A generalized canine transfer function accurately reconstructs central aortic pressure waveforms to enable enhanced pulse wave analysis.

Routine preclinical blood pressure evaluation is an important risk assessment tool. Although proximal aortic pressure is most relevant for key target organs, abdominal aortic pressures are more commonly recorded. Pulse pressure amplification and waveform distortion in abdominal waveforms make it inappropriate for central hemodynamic analytical methods without the use of a mathematical transfer function. Clinical transfer functions have been developed to estimate ascending aortic waveforms from brachial or radial artery waveforms in humans, but no preclinical analogues exist. The aim of this study was to develop a canine-specific transfer function to reconstruct thoracic aortic pressure waveforms from abdominal aortic data to enable the application of central hemodynamic analytical methods. Simultaneous abdominal and thoracic blood pressures were recorded from seven conscious, male beagle dogs administered 3 well-characterized pharmacologic standards and animals were appointed to a training (n = 3) or validation (n = 4) group at baseline and during dosing. A generalized transfer function was developed from the training group data and evaluated for its ability to synthesize thoracic pressure waves in the training and validation groups. Select hemodynamic parameters were evaluated in measured and synthesized thoracic data. There was a high degree of correlation between measured and synthesized thoracic parameters (r2 = 0.74-0.99). There was no difference between indices computed from synthesized or actual thoracic waveforms at baseline or after administration of pharmacologic standards. This work demonstrates that a generalized preclinical transfer function can reproduce thoracic pressure waves across a range of hemodynamic responses thus enabling the application of central hemodynamic analytical methods.

Development and characterization of canine-specific computational models to predict pulsatile arterial hemodynamics and ventricular-arterial coupling.

Pulsatile hemodynamics analyses provide important information about the ventricular-arterial system which cannot be inferred by standard blood pressure measurements. Pulse wave analysis (PWA), wave separation analysis (WSA), and wave power analysis (WPA) characterize arterial hemodynamics with limited preclinical applications. Integrating these tools into preclinical testing may enhance understanding of disease or therapeutic effects on cardiovascular function. We used a canine rapid ventricular pacing (RVP) heart failure model to: (1) Characterize hemodynamics in response to RVP and (2) assess analyses from flow waveforms synthesized from pressure compared to those derived from measured flow. Female canines (n = 7) were instrumented with thoracic aortic pressure transducers, ventricular pacing leads, and an ascending aortic flow probe. Data were collected at baseline, 1 week, and 1 month after RVP onset. RVP progressively reduced stroke volume (SV), the PWA SV estimator, and WSA and WPA pulsatility and wave reflection indices. Indices derived from synthesized flow exhibited similar directional changes and high concordance with measured flow calculations. Our data demonstrate the value of analytical hemodynamic methods to gain deeper insight into cardiovascular function in preclinical models. These approaches can provide complementary value to standard endpoints in evaluating potential effects of pharmaceutical agents intended for human use.

Immediate inhibition of spinal secretory phospholipase A2 prevents the pain and elevated spinal neuronal hyperexcitability and neuroimmune regulatory genes that develop with nerve root compression.

Cervical nerve root injury induces a host of inflammatory mediators in the spinal cord that initiate and maintain neuronal hyperexcitability and pain. Secretory phospholipase A2 (sPLA2) is an enzyme that has been implicated as a mediator of pain onset and maintenance in inflammation and neural injury. Although sPLA2 modulates nociception and excitatory neuronal signaling in vitro, its effects on neuronal activity and central sensitization early after painful nerve root injury are unknown. This study investigated whether inhibiting spinal sPLA2 at the time of nerve root compression (NRC) modulates the pain, dorsal horn hyperexcitability, and spinal genes involved in glutamate signaling, nociception, and inflammation that are seen early after injury. Rats underwent a painful C7 NRC injury with immediate intrathecal administration of the sPLA2 inhibitor thioetheramide-phosphorlycholine. Additional groups underwent either injury alone or sham surgery. One day after injury, behavioral sensitivity, spinal neuronal excitability, and spinal cord gene expression for glutamate receptors (mGluR5 and NR1) and transporters (GLT1 and EAAC1), the neuropeptide substance P, and pro-inflammatory cytokines (TNFα, IL1α, and IL1ß) were assessed. Treatment with the sPLA2 inhibitor prevented mechanical allodynia, attenuated neuronal hyperexcitability in the spinal dorsal horn, restored the proportion of spinal neurons classified as wide dynamic range, and reduced genes for mGluR5, substance P, IL1α, and IL1ß to sham levels. These findings indicate spinal regulation of central sensitization after painful neuropathy and suggest that spinal sPLA2 is implicated in those early spinal mechanisms of neuronal excitability, perhaps via glutamate signaling, neurotransmitters, or inflammatory cascades.

An inter-species computational analysis of vibrotactile sensitivity in Pacinian and Herbst corpuscles.

