How conductivity boundaries influence the electric field induced by transcranial magnetic stimulation in in vitro experiments.

BACKGROUND: Although transcranial magnetic stimulation (TMS) has become a valuable method for non-invasive brain stimulation, the cellular basis of TMS activation of neurons is still not fully understood. In vitro preparations have been used to understand the biophysical mechanisms of TMS, but in many cases these studies have encountered substantial difficulties in activating neurons. OBJECTIVE/HYPOTHESIS: The hypothesis of this work is that conductivity boundaries can have large effects on the electric field in commonly used in vitro preparations. Our goal was to analyze the resulting difficulties in in vitro TMS using a simulation study, using a charge-based boundary element model. METHODS: We decomposed the total electric field into the sum of the primary electric field, which only depends on coil geometry and current, and the secondary electric field arising from conductivity boundaries, which strongly depends on tissue and chamber geometry. We investigated the effect of the conductivity boundaries on the electric field strength for a variety of in vitro experimental settings to determine the sources of difficulty. RESULTS: We showed that conductivity boundaries can have large effects on the electric field in in vitro preparations. Depending on the geometry of the air-saline and the saline-tissue interfaces, the secondary electric field can significantly enhance, or attenuate the primary electric field, resulting in a much stronger or weaker total electric field inside the tissue; we showed this using a realistic preparation. Submerged chambers are generally much more efficient than interface chambers since the secondary field due to the thin film of saline covering the tissue in the interface chamber opposes the primary field and significantly reduces the total field in the tissue placed in the interface chamber. The relative dimensions of the chamber and the TMS coil critically determine the total field; the popular setup with a large coil and a small chamber is particularly sub-optimal because the secondary field due to the air-chamber boundary opposes the primary field, thereby attenuating the total field. The form factor (length vs width) of the tissue in the direction of the induced field can be important since a relatively narrow tissue enhances the total field at the saline-tissue boundary. CONCLUSIONS: Overall, we found that the total electric field in the tissue is higher in submerged chambers, higher if the chamber size is larger than the coil and if the shorter tissue dimension is in the direction of the electric field. Decomposing the total field into the primary and secondary fields is useful for designing in vitro experiments and interpreting the results.

Delays in latencies of median-nerve evoked magnetic fields in patients with succinic semialdehyde dehydrogenase deficiency.

OBJECTIVE: Succinic semialdehyde dehydrogenase deficiency (SSADHD) is a genetic disorder resulting in abnormal regulation of γ-aminobutyric acid, lipid metabolism, and myelin biogenesis, leading to ataxia, seizures, and cognitive impairment. Since the myelin sheath is thinner in a murine model of SSADHD compared to a wild type, we hypothesized that this also holds for human brain. We tested whether the conduction velocity in the somatosensory pathway is accordingly delayed. METHODS: Somatosensory evoked magnetic fields (SEF) produced by transcutaneous electrical stimulation of the median nerve were measured in 13 SSADHD patients, 11 healthy and 14 disease controls with focal epilepsy. The peak latencies of the initial four components (M1, M2, M3 and M4) were measured. RESULTS: The SEF waveforms and scalp topographies were comparable across the groups. The latencies were statistically significantly longer in the SSADHD group compared to the two controls. We found these latencies for the SSADHD, healthy and disease controls respectively to be: M1: (21.9 ± 0.8 ms [mean ± standard error of the mean], 20.4 ± 0.6 ms, and 21.0 ± 0.4 ms) (p < 0.05); M2: (36.1 ± 1.0 ms, 33.1 ± 0.6 ms, and 32.1 ± 1.1 ms) (p < 0.005); M3: (62.5 ± 2.4 ms, 54.7 ± 2.0 ms, and 49.9 ± 1.8 ms) (p < 0.005); M4: (86.2 ± 2.3 ms, 78.8 ± 2.8 ms, and 73.5 ± 2.9 ms) (p < 0.005). CONCLUSIONS: The SEF latencies are delayed in patients with SSADHD compared with healthy controls and disease controls. SIGNIFICANCE: This is the first study that compares conduction velocities in the somatosensory pathway in SSADHD, an inherited disorder of GABA metabolism. The longer peak latency implying slower conduction velocity supports the hypothesis that myelin sheath thickness is decreased in SSADHD.

