Menashe Zaaroor

Artifact correction and source analysis of early electroencephalographic responses evoked by transcranial magnetic stimulation over primary motor cortex.

Analyzing the brain responses to transcranial magnetic stimulation (TMS) using electroencephalography (EEG) is a promising method for the assessment of functional cortical connectivity and excitability of areas accessible to this stimulation. However, until now it has been difficult to analyze the EEG responses during the several tens of milliseconds immediately following the stimulus due to TMS-induced artifacts. In the present study we show that by combining a specially adapted recording system with software artifact correction it is possible to remove a major part of the artifact and analyze the cortical responses as early as 10 ms after TMS. We used this methodology to examine responses of left and right primary motor cortex (M1) to TMS at different intensities. Based on the artifact-corrected data we propose a model for the cortical activation following M1 stimulation. The model revealed the same basic response sequence for both hemispheres. A large part of the response could be accounted for by two sources: a source close to the stimulation site (peaking approximately 15 ms after the stimulus) and a midline frontal source ipsilateral to the stimulus (peaking approximately 25 ms). In addition the model suggests responses in ipsilateral temporo-parietal junction areas (approximately 35 ms) and ipsilateral (approximately 30 ms) and middle (approximately 50 ms) cerebellum. Statistical analysis revealed significant dependence on stimulation intensity for the ipsilateral midline frontal source. The methodology developed in the present study paves the way for the detailed study of early responses to TMS in a wide variety of brain areas.

Propulsion Method for Swimming Microrobots

This paper presents a novel swimming method mediated by traveling waves in elastic tails. The propulsion method is potentially appropriate for maneuvering microrobots inside the human body. The swimming action relies on the creation of a traveling wave along a piezoelectric layered beam divided into several segments. This requires that a voltage with the same frequency, but different phases and amplitudes, be applied to each segment. The swimming pattern was analyzed theoretically by solving the coupled electric-elastic-fluidic problem, and was optimized to attain reasonable thrust. It was found that despite extreme size limitations, a tail manufactured by current microelectromechanical-devices technology, using piezoelectric material, is able to swim in water at a speed of several centimeters per second. The swimming theory was verified experimentally using an upscaled model that produced propulsion of 0.04 mN, which matches closely the theoretically predicted propulsion

Novel magnetic technology for intraoperative intracranial frameless navigation: in vivo and in vitro results.

OBJECTIVE To characterize the accuracy of the Magellan electromagnetic navigation system (Biosense Webster, Tirat HaCarmel, Israel) and to demonstrate the feasibility of its use in image-guided neurosurgical applications. DESCRIPTION OF INSTRUMENTATION The Magellan system was developed to provide real-time tracking of the distal tips of flexible catheters, steerable endoscopes, and other surgical instruments, using ultra-low electromagnetic fields and a novel miniature position sensor for image-correlated intraoperative navigation and mapping applications. METHODS An image registration procedure was performed, and static and qualitative accuracies were assessed in a series of phantom, animal, and human neurosurgical studies. EXPERIENCE AND RESULTS During the human study phase, an accuracy error of up to 5 mm was deemed acceptable. Results demonstrated that this degree of accuracy was maintained throughout all procedures. All anatomic landmarks were reached with precision and were accurately viewed on the display screen. Navigation that relied on the system was also successful. No interference with operating room equipment was noted. The accuracy of the system was maintained during regular surgical procedures, using standard surgical tools. CONCLUSION The system provides precise lesion localization without limiting the line of vision, the mobility of the surgeon, or the flexibility of instruments. Electromagnetic navigation promises new advances in neuronavigation and frameless stereotactic surgery.

Neuroprotective effect of hyperbaric oxygen therapy in brain injury is mediated by preservation of mitochondrial membrane properties

Recent experimental data have shown that hyperbaric oxygen therapy (HBOT) was associated increased Bcl-2 expression at the injury site that correlated with reduced apoptosis. We hypothesized that HBOT mediated enhancement of Bcl-2 expression and increased intracellular oxygen bio-availability may both contribute to preserve mitochondrial integrity and reduce the activation of the mitochondrial pathway of apoptosis. For this purpose, a cortical lesion was created in the parietal cortex of Sprague-Dawley rats by dynamic cortical deformation (DCD) and outcome measures in non-treated animals were compared with that of HBOT treated rats. Morphological analysis showed a profound reduction in neuronal counts in the perilesional area and a marked rarefaction of the density of the axonal-dendritic network. In treated animals, however, there was a significant attenuation of the impact of DCD over perilesional neurons, characterized by significantly higher cell counts and denser axonal network. In mitochondria isolated from injured brain tissue, there was a profound loss of mitochondrial transmembrane potential (Deltapsi(M)) that proved to be substantially reversed by HBOT. This finding correlated with a significant reduction of caspases 3 and 9 activation in HBOT treated animals but not of caspase 8, indicating a selective effect over the intrinsic pathway of apoptosis. All together, our results indicate that the neuroprotective effect of HBOT may represent the consequence of preserved mitochondrial integrity and subsequent inhibition of the mPTP and reduction of the mitochondrial pathway of apoptosis.

