Comparison of Cortical Autonomic Network-Linked Sympathetic Excitation by Mueller Maneuvers and Breath-Holds in Subjects With and Without Obstructive Sleep Apnea.

In healthy young volunteers, acquisition of blood oxygen level-dependent (BOLD) magnetic resonance (MR) and muscle sympathetic nerve (MSNA) signals during simulation of obstructive or central sleep apnea identified cortical cardiovascular autonomic regions in which the BOLD signal changed synchronously with acute noradrenergic excitation. In the present work, we tested the hypothesis that such Mueller maneuvers (MM) and breath-holds (BH) would elicit greater concomitant changes in mean efferent nerve firing and BOLD signal intensity in patients with moderate to severe obstructive sleep apnea (OSA) relative to age- and sex-matched individuals with no or only mild OSA (Apnea Hypopnea Index, AHI, <15 events/h). Forty-six participants, 24 with OSA [59 ± 8 years; AHI 31 ± 18 events/h (mean ± SD); seven women] and 22 without (58 ± 11 years; AHI 7 ± 4; nine women), performed a series of three MM and three BH, in randomly assigned order, twice: during continuous recording of MSNA from the right fibular nerve and, on a separate day, during T2∗-weighted echo planar functional MR imaging. MSNA at rest was greater in those with OSA (65 ± 19 vs. 48 ± 17 bursts per 100 heart beats; p < 0.01). MM and BH elicited similar heart rate, blood pressure, and MSNA responses in the two cohorts; group mean BOLD data were concordant, detecting no between-group differences in cortical autonomic region signal activities. The present findings do not support the concept that recurring episodes of cyclical apnea during sleep alter cortical or peripheral neural responsiveness to their simulation during wakefulness by volitional Mueller maneuvers or breath-holds.

Cortical autonomic network gray matter and sympathetic nerve activity in obstructive sleep apnea.

The sympathetic excitation elicited acutely by obstructive apnea during sleep (OSA) carries over into wakefulness. We hypothesized that OSA induces structural changes in the insula and cingulate, key central autonomic network elements with projections to brainstem sympathetic premotor regions. The aims of this study were to (1) apply two distinct but complementary methods (cortical thickness analysis [CTA] and voxel-based morphometry [VBM]) to compare insula and cingulate gray matter thickness in participants without and with OSA; (2) determine whether oxygen desaturation index (ODI) relates to cortical thickness; and (3) determine whether cortical thickness or volume in these regions predicts muscle sympathetic nerve activity (MSNA) burst incidence (BI). Overnight polysomnography, anatomical magnetic resonance imaging, and MSNA data were acquired in 41 participants with no or mild OSA (n = 19; 59 ± 2 years [Mean ± SE]; six females; apnea-hypopnea index [AHI] 7 ± 1 events per hour) or moderate-to-severe OSA (n = 22; 59 ± 2 years; five females; AHI 31 ± 4 events per hour). Between-group CTA analyses identified cortical thinning within the left dorsal posterior insula and thickening within the left mid-cingulate cortex (LMCC), whereas VBM identified thickening within bilateral thalami (all [p < .05]). CTA revealed inverse relationships between ODI and bilateral dpIC and left posterior cingulate cortex (LPCC) or precuneus thickness. Positive correlations between BI and LMCC gray matter thickness or volume were evident with both methods and between BI and left posterior thalamus volume using VBM. In OSA, the magnitude of insular thinning, although a function of hypoxia severity, does not influence MSNA, whereas cingulate and thalamic thickening relate directly to the intensity of sympathetic discharge during wakefulness.

Arousal From Sleep and Sympathetic Excitation During Wakefulness.

