The Safety of Micro-Implants for the Brain.

Technological advancements in electronics and micromachining now allow the development of discrete wireless brain implantable micro-devices. Applications of such devices include stimulation or sensing and could enable direct placement near regions of interest within the brain without the need for electrode leads or separate battery compartments that are at increased risk of breakage and infection. Clinical use of leadless brain implants is accompanied by novel risks, such as migration of the implant. Additionally, the encapsulation material of the implants plays an important role in mitigating unwanted tissue reactions. These risks have the potential to cause harm or reduce the service of life of the implant. In the present study, we have assessed post-implantation tissue reaction and migration of borosilicate glass-encapsulated micro-implants within the cortex of the brain. Twenty borosilicate glass-encapsulated devices (2 × 3.5 × 20 mm) were implanted into the parenchyma of 10 sheep for 6 months. Radiographs were taken directly post-surgery and at 3 and 6 months. Subsequently, sheep were euthanized, and GFAP and IBA-1 histological analysis was performed. The migration of the implants was tracked by reference to two stainless steel screws placed in the skull. We found no significant difference in fluoroscopy intensity of GFAP and a small difference in IBA-1 between implanted tissue and control. There was no glial scar formation found at the site of the implant's track wall. Furthermore, we observed movement of up to 4.6 mm in a subset of implants in the first 3 months of implantation and no movement in any implant during the 3-6-month period of implantation. Subsequent histological analysis revealed no evidence of a migration track or tissue damage. We conclude that the implantation of this discrete micro-implant within the brain does not present additional risk due to migration.

Selective optogenetic stimulation of efferent fibers in the vagus nerve of a large mammal.

BACKGROUND: Electrical stimulation applied to individual organs, peripheral nerves, or specific brain regions has been used to treat a range of medical conditions. In cardiovascular disease, autonomic dysfunction contributes to the disease progression and electrical stimulation of the vagus nerve has been pursued as a treatment for the purpose of restoring the autonomic balance. However, this approach lacks selectivity in activating function- and organ-specific vagal fibers and, despite promising results of many preclinical studies, has so far failed to translate into a clinical treatment of cardiovascular disease. OBJECTIVE: Here we report a successful application of optogenetics for selective stimulation of vagal efferent activity in a large animal model (sheep). METHODS AND RESULTS: Twelve weeks after viral transduction of a subset of vagal motoneurons, strong axonal membrane expression of the excitatory light-sensitive ion channel ChIEF was achieved in the efferent projections innervating thoracic organs and reaching beyond the level of the diaphragm. Blue laser or LED light (>10 mW mm-2; 1 ms pulses) applied to the cervical vagus triggered precisely timed, strong bursts of efferent activity with evoked action potentials propagating at speeds of ∼6 m s-1. CONCLUSIONS: These findings demonstrate that in species with a large, multi-fascicled vagus nerve, it is possible to stimulate a specific sub-population of efferent fibers using light at a site remote from the vector delivery, marking an important step towards eventual clinical use of optogenetic technology for autonomic neuromodulation.

Injection Molded Liquid Crystal Polymer Package for Chronic Active Implantable Devices With Application to an Optogenetic Stimulator.

Implanted electronics require protection from the body's fluids to avoid moisture induced failure. This study presents an injection molded liquid crystal polymer (LCP) package to protect active implantable devices for chronic applications, such as in optogenetic research. The technology is applied and assessed through a custom package for a fully implantable optogenetic stimulation system, built on a versatile telemetry system that can incorporate additional stimulating and recording channels. An adapted quasi-steady state model predicts the lifetime of an enclosure, where the definition of the lifetime is the time before the internal relative humidity (RH) reaches a time constant, or 63%RH, a conservative limit to minimize the risk of corrosion. The lifetime of the LCP optogenetic device is 94 days, and can be extended to 326 days with the inclusion of 5% w/v silica gel desiccant. Samples of the LCP optogenetic device containing humidity sensors testing in saline at 38 °C support the RH change predictions. Desiccants inside the implant enclosure can store permeating moisture and prolong the life expectancy of LCP-based implants to years or decades. The results of this study demonstrates the feasibility of providing reliable protection for chronic optogenetic implants, and the technology can be transferred to other applications as an easily-manufactured, cost-effective, radiofrequency compatible alternative to hermetic packaging for chronic studies.