Ultrasound-Induced Membrane Hyperpolarization in Motor Axons and Muscle Fibers of the Crayfish Neuromuscular Junction.

OBJECTIVE: Focused ultrasound (FUS) can modulate neuronal activity by depolarization or hyperpolarization. Although FUS-evoked depolarization has been studied extensively, the mechanisms underlying FUS-evoked hyperpolarization (FUSH) have received little attention. In the study described here, we developed a procedure using FUS to selectively hyperpolarize motor axons in crayfish. As a previous study had reported that these axons express mechano- and thermosensitive two-pore domain potassium (K2P) channels, we tested the hypothesis that K2P channels underlie FUSH. METHODS: Intracellular recordings from a motor axon and a muscle fiber were obtained simultaneously from the crayfish opener neuromuscular preparation. FUSH was examined while K2P channel activities were modulated by varying temperature or by K2P channel blockers. RESULTS: FUSH in the axons did not exhibit a coherent temperature dependence, consistent with predicted K2P channel behavior, although changes in the resting membrane potential of the same axons indicated well-behaved K2P channel temperature dependence. The same conclusion was supported by pharmacological data; namely, FUSH was not suppressed by K2P channel blockers. Comparison between the FUS-evoked responses recorded in motor axons and muscle fibers revealed that the latter exhibited very little FUSH, indicating that the FUSH was specific to the axons. CONCLUSION: It is not likely that K2P channels are the underlying mechanism for FUSH in motor axons. Alternative mechanisms such as sonophore and axon-specific potassium channels were considered. Although the sonophore hypothesis could account for electrophysiological features of axonal recordings, it is not consistent with the lack of FUSH in muscle fibers. An axon-specific and mechanosensitive potassium channel is also a possible explanation.

Effects of Osmolarity on Ultrasound-Induced Membrane Depolarization in Isolated Crayfish Motor Axon.

We have previously identified a novel non-selective membrane conductance (gUS) opened by focused ultrasound (FUS) in crayfish motor axons. In the work described here, we studied gUS properties further by comparing FUS-evoked depolarization (FUSD) in control and hypotonic saline with 75% of control osmolarity. The FUS was a train of 20 FUS bursts (2.1 MHz and 50 µs per burst) delivered at 1 kHz. The amplitude, onset latency, frequency of occurrence and duration of FUSD were compared in a 15-min time window before and after switching to hypotonic saline. Significant increases were observed for amplitude (p < 0.001) and frequency of occurrence (p < 0.01) while the onset latency exhibited a significant decrease (p < 0.001). FUSD duration did not significantly differ. These results support predictions based on our hypothesis that gUS is mediated by opening of nanopores in the lipid bilayer and that stretching of axonal membrane caused by swelling at low osmolarity should increase the probability of nanopore formation under FUS. The FUSD parameters, in addition, exhibited time-dependent trends when the window of observation was expanded to 45 min in each saline. The statistical significance of amplitude and duration differed between 15- and 45-min time windows, indicating the presence of adaptive responses of axonal membrane to osmotic manipulation.

YO2 Induces Melanoma Cell Apoptosis through p53-Mediated LRP1 Downregulation.

The multifunctional endocytic receptor low-density lipoprotein receptor-related protein 1 (LRP1) has been implicated in melanoma growth. However, the mechanism of LRP1 expression in melanoma cells remains only partially understood. In most melanomas, the TP53 tumor suppressor is retained as a non-mutated, inactive form that fails to suppress tumors. We identify TP53 as a regulator of LRP1-mediated tumor growth. TP53 enhances the expression of miRNA miR-103/107. These miRNAs target LRP1 expression on melanoma cells. TP53 overexpression in human and murine melanoma cells was achieved using lentivirus or treatment with the small molecule YO-2, a plasmin inhibitor known to induce apoptosis in various cancer cell lines. TP53 restoration enhanced the expression of the tumor suppressor miR-103/107, resulting in the downregulation of LRP1 and suppression of tumor growth in vivo and in vitro. Furthermore, LRP1 overexpression or p53 downregulation prevented YO-2-mediated melanoma growth inhibition. We identified YO-2 as a novel p53 inducer in melanoma cells. Cotreatment of YO-2 with doxorubicin blocked tumor growth in vivo and in a murine melanoma model, suggesting that YO-2 exerts anti-melanoma effects alone or in combination with conventional myelosuppressive drugs.

