Signatures of Somatic Inhibition and Dendritic Excitation in Auditory Brainstem Field Potentials.

Extracellular voltage recordings (Ve ; field potentials) provide an accessible view of in vivo neural activity, but proper interpretation of field potentials is a long-standing challenge. Computational modeling can aid in identifying neural generators of field potentials. In the auditory brainstem of cats, spatial patterns of sound-evoked Ve can resemble, strikingly, Ve generated by current dipoles. Previously, we developed a biophysically-based model of a binaural brainstem nucleus, the medial superior olive (MSO), that accounts qualitatively for observed dipole-like Ve patterns in sustained responses to monaural tones with frequencies >∼1000 Hz (Goldwyn et al., 2014). We have observed, however, that Ve patterns in cats of both sexes appear more monopole-like for lower-frequency tones. Here, we enhance our theory to accurately reproduce dipole and non-dipole features of Ve responses to monaural tones with frequencies ranging from 600 to 1800 Hz. By applying our model to data, we estimate time courses of paired input currents to MSO neurons. We interpret these inputs as dendrite-targeting excitation and soma-targeting inhibition (the latter contributes non-dipole-like features to Ve responses). Aspects of inferred inputs are consistent with synaptic inputs to MSO neurons including the tendencies of inhibitory inputs to attenuate in response to high-frequency tones and to precede excitatory inputs. Importantly, our updated theory can be tested experimentally by blocking synaptic inputs. MSO neurons perform a critical role in sound localization and binaural hearing. By solving an inverse problem to uncover synaptic inputs from Ve patterns we provide a new perspective on MSO physiology.SIGNIFICANCE STATEMENT Extracellular voltages (field potentials) are a common measure of brain activity. Ideally, one could infer from these data the activity of neurons and synapses that generate field potentials, but this "inverse problem" is not easily solved. We study brainstem field potentials in the region of the medial superior olive (MSO); a critical center in the auditory pathway. These field potentials exhibit distinctive spatial and temporal patterns in response to pure tone sounds. We use mathematical modeling in combination with physiological and anatomical knowledge of MSO neurons to plausibly explain how dendrite-targeting excitation and soma-targeting inhibition generate these field potentials. Inferring putative synaptic currents from field potentials advances our ability to study neural processing of sound in the MSO.

Deep brain stimulation with short versus conventional pulse width in Parkinson's disease and essential tremor: A systematic review and meta-analysis.

BACKGROUND: To maximize clinical benefit and minimize stimulation-induced side effects, optimising deep brain stimulation (DBS) parameters is paramount. Recent literature suggests a potential benefit of short pulse width DBS (spDBS; ≤40 µs) over conventional pulse width DBS (cDBS; ≥60 µs) in movement disorders. OBJECTIVE: To compare therapeutic window (TW), therapeutic and side effects and energy consumption of spDBS and cDBS in movement disorders. METHODS: We systematically searched Medline, Embase, Cochrane Library and Web of Science. Appropriate paired analyses were performed. RESULTS: Nine Parkinson's disease (PD) (143 patients), 4 essential tremor (ET) (26 patients) and no dystonia studies were included in the meta-analysis. TW defined as therapeutic amplitude range was larger with spDBS vs. cDBS in PD (standardized mean difference (SMD) = -1.04, p < 0.001) and ET (SMD = -0.71, p < 0.001), but the TW in terms of charge per pulse (CPP) did not differ. In PD, no differences were found in therapeutic and side effects (MDS-UPDRS-III, speech and gait, dyskinesia, non-motor symptoms and quality of life). In ET, Fahn-Tolosa-Marin Tremor Rating Scale was lower with spDBS vs. cDBS (SMD = 0.36, p < 0.001). A qualitative analysis suggested fewer stimulation-induced side effects with spDBS. CPP was lower with spDBS vs. cDBS in PD (SMD = 0.79, p < 0.001) and ET (MD = 46.46 nC, p < 0.001), but real-world data on battery longevity are lacking. CONCLUSION: Although spDBS enlarges the TW as a wider amplitude range in both PD and ET, it does not alter TW defined by CPP. The therapeutic efficacy of spDBS is not different from cDBS in PD, but spDBS apparently induces more tremor reduction in ET.

Pathophysiology of renal hemodynamics and renal cortical microcirculation in a porcine model of elevated intra-abdominal pressure.