Intracranial pressure influences the level of sympathetic tone.

Sympathetic overdrive is associated with many diseases, but its origin remains an enigma. An emerging hypothesis in the development of cardiovascular disease is that the brain puts the utmost priority on maintaining its own blood supply; even if this comes at the "cost" of high blood pressure to the rest of the body. A critical step in making a causative link between reduced brain blood flow and cardiovascular disease is how changes in cerebral perfusion affect the sympathetic nervous system. A direct link between decreases in cerebral perfusion pressure and sympathetic tone generation in a conscious large animal has not been shown. We hypothesized that there is a novel control pathway between physiological levels of intracranial pressure (ICP) and blood pressure via the sympathetic nervous system. Intracerebroventricular infusion of saline produced a ramped increase in ICP of up to 20 mmHg over a 30-min infusion period (baseline 4.0 ± 1.1 mmHg). The ICP increase was matched by an increase in mean arterial pressure such that cerebral perfusion pressure remained constant. Direct recordings of renal sympathetic nerve activity indicated that sympathetic drive increased with increasing ICP. Ganglionic blockade, by hexamethonium, preventing sympathetic transmission, abolished the increase in arterial pressure in response to increased ICP and was associated with a significant decrease in cerebral perfusion pressure. This is the first study to show that physiological elevations in ICP regulate renal sympathetic activity in conscious animals. We have demonstrated a novel physiological mechanism linking ICP levels with sympathetic discharge via a possible novel intracranial baroreflex.

Exogenous and endogenous angiotensin-II decrease renal cortical oxygen tension in conscious rats by limiting renal blood flow.

KEY POINTS: Our understanding of the mechanisms underlying the role of hypoxia in the initiation and progression of renal disease remains rudimentary. We have developed a method that allows wireless measurement of renal tissue oxygen tension in unrestrained rats. This method provides stable and continuous measurements of cortical tissue oxygen tension (PO2) for more than 2 weeks and can reproducibly detect acute changes in cortical oxygenation. Exogenous angiotensin-II reduced renal cortical tissue PO2 more than equi-pressor doses of phenylephrine, probably because it reduced renal oxygen delivery more than did phenylephrine. Activation of the endogenous renin-angiotensin system in transgenic Cyp1a1Ren2 rats reduced cortical tissue PO2; in this model renal hypoxia precedes the development of structural pathology and can be reversed acutely by an angiotensin-II receptor type 1 antagonist. Angiotensin-II promotes renal hypoxia, which may in turn contribute to its pathological effects during development of chronic kidney disease. ABSTRACT: We hypothesised that both exogenous and endogenous angiotensin-II (AngII) can decrease the partial pressure of oxygen (PO2) in the renal cortex of unrestrained rats, which might in turn contribute to the progression of chronic kidney disease. Rats were instrumented with telemeters equipped with a carbon paste electrode for continuous measurement of renal cortical tissue PO2. The method reproducibly detected acute changes in cortical oxygenation induced by systemic hyperoxia and hypoxia. In conscious rats, renal cortical PO2 was dose-dependently reduced by intravenous AngII. Reductions in PO2 were significantly greater than those induced by equi-pressor doses of phenylephrine. In anaesthetised rats, renal oxygen consumption was not affected, and filtration fraction was increased only in the AngII infused animals. Oxygen delivery decreased by 50% after infusion of AngII and renal blood flow (RBF) fell by 3.3 ml min-1 . Equi-pressor infusion of phenylephrine did not significantly reduce RBF or renal oxygen delivery. Activation of the endogenous renin-angiotensin system in Cyp1a1Ren2 transgenic rats reduced cortical tissue PO2. This could be reversed within minutes by pharmacological angiotensin-II receptor type 1 (AT1 R) blockade. Thus AngII is an important modulator of renal cortical oxygenation via AT1 receptors. AngII had a greater influence on cortical oxygenation than did phenylephrine. This phenomenon appears to be attributable to the profound impact of AngII on renal oxygen delivery. We conclude that the ability of AngII to promote renal cortical hypoxia may contribute to its influence on initiation and progression of chronic kidney disease.

