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Biomedical subjects

Ronald M Harper

Publications and source records attributed to Ronald M Harper.

At least 19 recordsLinked to original sources
PubMed2006

Elevated mean diffusivity in widespread brain regions in congenital central hypoventilation syndrome.

PURPOSE: To investigate whether mean diffusivity (MD) values are altered in brain areas underlying cardiovascular and respiratory control in congenital central hypoventilation syndrome (CCHS). MATERIALS AND METHODS: Conventional and diffusion tensor imaging were performed in 15 CCHS and 30 control subjects, using a 3.0-Tesla MRI unit. Mean diffusivity maps were calculated from diffusion-weighted images, spatially normalized, smoothed, and compared between groups using analysis of covariance at each voxel with age as covariate. Global mean MD values of gray and white matter were determined in individual subjects and compared between groups and with age. RESULTS: Increased MD values appeared in CCHS over control subjects within multiple areas influencing breathing and cardiovascular control, including the midbrain, pons, and dorsal and ventral medulla. Other altered sites included cerebellar cortex and deep nuclei, basal ganglia, basal forebrain, and temporal and frontal cortices. Global mean MD values for gray and white matter did not differ between groups; however, gray matter MD values significantly increased with age (P < 0.02) in CCHS patients only. CONCLUSION: Increased MD values suggest regional alterations or injury; affected areas include brainstem sites classically associated with autonomic and respiratory control. Other altered regions mediate additional physiological characteristics impaired in CCHS.

Adolescent↗
PubMed2006

Signs and symptoms of sleep-disordered breathing in trauma survivors: a matched comparison with classic sleep apnea patients.

Chronic posttraumatic sleep disturbance may include sleep-disordered breathing (SDB), but this disorder of sleep respiration is usually not suspected in trauma survivors. Sleep breathing signs and symptoms were studied in 178 adults-all with SDB-including typical sleep clinic patients (N = 89) reporting classic snoring and sleepiness and crime victims (N = 89) with insomnia and posttraumatic stress. Significant differences (p < 0.0001) were common between groups. Sleep breathing complaints, loud snoring, marked obesity, and obstructive sleep apnea were prevalent in sleep clinic patients; crime victims reported more insomnia, nightmares, poor sleep quality, leg jerks, cognitive-affective symptoms, psychotropic medication usage, and less snoring but more upper airway resistance syndrome. Both groups reported high rates of fatigue or sleepiness, nocturia, morning dry mouth, and morning headaches. Awareness of these clinical features might enhance detection of SDB among trauma survivors.

Adult↗
PubMed2005

Regional brain response patterns to Cheyne-Stokes breathing.

Cheyne-Stokes breathing (CSB) results from impaired integration of sensory information with respiratory motor output; however, regions mediating the disturbed control are unknown. We examined functional magnetic resonance imaging signals during CSB within sleep to determine affected areas. Two male patients with severe obstructive sleep apnea were scanned while asleep over multiple sessions during which they exhibited CSB. Significant signal increases coincident with apneic periods emerged bilaterally in the cerebellar cortex, hippocampus, mediodorsal thalamus, frontal cortex and precentral gyrus. Signals declined bilaterally in the anterior cingulate cortex and postcentral gyrus. The reduced activation in primary sensory cortex and increased signals prior to breathing onset in the motor cortex are consistent with loss of sensory stimulation by airflow, and with anticipatory action of the motor cortex prior to initiation of breathing. Hippocampal and anterior cingulate cortex participation likely reflect previously-demonstrated roles for initiating inspiratory efforts and resolving sensory information and motor action, respectively.

Adult↗
PubMed2005

Neuroanatomic deficits in congenital central hypoventilation syndrome.

Congenital Central Hypoventilation Syndrome (CCHS) patients exhibit compromised autonomic regulation, reduced breathing drive during sleep, diminished ventilatory responses to chemoreceptor stimulation, and diminished air hunger perception. The syndrome provides an opportunity to partition neural processes regulating breathing and cardiovascular action. No obvious lesions appear with conventional magnetic resonance imaging; however, T2 relaxometry procedures can detect reduced cell or fiber density or diminished myelination not found with routine evaluation. High-resolution T1, proton density, and T2-weighted brain images were collected from 12 patients and 28 age- and gender-matched controls. Voxel-by-voxel T2 maps were generated from the proton density and T2-weighted images and evaluated by voxel-based-relaxometry procedures. Normalized and smoothed T2 maps were compared between groups using analysis of covariance at each voxel, with age and ventricle size included as covariates. Patients showed damaged or maldeveloped tissue, principally right-sided, including white matter from the level of the anterior cingulate cortex caudally to the level of the posterior cingulate and laterally to the posterior superior temporal cortex. Portions of the posterior, mid, and anterior cingulate, as well as the internal capsule, putamen, and globus pallidus and basal forebrain extending to the anterior and medial thalamus were affected. Deficits in the cingulum bundle and mid-hippocampus and ventral prefrontal cortex appeared, as well as the right cerebellar cortex and deep nuclei. Neuroanatomic deficiencies in limbic structures suggest a structural basis for reduced air hunger perception, thermoregulatory and autonomic deficiencies in the syndrome, while cerebellar deficits may also contribute to breathing and cardiovascular dysregulation.

