Defining the Boundaries of Patient Perception in Spinal Cord Stimulation Programming.

OBJECTIVES: Recent developments in spinal cord stimulation (SCS) programming have initiated new modalities of imperceptible stimulation. However, the boundaries of sensory perception are not well defined. The BEnchtop NEuromodulation Following endIng of Trial study aimed to create a map of perceptual threshold responses across a broad range of SCS parameters and programming to inform subperception therapy design. MATERIALS AND METHODS: This multicenter study was conducted at seven US sites. A total of 43 patients with low back and/or leg pain who completed a percutaneous commercial SCS trial were enrolled. Test stimulation was delivered through trial leads for approximately 90 minutes before removal. SCS parameters, including amplitude, frequency, pulse width (PW), electrode configuration, cycling, and multifrequency stimulation were varied during testing. Paresthesia threshold (PT), comfort level (CL), perceptual coverage area, and paresthesia quality (through patient selection of keywords) were collected. Differences were evaluated with analysis of variance followed by post hoc multiple comparisons using t-tests with Bonferroni correction. RESULTS: PT was primarily determined by PW and was insensitive to frequency for constant frequency stimulation (range: 20 Hz-10 kHz; F(1284) = 69.58, p < 0.0001). For all tests, CL was approximately 25% higher than PT. The dominant variable that influenced paresthesia quality was frequency. Sensations described as comfortable and tingling were most common for frequencies between 60 Hz and 2.4 kHz; unpleasant sensations were generally more common outside this range. Increasing distance between active electrodes from 7 mm to 14 mm, or cycling the SCS waveform at 1 Hz, decreased PT (p < 0.0001). Finally, PT for a low-frequency stimulus (ie, 60 Hz) was unaffected by mixing with a sub-PT high-frequency stimulus. CONCLUSIONS: In contrast to previous work investigating narrower ranges, PW primarily influenced PT, independently of frequency. Paresthesia quality was primarily influenced by pulse frequency. These findings advance our understanding of SCS therapy and may be used to improve future novel neuromodulation paradigms.

Cutting-Edge Technology for Rapid Bedside Assessment of Capillary Refill Time for Early Diagnosis and Resuscitation of Sepsis.

Sepsis currently affects over 30 million people globally with a mortality rate of ~30%. Prompt Emergency Department diagnosis and initiation of resuscitation improves outcomes; data has found an 8% increase in mortality for every hour delay in diagnosis. Once sepsis is recognized, the current Surviving Sepsis Guidelines for adult patients mandate the initiation of antibiotics within 3 h of emergency department triage as well as 30 milliliters per kilogram of intravenous fluids. While these are important parameters to follow, many emergency departments fail to meet these goals for a variety of reasons including turnaround on blood tests such as the serum lactate that may be delayed or require expensive laboratory equipment. However, patients routinely have vital signs assessed and measured in triage within 30 min of presentation. This creates a unique opportunity for implementation point for cutting-edge technology to significantly reduce the time to diagnosis of potentially septic patients allowing for earlier initiation of treatment. In addition to the practical and clinical difficulties with early diagnosis of sepsis, recent clinical trials have shown higher morbidity and mortality when septic patients are over-resuscitated. Technology allowing more real time monitoring of a patient's physiologic responses to resuscitation may allow for more individualized care in emergency department and critical care settings. One such measure at the bedside is capillary refill. This has shown favor in the ability to differentiate subsets of patients who may or may not need resuscitation and interpreting blood values more accurately (1, 2). This is a well-recognized measure of distal perfusion that has been correlated to sepsis outcomes. This physical exam finding is performed routinely, however, there is significant variability in the measurement based on who is performing it. Therefore, technology allowing rapid, objective, non-invasive measurement of capillary refill could improve sepsis recognition compared to algorithms that require lab tests included lactate or white blood count. This manuscript will discuss the broad application of capillary refill to resuscitation care and sepsis in particular for adult patients but much can be applied to pediatrics as well. The authors will then introduce a new technology that has been developed through a problem-based innovation approach to allow clinicians rapid assessment of end-organ perfusion at the bedside or emergency department triage and be incorporated into the electronic medical record. Future applications for identifying patient decompensation in the prehospital and home environment will also be discussed. This new technology has 3 significant advantages: [1] the use of reflected light technology for capillary refill assessment to provide deeper tissue penetration with less signal-to-noise ratio than transmitted infrared light, [2] the ability to significantly improve clinical outcomes without large changes to clinical workflow or provider practice, and [3] it can be used by individuals with minimal training and even in low resource settings to increase the utility of this technology. It should be noted that this perspective focuses on the utility of capillary refill for sepsis care, but it could be considered the next standard of care vital sign for assessment of end-organ perfusion. The ultimate goal for this sensor is to integrate it into existing monitors within the healthcare system.

