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We examined the effects of slow‐pulsed transcranial electrical stimulation (TES) in suppressing epileptiform discharges in seven adults with refractory epilepsy. An MRI‐based realistic head model was constructed for each subject and co‐registered with 256‐channel dense EEG (dEEG). Interictal spikes were localized, and TES targeted the cortical source of each subject's principal spike population. Targeted spikes were suppressed in five subject's (29/35 treatment days overall), and nontargeted spikes were suppressed in four subjects. Epileptiform activity did not worsen. This study suggests that this protocol, designed to induce long‐term depression (LTD), is safe and effective in acute suppression of interictal epileptiform discharges. [ABSTRACT FROM AUTHOR]

Our objective was to determine if there are any distinguishable phase cone clustering patterns present near to epileptic spikes. These phase cones arise from episodic phase shifts due to the coordinated activity of cortical neurons at or near to state transitions and can be extracted from the high-density scalp EEG recordings. The phase cone clustering activities in the low gamma band (30–50 Hz) and in the ripple band (80–150 Hz) were extracted from the analytic phase after taking Hilbert transform of the 256-channel high density (dEEG) data of adult patients. We used three subjects in this study. Spatiotemporal contour plots of the unwrapped analytic phase with 1.0 ms intervals were constructed using a montage layout of 256 electrode positions. Stable phase cone patterns were selected based on the criteria that the sign of the spatial gradient did not change for at least three consecutive time samples and the frame velocity was within the range of propagation velocities of cortical axons. These plots exhibited dynamical formation of phase cones which were higher in the seizure area as compared with the nearby surrounding brain areas. Spatiotemporal oscillatory patterns were also visible during ±5 sec period from the location of the spike. These results suggest that the phase cone activity might be useful for noninvasive localization of epileptic sites and also for examining the cortical neurodynamics near to epileptic spikes. [ABSTRACT FROM AUTHOR]

High density scalp EEG and subdural ECoG recordings provide an opportunity to map the electrical activity of the cortex with high spatial resolution. The spatial power spectral densities conform to a power law distribution with some nonlinear variations. The spatiotemporal patterns of phase derived from these data sets have unique features, such as, amplitude and phase modulation waves and also exhibited formation of spatial phase cluster patterns. These unique features represent different cognitive states and are different between normal and diseased states. Reported results show that the rate of formation of phase cluster patterns derived from the seizure-free interictal EEG data are higher in epileptogenic zones as compared with nearby normal areas of the brain. [ABSTRACT FROM AUTHOR]

Abstract: The purpose of this study is to determine regions of cerebral cortex activated during the onset and propagation of dense array electroencephalographic (dEEG) epileptiform discharges in patients with juvenile myoclonic epilepsy (JME), through the use of 256 channel, dense array scalp EEG recordings. Ten patients (16–58 years old) with the clinical diagnosis of JME comprised the study group. In all cases the MRI and neurological exams were normal, while standard EEG recordings documented typical “generalized” 4–6 Hz epileptiform patterns. Outpatient dEEG recordings captured epileptiform discharges in each patient. Localization of onset and spread of discharges in relation to a standard MRI model was accomplished by applying dipole fits and a distributed linear inverse method of cortically constrained source analysis. All patients showed epileptiform discharges that localized to sources that included orbitofrontal/medial frontopolar cortex, while basal–medial temporal lobe sources were observed in 5/10 subjects. In many ways similar to discharges of typical absence, epileptiform patterns in JME are usually irregular and frequently include temporal lobe structures as the dominant contributors to the discharges. We find that epileptiform discharges in patients with JME are not “generalized” in the sense of bilaterally synchronous diffuse onset. Rather, discharges have both localized onsets and a restricted cortical network during propagation that includes regions of frontal and temporal cortex. [Copyright &y& Elsevier]

Abstract: Power density spectra and phase synchrony measurements were taken from intracranial electrode grids implanted in epileptic subjects. Comparisons were made between data from the waking state and from the period of unconsciousness immediately following a generalised tonic–clonic seizure. Power spectra in the waking state resembled coloured noise. Power spectra in the unconscious state resembled coloured noise from 1 to about 5Hz, but at higher frequencies changed in two out of three subjects to resemble white noise. This boosted unconscious gamma power to a higher level than conscious gamma power. For both gamma and beta passbands, synchrony measurements showed more widespread phase synchrony in the unconscious than the conscious state. We conclude that neither gamma activity per se nor phase synchrony per se are neural correlates of consciousness. [Copyright &y& Elsevier]