Adolescent↗
PubMed2005

Inspiratory loading elicits aberrant fMRI signal changes in obstructive sleep apnea.

We hypothesized that neural processes mediating deficient sensory and autonomic regulatory mechanisms in obstructive sleep apnea (OSA) would be revealed by responses to inspiratory loading in brain regions regulating sensory and motor control. Functional magnetic resonance imaging (fMRI) signals and physiologic changes were assessed during baseline and inspiratory loading in 7 OSA patients and 11 controls, all male and medication-free. Heart rate increases to inspiratory loading began earlier and load pressures were achieved later in OSA patients. Comparable fMRI changes emerged in multiple brain regions in both groups, including limbic, cerebellar, midbrain, and primary motor cortex. However, in OSA subjects, altered signals appeared in primary sensory thalamus and sensory cortex, supplementary motor cortex, cerebellar cortex and deep nuclei, cingulate, medial temporal, and insular cortices, right hippocampus, and midbrain. Signal delays occurred in basal ganglia. We conclude that areas mediating sensory and autonomic processes, and motor timing, are affected in OSA; many of these areas overlap regions of previously demonstrated gray matter loss.

Adult↗
PubMed2005

Aberrant neural responses to cold pressor challenges in congenital central hypoventilation syndrome.

Patients with congenital central hypoventilation syndrome (CCHS), a condition characterized by impaired ventilatory responses to chemoreceptor stimulation, do not show the normal increase in respiratory rate and respiratory-related heart rate variation to cold forehead stimulation, a challenge that bypasses central chemoreceptors. We hypothesized that a forehead cold pressor challenge would reveal abnormal neural response patterns, as assessed by functional magnetic resonance imaging, in brain regions that are responsible for the integration of cold afferent stimulation with respiratory and cardiovascular output in patients with CCHS. Primary sensory thalamic and cortical areas for the forehead showed diminished responses in 13 patients with CCHS (ventilator dependent during sleep but not waking, no Hirschsprung's disease) compared with 14 control subjects, despite initial signal changes in the cortex being similar in both groups. Cerebellar cortex and deep nuclei; basal ganglia; and middle to posterior cingulate, insular, frontal, and temporal cortices showed reduced signal rises in patients with CCHS. Areas within the frontal and anterior cingulate cortices exhibited marked signal declines in control subjects but little change in patients with CCHS. No response occurred in either group in the dorsal medulla, but medial and ventral medullary areas showed enhanced signals in patients with CCHS. The cold pressor stimulation did not recruit dorsal medullary sites that would be affected by PHOX2B (a mutation of which is associated with the syndrome) expression in either group but demonstrated deficient cerebellar and medial medullary influences that, by action on rostral sites, may underlie the loss of respiratory responses.

Adolescent↗
PubMed2005

FMRI responses to hyperoxia in congenital central hypoventilation syndrome.

Congenital Central Hypoventilation Syndrome (CCHS) patients show partial retention of peripheral chemoreception despite impaired ventilatory responses to CO2 and hypoxia. The condition allows examination of central responses to hyperoxia, which minimizes afferent traffic from peripheral chemoreceptors. We used functional magnetic resonance imaging to assess blood oxygen level-dependent signals over the brain during a baseline and subsequent 2-min hyperoxia (100% O2) period in 14 CCHS and 15 control subjects. After partitioning gray matter and correcting for global effects, the images were analyzed using volume-of-interest time trends followed by repeated-measures ANOVA and conventional cluster analyses. Respiratory rates initially (first 20 s) fell in CCHS, but rose in control subjects; CCHS heart rate increased in the first minute, and then decreased in the second minute, as in controls, but with muted rise and extent of decline. Multiple sites within the cerebellum, midbrain, and pons responded similarly to the challenge in both groups. Response patterns differed early in the right amygdala, paralleling initial respiratory pattern deficits, and late in the right insula, concomitant with cardiac rate differences. Signals also differed between groups in the medial and anterior cingulate, hippocampus, head of caudate, and lentiform nuclei, as well as pontine and midbrain structures and regions within the superior temporal and inferior frontal cortical gyri. The findings emphasize that structures that can alter respiratory timing, such as the amygdala, and modulate sympathetic outflow, such as the right insula, are deficient in CCHS. Medullary and pontine areas targeted by PHOX2B expression are also affected.