Prolonged and Continuous Measurement of Kidney Oxygenation in Conscious Rats.

A relative deficiency in kidney oxygenation, i.e., renal hypoxia, may contribute to the initiation and progression of acute and chronic kidney disease. A critical barrier to investigate this is the lack of methods allowing measurement of the partial pressure of oxygen in kidney tissue for long periods in vivo. We have developed, validated, and tested a novel telemetric method that can do this. Here we provide details on the calibration, implantation, implementation for data recording, and reuse of this telemetry-based technology for measurement of medullary tissue oxygen tension in conscious, unrestrained rats. This technique provides an important additional tool for investigating the impact of renal hypoxia in biology and pathophysiology.

New multimodal data obtained in-vivo from a single ultra-miniature transducer.

Recent advances in multimodal sensing technology and sensor miniaturization technologies are paving the way for a new era in physiological measurement. Traditional approaches have integrated several transducers on a single silicon chip or packaged several sensing elements within a biocompatible catheter. Thermal and electrical cross-talk between sensors, time-lag between parallel measurements, lower yields associated with the increased complexity, and restrictions on the minimum size are challenges presented by these approaches. We present an alternative method which enables simultaneous measurement of temperature, pressure and heart rate to be obtained from a single ultra-miniature solid-state transducer. For the first time multimodal data were obtained from the sensor located within the abdominal aortas of five rats. The catheter-tip sensor interfaces with a fully implanted and inductively powered telemetry device capable of operating for the lifetime of the animal. Results of this study demonstrate good agreement between the core-temperature measurement from the catheter-tip sensor and the reference sensor with mean difference between the two sensors of 0.03 °C ± 0.02 °C (n = 5, 7 days). Real-time data obtained in the undisturbed rat, revealed fluctuations associated with the rest-activity cycle, in temperature, mean arterial pressure and heart rate. The stress response was shown to elicit an elevation in the core temperature of 1.5 °C. This was heralded by an elevation in mean arterial pressure of 35 mmHg and heart rate of 160 bpm. Obtaining multiple parameters from a single transducer goes a considerable way towards overcoming challenges of the prior art.

Recording of intracranial pressure in conscious rats via telemetry.

Although cerebral perfusion pressure (CPP) is known to be fundamental in the control of normal brain function, there have been no previous long-term measurements in animal models. The aim of this study was to explore the stability and viability of long-term recordings of intracranial pressure (ICP) in freely moving rats via a telemetry device. We also developed a repeatable surgical approach with a solid-state pressure sensor at the tip of the catheter placed under the dura and in combination with arterial pressure (AP) measurement to enable the calculation of CPP. Telemeters with dual pressure catheters were implanted in Wistar rats to measure ICP and AP. We found that the signals were stable throughout the 28-day recording period with an average ICP value of 6 ± 0.8 mmHg. Significant light-dark differences were found in AP (3.1 ± 2.7 mmHg, P = 0.02) and HR (58 ± 12 beats/min, P = 0.003), but not ICP (0.3 ± 0.2 mmHg, P >0.05) or CPP (2.6 ± 2.8 mmHg, P > 0.05). Use of kaolin to induce hydrocephalus in several rats demonstrates the ability to measure changes in ICP throughout disease progression, validating this new solution for chronic measurement of ICP, CPP, and AP in conscious rats.

Arterial baroreceptor reflex control of renal sympathetic nerve activity following chronic myocardial infarction in male, female, and ovariectomized female rats.