A 13-year-old girl presented with refractory seizures since the age of 5 years. Clinical exam and MRI studies were normal. Ictal EEG discharges suggested possible left posterior quadrant distribution but were not well localized with standard methods. A seizure was recorded during 128-channel EEG video long-term monitoring prior to invasive recordings. Applying a source analysis method, seizure onset and propagation patterns were calculated and displayed on an MRI model. The onset was localized to the left inferior posterior occipital cortex, followed by propagation to the right, then left, posterior cerebral hemispheres, and finally to the left superior-medial parietal lobe. These patterns were replicated closely on subsequent invasive recordings. Surgery was based on intracranial findings and she is seizure-free 30 months after resection. Noninvasive dense-array EEG, used in conjunction with realistic source analysis methods, may have the potential to assist in localizing seizure onsets when standard methods fail. Copyright © 2008 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Dense array EEG is a method of recording electroencephalography (EEG) with many more electrodes (up to 256) than is utilized with standard techniques that typically employ 19–21 scalp electrodes. The rationale for this approach is to enhance the spatial resolution of scalp EEG. In our research, dense array EEG is used in conjunction with a realistic model of head tissue conductivity and methods of electrographic source analysis to determine cerebral cortical localization of epileptiform discharges. In studies of patients with absence seizures, only localized cortical regions are involved during the attack. Typically, absences are accompanied by “wave–spike” complexes that show, both at the beginning and throughout the ictus, repetitive cycles of stereotyped, localized involvement of mainly mesial and orbital frontal cortex. Dense array EEG can also be used for long-term EEG video monitoring (LTM). We have used dense array EEG LTM to capture seizures in over 40 patients with medically refractory localization-related epilepsy, including both temporal and extra temporal cases, where standard LTM failed to reveal reliable ictal localization. One research goal is to test the validity of dense array LTM findings by comparison with invasive LTM and surgical outcome. Collection of a prospective series of surgical candidates who undergo both procedures is currently underway. Analysis of subjects with either generalized or localization-related seizures suggest that all seizures, including those traditionally classified as “generalized,” propagate through discrete cortical networks. Furthermore, based on initial review of propagation patterns, we hypothesize that all epileptic seizures may be fundamentally corticothalamic or corticolimbic in nature. Dense array EEG may prove useful in noninvasive ictal localization, when standard methods fail. Future research will determine if the method will reduce the need for invasive EEG recordings, or assist in the appropriate placement of novel treatment devices. [ABSTRACT FROM AUTHOR]

Abstract: Our objective was to examine how the scalp potentials and the magnetic fields of a sulcus change if the cortex in the walls is partially or fully active. The scalp potentials and magnetic fields of a part of the central sulcus were simulated with a finite element model of the head constructed from the segmented MRI images of an adult male subject. The electrical activity was modeled with current dipoles (0.1 mA meter) oriented perpendicular to the curved cortical surface. The fields of scalp EEG were computed using an adaptive finite element solver. The magnetic fields at a surface 1.0 cm above the scalp were computed using Biot-Savart law. Three distributions of activity were studied: the total sulcus; the superficial half and the deep half. Contour plots of EEG and MEG were constructed for each case. The spatial patterns of the scalp potential contours were significantly different for the partial vs. full activation. Each partial activation gave a uniquely different configuration of peak MEG and EEG locations that could have diagnostic utility. The spatial shifts in the peaks were more pronounced for the MEG compared with the EEG. These results indicate that scalp potentials and fields change significantly when the electrical and magnetic manifestations of activity are selective in the walls of a sulcus. [Copyright &y& Elsevier]