BACKGROUND: Elevated intra-abdominal pressure (IAP) has been shown to impair renal perfusion and renal function. This study was designed to further investigate the effects of elevated IAP on renal venous hemodynamics and renal perfusion pressure (RPP). Another aim was to evaluate the renal cortical microcirculation by sidestream dark field (SDF) imaging in a porcine model of elevated IAP. METHODS: In 11 pigs, IAP was increased stepwise while renal hemodynamics and urinary output were recorded. RPP (RPP = mean arterial pressure minus IAP) and renal filtration gradient (RFG = mean arterial pressure minus 2xIAP) were calculated. Renal cortical microcirculatory perfusion was assessed by calculating the microvascular flow index (MFI) based on SDF data. RESULTS: With IAP elevated to 30 mm Hg, renal arterial and venous flow decreased in parallel by 34% (p < 0.05) and RPP decreased by 12% (p < 0.05). With increasing IAP, renal vascular resistance increased and MFI decreased significantly. RFG showed a moderate correlation with renal blood flow (r = 0.39, p < 0.05) and MFI (r = 0.46, p < 0.005), whereas RPP did not. CONCLUSIONS: In a porcine model of IAP-induced renal impairment, we observed a parallel decrease in renal venous and arterial blood flow together with blood flow redistribution away from the kidney. SDF imaging was used for the first time to assess renal cortical microcirculation and MFI was found to decrease with increasing IAP. RFG, as a clinical estimator of renal perfusion, correlated moderately with renal blood flow and microcirculatory perfusion, whereas RPP did not. Increased renal vascular resistance with elevated IAP might account for this.

Variations on a Dexterous theme: peripheral time-intensity trading.

Sound pressure level changes can affect the timing of spiketrains. Timing of spiketrains is critical for sensitivity to interaural timing differences (ITDs). Interaural level differences (ILDs) can therefore affect the ITD cue. It has been hypothesized that ILDs may be coded indirectly through a peripheral conversion of level to time (but it should be cautioned that the changes in phase with SPL in low-CF AN fibers of the cat are more complicated) (Jeffress, L.A., 1948. A place theory of sound localization. J. Comp. Physiol. Psychol. 41, 35-39). We tested this conversion by recording from auditory nerve fibers to broadband noise at different SPLs. For each fiber, correlograms were constructed to compare timing to fine-structure across SPLs. We find generally a decrease in the time delay between spikes and the stimulus with increasing SPL. However, the magnitudes of the shift in time are surprisingly small, and dependent on characteristic frequency (CF): the largest shifts are approximately 10 micros/dB and occur at the lowest CFs. Nevertheless, the effects of level on spike timing are systematic and of a magnitude to which the binaural system is sensitive. Thus, even though the results indicate that ILD is not traded for ITD in a simple way, the possibility that low-frequency ILDs affect the binaural percept via a peripheral level-to-time conversion cannot be excluded.

Full or pressure limited reperfusion of an acute myocardial infarct results in a different wall thickness and deformation of the distal myocardium--implications for clinical reperfusion strategies.

AIM: The study aim was to determine the sequence of changes in both wall thickness and function in 'at risk' myocardium (using M-mode and radial strain/strain-rate imaging) induced by reperfusion of an acute transmural infarction, and to relate these changes to the presence or absence of a pressure-limiting stenosis in the infarct related epicardial vessel. METHODS: Eighteen closed-chest pigs were randomized into two groups (each with nine animals). In Group I, 4 weeks prior to induction of an acute transmural infarct, a copper coated stent was implanted in the proximal circumflex artery (Cx) to create a coronary artery stenosis of between 30 and 95% lumen diameter. At 4 weeks, the stenotic Cx vessel was occluded for 90 min by inflation of a PTCA balloon placed proximal to the stenosis to produce an acute transmural infarction. In Group II (the control group), 90 min Cx occlusion was performed in a normal vessel. In both groups the resulting acute transmural infarction was reperfused after 90 min by removing the PTCA balloon. For both groups, cardiac ultrasound data, including strain/strain-rate imaging, were collected at all stages of the investigation for subsequent offline analysis. RESULTS: In both groups, acute reperfusion (TIMI flow 3 or 2), immediately increased infarct zone end-diastolic wall thickness due to the development of oedema. The acute increase in wall thickness was significantly higher in the non-stenotic animals as compared to the ones with a residual stenosis. Neither of the groups showed any tendency to normalize deformation (strain) during the reperfusion period. CONCLUSION: In this experimental study, the measurement of end-diastolic wall thickness was a simple and non-invasive tool to monitor acute infarct reperfusion. It also provided information on the presence of a flow limiting stenosis in the infarct related artery after restoration of the flow. The deformation of the myocardium remained impaired during early reperfusion, whether reflow was at full pressure or low pressure due to a residual stenosis in the infarct related artery.

Numerical assessment of the impact of a flow wire on its velocity measurements.

Blood flow velocities can be measured using a Doppler flow wire. This numerical study evaluates the impact of a 0.014" flow wire on the measured frequencies in a straight artery with diameters of 3 mm and 4 mm, under steady and pulsatile flow conditions. Simulations were performed with the wires positioned differently in the artery (perfectly centred and at an offset of 0.5 mm from the wall) and with different types of wire (tilted and straight). Measurements were taken at range gates from 4 mm to 10 mm. During simulations using a 3-mm vessel under pulsatile flow conditions, the relative error between the measured and reference maximum frequency (occurring in absence of the wire) decreased from 17.7% to 11.6% (with a mean value of 14.9%). During simulations using an off-centre 1.5 degree tilted wire, the mean error was approximately 5%. Therefore, our study suggests that that a centrally positioned flow wire is unfavourable for measuring flow velocities.

