Robert C. Frysinger’s research while affiliated with University of California, Los Angeles and other places

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Publications (42)


Inspiratory loading elicits aberrant fMRI signal changes in obstructive sleep apnea
  • Article

April 2006

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21 Reads

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127 Citations

Respiratory Physiology & Neurobiology

Katherine E Macey

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Mary A Woo

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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.


Functional magnetic resonance imaging responses to expiratory loading in obstructive sleep apnea

December 2003

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75 Reads

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133 Citations

Respiratory Physiology & Neurobiology

Obstructive sleep apnea (OSA) is characterized by diminished upper airway muscle phasic and tonic activation during sleep, but enhanced activity during waking. We evaluated neural mechanisms underlying these patterns with functional magnetic resonance imaging procedures during baseline and expiratory loading conditions in nine medication-free OSA and 16 control subjects. Both groups developed similar expiratory loading pressures, but appropriate autonomic responses did not emerge in OSA cases. Reduced neural signals emerged in OSA cases within the frontal cortex, anterior cingulate, cerebellar dentate nucleus, dorsal pons, anterior insula and lentiform nuclei. Signal increases in OSA over control subjects developed in the dorsal midbrain, hippocampus, quadrangular cerebellar lobule, ventral midbrain and ventral pons. Fastigial nuclei and the amygdala showed substantially increased variability in OSA subjects. No group differences were found in the thalamus. OSA patients show aberrant responses in multiple brain areas and inappropriate cardiovascular responses to expiratory loading, perhaps as a consequence of previously-demonstrated limbic, cerebellar and motor area gray matter loss.


Fig. 3. Top: regions showing signal increases that correlated significantly (P 0.01) with inverse heart rate in control subjects evoked by the cold pressor challenge. Regions showing significant increases included the cerebellum (1-2), thalamus (5-7; A, C), insular cortex (3-8; A-F), hippocampus, amygdala, and superior temporal cortex (2-4; C-D), frontal cortex (3-4; G-H), and cingulate regions (8-10; G-H). The regions are overlaid onto the mean of the 16 control subjects' anatomic images. The color bar codes t statistic. Bottom: slice levels for 1-10 in the axial plane and A-H in the coronal plane are shown in the outline drawings.
Fig. 4. Regions showing significant (P 0.05) signal increases that correlated with inverse heart rate in major brain structures. Significance levels (t statistic) are conveyed in the color bar and overlaid onto a mean of a set of anatomic images (16 control, 10 OSA) in sagittal, coronal, and axial views. The signal intensity changes, plotted over time, for each cluster at the center of the cross hairs are shown on the right. Time 0 represents onset of challenge. * Significant between-group differences are shown at the relevant time points (P 0.05).
FMRI responses to cold pressor challenges in control and obstructive sleep apnea subjects
  • Article
  • Full-text available

May 2003

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65 Reads

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164 Citations

Journal of Applied Physiology: Respiratory, Environmental and Exercise Physiology

Obstructive sleep apnea (OSA) patients exhibit altered sympathetic outflow, which may reveal mechanisms underlying the syndrome. We used functional MRI (fMRI) in 16 control and 10 OSA subjects who were free of cardiovascular or mood-altering drugs to examine neural responses to a forehead cold pressor challenge, which elicits respiratory slowing, bradycardia, and enhanced sympathetic outflow. The magnitude of cold-induced bradycardia was smaller, and respiratory slowing showed greater intersubject variability and reached a nadir later in OSA patients. Both groups showed similar signal changes to cold stimulation in multiple brain sites. However, signal increases emerged in OSA over controls in anterior and posterior cingulate and cerebellar and frontal cortex, whereas signals markedly declined in the ventral thalamus, hippocampus, and insula rather than rising as in controls. Anomalous responses often paralleled changes in breathing and heart rate. Medullary, midbrain areas and lentiform and cerebellar dentate nuclei also showed lower signals in OSA cases. Cold pressor physiological responses are modified in OSA and may result from both diminished and exaggerated responses in multiple brain structures.