Abstract: Objective: To transfer to the clinic for humans the technology and theory for high-resolution EEG analysis that have been developed in the laboratory with animals. Methods: EEGs were recorded at high spatial resolution from a 1×1cm 8×8 electrode array on the right inferior temporal gyrus of a patient undergoing preoperative monitoring for epilepsy surgery. Cosines were fitted to EEG segments to measure frequency and phase and compute location, size, latency, phase velocity, duration, and recurrence rate of radially symmetric spatial patterns called phase cones. The Hilbert transform was also used to get high temporal resolution. Results: In the awake state, the power spectral density (PSD) showed power-law decrease in log power with log frequency at 1/f α , α∼2, but with peaks in the standard empirical ranges. The phase in beta and gamma ranges had spatial gradients in conic form. Resetting of these stable spatial patterns of phase cones was spatially coincident at intermittent discontinuities (‘phase slip’) recurring at theta rates. Cones had half power diameters from 2 to 50+mm; their durations had power-law distributions with values ranging from 6 to 300+ms depending on length of the analysis window. In slow wave sleep PSD decreased at 1/f α , α∼3,with loss of beta–gamma spectral peaks and diminished or absent oscillations and spatiotemporal phase structure. Conclusions: Spatiotemporal structures in awake human and rabbit EEG showed striking similarities. The only clear differences were ascribable to differing scales of measurement. These fine spatiotemporal structures of EEG were diminished or lost in slow wave sleep. Significance: The fine structure indicates that neocortical stability is sustained at self-organized criticality; that synaptic input in the awake state drives neocortex away from criticality causing beta–gamma oscillations in re-stabilizing ‘neural avalanches’; and that diminished input in slow wave sleep allows return toward criticality but with some added risk of instability and seizure. [Copyright &y& Elsevier]

Abstract: Background: Vagus nerve stimulation (VNS) is an FDA-approved treatment for medically intractable epilepsy. The effect of this therapy on body weight is unclear. VNS could cause weight loss by engaging vagal afferents from the gastrointestinal tract mediating satiety. Methods: We performed a retrospective analysis of body weight changes over a period up to 2 years following VNS implantation. We studied 21 patients (13 M/8 F) 35±12 years old, who received a Cyberonics VNS Therapy System for medically intractable epilepsy between April 1998 and May 2004. The mean±SD duration of follow-up was 613.1±389.1 days. The study had 80% power with a type I error of 0.05 to detect a 5% weight change. Data were analyzed with repeated-measures ANOVA. Results: Weight changes relative to baseline at 30, 60, 120, 360, 480, and 720 days were −0.17±2.33, +0.33±2.64, −0.32±3.56, +1.09±5.97, +1.06±7.47, and +0.33±3.69%, respectively. At all time points these differences failed to reach statistical significance. Conclusions: Vagus nerve stimulation with parameters typically used in the treatment of patients with epilepsy was not associated with clinically significant weight changes. A well-controlled prospective study is necessary for more precise evaluation of the effect of VNS therapy on body weight. [Copyright &y& Elsevier]

Abstract: Mesoscopic patterns of neural activity were sought in multichannel EEGs of rabbits that were trained to respond to conditioned stimuli (CSs) in visual, auditory and somatic modalities. Spatiotemporal patterns were sought of oscillations in the beta and gamma ranges. The techniques required for preprocessing EEGs in search of global patterns were diametrically opposed to those needed for localization of modular EEG signals. Frames were found in the form of intermittent spatial patterns of phase and amplitude modulation (AM and PM) of carrier waves in beta and gamma ranges that served to classify EEG frames with respect to CSs. A model based on the intentional action–perception cycle is proposed to complement the information processing model. [Copyright &y& Elsevier]

Summary: Purpose: To determine whether specific regions of cerebral cortex are activated at the onset and during the propagation of absence seizures. Methods: Twenty-five absence seizures were recorded in five subjects (all women; age 19-5 8 years) with primary generalized epilepsy. To improve spatial resolution, all studies were per- formed with dense-array, 256-channel scalp EEG. Source analysis was conducted with equivalent dipole (BESA) and smoothed linear inverse (LORETA) methods. Analyses were applied to the spike components of each spike-wave burst in each seizure, with sources visualized with standard brain models. Results: For each patient, the major findings were apparent on inspection of the scalp EEG maps and waveforms, and the two methods of source analysis gave generally convergent results. The onset of seizures was typically associated with activation of discrete, often unilateral areas of dorsolateral frontal or orbital frontal lobe. Consistently across all seizures, the negative slow wave was maximal over frontal cortex, and the spike that appeared to follow the slow wave was highly localized over frontopolar regions of orbital frontal lobe. In addition, sources in dorsomedial frontal cortex were engaged for each spike-wave cycle. Although each patient showed unique features, the absence seizures of all patients showed rapid, stereotyped evolution to engage both mesial frontal and orbital frontal cortex sources during the repeating cycles of spike-wave activity. Conclusions: These data suggest that absence seizures are not truly "generalized," with immediate global cortical involvement, but rather involve selective cortical networks, including orbital frontal and mesial frontal regions, in the propagation of ictal discharges. Key Words: Absence seizures-EEG-Source analysis-Dipole-Cerebral cortex-Thalamus. [ABSTRACT FROM AUTHOR]