Neural activity propagation in an unfolded hippocampal preparation with a penetrating micro-electrode array.

This protocol describes a method for preparing a new in vitro flat hippocampus preparation combined with a micro-machined array to map neural activity in the hippocampus. The transverse hippocampal slice preparation is the most common tissue preparation to study hippocampus electrophysiology. A longitudinal hippocampal slice was also developed in order to investigate longitudinal connections in the hippocampus. The intact mouse hippocampus can also be maintained in vitro because its thickness allows adequate oxygen diffusion. However, these three preparations do not provide direct access to neural propagation since some of the tissue is either missing or folded. The unfolded intact hippocampus provides both transverse and longitudinal connections in a flat configuration for direct access to the tissue to analyze the full extent of signal propagation in the hippocampus in vitro. In order to effectively monitor the neural activity from the cell layer, a custom made penetrating micro-electrode array (PMEA) was fabricated and applied to the unfolded hippocampus. The PMEA with 64 electrodes of 200 µm in height could record neural activity deep inside the mouse hippocampus. The unique combination of an unfolded hippocampal preparation and the PMEA provides a new in-vitro tool to study the speed and direction of propagation of neural activity in the two-dimensional CA1-CA3 regions of the hippocampus with a high signal to noise ratio.

A high aspect ratio microelectrode array for mapping neural activity in vitro.

A novel high-aspect-ratio penetrating microelectrode array was designed and fabricated for the purpose of recording neural activity. The array allows two dimensional recording of 64 sites in vitro with high aspect ratio penetrating electrodes. Traditional surface electrode arrays, although easy to fabricate, do not penetrate to the viable tissue such as central hippocampus slices and thus have a lower signal/noise ratio and lower selectivity than a penetrating array. In the unfolded hippocampus preparation, the CA1-CA3 pyramidal cell layer in the whole unfolded rodent hippocampus preparation is encased by the alveus on one side and the Schaffer tract on the other and requires penetrating electrodes for high signal to noise ratio recording. An array of 64 electrode spikes, each with a target height of 200µm and diameter of 20µm, was fabricated in silicon on a transparent glass substrate. The impedance of the individual electrodes was measured to be approximately 1.5MΩ±497kΩ. The signal to noise ratio was measured and found to be 19.4±3dB compared to 3.9±0.8dB S/N for signals obtained with voltage sensitive dye RH414. A mouse unfolded hippocampus preparation was bathed in solution containing 50 micro-molar 4-amino pyridine and a complex two dimensional wave of activity was recorded using the array. These results indicate that this novel penetrating electrode array is able to obtain data superior to that of voltage sensitive dye techniques for broad field two-dimensional neuronal activity recording. When used with the unfolded hippocampus preparation, the combination forms a uniquely capable tool for imaging hippocampal network activity in the entire hippocampus.

Orthogonal wave propagation of epileptiform activity in the planar mouse hippocampus in vitro.

PURPOSE: In vitro brain preparations have been used extensively to study the generation and propagation of epileptiform activity. Transverse and longitudinal slices of the rodent hippocampus have revealed various patterns of propagation. Yet intact connections between the transverse and longitudinal pathways should generate orthogonal (both transverse and longitudinal) propagation of seizures involving the entire hippocampus. This study utilizes the planar unfolded mouse hippocampus preparation to reveal simultaneous orthogonal epileptiform propagation and to test a method of arresting propagation. METHODS: This study utilized an unfolded mouse hippocampus preparation. It was chosen due to its preservation of longitudinal neuronal processes, which are thought to play an important role in epileptiform hyperexcitability. 4-Aminopyridine (4-AP), microelectrodes, and voltage-sensitive dye imaging were employed to investigate tissue excitability. KEY FINDINGS: In 50-µm 4-AP, stimulation of the stratum radiatum induced transverse activation of CA3 cells but also induced a longitudinal wave of activity propagating along the CA3 region at a speed of 0.09 m/s. Without stimulation, a wave originated at the temporal CA3 and propagated in a temporal-septal direction could be suppressed with glutamatergic receptor antagonists. Orthogonal propagation traveled longitudinally along the CA3 pathway, secondarily invading the CA1 region at a velocity of 0.22 ± 0.024 m/s. Moreover, a local lesion restricted to the CA3 region could arrest wave propagation. SIGNIFICANCE: These results reveal a complex two-dimensional epileptiform wave propagation pattern in the hippocampus that is generated by a combination of synaptic transmission and axonal propagation in the CA3 recurrent network. Epileptiform propagation block via a transverse selective CA3 lesion suggests a potential surgical technique for the treatment of temporal lobe epilepsy.