The interaural time difference pathway: a comparison of spectral bandwidth and correlation sensitivity at three anatomical levels.

Temporal differences between the two ears are critical for spatial hearing. They can be described along axes of interaural time difference (ITD) and interaural correlation, and their processing starts in the brainstem with the convergence of monaural pathways which are tuned in frequency and which carry temporal information. In previous studies, we examined the bandwidth (BW) of frequency tuning at two stages: the auditory nerve (AN) and inferior colliculus (IC), and showed that BW depends on characteristic frequency (CF) but that there is no difference in the mean BW of these two structures when measured in a binaural, temporal framework. This suggested that there is little frequency convergence in the ITD pathway between AN and IC and that frequency selectivity determined by the cochlear filter is preserved up to the IC. Unexpectedly, we found that AN and IC neurons can be similar in CF and BW, yet responses to changes in interaural correlation in the IC were different than expected from coincidence patterns ("pseudo-binaural" responses) in the AN. To better understand this, we here examine the responses of bushy cells, which provide monaural inputs to binaural neurons. Using broadband noise, we measured BW and correlation sensitivity in the cat trapezoid body (TB), which contains the axons of bushy cells. This allowed us to compare these two metrics at three stages in the ITD pathway. We found that BWs in the TB are similar to those in the AN and IC. However, TB neurons were found to be more sensitive to changes in stimulus correlation than AN or IC neurons. This is consistent with findings that show that TB fibers are more temporally precise than AN fibers, but is surprising because it suggests that the temporal information available monaurally is not fully exploited binaurally.

Relationship between Abdominal Pressure, Pulmonary Compliance, and Cardiac Preload in a Porcine Model.

Rationale. Elevated intra-abdominal pressure (IAP) may compromise respiratory and cardiovascular function by abdomino-thoracic pressure transmission. We aimed (1) to study the effects of elevated IAP on pleural pressure, (2) to understand the implications for lung and chest wall compliances and (3) to determine whether volumetric filling parameters may be more accurate than classical pressure-based filling pressures for preload assessment in the setting of elevated IAP. Methods. In eleven pigs, IAP was increased stepwise from 6 to 30 mmHg. Hemodynamic, esophageal, and pulmonary pressures were recorded. Results. 17% (end-expiratory) to 62% (end-inspiratory) of elevated IAP was transmitted to the thoracic compartment. Respiratory system compliance decreased significantly with elevated IAP and chest wall compliance decreased. Central venous and pulmonary wedge pressure increased with increasing IAP and correlated inversely (r = -0.31) with stroke index (SI). Global end-diastolic volume index was unaffected by IAP and correlated best with SI (r = 0.52). Conclusions. Increased IAP is transferred to the thoracic compartment and results in a decreased respiratory system compliance due to decreased chest wall compliance. Volumetric filling parameters and transmural filling pressures are clearly superior to classical cardiac filling pressures in the assessment of cardiac preload during elevated IAP.

The quantification of dipyridamole induced changes in regional deformation in normal, stunned or infarcted myocardium as measured by strain and strain rate: an experimental study.

UNLABELLED: Strain rate imaging (SRI) during dobutamine stress-echocardiography (DSE) has been shown to differentiate between ischemic substrates based on the segmental response. Dipyridamole stress echo (DIPSE) is currently used as an alternative to DSE in detecting coronary artery disease. The aim of this study was: (a) to determine the normal response in peak-systolic myocardial strain (S) and strain-rate (SR) during DIPSE and (b) to compare the S and SR responses of DSE and DIPSE in the same chronically ischemic/infarcted segments in the setting of single vessel disease. METHODS: The deformation response to DIPSE was studied in 7 normal pigs and in an additional 18 pigs, with a spectrum of ischemic substrates. S and SR data were extracted from a posterior wall "at risk" segment at baseline and during both DSE and DIPSE. The animals were divided into different ischemic substrate (stunning, non-transmural and transmural infarction), based on the DSE response as previously suggested. RESULTS: In normal myocardium, dipyridamole induced no changes in regional systolic deformation neither during nor after the infusion. Furthermore there was no detectable response in S and SR in segments with either a non-transmural or a transmural infarction. However, in myocardial segments with a DSE "stunning response", both end systolic S and peak-systolic SR tended to "normalize" at peak dipyridamole dose. CONCLUSIONS: These results suggest that dipyridamole does not induce changes in regional deformation in normal or (partially) infarcted myocardium. Only in stunned myocardium (in the setting of single-vessel disease), dipyridamole tends to normalize deformation.