Purpose: To study whether respiratory alteration caused by vagal nerve stimulation (VNS) can change end-tidal carbon dioxide (EtCO2) levels. Methods: We performed polygraphic recordings including capnographic monitoring during daytime sleep on adults with VNS therapy. Results: Ten of 13 patients showed VNS-induced alterations in the frequency or amplitude of respiration. Five patients had a consistent increase in respiratory rate with a simultaneous, consistent and significant decrease (p < 0.01; 5–22%) in EtCO2 during VNS. Three subjects showed occasional decreases in EtCO2 during VNS, and two showed no clearly detectable VNS-related EtCO2 changes. Conclusions: Our findings suggest that VNS may alter brain CO2 levels through changes in respiration. Because carbon dioxide (CO2) has potent effects on various brain functions, it is possible that these transient CO2 changes may have an effect on the state transitions between interictal and preictal states. [ABSTRACT FROM AUTHOR]

Purpose: To determine which patients with evidence of medically refractory bitemporal epilepsy are potentially good candidates for surgical therapy. Methods: We reviewed 42 adults with intractable seizures who were found to have bitemporal ictal onsets, based on scalp video-EEG long-term monitoring (LTM). All underwent invasive LTM before surgery. Surgical outcomes were classified as seizure free, > 75% reduction in seizures, or < 75% reduction in seizures, =1 year after resection. We related the following factors to outcome: (a) > 75% preponderance of interictal scalp EEG discharges to one temporal region; (b) magnetic resonance imaging (MRI) findings; (c) lateralizing deficits on verbal or visual reproduction memory testing; and (d) memory failure with injection contralateral to side of surgery on Wada testing. Results: Twenty-six (62%) of 42 patients had unilateral ictal onsets based on intracranial studies. Seizure freedom (occurring in 64% of this group), or > 75% seizure reduction (found in 12% of subjects) occurred only when at least one of the following three factors was concordant with the side of surgery: preponderance of interictal scalp EEG discharges, unilateral temporal lesion on MRI, or lateralizing verbal or visual reproduction memory deficits on neuropsychological tests (p = 0.004). Seven subjects with bilateral ictal onsets based on intracranial studies had resections based on preponderance of seizures to one side, or other lateralizing noninvasive abnormality. Five of these (all of whom had ≥ 80% of seizures originating from one side) had > 75% reduction in seizures. Conclusions: Invasive monitoring to pursue possible surgical therapy for patients with surface EEG evidence of bitemporal epilepsy may be justified only when some lateralizing feature is found in other noninvasive assessments. [ABSTRACT FROM AUTHOR]

Objective: Evaluate spectral scaling properties of scalp electroencephalogram (EEG) and electromyogram (EMG), optimal spacing of electrodes, and strategies for mitigating EMG.Methods: EEG was recorded referentially from 9 subjects with a 64 channel linear array (electrodes 3 mm apart) placed parasagittally or transversely on forehead or occiput, at rest with eyes open or closed, or with deliberate EMG. Temporal (PSDt) and spatial (PSDx) power spectral densities were calculated with one-dimensional fast Fourier transform (FFT) for comparison with earlier analyses of intracranial EEG.Results: Scaling of PSDt from scalp resembled that from pia: near-linear decrease in log power with increasing log frequency (1/fα). Scalp PSDx decreased non-linearly and more rapidly than PSDx from pia. Peaks in PSDt (especially 4–12 Hz) and PSDx (especially 0.1–0.4 cycles/cm) revealed departures from 1/fα. EMG power in PSDt was more “white” than 1/fα.Conclusions: Smearing by dura–skull–scalp distorts PSDx more than PSDt of scalp EEG from 1/fα scaling at the pia. Spatial spectral peaks suggest that optimal scalp electrode spacing might be ∼1 cm to capture non-local EEG components having the texture of gyri. Mitigation of EMG by filtering is unsatisfactory. A criterion for measuring EMG may support biofeedback for training subjects to reduce their EMG.Significance: High-density recording and log–log spectral display of EEG provide a foundation for holist studies of global human brain function, as an alternative to network approaches that decompose EEG into localized, modular signals for correlation and coherence. [Copyright &y& Elsevier]