Vibration sensing is ubiquitous among vertebrates, with the sensory end organ generally being a multilayered ellipsoidal structure. There is, however, a wide range of sizes and structural arrangements across species. In this work, we applied our earlier computational model of the Pacinian corpuscle to predict the sensory response of different species to various stimulus frequencies, and based on the results, we identified the optimal frequency for vibration sensing and the bandwidth over which frequencies should be most detectable. We found that although the size and layering of the corpuscles were very different, almost all of the 19 species studied showed very similar sensitivity ranges. The human and goose were the notable exceptions, with their corpuscle tuned to higher frequencies (130-170 versus 40-50 Hz). We observed no correlation between animal size and any measure of corpuscle geometry in our model. Based on the results generated by our computational model, we hypothesize that lamellar corpuscles across different species may use different sizes and structures to achieve similar frequency detection bands.

Changes in Neuronal Activity in the Anterior Cingulate Cortex and Primary Somatosensory Cortex With Nonlinear Burst and Tonic Spinal Cord Stimulation.

INTRODUCTION: Although nonlinear burst and tonic SCS are believed to treat neuropathic pain via distinct pain pathways, the effectiveness of these modalities on brain activity in vivo has not been investigated. This study compared neuronal firing patterns in the brain after nonlinear burst and tonic SCS in a rat model of painful radiculopathy. METHODS: Neuronal activity was recorded in the ACC or S1 before and after nonlinear burst or tonic SCS on day 7 following painful cervical nerve root compression (NRC) or sham surgery. The amplitude of nonlinear burst SCS was set at 60% and 90% motor threshold to investigate the effect of lower amplitude SCS on brain activity. Neuronal activity was recorded during and immediately following light brush and noxious pinch of the paw. Change in neuron firing was measured as the percent change in spikes post-SCS relative to pre-SCS baseline. RESULTS: ACC activity decreases during brush after 60% nonlinear burst compared to tonic (p < 0.05) after NRC and compared to 90% nonlinear burst (p < 0.04) and pre-SCS baseline (p < 0.03) after sham. ACC neuron activity decreases (p < 0.01) during pinch after 60% and 90% nonlinear burst compared to tonic for NRC. The 60% of nonlinear burst decreases (p < 0.02) ACC firing during pinch in both groups compared to baseline. In NRC S1 neurons, tonic SCS decreases (p < 0.01) firing from baseline during light brush; 60% nonlinear burst decreases (p < 0.01) firing from baseline during brush and pinch. CONCLUSIONS: Nonlinear burst SCS reduces firing in the ACC from a painful stimulus; a lower amplitude nonlinear burst appears to have the greatest effect. Tonic and nonlinear burst SCS may have comparable effects in S1.

Computational and Psychophysical Experiments on the Pacinian Corpuscle's Ability to Discriminate Complex Stimuli.

Recognizing and discriminating vibrotactile stimuli is an essential function of the Pacinian corpuscle. This function has been studied at length in both a computational and an experimental setting, but the two approaches have rarely been compared, especially when the computational model has a high level of structural detail. In this paper, we explored whether the predictions of a multiscale, multiphysical computational model of the Pacinian corpuscle can predict the outcome of a corresponding psychophysical experiment. The discrimination test involved either two simple stimuli with frequency in the 160-500 Hz range, or two complex stimuli formed by combining the waveforms for a 100-Hz stimulus with a second stimulus in the 160-500 Hz range. The subjects' ability to distinguish between the simple stimuli increased as the frequency increased, a result consistent with the model predictions for the same stimuli. The model also predicted correctly that subjects would find the complex stimuli more difficult to distinguish than the simple ones and also that the discriminability of the complex stimuli would show no trend with frequency difference.

A finite-element model of mechanosensation by a Pacinian corpuscle cluster in human skin.

The Pacinian corpuscle (PC) is the cutaneous mechanoreceptor responsible for sensation of high-frequency (20-1000 Hz) vibrations. PCs lie deep within the skin, often in multicorpuscle clusters with overlapping receptive fields. We developed a finite-element mechanical model of one or two PCs embedded within human skin, coupled to a multiphysics PC model to simulate action potentials elicited by each PC. A vibration was applied to the skin surface, and the resulting mechanical signal was analyzed using two metrics: the deformation amplitude ratio ([Formula: see text], [Formula: see text] and the phase shift of the vibration ([Formula: see text], [Formula: see text] between the stimulus and the PC. Our results showed that the amplitude attenuation and phase shift at a PC increased with distance from the stimulus to the PC. Differences in amplitude ([Formula: see text] and phase shift ([Formula: see text] between the two PCs in simulated clusters directly affected the interspike interval between the action potentials elicited by each PC ([Formula: see text]. While [Formula: see text] had a linear relationship with [Formula: see text], [Formula: see text]'s effect on [Formula: see text] was greater for lower values of [Formula: see text]. In our simulations, the separation between PCs and the distance of each PC from the stimulus location resulted in differences in amplitude and phase shift at each PC that caused [Formula: see text] to vary with PC location. Our results suggest that PCs within a cluster receive different mechanical stimuli which may enhance source localization of vibrotactile stimuli, drawing parallels to sound localization in binaural hearing.