Influence of unfused cranial bones on magnetoencephalography signals in human infants.

OBJECTIVE: To clarify the effects of unfused cranial bones on magnetoencephalography (MEG) signals during early development. METHODS: In a simulation study, we compared the MEG signals over a spherical head model with a circular hole mimicking the anterior fontanel to those over the same head model without the fontanel for different head and fontanel sizes with varying skull thickness and conductivity. RESULTS: The fontanel had small effects according to three indices. The sum of differences in signal over a sensor array due to a fontanel, for example, was < 6% of the sum without the fontanel. However, the fontanel effects were extensive for dipole sources deep in the brain or outside the fontanel for larger fontanels. The effects were comparable in magnitude for tangential and radial sources. Skull thickness significantly increased the effect, while skull conductivity had minor effects. CONCLUSION: MEG signal is weakly affected by a fontanel. However, the effects can be extensive and significant for radial sources, thicker skull and large fontanels. The fontanel effects can be intuitively explained by the concept of secondary sources at the fontanel wall. SIGNIFICANCE: The minor influence of unfused cranial bones simplifies MEG analysis, but it should be considered for quantitative analysis.

Alkaline brain pH shift in rodent lithium-pilocarpine model of epilepsy with chronic seizures.

Brain pH is thought to be important in epilepsy. The regulation of brain pH is, however, still poorly understood in animal models of chronic seizures (SZ) as well as in patients with intractable epilepsy. We used chemical exchange saturation transfer (CEST) MRI to noninvasively determine if the pH is alkaline shifted in a rodent model of the mesial temporal lobe (MTL) epilepsy with chronic SZ. Taking advantage of its high spatial resolution, we determined the pH values in specific brain regions believed to be important in this model produced by lithium-pilocarpine injection. All animals developed status epilepticus within 90 min after the lithium-pilocarpine administration, but one animal died within 24 hrs. All the surviving animals developed chronic SZ during the first 2 months. After SZ developed, brain pH was determined in the pilocarpine and control groups (n = 8 each). Epileptiform activity was documented in six pilocarpine rats with scalp EEG. The brain pH was estimated using two methods based on magnetization transfer asymmetry and amide proton transfer ratio. The pH was alkaline shifted in the pilocarpine rats (one outlier excluded) compared to the controls in the hippocampus (7.29 vs 7.17, t-test, p < 0.03) and the piriform cortex (7.34 vs. 7.06, p < 0.005), marginally more alkaline in the thalamus (7.13 vs. 7.01, p < 0.05), but not in the cerebral cortex (7.18 vs. 7.08, p > 0.05). Normalizing the brain pH may lead to an effective non-surgical method for treating intractable epilepsy as it is known that SZ can be eliminated by lowering the pH.

A 3-axis coil design for multichannel TMS arrays.