Objective: Airway microvascular leakage is considered to be an important component of airway inflammation in asthma. In the present study we examined the effect of interleukin-1β (IL-1β) and tumour necrosis factor-α (TNFα) on airway microvascular leakage in vivo . Methodology: Tracheal Evans blue extravasation was examined in an isolated tracheal segment, in anaesthetized mechanically ventilated guinea pigs. Baseline tracheal microvascular leakage was measured in five animals. As a control group for aerosol challenge, the isolated tracheal segment (n = 5) underwent saline aerosol challenge. To test whether a combination of IL-1β (10 ng/mL) and TNFα (100 ng/mL) induced Evans blue extravasation, the trachea was exposed to an aerosol of these cytokines (n = 5). As a positive control the tracheal segment was challenged with histamine aerosol (5 × 10–2 mol) (n = 3). All aerosol challenges were for 1 min. Results: TNFα and IL-1β aerosol challenge significantly increased Evans blue extravasation (28.9 ± 1.6 μg/g wet tissue, mean ± SE) compared to saline challenge (13.8 ± 3.0 μg/g; P < 0.05). Tracheal dye extravasation without aerosol challenge, was not significantly different from saline-challenged animals (17.5 ± 2.9 and 13.8 ± 3.0 μg/g, respectively). Histamine significantly increased Evans blue extravasation (50.1 ± 4.8 μg/g; P < 0.05) compared to saline challenge. Conclusion: Pro-inflammatory cytokines, TNFα and IL-1β are able to induce significant microvascular leakage in the guinea pig trachea. [ABSTRACT FROM AUTHOR]

Objective:In vivo airway hyperresponsiveness has been demonstrated following inhalation of specific cytokines in normal individuals. Whether this airway hyperresponsiveness results from a direct effect of cytokines on airway smooth muscle contractility, or via changes in airway wall structure is not known. The aim of the present study was to determine the effect of the pro-inflammatory cytokines interleukin-1β (IL-1β) and tumour necrosis factor-α (TNF-α) on airway smooth muscle contractility in vitro. Methodology: Ovine tracheal smooth muscle strips were incubated for 18 h at room temperature in Dulbecco’s modified Eagle’s medium, supplemented with antibiotics, with IL-1β (10 ng/mL) and TNF-α (100 ng/mL), in an atmosphere of 5%CO2: 95%O2. Following incubation cumulative concentration–response curves to acetylcholine (ACh) and neurokinin A (NKA) were obtained. Antagonist affinity studies were performed to determine whether the cytokine-induced enhanced contractility to ACh and NKA resulted from a functional alteration to specific M3 and NK2 receptors. Cumulative concentration–response curves to NKA were performed in the presence of phosphoramidon to determine if the enhanced contractility to NKA following cytokine exposure was due to a reduction in endogenous neutral endopeptidase activity. To assess the calcium dependence of the hyperresponsiveness, cumulative concentration–responses to ACh were conducted in calcium-free Krebs’–Henseleit solution. Results: Pre-incubation with TNF-α and IL-1β caused a significant leftward shift, and an increase in the magnitude, of the concentration–response curves to both ACh and NKA. No difference in M3 and NK2 receptor antagonist affinity (pA2) values between the control and cytokine-treated tissue was observed. Neurokinin A contractility in the presence of phosphoramidon indicated that the enhanced contractility following cytokine exposure was not due to a reduction in endogenous neutral endopeptidase activity. Removal of extracellular calcium ions attenuated the contractile response to low concentrations of ACh in the control and cytokine-pretreated tissue. However, enhanced contractility following TNF-α and IL-1β pretreatment was still present. Conclusion: Pro-inflammatory cytokines induce in vitro hyperresponsiveness in normal airway smooth muscle via a mechanism involving intracellular calcium mobilization. [ABSTRACT FROM AUTHOR]