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Neural responses during Valsalva maneuvers in obstructive sleep apnea syndrome

April 2003

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35 Reads

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111 Citations

Journal of Applied Physiology: Respiratory, Environmental and Exercise Physiology

The repetitive upper airway muscle atonic episodes and cardiovascular sequelae of obstructive sleep apnea (OSA) suggest dysfunction of specific neural sites that integrate afferent airway signals with autonomic and somatic outflow. We determined neural responses to the Valsalva maneuver by using functional magnetic resonance imaging. Images were collected during a baseline and three Valsalva maneuvers in 8 drug-free OSA patients and 15 controls. Multiple cortical, midbrain, pontine, and medullary regions in both groups showed intensity changes correlated to airway pressure. In OSA subjects, the left inferior parietal cortex, superior temporal gyrus, posterior insular cortex, cerebellar cortex, fastigial nucleus, and hippocampus showed attenuated signal changes compared with controls. Enhanced responses emerged in the left lateral precentral gyrus, left anterior cingulate, and superior frontal cortex of OSA patients. The anterior cingulate, cerebellar cortex, and posterior insula exhibited altered response timing patterns between control and OSA subjects. The response patterns in OSA subjects suggest deficits in particular neural pathways that normally mediate the Valsalva maneuver and compensatory actions in other structures.


Brain Responses Associated With the Valsalva Maneuver Revealed by Functional Magnetic Resonance Imaging

January 2003

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243 Reads

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145 Citations

Journal of Neurophysiology

The Valsalva maneuver, a test frequently used to evaluate autonomic function, recruits discrete neural sites. The time courses of neural recruitment relative to accompanying cardiovascular and breathing patterns are unknown. We examined functional magnetic resonance imaging signal changes within the brain to repeated Valsalva maneuvers and correlated these changes with physiological trends. In 12 healthy subjects (age, 30-58 yr), a series of 25 volumes (20 gradient echo echo-planar image slices per volume) was collected using a 1.5-Tesla scanner during a 60-s baseline and 90-s challenge period consisting of three Valsalva maneuvers. Regions of interest were examined for signal intensity changes over baseline and challenge conditions in cardiorespiratory-related regions. In addition, whole brain correlations between signal intensity and heart rate and airway load pressure were performed on a voxel-by-voxel basis. Significant signal changes, correlated with the time course of load pressure and heart rate, emerged within multiple areas, including the amygdala and hippocampus, insular and lateral frontal cortices, dorsal pons, dorsal medulla, lentiform nucleus, and fastigial and dentate nuclei of the cerebellum. Signal intensities peaked early in the Valsalva maneuver within the hippocampus and amygdala, later within the dorsal medulla, pons and midbrain, and deep cerebellar nuclei, and last within the lentiform nuclei and the lateral prefrontal cortex. The ventral pontine signals increased during the challenge, but not in a fashion correlated to load pressure or heart rate. Sites showing little or no correlation included the vermis and medial prefrontal cortex. These data suggest an initiating component arising in rostral brain areas, a later contribution from cerebellar nuclei, basal ganglia, and lateral prefrontal cortex, and a role for the ventral pons in mediating longer term processes.


Fig. 1. (a) The shading indicates a region of statistically significant reduction in gray matter concentration within the left hippocampus for the group overlaid on a standard brain template. Cross hairs indicate voxel of maximum significance ( p 1⁄4 0 : 004, F ð 1 ; 11 Þ 1⁄4 78 corrected for multiple comparisons based on a priori, bilateral, hippocampal region of interest) at 2 34 (left), 2 20 (posterior), 2 20 (superior) mm relative to the midline of the anterior commissure; the images are oriented to a horizontal plane through the anterior and posterior commissures (R, right; A, anterior). (b) Individual gray matter signal changes from the seven control and seven OSA patients in the left hippocampus (upper panel) at the voxel of maximum significance indicated in (a) and at the comparable voxel within the right hippocampus (lower panel; i.e. 34 (right), 2 20 (posterior), 2 20 (superior) mm); the change at this focus failed to reach significance, due to the increased variability of the data. 
Brain Morphology Associated with Obstructive Sleep Apnea

December 2002

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164 Reads

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595 Citations

American Journal of Respiratory and Critical Care Medicine

Obstructive sleep apnea (OSA) is characterized by repeated occurrences of hypoxic, hypercapnic, and transient blood pressure elevation episodes that may damage or alter neural structures. Underdeveloped structures or pre-existing damage in brain areas may also contribute to the genesis of the syndrome. Brain morphology in 21 patients with OSA and in 21 control subjects was assessed using high-resolution T1-weighted magnetic resonance imaging. Three-dimensional brain images were obtained with voxels of approximately 1 mm3. Images were spatially normalized and segmented into gray matter, white matter, and cerebrospinal fluid. For each segment, regional volumetric differences were determined relative to age, handedness, and group (patients with OSA versus control subjects), using voxel-based morphometry, with OSA effects weighted by disease severity. A significant age effect on total gray matter was found in control subjects but not in patients with OSA. Diminished regional and often unilateral gray matter loss was apparent in multiple sites of the brain in patients with OSA, including the frontal and parietal cortex, temporal lobe, anterior cingulate, hippocampus, and cerebellum. Unilateral loss in well-perfused structures suggests onset of neural deficits early in the OSA syndrome. The gray matter loss occurs within sites involved in motor regulation of the upper airway as well as in areas contributing to cognitive function.