PURPOSE: Multichannel Transcranial Magnetic Stimulation (mTMS) arrays enable multiple sites to be stimulated simultaneously or sequentially under electronic control without moving the system's stimulation coils. Here, we build and characterize the performance of a novel modular 3-axis TMS coil that can be utilized as a unit element in large-scale multichannel TMS arrays. METHODS: We determined the basic physical characteristics of the 3-axis TMS coil x-, y- and z-elements using a custom 2-channel programmable stimulator prototype. We mapped the temporal rate-of-change of the induced magnetic field (dB/dt) on a 2D plane parallel to the coil surface (including an extended line for full spatial coverage) and compared those values with predictions from magnetic field simulations. Temperature measurements were carried out to assess the incorporated air-cooling method. We measured the mutual and self-inductances of the x/y/z-elements to assess coupling between them. Additionally, we measured and calculated the coupling between z-elements in the array configuration. Finally, we performed electric field simulations to evaluate the stimulation intensity and focality of the coil and compared the results to conventional TMS coils as well as demonstrated suitability of the 3-axis coil for a multichannel array configuration. RESULTS: The experimentally obtained dB/dt values validated the computational model of the 3-axis coil and therefore confirmed that both the coil and stimulator system are operating as intended. The air-cooling system was effective for brief high-frequency pulse trains and extended single- and paired-pulse TMS protocols. The electromagnetic simulations suggested that an array of the 3-axis coils would have comparable stimulation intensity to conventional TMS coils, therefore enabling clearly suprathreshold stimulation of the human brain. The recorded coil coupling between the x/y/z-elements was < 1% and the maximal coupling between z-elements in the array configuration was 1.8% and 3.4% for the measured and calculated values, respectively. CONCLUSION: We presented a 3-axis coil intended for multichannel TMS arrays. The electromagnetic measurements and simulations verified that the coil fabrication met the desired specifications and that the inductive coupling between the elements was negligible. The air-cooled 3-axis TMS coil appears suitable to be used as an element in multichannel TMS arrays.

Boundary Element Fast Multipole Method for Enhanced Modeling of Neurophysiological Recordings.

OBJECTIVE: A new numerical modeling approach is proposed which provides forward-problem solutions for both noninvasive recordings (EEG/MEG) and higher-resolution intracranial recordings (iEEG). METHODS: The algorithm is our recently developed boundary element fast multipole method or BEM-FMM. It is based on the integration of the boundary element formulation in terms of surface charge density and the fast multipole method originating from its inventors. The algorithm still possesses the major advantage of the conventional BEM - high speed - but is simultaneously capable of processing a very large number of surface-based unknowns. As a result, an unprecedented spatial resolution could be achieved, which enables multiscale modeling. RESULTS: For non-invasive EEG/MEG, we are able to accurately solve the forward problem with approximately 1 mm anatomical resolution in the cortex within 1-2 min given several thousand cortical dipoles. Targeting high-resolution iEEG, we are able to compute, for the first time, an integrated electromagnetic response for an ensemble (2,450) of tightly packed realistic pyramidal neocortical neurons in a full-head model with 0.6 mm anatomical cortical resolution. The neuronal arbor is comprised of 5.9 M elementary 1.2 µm long dipoles. On a standard server, the computations require about 5 min. CONCLUSION: Our results indicate that the BEM-FMM approach may be well suited to support numerical multiscale modeling pertinent to modern high-resolution and submillimeter iEEG. SIGNIFICANCE: Based on the speed and ease of implementation, this new algorithm represents a method that will greatly facilitate simulations at multi-scale across a variety of applications.

Direct Activation of Cortical Neurons in the Primary Somatosensory Cortex of the Rat in Vivo Using Focused Ultrasound.

We address the recent controversy over whether focused ultrasound (FUS) activates cortical neurons directly or indirectly by initially activating auditory pathways. We obtained two types of evidence that FUS can directly activate cortical neurons. The depth profile of the local field potential (LFP) in the barrel cortex of the rat in vivo indicated a generator was located within the cortical gray matter. The onset and peak latencies of the initial component p1 were 3.2 ± 0.25 ms (mean ± standard error of the mean) and 7.6 ± 0.12 ms, respectively, for the direct cortical response (DCR), 6.8 ± 0.40 and 14.3 ± 0.54 ms for the FUS-evoked LFP (4 MHz, 3.2 MPa, 50 or 300 µs/pulse, 1-20 pulses at 1 kHz) and 6.9 ± 0.51 and 15.8 ± 0.94 ms for the LFP evoked by 1-ms deflection of the C2 whisker projecting to the same area. The peak latency of the FUS p1 was statistically (t-test) longer than the DCR, but shorter than the whisker p1 at p < 0.005.

Epileptic Activity Intrinsically Generated in the Human Cerebellum.

