI). Functional images of the whole brain were acquired in eight subjects by using T2-weighted echo planar imaging (blood oxygen level development) every 6.2 s. Sequences of images were acquired during 12 periods of 31-s “isometric” rhythmic tongue contraction alternated with 12 periods of 31-s tongue relaxation. Noise arising from cardiac- and respiratory-related movement was removed either by filtration (high pass; cutoff 120 s) or by inclusion in the statistical analysis as confounding effects of no interest. For the group, tongue contraction was associated with significant signal increases ( P < 0.05 corrected for multiple comparisons) in the sensorimotor cortex, supplementary motor area, operculum, insula, thalamus, and cerebellum. For the group and for six of eight individuals, significant signal increases were also seen within the medulla ( P < 0.001, predefined region of interest with no correction for multiple comparisons); this signal is most likely to reflect neuronal activation associated with the hypoglossal motor nuclei. The data demonstrate that fMRI can be used to detect, simultaneously, the cerebral and brain stem control of tongue movement.

Multiple factors may contribute to the dyspnea associated with restrictive ventilatory disease (RVD). Simple models that examine specific features of this problem are likely to provide insight into the mechanisms. Previous models of RVD utilizing elastic loads may not represent completely the impact on pulmonary and chest wall receptors derived from breathing at low thoracic volumes. The purpose of this study was to investigate the sensory consequences of breathing at low lung volumes induced by external thoracic restriction in an attempt to further elucidate the etiology of dyspnea in this setting. Ten men were studied, with and without an inelastic corset applied at residual volume (restriction resulted in mean reductions in vital capacity, functional residual capacity, residual volume, and forced expired volume in 1 s of 44, 31, 12.5, and 42%, respectively). During 10-min steady-state exercise tests (at a workload set to achieve approximately 65% maximum heart rate), restriction resulted in significant increases, compared with control, in minute ventilation (61 vs. 49 l/min), respiratory frequency (43 vs. 23 breaths/min), and visual analog scale measurements of respiratory discomfort (65 vs. 20 mm). Alveolar hyperventilation (end-tidal PCO2 = 39 vs. 44 Torr for control) and mild O2 desaturation (arterial blood O2 saturation = 93 vs. 95% for control) occurred. Hypoxemia, atelectasis, increased work and effort of breathing, or a decrease in the volume-related feedback from chest wall and/or lungs could be responsible for the increased dyspnea reported. External thoracic restriction provides a useful model to study mechanisms of dyspnea in RVD.