Fig. 1. Traces of arterial pressure, heart rate (in beats/min), respiratory rate (in breaths/min), and extent of thoracic wall movement during baseline and after bolus intravenous delivery of 20-30 g/kg 5-hydroxytryptamine (5-HT) (A), 10 g/kg 5-HT (B), and saline (C). Vertical dashed lines indicate start of challenge. Values are means SE.
Fig. 2. Signal-intensity changes in regions of the medulla (A), cerebellum (B), pons and midbrain (C), and hypothalamus and amygdala (D) after an equivalent volume of intravenous saline. Vertical dashed lines indicate start of challenge. Values are means SE.
Fig. 4. Signal-intensity changes at 2 dose levels of 5-HT, combined with signal changes overlaid on comparable anatomic images in cerebellum [fastigial (A), interpositus and dentate nuclei (B), and cerebellar vermis (C)], and cerebellum-related regions [inferior olivary nucleus (D) and dorsolateral pons (E)], and the parapyramidal region (F). Stereotactic designations and pseudocolor calculations are as for Fig. 3. Vertical dashed lines indicate start of challenge. *Significance difference compared with baseline, P 0.005.
Fig. 6. Traces of arterial pressure, heart rate (in beats/min), and respiratory rate (in breaths/min) after highdose 5-HT administration, together with signal values from each sampled area over the baseline and course of this challenge. Values are means SE. Signal changes are grouped by timing of initial changes to the challenges: early, mid, or late onset. Early-onset declines developed primarily from medullary sites, as well as the cerebellar fastigial nucleus. Sites slightly delayed in responses include the parapyramidal region, the interpositus and dentate cerebellar nuclei, and the dorsolateral pons. Late-onset response increases emerged principally from rostral brain stem and forebrain sites but also from inferior olive, spinal trigeminal nucleus, and caudal nucleus of the solitary tract. Note the late-onset decreased response from the cerebellar vermis. Vertical dashed lines indicate start of challenge, termination of apnea, and return of respiratory rate to baseline.
Neural responses to intravenous serotonin revealed by functional magnetic resonance imaging

February 2002

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80 Reads

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13 Citations

Journal of Applied Physiology: Respiratory, Environmental and Exercise Physiology

We examined the sequence of neural responses to the hypotension, bradycardia, and apnea evoked by intravenous administration of 5-hydroxytryptamine (serotonin). Functional magnetic resonance imaging signal changes were assessed in nine isoflurane-anesthetized cats during baseline and after a bolus intravenous low dose (10 microg/kg) or high dose (20-30 microg/kg) of 5-hydroxytryptamine. In all cats, high-dose challenges elicited rapid-onset, transient signal declines in the intermediate portion of the solitary tract nucleus, caudal midline and caudal and rostral ventrolateral medulla, and fastigial nucleus of the cerebellum. Slightly delayed phasic declines appeared in the dentate and interpositus nuclei and dorsolateral pons. Late-developing responses also emerged in the solitary tract nucleus, parapyramidal region, periaqueductal gray, spinal trigeminal nucleus, inferior olivary nucleus, cerebellar vermis, and fastigial nucleus. Amygdala and hypothalamic sites showed delayed and prolonged signal increases. Intravenous serotonin infusion recruits cerebellar, amygdala, and hypothalamic sites in addition to classic brain stem cardiopulmonary areas and exhibits site-specific temporal patterns.


A device for feline head positioning and stabilization during magnetic resonance imaging

October 2001

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15 Reads

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5 Citations

Magnetic Resonance Imaging

Minimization of head movement and reproduction of standard head positions are essential for reliable brain functional magnetic resonance imaging. Devices for stabilization and alignment of feline preparations are not available currently. We describe a system that involves minimal surgery, allows for both acute and chronic atraumatic positioning, and has the potential to be used for unanesthetized animals. The device uses non-metallic materials and stabilizes the head by means of an apparatus that fixes the head with nylon screws and dental cement in the frontal sinuses. Application of the head-stabilizing device decreases head movements by more than a factor of ten. Anatomical images show that this device provides 3 dimensional head placement at a precision comparable to that of a stereotactic frame, i.e. within 1 mm.