Neoplastic or dysplastic neuronal tissue in the brain stem and cerebellum can become epileptogenic in pediatric patients. However, it is unknown whether such tissue may transform intrinsic properties of the human cerebellum, making it capable of generating epileptic population activity. We noninvasively detected epileptiform signals unaveraged in a pediatric patient with epilepsy due to a tumor in the middle cerebellar peduncle. Analysis of generators of the signals revealed that the cerebellum ipsilateral and contralateral to the tumor was the dominant interictal spike generator and could initiate ictal activity, suggesting that human cerebellum may become capable of intrinsically generating epileptic activity. ANN NEUROL 2020;88:418-422.

Vibrotactile piezoelectric stimulation system with precise and versatile timing control for somatosensory research.

BACKGROUND: Tactile stimulations systems are useful for studying the somatosensory system in children because they are innocuous and safe. Stimulators based on piezoelectric actuator are useful, but there is still a need for such systems capable of providing accurate and versatile control of timing and pattern of activation. NEW METHOD: We have implemented a vibrotactile stimulating system useful for behavioral and electroencephalography (EEG) and magnetoencephalography (MEG) research. Our design goal was to create a system capable of providing up to five independently controlled mechanical stimulations with precise timing. We developed a Graphic User Interface (GUI) in LabVIEW, which controls a commercially available piezoelectric braille stimulator using an Arduino based controller. We made a customized braille stimulator based on the Metec Braille device. RESULTS: Our system can control up to five tactile stimulators with independent timing control and negligible errors. Although it can be directly used for behavioral and EEG research, the piezoelectric stimulators in our system generate stimulus artifacts that interfere with MEG recordings. A moving averaging subtraction algorithm we developed can remove the artifact. The stimulator can be used to measure somatic evoked magnetic fields from the somatosensory cortex of a child without the artifact. COMPARISON TO EXISTING METHODS: Our system provides an accurate independent control of one or more piezoelectric actuators using a GUI-based easy-to-control programming approach based on recent advances in embedded systems and software. Versatility and precise stimulation timing distinguish our system compared to existing somatic stimulators. CONCLUSIONS: Our system may be useful for somatic research.

Focused ultrasound transiently increases membrane conductance in isolated crayfish axon.

We report a novel phenomenon produced by focused ultrasound (US) that may be important for understanding its effects on cell membranes. When a US burst (2.1 MHz, 1-mm focal diameter, 0.1-1 MPa) was focused on a motor axon of the crayfish neuromuscular junction, it consistently produced a fast hyperpolarization, which was followed or superseded by subthreshold depolarizations or action potentials in a stochastic manner. The depolarization persisted in the presence of voltage-gated channel blockers [1 µM TTX ( INa), 50 µM ZD7288 ( Ih), and 200 µM 4-aminopyridine ( IK)] and typically started shortly after the onset of a 5-ms US burst, with a mean latency of 3.35 ± 0.53 ms (SE). The duration and amplitude of depolarizations averaged 2.13 ± 0.87 s and 10.1 ± 2.09 mV, with a maximum of 200 s and 60 mV, respectively. The US-induced depolarization was always associated with a decrease in membrane resistance. By measuring membrane potential and resistance during the US-induced depolarization, the reversal potential of US-induced conductance ( gus) was estimated to be -8.4 ± 2.3 mV, suggesting a nonselective conductance. The increase in gus was 10-100 times larger than the leak conductance; thus it could significantly influence neuronal activity. This change in conductance may be due to stimulation of mechanoreceptors. Alternatively, US may perturb the lateral motion of phospholipids and produce nanopores, which then increase gus. These results may be important for understanding mechanisms underlying US-mediated modulation of neuronal activity and brain function. NEW & NOTEWORTHY We report a specific increase in membrane conductance produced by ultrasound (US) on neuronal membrane. When a 5-ms US tone burst was focused on a crayfish motor axon, it stochastically triggered either depolarization or a spike train. The depolarization was up to 60 mV in amplitude and 200 s in duration and therefore could significantly influence neuronal activity. Depolarization was still evoked by US burst in the presence of Na+ and Ca2+ channel blockers and had a reversal potential of -8.4 ± 2.3 mV, suggesting a nonselective permeability. US can be applied noninvasively in the form of a focused beam to deep brain areas through the skull and has been shown to modulate brain activity. Understanding the depolarization reported here should be helpful for improving the use of US for noninvasive modulation and stimulation in brain-related disease.