Obstructive apnea during sleep elevates the set point for efferent sympathetic outflow during wakefulness. Such resetting is attributed to hypoxia-induced upregulation of peripheral chemoreceptor and brain stem sympathetic function. Whether recurrent arousal from sleep also influences daytime muscle sympathetic nerve activity is unknown. We therefore tested, in a cohort of 48 primarily nonsleepy, middle-aged, male (30) and female (18) volunteers (age: 59±1 years, mean±SE), the hypothesis that the frequency of arousals from sleep (arousal index) would relate to daytime muscle sympathetic burst incidence, independently of the frequency of apnea or its severity. Polysomnography identified 24 as having either no or mild obstructive sleep apnea (apnea-hypopnea index <15 events/h) and 24 with moderate-to-severe obstructive sleep apnea (apnea-hypopnea index >15 events/h). Burst incidence correlated significantly with arousal index (r=0.53; P<0.001), minimum oxygen saturation (r=-0.43; P=0.002), apnea-hypopnea index (r=0.41; P=0.004), age (r=0.36; P=0.013), and body mass index (r=0.33; P=0.022) but not with oxygen desaturation index (r=0.28; P=0.056). Arousal index was the single strongest predictor of muscle sympathetic nerve activity burst incidence, present in all best subsets regression models. The model with the highest adjusted R2 (0.456) incorporated arousal index, minimum oxygen saturation, age, body mass index, and oxygen desaturation index but not apnea-hypopnea index. An apnea- and hypoxia-independent effect of sleep fragmentation on sympathetic discharge during wakefulness could contribute to intersubject variability, age-related increases in muscle sympathetic nerve activity, associations between sleep deprivation and insulin resistance or insomnia and future cardiovascular events, and residual adrenergic risk with persistence of hypertension should therapy eliminate obstructive apneas but not arousals.

Association between resting-state brain functional connectivity and muscle sympathetic burst incidence.

The insula (IC) and cingulate are key components of the central autonomic network and central nodes of the salience network (SN), a set of spatially distinct but temporally correlated brain regions identified with resting-state (task free) functional MRI (rsMRI). To examine the SN's involvement in sympathetic outflow, we tested the hypothesis that individual differences in intrinsic connectivity of the SN correlate positively with resting postganglionic muscle sympathetic nerve activity (MSNA) burst incidence (BI) in subjects without and with obstructive sleep apnea (OSA). Overnight polysomnography, 5-min rsMRI, and fibular MSNA recording were performed in 36 subjects (mean age 57 yr; 10 women, 26 men). Independent component analysis (ICA) of the entire cohort identified the SN as including bilateral IC, pregenual anterior cingulate cortex (pgACC), midcingulate cortex (MCC), and the temporoparietal junction (TPJ). There was a positive correlation between BI and the apnea-hypopnea index (AHI) (P < 0.001), but dual-regression analysis identified no differences in SN functional connectivity between subjects with no or mild OSA (n = 17) and moderate or severe (n = 19) OSA. Correlation analysis relating BI to the strength of connectivity within the SN revealed large (i.e., spatial extent) and strong correlations for the left IC (P < 0.001), right pgACC/MCC (P < 0.006), left TPJ (P < 0.004), thalamus (P < 0.035), and cerebellum (P < 0.013). Indexes of sleep apnea were unrelated to BI and the strength of SN connectivity. There were no relationships between BI and default or sensorimotor network connectivity. This study links connectivity within the SN to MSNA, demonstrating several of its nodes to be key sympathoexcitatory regions.

Nerve injury triggers changes in the brain.

It is well known that the adult brain is capable of profound plasticity. Much of our understanding of the mechanisms underlying injury-induced changes in the brain is based on animal models. The development of sophisticated noninvasive neuroimaging techniques over the past decade provides a unique opportunity to examine brain plasticity in humans. In this article, the authors examine the consequences of nerve injury and surgical repair on peripheral nerve degeneration and regeneration and review classic animal literature that laid the foundation of injury-induced plasticity research. They relate these concepts to recent findings of functional and structural changes in the human brain following peripheral nerve injury. They then present a working theoretical model that links behavioral outcomes of nerve injury with functional and structural brain plasticity and personality.

Cognitive and default-mode resting state networks: do male and female brains "rest" differently?