Purpose: Voluntary hyperventilation has been advocated for many decades as an “activating” procedure to provoke clinical seizures and epileptiform discharges in subjects with suspected epilepsy who undergo standard EEG recordings. This study was undertaken to determine the effects of hyperventilation in patients with proven epilepsy. Methods: We examined the records of 433 consecutive patients with proven epilepsy, as documented by long-term video-EEG studies. The patients underwent 5 min of voluntary hyperventilation during standard EEG recordings. All EEGs were interpreted by board-certified electroencephalographers. The patients ranged in age from 10 to 64 years; 384 (88.7%) had localization-related and 48 (11.3%) generalized epilepsy syndromes. Results: Hyperventilation was associated with a clinical seizure in two (0.46%) of the subjects (partial seizures in both cases). Interictal epileptiform discharges were interpreted as showing in increase in frequency during hyperventilation in 19 (4.4%) patients, when compared with the baseline EEG. Conclusions: Voluntary hyperventilation in patients with unequivocal epilepsy is rarely associated with either clinical seizures or an increase in frequency of epileptiform discharges. [ABSTRACT FROM AUTHOR]

Presents a response by the author to a letter to the editor about his article on the behavior of distributed linear inverse solutions.

Presents a letter to the editor responding to comments made on the author's article about the effectiveness of voluntary hyperventilation in eliciting seizures in patients with proven epilepsy.

Bronchial artery embolization is an effective treatment for patients with hemoptysis. Serious complications are rare, but may occur if the arterial supply to other structures is compromised. We present a case of unilateral diaphragmatic paralysis following bronchial artery embolization in a patient with cystic fibrosis. We believe that the diaphragmatic paralysis was due to the inadvertent obstruction of the left pericardiacophrenic artery during the embolization procedure, with compromise of the phrenic nerve blood supply. This resulted in a significant loss of lung function in our patient, who did not recover despite the subsequent return of diaphragmatic function. [ABSTRACT FROM AUTHOR]

An abstract of the article "ACE-Targeted eNOS and BMPR2 Gene Therapy Attenuates Pulmonary Hypertension in a Chronic Hypoxia Rat Model," by Ann M. Reynolds and colleagues is presented.

Abstract: Objective: In cats, spike-wave (SW) seizures have been observed to emerge from cortical slow oscillations (CSOs) and spindles in sleep. We examined a patient’s generalized SW seizures that appeared to emerge from CSOs in sleep. Methods: Dense array (256-channel) electroencephalographic (dEEG) data were recorded during long-term monitoring for localizing seizure onset for neurosurgical planning. CSOs were identified on the basis of topographic criteria from dEEG studies of normal human sleep. SW discharges were identified in the surface dEEG and examined with distributed linear inverse neural source estimation. Results: This patient’s SW discharges appeared to emerge from a series of CSOs that engaged the left frontal pole. Furthermore, 12Hz sleep spindles in this patient were often synchronized in time with the CSOs, and in some instances they shared a similar localization over the left frontal pole at the point of seizure onset. Conclusions: The initial discharges of each seizure engaged both the left frontal pole, which was the primary neural source of this patient’s CSOs, and the left temporal lobe, which seemed critical for the evolution of this patient’s seizures. Significance: The correlation of SW seizures with CSOs in animal studies may be observed in humans as well, providing clues to the pathology of arousal regulation in some cases of nocturnal epilepsy. [Copyright &y& Elsevier]

Idiopathic pulmonary arterial hypertension (PAH) is characterized by proliferation of pulmonary vascular endothelial and smooth muscle cells causing increased vascular resistance and right heart failure. Mutations in the bone morphogenetic protein receptor type 2 (BMPR2) are believed to cause the familial form of the disease. Reduced expression of BMPR2 is also noted in secondary PAH. Recent advances in the therapy of PAH have improved quality of life and survival, but many patients continue to do poorly. The possibility of treating PAH via improving BMPR2 signaling is thus a rational consideration. Such an approach could be synergistic with or additive to current treatments. We developed adenoviral vectors containing the BMPR2 gene. Transfection of cells in vitro resulted in upregulation of SMAD signaling and reduced cell proliferation. Targeted delivery of vector to the pulmonary vascular endothelium of rats substantially reduced the pulmonary hypertensive response to chronic hypoxia, as reflected by reductions in pulmonary artery and right ventricular pressures, right ventricular hypertrophy, and muscularization of distal pulmonary arterioles. These data provide further evidence for a role for BMPR2 in PAH and provide a rationale for the development of therapies aimed at improving BMPR2 signaling. [ABSTRACT FROM AUTHOR]