Adolescent↗
PubMed2005

Functional abnormalities in brain areas that mediate autonomic nervous system control in advanced heart failure.

BACKGROUND: Heart failure patients show substantial gray matter loss in brain areas that mediate autonomic control. Those injuries may lead to the aberrant autonomic patterns found in the syndrome. The purpose of this study was to determine if functional responses in the brain to an autonomic challenge would differ from normal patterns and would appear in areas of previously-demonstrated gray matter loss. METHODS AND RESULTS: We subjected 6 heart failure patients (left ventricular ejection fraction 0.15 +/- 0.08; age 49 +/- 12 years) and 16 controls (age 48 +/- 11 years) to a forehead cold pressor challenge that would enhance sympathetic outflow and assessed functional magnetic resonance image signals over the entire brain during a 54-second baseline and 90-second challenge. Application of the cold stimulus elicited aberrant responses in the anterior and posterior hypothalamus, bilateral amygdala, hippocampus, cerebellar cortex, insular cortex, mid/posterior cingulate cortex, right ventral frontal cortex, and temporal and frontal cortices. Many of the areas neighbored or overlaid regions of previously demonstrated gray matter damage. Both classical autonomic control regions, as well as brain areas modulating these sites showed deficient responses, some of which appeared to be of an overdampened or underdampened nature. CONCLUSION: The findings suggest that the earlier demonstrated changes in brain structure in heart failure result in aberrant functional neural responses; these dysfunctions may contribute to progression of the pathology in heart failure.

Adult↗
PubMed2004

Intermittent hypoxia damages cerebellar cortex and deep nuclei.

Obstructive sleep apnea patients show cerebellar cortex and deep nuclei gray matter loss, a possible consequence of intermittent hypoxia (IH) accompanying the syndrome. We exposed Sprague-Dawley rats (n=24) to room air only or 10.3% O2, balance N2, alternating every 480 s (240 s duty cycle) with room air for 5, 10, 15, 20 or 30 h (7.5 h per day) during light periods. IH-exposed rats showed increased numbers of damaged Purkinje cells (31.1, 50.5, 54.7, 65.2, and 94.4% for 5, 10, 15, 20 and 30 h groups, respectively; p<0.001 for slopes of the total, swollen/autolysed, and shrunken/dark cell counts), as assessed by hematoxylin and eosin staining. Anti-caspase-3 antibody density increased in the fastigial nuclei subsequent to 5-h exposure. Short-term IH exposure elicits dose-dependent cerebellar Purkinje and fastigial neuron damage.

Animals↗
PubMed2004

Geniohyoid muscle properties and myosin heavy chain composition are altered after short-term intermittent hypoxic exposure.

Patients with obstructive sleep apnea (OSA) often exhibit fatigued or inefficient upper airway dilator and constrictor muscles; an upper airway dilator, the geniohyoid (GH) muscle, is a particular example. Intermittent hypoxia (IH) is a frequent concomitant of OSA, and it may trigger muscle fiber composition changes that are characteristic of a fatigable nature. We examined effects of short-term IH on diaphragmatic and GH muscle fiber composition and fatigue properties by exposing 24 rats to alternating 10.3% O(2)-balance N(2) and room air every 480 s (240 s duty cycle) for a total duration of 5, 10, 15, 20, or 30 h. Sternohyoid fiber composition was also examined. Control animals were exposed to room air on the same schedule. Single-fiber analyses showed that GH muscle fiber types changed completely from myosin heavy chain (MHC) type 2A to MHC type 2B after 10 h of exposure, and the conversion was maintained for at least 30 h. Sternohyoid muscle fibers showed a delayed transition from MHC type 2A/2B to MHC type 2B. In contrast, major fiber types of the diaphragm were not significantly altered. The GH muscles showed similar tension-frequency relationships in all groups, but an increased fatigability developed, proportional to the duration of IH treatment. We conclude that short-term IH exposure alters GH muscle composition and physical properties toward more fatigable, fast-twitch types and that it may account for the fatigable upper airway fiber types found in sleep-disturbed breathing.

Adaptation, Physiological↗
PubMed2004

Functional magnetic resonance imaging during hypotension in the developing animal.