There is controversy regarding whether the arterial baroreflex control of renal sympathetic nerve activity (SNA) in heart failure is altered. We investigated the impact of sex and ovarian hormones on changes in the arterial baroreflex control of renal SNA following a chronic myocardial infarction (MI). Renal SNA and arterial pressure were recorded in chloralose-urethane anesthetized male, female, and ovariectomized female (OVX) Wistar rats 6-7 wk postsham or MI surgery. Animals were grouped according to MI size (sham, small and large MI). Ovary-intact females had a lower mortality rate post-MI (24%) compared with both males (38%) and OVX (50%) (P < 0.05). Males and OVX with large MI, but not small MI, displayed an impaired ability of the arterial baroreflex to inhibit renal SNA. As a result, the male large MI group (49 ± 6 vs. 84 ± 5% in male sham group) and OVX large MI group (37 ± 3 vs. 75 ± 5% in OVX sham group) displayed significantly reduced arterial baroreflex range of control of normalized renal SNA (P < 0.05). In ovary-intact females, arterial baroreflex control of normalized renal SNA was unchanged regardless of MI size. In males and OVX there was a significant, positive correlation between left ventricle (LV) ejection fraction and arterial baroreflex range of control of normalized renal SNA, but not absolute renal SNA, that was not evident in ovary-intact females. The current findings demonstrate that the arterial baroreflex control of renal SNA post-MI is preserved in ovary-intact females, and the state of left ventricular dysfunction significantly impacts on the changes in the arterial baroreflex post-MI.

MRI interactions of a fully implantable pressure monitoring device.

PURPOSE: To investigate the potential patient risk and interactions between a prototype implantable pressure monitoring device and a 3T clinical magnetic resonance imaging (MRI) machine to guide device design towards MR Conditional safety approval. MATERIALS AND METHODS: The pressure monitor device contained a catheter-mounted piezo-resistive pressure sensor, rechargeable battery, wireless communication system, and inductive pickup coil. Standard testing methods were used to guide experiments to investigate static field induced force and torque, radiofrequency (RF)-induced heating, image artifacts, and the MR's effect on device function. The specific clinical application of intracranial pressure monitoring was considered. RF-induced heating experiments were supported by numerical modeling of the RF body coil, the device, and experimental phantom. RESULTS: Sensing catheter lead length and configuration was an important component of the device design. A short 150 mm length catheter produced a heating effect of less than 2°C and a long 420 mm length catheter caused heating of 7.2°C. Static magnetic field interactions were below standard safety risk levels and the MR did not interfere with device function; however, artifacts have the potential to interfere with image quality. CONCLUSION: Investigation of MR interactions at the prototype stage provides useful implantable device design guidance and confidence that an implantable pressure monitor may be able to achieve MR Conditional safety approval.

Chronic measurement of left ventricular pressure in freely moving rats.

Measurements of left ventricular pressure (LVP) in conscious freely moving animals are uncommon, yet could offer considerable opportunity for understanding cardiovascular disease progression and treatment. The aim of this study was to develop surgical methods and validate the measurements of a new high-fidelity, solid-state pressure-sensor telemetry device for chronically measuring LVP and dP/dt in rats. The pressure-sensor catheter tip (2-Fr) was inserted into the left ventricular chamber through the apex of the heart, and the telemeter body was implanted in the abdomen. Data were measured up to 85 days after implant. The average daytime dP/dt max was 9,444 ± 363 mmHg/s, ranging from 7,870 to 10,558 mmHg/s (n = 7). A circadian variation in dP/dt max and heart rate (HR) was observed with an average increase during the night phase in dP/dt max of 918 ± 84 mmHg/s, and in HR of 38 ± 3 bpm. The ß-adrenergic-agonist isoproterenol, ß1-adrenergic agonist dobutamine, Ca(2+) channel blocker verapamil, and the calcium sensitizer levosimendan were administered throughout the implant period, inducing dose-dependent time course changes and absolute changes in dP/dt max of -6,000 to +13,000 mmHg/s. The surgical methods and new technologies demonstrated long-term stability, sensitivity to circadian variation, and the ability to measure large drug-induced changes, validating this new solution for chronic measurement of LVP in conscious rats.

Telemetry-based oxygen sensor for continuous monitoring of kidney oxygenation in conscious rats.