Noise cancellation for a whole-head magnetometer-based MEG system in hospital environment.

We describe a strategy of removing magnetic field interference for a whole-head pediatric magnetoencephalography (MEG) system ("babyMEG") installed in a hospital. The 375-channel sensor array of babyMEG consists entirely of magnetometers in two layers to maximize the sensitivity for detecting MEG signals from infants, toddlers, and young children. It is equipped with a continuously operating closed-cycle helium recycler to reduce the operating costs. These two features pose special challenges for noise cancellation. Our strategy uses a combination of several methods. The system is installed in a light-weight, magnetically shielded room (MSR) equipped with an active external shielding. In addition we employ two software-based techniques - a signal space projection (SSP) technique and a synthetic gradiometer (SG) method - for removing the environmental magnetic noise in real time and displaying the output online. The shielding effects are: passive shielding - 36 dB, active shielding - 12 dB, SSP - 40 dB and SG - 40 dB, for a combined maximum shielding of about 90 dB at 0.1 Hz. We evaluated the performance of the babyMEG after applying the noise cancellation techniques. The dipole localization errors were <3 mm after averaging 50 epochs with empty room noise in a simulation study for dipoles >10 nAm, which is in the low range of empirically observed dipole moments. In a phantom study with realistic environmental noise, we could clearly recover an evoked cortical magnetic field produced by a 20 nAm dipole after averaging 50 epochs. The localization error was ~6 mm after averaging 20 epochs. In infants, we could clearly detect a somatic evoked field after averaging ~20 responses. The unique two-layer sensor design combined with the SSP or SG provides effective noise suppression for a magnetometer-based pediatric MEG system in hospital environment with the closed-cycle helium recycler operating continuously during MEG measurements.

MNE Scan: Software for real-time processing of electrophysiological data.

BACKGROUND: Magnetoencephalography (MEG) and Electroencephalography (EEG) are noninvasive techniques to study the electrophysiological activity of the human brain. Thus, they are well suited for real-time monitoring and analysis of neuronal activity. Real-time MEG/EEG data processing allows adjustment of the stimuli to the subject's responses for optimizing the acquired information especially by providing dynamically changing displays to enable neurofeedback. NEW METHOD: We introduce MNE Scan, an acquisition and real-time analysis software based on the multipurpose software library MNE-CPP. MNE Scan allows the development and application of acquisition and novel real-time processing methods in both research and clinical studies. The MNE Scan development follows a strict software engineering process to enable approvals required for clinical software. RESULTS: We tested the performance of MNE Scan in several device-independent use cases, including, a clinical epilepsy study, real-time source estimation, and Brain Computer Interface (BCI) application. COMPARISON WITH EXISTING METHOD(S): Compared to existing tools we propose a modular software considering clinical software requirements expected by certification authorities. At the same time the software is extendable and freely accessible. CONCLUSION: We conclude that MNE Scan is the first step in creating a device-independent open-source software to facilitate the transition from basic neuroscience research to both applied sciences and clinical applications.

Development of Auditory Evoked Responses in Normally Developing Preschool Children and Children with Autism Spectrum Disorder.