Hypotension in adult animals recruits brain sites extending from cerebellar cortex to the midbrain and forebrain, suggesting a range of motor and endocrine reactions to maintain perfusion. We hypothesized that comparable neural actions during development rely more extensively on localized medullary processes. We used functional MRI to assess neural responses during sodium nitroprusside challenges in 14 isoflurane-anesthetized kittens, aged 14-25 days, and seven adult cats. Baseline arterial pressure increased with age in kittens, and basal heart rates were higher. The magnitude of depressor responses increased with age, while baroreceptor reflex sensitivity initially increased over those of adults. In contrast to a decline in adult cats, functional MRI signal intensity increased significantly in dorsal and ventrolateral medullary regions and the midline raphe in the kittens during the hypotensive challenges. In addition, significant signal intensity differences emerged in cerebellar cortex and deep nuclei, dorsolateral pons, midbrain tectum, hippocampus, thalamus, and insular cortex. The altered neural responses in medullary baroreceptor reflex sites may have resulted from disinhibitory or facilitatory influences from cerebellar and more rostral structures as a result of inadequately developed myelination or other neural processes. A comparable immaturity of blood pressure control mechanisms in humans would have significant clinical implications.

Age Factors↗
PubMed2004

Temporal trends of cardiac and respiratory responses to ventilatory challenges in congenital central hypoventilation syndrome.

Congenital central hypoventilation syndrome (CCHS) patients exhibit respiratory deficits to ventilatory challenges, diminished breathing drive during sleep, and reduction of respiratory-related heart rate variation, but at least partially preserved peripheral chemoreception. We hypothesized that integration of afferent activity with respiratory motor output is deficient in CCHS, rather than chemoreceptor failure, and that examination of trends in heart and breathing rates and variabilities following ventilatory challenges may clarify the deficient mechanisms. Twelve children with CCHS and 12 age- and gender-matched control cases were subjected to hyperoxic hypercapnic, poikylocapnic hypoxic, and hyperoxic challenges while supine. Heart and respiratory rates and variabilities during 60-s baseline and 120-s challenge periods were assessed. Hypoxia and hypercapnia enhanced breathing rate in control subjects; in CCHS cases, the rise differed during hypercapnia and did not occur to hypoxia. Hyperoxia showed initial transient patterns in breathing rate that differed between groups. A heart rate increase to hypoxia and late decline to hyperoxia were muted in CCHS patients. In hypercapnia, heart rate followed similar rising patterns in both groups. Overall CCHS heart rate variability was lower in baseline and challenge periods, principally due to diminished respiratory-related variation, especially during hypercapnia. No heart rate variability group differences emerged in hypoxia, and only a late increase for CCHS cases developed in hyperoxia. The findings indicate retention of aspects of chemoreceptor sensitivity in CCHS cases. The heart rate alterations to ventilatory challenges suggest specific compensatory responses of a slower nature remain intact in CCHS, whereas other rapidly changing components are deficient.

Adolescent↗
PubMed2004

Activity changes of the cat paraventricular hypothalamus during stressor exposure.

Dorso-medial paraventricular hypothalamus (PVH) activity was assessed by light scattering procedures in freely behaving cats during auditory stressor exposure. Acoustic noise (> 95dB) raised plasma ACTH concentrations, somatic muscle tonus, respiratory frequency and cardiac rates; PVH activity peaked 0.8s following stimulation, and then markedly declined below baseline to a trough at 9.7s. Hypothalamic responses were not uniformly distributed across the recorded PVH field. Activity changes emerged from subregions within the visualized area, and were widespread at the overall activity zenith and nadir. Isolated pixels appeared opposite in activity pattern to overall changes. We suggest that transient activity increases represent initial PVH neural stress responses, and that subsequent profound declines result from neural inhibitory feedback.

Acoustic Stimulation↗
PubMed2004

A method for removal of global effects from fMRI time series.

We present a technique for removing global effects from functional magnetic resonance imaging (fMRI) images, using a voxel-level linear model of the global signal (LMGS). The procedure does not assume low-frequency global effects and is based on the assumption that the global signal (the time course of the average intensity per volume) is replicated in the same pattern throughout the brain, although not necessarily at the same magnitude. A second assumption is that all effects that match the global signal are of no interest and can be removed. The method involves modeling the time course of each voxel to the global signal and removing any such global component from the voxel's time course. A challenge that elicits a large change in the global blood oxygenation level-dependent (BOLD) signal, inspired hypercapnia (5% CO(2)/95% O(2)), was administered to 14 subjects during a 144-s, 24-scan fMRI procedure; baseline series were also collected. The method was applied to these data and compared to intensity normalization and low-frequency spline detrending. A large global BOLD signal increase emerged to the hypercapnic challenge. Intensity normalization failed to remove global components due to regional variability. Both LMGS and spline detrending effectively removed low-frequency components, but unlike spline detrending (which is designed to remove only low frequency trends), the LMGS removed higher-frequency global fluctuations throughout the challenge and baseline series. LMGS removes all effects correlated with the global signal, and may be especially useful for fMRI data that include large global effects and for generating detrended images to use with subsequent volume-of-interest (VOI) analyses.