Fig. 2. Breathing rate in percent change from the baseline (top) and heart rate in percent change from the baseline (bottom) for all four subjects. Time 0 s represents start of challenge time (dashed line).  
Fig. 3. Respiratory effort (top), breathing rate in percent change from baseline (middle), and heart rate in percent change from baseline (bottom) for one subject. Time 0 s represents start of challenge time (dashed line).  
Neural signal changes associated with cardiac and respiratory measures vs boxcar analysis in functional magnetic resonance imaging (fMRI)

February 2001

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213 Reads

Functional magnetic resonance imaging (fMRl) was used to measure signal changes in the brain during a respiratory challenge that elevated blood pressure. Subjects were scanned during a baseline period and during a Valsalva maneuver. Results were compared using fixed-effects analysis with the SPM99 package, and examined once using a boxcar model and once by models generated from changes in cardiac and respiratory signals during the breathing challenge. Models based on physiological measures resulted in greater localization of signal changes.


Citations (37)


... 28,29 Lateralized insular responses are also relevant to epilepsy, because a propensity exists for some types of seizure discharge to occur during sleep states. Seizure discharge can exert profound influences on arterial blood pressure and heart rate, 30 and a unilateral seizure focus could trigger unique autonomic responses. The influence of cortical structures on subcortical sites carries significant import for cardiorespiratory control. ...

Reference:

Cardiovascular Physiology: Central and Autonomic Regulation
State-dependent cardiac and respiratory changes associated with complex partial epilepsy
  • Citing Article
  • January 1987

... Synaptic plasticity, which is suggested as a model for processes of learning and memory formation, has been extensively described in the hippocampus (Bliss & Collingridge, 1993). However, relatively little is known about synaptic plasticity in the amygdala, which is involved in the integration and control of emotional and autonomic behaviour (Kapp et al., 1981;Rogan & LeDoux, 1996;Swanson & Petrovich, 1998), e.g. conditioned fear and anxiety (Davis et al., 1994;Maren & Fanselow, 1996;Pitkanen et al., 1997), whereby the different subnuclei within the amygdala seem to play different roles in the development and expression of conditioned fear (Killcross et al., 1997). ...

The amygdala, emotion and cardiovascular conditioning
  • Citing Article
  • January 1981

... An electrocardiogram (ECG) was obtained using standard MR-compatible surface electrodes and oxygen saturation was measured using a Nonin oximeter. The ECG and oximetry signals were fed to low noise amplifiers (Parker et al. 1999) and transferred outside the MR room via infrared devices (Harper et al. 2001). Thoracic wall movement was monitored using an air-filled bag placed against the thoracic wall and held in place using a cloth belt. ...

Infrared transfer of electrophysiologic signals during magnetic resonance imaging

Sleep research online: SRO

... Thus, given the described adverse conditions related to imbalances of both cardiac and respiratory systems, investigation of risks associated with late prematurity should include a focus on the dynamic interaction in the cardiorespiratory network. Regulation and autonomic control of respiratory and cardiovascular interactions are crucial for the maintenance of homeostasis during sleep (Harper et al., 1988). In adults, many studies have shown evidence that cardiorespiratory imbalance is associated with obstructive sleep apnea and heart failure, resulting in higher sympathetic tone and potentially ultimately triggering life-threatening events (Harper et al., 2012). ...

Cardiac and Respiratory Interactions Maintaining Homeostasis During Sleep
  • Citing Chapter
  • January 1988

... It is known that cardiorespiratory function in REM sleep is different from that in quiet sleep (1, 3,6,8,9,19) and some efforts (20)(21)(22) have been made to distinguish states of consciousness in adult humans using heart rate. Such investigations have been scarce in the young, and the recent attempts of Harper et al. (23,24) provide important initial observations in this direction. In the current work we study how, and with what confidence, one can use this difference in cardiorespiratory function to distinguish REM from quiet sleep in early life. ...

Machine classification of infant sleep states utilizing cardiorespiratory measures
  • Citing Article
  • January 1985

... Gary Sieck later moved to the Mayo Clinic, distinguishing himself with respiratory muscle descriptions, and was President of the American Physiological Society.During this period, Jing-Xi Zhang, the first neuroscience graduate student to the US from mainland China, joined the lab. Among a large number of other studies, Jing-Xi found respiratory and cardiacrelated neurons in the amygdala central nucleus,129 and blocked the amygdala stimulation breathing influence with a cryoprobe constructed from a Volkswagen fuel injector 130 (I am sad to say, my VW ...