The precise roles of hypoxia in the initiation and progression of kidney disease remain unresolved. A major technical limitation has been the absence of methods allowing long-term measurement of kidney tissue oxygen tension (Po2) in unrestrained animals. We developed a telemetric method for the measurement of kidney tissue Po2 in unrestrained rats, using carbon paste electrodes (CPEs). After acute implantation in anesthetized rats, tissue Po2 measured by CPE-telemetry in the inner cortex and medulla was in close agreement with that provided by the "gold standard" Clark electrode. The CPE-telemetry system could detect small changes in renal tissue Po2 evoked by mild hypoxemia. In unanesthetized rats, CPE-telemetry provided stable measurements of medullary tissue Po2 over days 5-19 after implantation. It also provided reproducible responses to systemic hypoxia and hyperoxia over this time period. There was little evidence of fibrosis or scarring after 3 wk of electrode implantation. However, because medullary Po2 measured by CPE-telemetry was greater than that documented from previous studies in anesthetized animals, this method is presently best suited for monitoring relative changes rather than absolute values. Nevertheless, this new technology provides, for the first time, the opportunity to examine the temporal relationships between tissue hypoxia and the progression of renal disease.

Effects of sex and ovarian hormones on the initial renal sympathetic nerve activity response to myocardial infarction.

The physiological mechanisms contributing to sex differences following myocardial infarction (MI) are poorly understood. Given the strong relationship between sympathetic nerve activity (SNA) and outcome, we hypothesized there may be a sex difference in SNA responses to MI. In anaesthetized, open-chest male, female and ovariectomized (OVX) female Wistar rats, mean arterial pressure, heart rate and renal SNA were recorded in response to ligation of the left coronary artery. In males, renal SNA increased by 30 ± 6% in the first minute of coronary occlusion (P < 0.05) and remained elevated at 18 ± 7% above baseline (P < 0.05) at 2 h following MI. In response to MI, ovary-intact females displayed no change in renal SNA, whereas OVX females displayed a significant increase, similar to that seen in the males (increases of 43 ± 11% at 1 min and 21 ± 7% at 2 h post-MI, P < 0.05 versus intact females). Arterial baroreflex control of renal SNA had a smaller range in females (ovary intact and OVX) than males; no changes in arterial baroreflex responses were observed 1 h post-MI in males or females. Denervating the arterial baroreceptors abolished the renal SNA response to MI in the males, whereas in ovary-intact females and OVX females the response was unaltered. These findings suggest that ovarian hormones are able to blunt the initial sympathetic activation post-MI in females and that the importance of the arterial baroreflex in mediating initial sympathetic activation post-MI is different between the sexes.

Renal sympathetic nerve activity during asphyxia in fetal sheep.

The sympathetic nervous system (SNS) is an important mediator of fetal adaptation to life-threatening in utero challenges, such as asphyxia. Although the SNS is active well before term, SNS responses mature significantly over the last third of gestation, and its functional contribution to adaptation to asphyxia over this critical period of life remains unclear. Therefore, we examined the hypotheses that increased renal sympathetic nerve activity (RSNA) is the primary mediator of decreased renal vascular conductance (RVC) during complete umbilical cord occlusion in preterm fetal sheep (101 ± 1 days; term 147 days) and that near-term fetuses (119 ± 0 days) would have a more rapid initial vasomotor response, with a greater increase in RSNA. Causality of the relationship of RSNA and RVC was investigated using surgical (preterm) and chemical (near-term) denervation. All fetal sheep showed a significant increase in RSNA with occlusion, which was more sustained but not significantly greater near-term. The initial fall in RVC was more rapid in near-term than preterm fetal sheep and preceded the large increase in RSNA. These data suggest that although RSNA can increase as early as 0.7 gestation, it is not the primary determinant of RVC. This finding was supported by denervation studies. Interestingly, chemical denervation in near-term fetal sheep was associated with an initial fall in blood pressure, suggesting that by 0.8 gestation sympathetic innervation of nonrenal vascular beds is critical to maintain arterial blood pressure during the rapid initial adaptation to asphyxia.