Comparison of Effects of Equiosmolar Doses of Mannitol and Hypertonic Saline on Cerebral Blood Flow and Metabolism in Traumatic Brain Injury

The potential superiority of hypertonic saline (HTS) over mannitol (MTL) for control of intracranial pressure (ICP) following traumatic brain injury (TBI) is still debated. Forty-seven severe TBI patients with increased ICP were prospectively recruited in two university hospitals and randomly treated with equiosmolar infusions of either MTL 20% (4 mL/kg; n=25 patients) or HTS 7.5% (2 mL/kg; n=22 patients). Serum sodium, hematocrit, ICP, arterial blood pressure, cerebral perfusion pressure (CPP), shear rate, global indices of cerebral blood flow (CBF) and metabolism were measured before, and 30 and 120 min following each infusion during the course of illness. Outcome was assessed at 6 months. Both HTS and MTL effectively and equally reduced ICP levels with subsequent elevation of CPP and CBF, although this effect was significantly stronger and of longer duration after HTS and correlated with improved rheological blood properties induced by HTS. Further, effect of HTS on ICP appeared to be more robust in patients with diffuse brain injury. In contrast, oxygen and glucose metabolic rates were left equally unaffected by both solutions. Accordingly, there was no significant difference in neurological outcome between the two groups. In conclusion, MTL was as effective as HTS in decreasing ICP in TBI patients although both solutions failed to improved cerebral metabolism. HTS showed an additional and stronger effect on cerebral perfusion of potential benefit in the presence of cerebral ischemia. Treatment selection should therefore be individually based on sodium level and cerebral hemodynamics.

LTP-like changes induced by paired associative stimulation of the primary somatosensory cortex in humans : source analysis and associated changes in behaviour

Paired associative stimulation (PAS), which combines repetitive peripheral nerve stimulation with transcranial magnetic stimulation (TMS), may induce neuroplastic changes in somatosensory cortex (S1), possibly by long‐term potentiation‐like mechanisms. We used multichannel median nerve somatosensory evoked potential (MN‐SSEP) recordings and two‐point tactile discrimination testing to examine the location and behavioural significance of these changes. When TMS was applied to S1 near‐synchronously to an afferent signal containing mechanoreceptive information, MN‐SSEP changes (significant at 21–31 ms) could be explained by a change in a tangential source located in Brodmann area 3b, with their timing and polarity suggesting modification of upper cortical layers. PAS‐induced MN‐SSEP changes between 28 and 32 ms were linearly correlated with changes in tactile discrimination. Conversely, when the near‐synchronous afferent signal contained predominantly proprioceptive information, PAS‐induced MN‐SSEP changes (20–29 ms) were shifted medially, and tactile performance remained stable. With near‐synchronous mechanoreceptive stimulation subtle differences in the timing of the two interacting signals tended to influence the direction of tactile performance changes. PAS performed with TMS delivered asynchronously to the afferent pulse did not change MN‐SSEPs. Hebbian interaction of mechanoreceptive afferent signals with TMS‐evoked activity may modify synaptic efficacy in superficial cortical layers of Brodmann area 3b and is associated with timing‐dependent and qualitatively congruent behavioural changes.

CoCl(2) induces apoptosis via the 18 kDa translocator protein in U118MG human glioblastoma cells.

The 18 kDa translocator protein (TSPO), formerly known as the peripheral-type benzodiazepine receptor, has been reported to be closely associated with the mitochondrial permeability transition pore (MPTP). TSPO is believed to exert pro-apoptotic functions via modulation of MPTP opening. Cobalt chloride (CoCl(2)), which is sometimes used as a hypoxia mimicking agent, is also known to be able to induce apoptosis. One of our questions was whether CoCl(2) may induce apoptosis via the TSPO. To address this question, we used the U118MG human glioblastoma cell line. We applied the specific TSPO ligand, PK 11195, as well as TSPO knockdown with siRNA and studied their influence on the effects of CoCl(2) on cell death, including activation of the mitochondrial apoptosis pathway. To assay TSPO expression, we applied binding assays and Western blotting to whole cell homogenates and mitochondrial fractions. To assay activation of the mitochondrial apoptosis pathway, including some of the cellular mechanisms involved, we determined the incidence of collapse of the mitochondrial membrane potential (Deltapsi(m)) and cardiolipin oxidation and measured the level of DNA fragmentation to assay apoptotic rates. We found that the TSPO ligand, PK 11195, significantly counteracted induction of cell death by 0.4 mM CoCl(2), including apoptosis, collapse of the Deltapsi(m), and cardiolipin oxidation. Moreover, we found that TSPO knockdown with siRNA fully protected against mentioned cell death mechanisms. Thus, we found that the TSPO is required for cell death induction by CoCl(2), including apoptosis. In conclusion, our studies show that activation of TSPO by CoCl(2) application is required for ROS generation, leading to cardiolipin oxidation, and collapse of the Deltapsi(m), as induced by CoCl(2).