The cortical responses to auditory stimuli undergo rapid and dramatic changes during the first 3 years of life in normally developing (ND) children, with decreases in latency and changes in amplitude in the primary peaks. However, most previous studies have focused on children >3 years of age. The analysis of data from the early stages of development is challenging because the temporal pattern of the evoked responses changes with age (e.g., additional peaks emerge with increasing age) and peak latency decreases with age. This study used the topography of the auditory evoked magnetic field (AEF) to identify the auditory components in ND children between 6 and 68 months (n = 48). The latencies of the peaks in the AEF produced by a tone burst (ISI 2 ± 0.2 s) during sleep decreased with age, consistent with previous reports in awake children. The peak latencies of the AEFs in ND children and children with autism spectrum disorder (ASD) were compared. Previous studies indicate that the latencies of the initial components of the auditory evoked potential (AEP) and the AEF are delayed in children with ASD when compared to age-matched ND children >4 years of age. We speculated whether the AEF latencies decrease with age in children diagnosed with ASD as in ND children, but with uniformly longer latencies before the age of about 4 years. Contrary to this hypothesis, the peak latencies did not decrease with age in the ASD group (24-62 months, n = 16) during sleep (unlike in the age-matched controls), although the mean latencies were longer in the ASD group as in previous studies. These results are consistent with previous studies indicating delays in auditory latencies, and they indicate a different maturational pattern in ASD children and ND children. Longitudinal studies are needed to confirm whether the AEF latencies diverge with age, starting at around 3 years, in these 2 groups of children.

Versatile synchronized real-time MEG hardware controller for large-scale fast data acquisition.

Versatile controllers for accurate, fast, and real-time synchronized acquisition of large-scale data are useful in many areas of science, engineering, and technology. Here, we describe the development of a controller software based on a technique called queued state machine for controlling the data acquisition (DAQ) hardware, continuously acquiring a large amount of data synchronized across a large number of channels (>400) at a fast rate (up to 20 kHz/channel) in real time, and interfacing with applications for real-time data analysis and display of electrophysiological data. This DAQ controller was developed specifically for a 384-channel pediatric whole-head magnetoencephalography (MEG) system, but its architecture is useful for wide applications. This controller running in a LabVIEW environment interfaces with microprocessors in the MEG sensor electronics to control their real-time operation. It also interfaces with a real-time MEG analysis software via transmission control protocol/internet protocol, to control the synchronous acquisition and transfer of the data in real time from >400 channels to acquisition and analysis workstations. The successful implementation of this controller for an MEG system with a large number of channels demonstrates the feasibility of employing the present architecture in several other applications.

The role of plasmin in the pathogenesis of murine multiple myeloma.

Aside from a role in clot dissolution, the fibrinolytic factor, plasmin is implicated in tumorigenesis. Although abnormalities of coagulation and fibrinolysis have been reported in multiple myeloma patients, the biological roles of fibrinolytic factors in multiple myeloma (MM) using in vivo models have not been elucidated. In this study, we established a murine model of fulminant MM with bone marrow and extramedullar engraftment after intravenous injection of B53 cells. We found that the fibrinolytic factor expression pattern in murine B53 MM cells is similar to the expression pattern reported in primary human MM cells. Pharmacological targeting of plasmin using the plasmin inhibitors YO-2 did not change disease progression in MM cell bearing mice although systemic plasmin levels was suppressed. Our findings suggest that although plasmin has been suggested to be a driver for disease progression using clinical patient samples in MM using mostly in vitro studies, here we demonstrate that suppression of plasmin generation or inhibition of plasmin cannot alter MM progression in vivo.

Pharmacological targeting of plasmin prevents lethality in a murine model of macrophage activation syndrome.

Macrophage activation syndrome (MAS) is a life-threatening disorder characterized by a cytokine storm and multiorgan dysfunction due to excessive immune activation. Although abnormalities of coagulation and fibrinolysis are major components of MAS, the role of the fibrinolytic system and its key player, plasmin, in the development of MAS remains to be solved. We established a murine model of fulminant MAS by repeated injections of Toll-like receptor-9 (TLR-9) agonist and d-galactosamine (DG) in immunocompetent mice. We found plasmin was excessively activated during the progression of fulminant MAS in mice. Genetic and pharmacological inhibition of plasmin counteracted MAS-associated lethality and other related symptoms. We show that plasmin regulates the influx of inflammatory cells and the production of inflammatory cytokines/chemokines. Collectively, our findings identify plasmin as a decisive checkpoint in the inflammatory response during MAS and a potential novel therapeutic target for MAS.