Cardiovascular and autonomic responses to sexual activity in the rabbit.

1. Sexual intercourse is associated with an increased risk of death from arrhythmia development, myocardial infarction or stroke. It is unclear whether this increased risk is due to physical exertion alone or whether it is an inherent aspect of sexual activity itself. 2. Using a telemetric approach, we show that sexual activity is associated with transient (8-14 s) but profound increases in renal sympathetic nerve activity (RSNA; up to 22-fold that of baseline) in both male and female rabbits. This increase was significantly greater than that observed during physical exertion (three- to sixfold increase in RSNA). 3. In addition, we observed rapid transitions in male rabbits from tachycardia (422 ± 21 b.p.m.; P < 0.01) to bradycardia (186 ± 28 b.p.m.; P < 0.05) during and immediately following coitus. This suggests simultaneous activation of both the sympathetic and parasympathetic nervous systems. 4. The present study provides the first real-time insight into the extreme variation in neural and cardiovascular function occurring during sexual activity in normal healthy rabbits. Little is known about how the physiological responses to sexual activity may change under disease or drug-treatment states, and these findings may prove of use to these areas in future.

High dietary salt and angiotensin II chronically increase renal sympathetic nerve activity: a direct telemetric study.

Overactivity of the sympathetic nervous system has long been implicated in the hypertensive response to elevated angiotensin II (Ang II) levels. Although recent studies suggest that high dietary salt may alter cardiovascular responses to Ang II, direct evidence demonstrating chronic activation of sympathetic nerve activity is lacking. The objective of this study was to determine whether a low dose of Ang II, on a background of high salt intake, would result in a chronic increase in renal sympathetic nerve activity (RSNA). Arterial pressure and RSNA were recorded via telemetry. Two groups of rabbits were studied: 1 group drank a 0.9% NaCl solution and received Ang II (20 ng/kg per minute for 21 days, Salt+Ang), and the other drank tap water throughout and was not infused with Ang II (Control). In the Salt+Ang group, mean arterial pressure increased over the first week and remain elevated by 18.5±4.1 mm Hg at day 21. RSNA was not significantly different between groups on day 7 but was significantly elevated in the Salt+Ang group on day 21 (13.5±3.2% compared with 6.8±0.8% in the Control group; P<0.05). Baroreflex control of RSNA showed a rightward shift on day 21, but not day 7, and baroreflex responses indicated that RSNA could not be completely suppressed when arterial pressure was increased. No changes were observed in either mean arterial pressure or RSNA variables in the Control group. Our results support the hypothesis that elevated Ang II levels, in conjunction with a high salt diet, have the ability to chronically increase RSNA and, thus, potentially contribute to the maintenance of hypertension.

A fully implantable telemetry system for the chronic monitoring of brain tissue oxygen in freely moving rats.

The ability to monitor tissue oxygen concentration in a specific region of the brain in a freely moving animal could provide a new paradigm in neuroscience research. We have developed a fully implantable telemetry system for the continuous and chronic recording of brain tissue oxygen (PO(2,BR)) in conscious animals. A telemetry system with a sampling rate of 2kHz was combined with a miniaturized potentiostat to amperiometrically detect oxygen concentration with carbon paste electrodes. Wireless power was employed to recharge the telemeter battery transcutaneously for potential lifetime monitoring. Rats were implanted with the telemeter in the peritoneal cavity and electrodes stereotaxically implanted into the brain (striatum or medulla oblongata). While the animals were living in their home cages the sensitivity to changes in oxygen was validated by repeatedly altering the inspired oxygen (10%, 100%, respectively) or a pharmacological stimulus (carbonic anhydrase inhibitor: acetazolamide 50mg/kg IP). Basal level of PO(2,BR) was monitored for 3weeks and showed good overall stability and good correlation to movement such as grooming. During hypoxia, PO(2,BR) decreased significantly by -51%±2% from baseline, whereas it increased by 34%±3% during hyperoxia. Following the systemic administration of acetazolamide, PO(2,BR) increased by 38%±4%. We propose this new technology provides a robust method to measure changes in oxygen concentration in specific areas of the brain, in conscious freely moving rats. The ability to track long term changes with disease progression or drug treatment may be enabled.