Variability in human behavior related to sex is supported by neuroimaging studies showing differences in brain activation patterns during cognitive task performance. An emerging field is examining the human connectome, including networks of brain regions that are not only temporally-correlated during different task conditions, but also networks that show highly correlated spontaneous activity during a task-free state. Both task-related and task-free network activity has been associated with individual task performance and behavior under certain conditions. Therefore, our aim was to determine whether sex differences exist during a task-free resting state for two networks associated with cognitive task performance (executive control network (ECN), salience network (SN)) and the default mode network (DMN). Forty-nine healthy subjects (26 females, 23 males) underwent a 5-min task-free fMRI scan in a 3T MRI. An independent components analysis (ICA) was performed to identify the best-fit IC for each network based on specific spatial nodes defined in previous studies. To determine the consistency of these networks across subjects we performed self-organizing group-level ICA analyses. There were no significant differences between sexes in the functional connectivity of the brain areas within the ECN, SN, or the DMN. These important findings highlight the robustness of intrinsic connectivity of these resting state networks and their similarity between sexes. Furthermore, our findings suggest that resting state fMRI studies do not need to be controlled for sex.

Chronic pain and sensorimotor deficits following peripheral nerve injury.

Following upper limb peripheral nerve transection and surgical repair (PNIr) patients frequently exhibit sensory and motor deficits, but only some develop chronic neuropathic pain. Thus, the sensorimotor outcome of PNIr may be impacted by individual factors. Therefore, our aims were to determine if patients with chronic neuropathic pain (PNI-P) following PNIr (1) are distinguished from patients without pain (PNI-NP) and healthy controls (HCs) by the psychological factors of pain catastrophizing, neuroticism or extraversion, and (2) exhibit more severe sensorimotor deficits than patients who did not develop chronic pain (PNI-NP). Thirty-one patients with complete median and/or ulnar nerve transection (21 PNI-NP, 10 PNI-P) and 21 HCs completed questionnaires to assess pain characteristics, pain catastrophizing, neuroticism and extraversion and underwent sensorimotor evaluation. Nerve conduction studies revealed incomplete sensorimotor peripheral recovery based on abnormal sensory and motor latency and amplitude measures in transected nerves. The patients also had significant deficits of sensory function (two-point discrimination and vibration, touch, and warmth detection), sensorimotor integration, and fine motor dexterity. Compared to PNI-NP patients, PNI-P patients had higher vibration detection thresholds, performed worse on sensory-motor integration tasks, had greater motor impairment, and showed more impaired nerve conduction. Furthermore, PNI-P patients had reduced cold pain tolerance, elevated pain intensity and unpleasantness during the cold pressor test, and they scored higher on neuroticism and pain-catastrophizing scales. These data demonstrate that chronic neuropathic pain following PNIr is associated with impaired nerve regeneration, profound sensorimotor deficits and a different psychological profile that may be predictive of poor recovery after injury.

Cutting your nerve changes your brain.

Following upper limb peripheral nerve transection and surgical repair, some patients regain good sensorimotor function while others do not. Understanding peripheral and central mechanisms that contribute to recovery may facilitate the development of new therapeutic interventions. Plasticity following peripheral nerve transection has been demonstrated throughout the neuroaxis in animal models of nerve injury. However, the brain changes that occur following peripheral nerve transection and surgical repair in humans have not been examined. Furthermore, the extent to which peripheral nerve regeneration influences functional and structural brain changes has not been characterized. Therefore, we asked whether functional changes are accompanied by grey and/or white matter structural changes and whether these changes relate to sensory recovery? To address these key issues we (i) assessed peripheral nerve regeneration; (ii) measured functional magnetic resonance imaging brain activation (blood oxygen level dependent signal; BOLD) in response to a vibrotactile stimulus; (iii) examined grey and white matter structural brain plasticity; and (iv) correlated sensory recovery measures with grey matter changes in peripheral nerve transection and surgical repair patients. Compared to each patient's healthy contralesional nerve, transected nerves have impaired nerve conduction 1.5 years after transection and repair, conducting with decreased amplitude and increased latency. Compared to healthy controls, peripheral nerve transection and surgical repair patients had altered blood oxygen level dependent signal activity in the contralesional primary and secondary somatosensory cortices, and in a set of brain areas known as the 'task positive network'. In addition, grey matter reductions were identified in several brain areas, including the contralesional primary and secondary somatosensory cortices, in the same areas where blood oxygen level dependent signal reductions were identified. Furthermore, grey matter thinning in the post-central gyrus was negatively correlated with measures of sensory recovery (mechanical and vibration detection) demonstrating a clear link between function and structure. Finally, we identified reduced white matter fractional anisotropy in the right insula in a region that also demonstrated reduced grey matter. These results provide insight into brain plasticity and structure-function-behavioural relationships following nerve injury and have important therapeutic implications.