Alteration in brain natriuretic peptide (BNP) plasma concentration following severe traumatic brain injury.

SummaryBackground. Brain natriuretic peptide (BNP) is a potent natriuretic and vasodilator factor which, by its systemic effects, can decrease cerebral blood flow (CBF). In aneurysmal subarchnoid hemorrhage (aSAH), BNP plasma concentrations were found to be associated with hyponatremia and were progressively elevated in patients who eventually developed delayed ischemic deficit secondary to vasospasm. The purpose of the present study was to evaluate trends in BNP plasma concentrations during the acute phase following severe (traumatic brain injury) TBI.Methods. BNP plasma concentration was evaluated in 30 patients with severe isolated head injury (GCS < 8 on admission) in four time periods after the injury (period 1: days 1–2; period 2: days 4–5; period 3: days 7–8; period 4: days 10–11). All patients were monitored for ICP during the first week after the injury.Findings. The initial BNP plasma concentrations (42 ± 36.9 pg/ml) were 7.3 fold (p < 0.01) higher in TBI patients as compared to the control group (5.78 ± 1.90 pg/ml). BNP plasma concentrations were progressively elevated through days 7–8 after the injury in patients with diffused SAH as compared to patients with mild or no SAH (p < 0.001) and in patients with elevated ICP as compared to patients without elevated ICP (p < 0.001). Furthermore, trends in BNP plasma concentrations were significantly and positively associated with poor outcome.Interpretation. BNP plasma concentrations are elevated shortly after head injury and are continuously elevated during the acute phase in patients with more extensive SAH and in those with elevated ICP, and correlate with poor outcomes. Further studies should be undertaken to evaluate the role of BNP in TBI pathophysiology.

Comparison of moderate hyperventilation and mannitol for control of intracranial pressure control in patients with severe traumatic brain injury--a study of cerebral blood flow and metabolism.

SummaryObjective. To compare the respective effects of established measures used for management of traumatic brain injury (TBI) patients on cerebral blood flow (CBF) and cerebral metabolic rates of oxygen (CMRO2), glucose (CMRGlc) and lactate (CMRLct). Methods. Thirty-six patients suffering from severe traumatic brain injury (TBI) were prospectively evaluated. In all patients baseline assessments were compared with that following moderate hyperventilation (reducing PaCO2 from 36 ± 4 to 32 ± 4 mmHg) and with that produced by administration of 0.5 gr/kg mannitol 20% intravenously. Intracranial and cerebral perfusion pressure (ICP, CPP), CBF and arterial jugular differences in oxygen, glucose and lactate contents were measured for calculation of CMRO2, CMRGlc and CMRLct. Results. Following hyperventilation, CBF was significantly reduced (P < 0.0001). CBF remained most often above the ischemic range although values less than 30 ml·100 gr−1·min−1 were found in 27.8% of patients. CBF reduction was associated with concurrent decrease in CMRO2, anaerobic hyperglycolysis and subsequent lactate production. In contrast, mannitol resulted in significant albeit moderate improvement of cerebral perfusion. However, administration of mannitol had no ostensible effect either on oxidative or glucose metabolism and lactate balance remained mostly unaffected. Conclusions. Moderate hyperventilation may exacerbate pre-existing impairment of cerebral blood flow and metabolism in TBI patients and should be therefore carefully used under appropriate monitoring. Our findings rather support the use of mannitol for ICP control.

Motor cortex activation by H-coil and figure-8 coil at different depths. Combined motor threshold and electric field distribution study.

OBJECTIVE To compare the ability of an H-coil and figure-8 coil to stimulate different motor cortex regions. METHODS The resting (rMT) and active (aMT) motor thresholds were measured for the right hand APB and leg AHB muscles in 10 subjects, using an H-coil and a figure-8 coil. The electric field distribution induced by the coils was measured in a head model. The combination of the hand and leg MTs with the field measurements was used to determine the depth of hand and leg motor areas via the intersection points. RESULTS The rMT and aMT of both APB and AHB were significantly lower for the H-coil. The ratio and difference between the leg and hand rMT and aMT were significantly lower for the H-Coil. Electric field measurements revealed significantly more favorable depth profile and larger volume of stimulation for the H-coil. The averaged intersection for the APB was at a distance from coil of 1.83±0.54cm and at an intensity of 97.8±21.4V/m, while for the AHB it was at a distance of 2.73±0.44cm and at an intensity of 118.6±21.3V/m. CONCLUSION The results suggest a more efficient activation of deeper motor cortical regions using the H-coil. SIGNIFICANCE The combined evaluation of MTs by H- and figure-8 coils allows measurement of the individual depth of different motor cortex regions. This could be helpful for optimizing stimulation parameters for TMS treatment.