Adolescent↗
PubMed2003

Global BOLD MRI changes to ventilatory challenges in congenital central hypoventilation syndrome.

We evaluated global blood oxygen level dependent (BOLD) signal changes in gray and white matter in 14 congenital central hypoventilation syndrome (CCHS) and 14 control subjects. One baseline image series with room air and three series with 30 s room air followed by 120 s hypercapnia (5% CO2/95% O2), hypoxia (15% O2/85% N2) or hyperoxia (100% O2) were collected. Hypercapnia and hyperoxia raised, and hypoxia lowered gray and white matter global signal in both groups, with smaller changes in white matter. Signal changes in CCHS cases were lower than control subjects for hypercapnia in gray and white matter, slightly more-enhanced in hypoxia, and, except for initial transient responses, were nearly comparable during hyperoxia. Initial signal rate or pattern changes emerged in all three challenges in gray or white matter in control, but not CCHS cases. Neural or vascular mechanisms mediate perfusion differently in CCHS; the aberrant initial transient responses may reflect deficiencies in rapidly-varying physiologic interactions in the syndrome.

Adolescent↗
PubMed2003

Functional magnetic resonance signal changes in neural structures to baroreceptor reflex activation.

The sequence of neural responses to exogenous arterial pressure manipulation remains unclear, especially for extramedullary sites. We used functional magnetic resonance imaging procedures to visualize neural responses during pressor (phenylephrine) and depressor (sodium nitroprusside) challenges in seven isoflurane-anesthetized adult cats. Depressor challenges produced signal-intensity declines in multiple cardiovascular-related sites in the medulla, including the nucleus tractus solitarius, and caudal and rostral ventrolateral medulla. Signal decreases also emerged in the cerebellar vermis, inferior olive, dorsolateral pons, and right insula. Rostral sites, such as the amygdala and hypothalamus, increased signal intensity as arterial pressure declined. In contrast, arterial pressure elevation elicited smaller signal increases in medullary regions, the dorsolateral pons, and the right insula and signal declines in regions of the hypothalamus, with no change in deep cerebellar areas. Responses to both pressor and depressor challenges were typically lateralized. In a subset of animals, barodenervation resulted in rises and falls of blood pressure that were comparable to these resulting from the pharmacological challenges but different regional neural responses, indicating that the regional signal intensity responses did not derive from global perfusion effects but from baroreceptor mediation of central mechanisms. The findings demonstrate widespread lateralized distribution of neural sites responsive to blood pressure manipulation. The distribution and time course of neural responses follow patterns associated with early and late compensatory reactions.

Anesthesia↗
PubMed2003

Late-developing rostral ventrolateral medullary surface responses to cardiovascular challenges during sleep.

Pressor and depressor manipulations are usually followed by compensatory autonomic, respiratory, somatomotor or arousal responses that limit the extent of blood pressure change. Of neural sites participating in blood pressure control, the rostral ventrolateral medullary surface (RVLMS) contributes significantly, and exhibits rapid-onset overall activity declines and increases to pressor and depressor challenges, respectively. In addition, longer-latency physiological responses develop that further compensate for the homeostatic challenge; some of these later influences are associated with arousal. Late-developing RVLMS activity changes accompanying physiologic responses that normalize a cardiovascular manipulation may provide insights into compensatory neural mechanisms during sleep following sustained or extreme blood pressure changes. We used intrinsic optical imaging procedures in seven unanesthetized adult cats to examine RVLMS and control site responses to pressor and depressor challenges during sleep that resulted in somatomotor, respiratory, heart rate or electroencephalographic indications of late-developing (post-baroreflex) compensatory responses. Although initial RVLMS responses differed in direction between pressor and depressor challenges, neural activity increased later in both manipulations, coincident with overt physiological manifestations indicative of compensatory responses, including arousal. Arousal occurred in 44% of blood pressure challenges. Comparable late-developing neural activity increases were not apparent in control sites. Latencies of late RVLMS responses during rapid eye movement sleep were significantly longer than in quiet sleep for pressor challenges. The pattern of the late RVLMS responses was not dependent on arousal, and suggests that the RVLMS participates in both the early baroreflex response and the late-developing compensatory actions.

Animals↗