Stability of tactile- and pain-related fMRI brain activations: an examination of threshold-dependent and threshold-independent methods.

Functional MRI can be used to assess brain plasticity over time. To confidently attribute changes in activation patterns to cortical plasticity, it is important to establish the stability of cortical activation patterns. Because little is known concerning the stability of somatosensory-evoked brain responses, we assessed the reproducibility of within-subject responses in key somatosensory regions [thalamus, primary and secondary cortex (S1, S2)] to tactile and painful stimuli using threshold-dependent and threshold-independent analyses. Six subjects underwent four biweekly scanning sessions during which tactile and painful stimuli were applied to the hand. Standard thresholding and voxel counting techniques were compared with a novel threshold-independent method utilizing percent signal change within the regions of interest. Contralateral S1 and S2 were qualitatively reproducible during tactile stimulation, with overlapping activations >85% of the time. S2 was also highly reproducible during painful stimulation (88%), whereas S1 was less reproducible (44%). However, activation in the thalamus to both tactile and painful stimulation was highly variable. Ipsilateral activation was consistent within S2 but sparse within S1 and thalamus. Deactivations within ipsilateral S1 occurred 48% of the time with tactile stimuli, and 90% of the time with painful stimuli. Within contralaterally activated regions intraclass correlations (ICCs) were very high using the unthresholded method regardless of the type of stimulation, whereas much lower ICCs arose from the thresholded analyses. These data indicate that a threshold-independent analysis can produce more reproducible outcomes than a standard threshold-dependent analysis.

Two systems of resting state connectivity between the insula and cingulate cortex.

The insula and cingulate cortices are implicated in emotional, homeostatic/allostatic, sensorimotor, and cognitive functions. Non-human primates have specific anatomical connections between sub-divisions of the insula and cingulate. Specifically, the anterior insula projects to the pregenual anterior cingulate cortex (pACC) and the anterior and posterior mid-cingulate cortex (aMCC and pMCC); the mid-posterior insula only projects to the posterior MCC (pMCC). In humans, functional neuroimaging studies implicate the anterior insula and pre/subgenual ACC in emotional processes, the mid-posterior insula with awareness and interoception, and the MCC with environmental monitoring, response selection, and skeletomotor body orientation. Here, we tested the hypothesis that distinct resting state functional connectivity could be identified between (1) the anterior insula and pACC/aMCC; and (2) the entire insula (anterior, middle, and posterior insula) and the pMCC. Functional connectivity was assessed from resting state fMRI scans in 19 healthy volunteers using seed regions of interest in the anterior, middle, and posterior insula. Highly correlated, low-frequency oscillations (< 0.05 Hz) were identified between specific insula and cingulate subdivisions. The anterior insula was shown to be functionally connected with the pACC/aMCC and the pMCC, while the mid/posterior insula was only connected with the pMCC. These data provide evidence for a resting state anterior insula-pACC/aMCC cingulate system that may integrate interoceptive information with emotional salience to form a subjective representation of the body; and another system that includes the entire insula and MCC, likely involved in environmental monitoring, response selection, and skeletomotor body orientation.

Human anterior cingulate cortex neurons encode cognitive and emotional demands.

The cortical mechanisms and substrates of cognitive and emotional demands are poorly understood. Lesion studies and functional imaging implicate the anterior cingulate cortex (ACC). The caudal ACC (cACC) has been implicated in cognitive processes such as attention, salience, interference, and response competition, mostly on the basis of neuroimaging results. To test the hypothesis that individual cACC neurons subserve these functions, we monitored neuronal activity from single cells in the cACC while subjects were engaged in a mental arithmetic task, the cognitively demanding counting Stroop task, and/or the emotional Stroop interference task. We now report the first direct measures of single neurons in humans identifying a population of cACC neurons that respond differentially or in a graded manner to cognitively demanding high- and low-conflict Stroop tasks, including those with emotional valence. These data indicate that cACC neurons may be acting as salience detectors when faced with conflict and difficult or emotional stimuli, consistent with neuroimaging results of cACC responses to abrupt sensory, novel, task-relevant, or painful stimuli.