Neuronal discharge patterns in the central nucleus of the amygdala during sleep-waking states
  • Citing Article
  • January 1983

... Whalen and Kapp (1991) reported that the amplitude of the rabbit's nictitating membrane reflex (NMR) was enhanced by stimulation of the central nucleus of the amygdala that also evoked bradycardia but that it was inhibited by stimulation of other regions of the amygdala that concomitantly evoked tachycardia. From these results, Whalen and Kapp (1991) proposed that heart rate change and reflex modification covaried, with heart rate decreases accompanying facilitation and heart rate increases accompanying inhibition of the magnitude of the response (see also Gary Bobo & Bonvallet, 1975;Gebber & Klevans, 1972;Kapp, Whalen, Supple, & Pascoe, 1992;Marks, Frysinger, Trelease, & Harper, 1983;Pascoe, Bradley, & Spyer, 1989;Schlor, Stumpf, & Stock, 1984). Although none of these researchers explicitly postulated a causal relation between HR changes and alterations in reflex amplitude, the findings that the two measures occur together suggest that they are somehow related. ...

Temporal patterning of the baroreflex in response to induced transient hypertension
  • Citing Article
  • January 1983

... Having demonstrated effects of global lesions, extensive evidence came to the forefront demonstrating that effects of a particular amygdala nucleus lesion will differ from those of a discrete lesion of another nucleus or of a large gross With respect to memory fhnction, the central nucleus of the amygdala (CN) has played a critical role in classical conditioning of heart rate (Kapp et al., 1982) identifying reductions in reward magnitude (Kesner et a 1 ., 1 989) and expression of conditioned fear (conditioned freezing) (LeDoux, 1993;Killcross et al., 1997). The hasolateral nucleus of the amygdala (ABL) has been identified as the sensory interface of fear conditioning (LeDou. ...

The Amygdala Central Nucleus: Contributions to Conditioned Cardiovascular Responding during Aversive Pavlovian Conditioning in the Rabbit
  • Citing Chapter
  • January 1982

Advances in Behavioral Biology

... Another potential site of action is the amygdala, which has a relatively dense concentration of NMDA binding sites (Monaghan & Cotman, 1985) and expresses LTP (Chapman, Kairiss, Keenan, & Brown, 1990;Clugnet & LeDoux, 1990;Maren & Fanselow, 1995). The amygdala mediates attention and learning in a variety of aversively motivated situations (Gallagher & Holland, 1994;Hitchcock & Davis, 1987;Kapp, Markgraf, Wilson, Pascoe, & Supple, 1991;LeDoux, Ciccetti, Xagoraris, & Romanski, 1990;LeDoux, Iwata, Cicchetti, & Reis, 1986), including acquisition of the conditioned eyeblink response in rabbits (Kapp, Frysinger, Gallagher, & Bretschneider, 1979;Weisz et al., 1992) and rats (Shors, Mathew, White, Selcher, & Servatius, 1996). In addition, NMDA antagonists injected directly into the amygdala impair or prevent acquisition in many of these same tasks (Campeau et al., 1992;Falls, Miserendino, & Davis, 1992;Kim et al., 1991;Kim & McGaugh, 1992). ...

Effects of amygdala and stiea terminalis lesions on aversive conditioning in the rabbit
  • Citing Article
  • January 1977

... Interestingly, at the same time as these influential demonstrations, evidence emerged that other portions of the medial temporal lobe also had specialized roles in learning and memory. For example, the amygdala was implicated in both aversive and appetitive classical conditioning (Bagshaw and Benzies 1968;Davis 1986;Everitt, Cador, and Robbins 1989;Everitt et al. 1991;Hiroi and White 1991;Jones and Mishkin 1972;Kapp et al. 1979;LeDoux 1993;Weiskrantz 1956) and the perirhinal cortex was shown to be important for object and complex scene learning and memory processes (Gaffan 1994;Kolb et al. 1994;Mumby and Pinel 1994;Zola-Morgan et al. 1993). Taken together, this body of work has been interpreted as suggesting that the HPC, amygdala, and perirhinal cortex are central neural structures of separate learning and memory systems that can operate in parallel and on their own (White and McDonald 2002). ...

Amygdala central nucleus lesions: Effect on heart rate conditioning in the rabbit
  • Citing Article
  • January 1980

Physiology & Behavior