Baroreflex control of renal sympathetic nerve activity and heart rate in near-term fetal sheep.

Late preterm infants, born between 34 and 36 weeks gestation, have significantly higher morbidity than neonates born at full term, which may be partly related to reduced sensitivity of the arterial baroreflex. The present study assessed baroreflex control of heart rate (HR) and renal sympathetic nerve activity (RSNA) in near-term fetal sheep at 123 ± 1 days gestation. At this age, although fetuses are not fully mature in some respects (term is 147 days), sleep-state cycling is established [between high-voltage, low-frequency (HV) and low-voltage, high-frequency (LV) sleep], and neural myelination is similar to the term human infant. Fetal sheep were instrumented to record blood pressure (BP), HR (n = 15) and RSNA (n = 5). Blood pressure was manipulated using vasoactive drugs, phenylephrine and sodium nitroprusside. In both HV and LV sleep, phenylephrine was associated with increased arterial BP and decreased HR. In HV sleep, phenylephrine was associated with a fall in RSNA, from 124 ± 14 to 58 ± 11% (P < 0.05), but no significant change in RSNA in LV sleep. In contrast, the fall in BP after sodium nitroprusside was associated with a significant increase in HR during LV but not HV sleep, and there was no significant effect of hypotension on RSNA. These data demonstrate that in near-term fetal sheep baroreflex activity is only partly active and is highly modulated by sleep state. Critically, there was no RSNA response to marked hypotension; this finding has implications for the ability of the late preterm fetus to adapt to low BP.

Maturation-related changes in the pattern of renal sympathetic nerve activity from fetal life to adulthood.

Sympathetic nerve activity (SNA) has two main properties, the presence of co-ordinated bursts of activity, indicative of many nerve fibres firing at a similar time, and entrainment of the bursts to the cardiac cycle, due to inhibitory input from baroreceptors to a network of cell groups within the CNS. Although this patterning is used as a 'gold standard' for the identification of successful nerve recordings, the maturation of these basic features of SNA from fetal life to adulthood has not been investigated. Using a telemetry-based nerve amplifier, renal SNA (RSNA) was recorded in preterm (99 ± 1 days gestation; term 147 days) and near-term fetal sheep (119 ± 0 days gestation), without anaesthesia or paralysis, and contrasted with RSNA recorded in adult sheep. All three age groups showed a classic bursting pattern of RSNA and co-ordination of bursts with the cardiac cycle. However, the delay between diastole and the next peak in RSNA was longest in preterm fetuses (319 ± 1 ms), compared with near-term fetuses (250 ± 13 ms), and shortest in the adult sheep (174 ± 38 ms). This was independent of the maturational decrease in heart rate. The near-term fetuses showed a marked but sleep-state-dependent increase in resting RSNA compared with preterm fetuses. Although entrainment with the pressure pulse suggests that the intricate circuitry within the CNS is developed in the preterm fetus, the decrease in the length of the delay suggests continuing maturation of this key feature of RSNA in the last third of gestation and after birth.

A high bandwidth fully implantable mouse telemetry system for chronic ECG measurement.

We report on the development of a novel system that enables the wireless transmission of high-bandwidth physiological data from a freely moving mouse. The system employs inductive power transfer (IPT) to continuously power a battery-less transmitter using an array of overlapping planar coils placed under the animal. This arrangement provides a minimum of 20 mW at all locations and orientations across the mouse cage by selecting a coil which will sufficiently power the transmitter. Coil selection is performed by feedback control across the 2.4 GHz wireless link. A device was constructed utilizing this novel IPT system and was used to capture high-fidelity electrocardiogram (ECG) signal sampled at 2 kHz in mice. Various attributes of the ECG signal such as QT, QRS, and PR intervals could be obtained with a high degree of accuracy. This system potentially provides lifetime continuous high bandwidth measurement of physiological signals from a fully implanted telemeter in a freely moving mouse.