Abstract: New bedside long-term DC-coupled EEG techniques have demonstrated that infraslow (<0.5 Hz) activity lateralizes temporal lobe seizures (Vanhatalo, S., Holmes, M.D., Tallgren, P., Voipio, J., Kaila, K., Miller, J.W., 2003a. Very slow EEG responses indicate the laterality of temporal lobe seizures: a DC-EEG study. Neurology 60, 1098–1104). However, even high amplitude infraslow activity is difficult to localize by simple visual inspection if there is overlying faster EEG activity or slow artifact. In this study, we address this with improved DC-coupled EEG recording and analysis techniques and also extend observation to both temporal and extratemporal seizures. Recordings were performed during presurgical evaluation of medically intractable epilepsy, with 20 seizures in 11 patients analyzed. A commercial DC-coupled recording device was used, with sintered Ag/AgCl electrodes in a standard 10-10 system array, with additional anterior temporal and subtemporal electrodes. Seizures were localized with a software package by means of source montage analysis. Infraslow signals occurred with all seizures, often with amplitude orders of magnitude higher than conventional frequencies (0.5 to 70 Hz). The most reliable method to localize these signals and distinguish them from artifacts used a source montage after low-pass filtering below 0.5 Hz. Five of the eight patients who received epilepsy surgery had follow-up documenting significant seizure reduction, and infraslow signal analysis correctly localized the region of seizure onset in all five, while conventional noninvasive EEG recording and analysis localized only three of the five. Several seizures were also analyzed using principle component analysis source localization methods, with the results less consistently localizing than source montage analysis. DC-coupled EEG recordings give clinically useful information to noninvasively localize the seizure focus. The value of this method is increased by source analysis tools that reveal localized changes more clearly than direct visual inspection. [Copyright &y& Elsevier]

Abstract: Visual evoked potentials are useful clinical tools to study visual pathways of the brain. Although the temporal resolution is unsurpassed by other brain imaging technologies, the spatial resolution is diminished or blurred by the low conductance of the electrical signals through the skull. Methods have been proposed to improve the spatial resolution by downwardly projecting the electrical signals measured on the scalp to the surface of the cerebral cortex through the inverse solution of the equations governing static current flow. We describe the adaptation and combination of commercially available engineering software programs to solve this inverse problem and report the results of a sample run of the system. Before deblurring, the visual evoked potentials appeared to be diffusely localized over the posterior scalp. After deblurring, the visual evoked potentials were only found at the electrodes closest to the visual cortex, as would be predicted by our current knowledge of neuroanatomy. [Copyright &y& Elsevier]

Summary: Purpose: To examine the subgroup of patients with medically intractable epilepsy receiving temporal lobectomies who have pathologically verified mesial temporal sclerosis (MTS) and to determine the relation of demographic and clinical factors, results of diagnostic testing, and details of the surgical procedure with prognosis for achieving control of seizures. Methods: All patients receiving surgical treatment for intractable epilepsy between 1991 and 1998 at the University of Washington were reviewed. There were 118 patients who met inclusion criteria of adequate pathological analysis showing MTS without a progressive process and a minimum of 1-year follow-up. Results: Only personal history of status epilepticus demonstrated significant (p = 0.0276) prediction of outcome, increasing the risk of surgical failure. No other factors were significant predictors of outcome, including history of febrile seizures, possible etiologic factors, EEG, magnetic resonance imaging (MRI) or neuropsychological testing results, or extent of resection. Conclusions: Many factors that have been previously described to predict favorable outcome in the overall group of patients receiving temporal lobe resections for intractable epilepsy are, in fact, predictors of MTS and lose their predictive value when the subgroup of patients with confirmed MTS is examined. Neurosurgical treatment of MTS can be very effective even in the presence of significant etiologic factors, or of bilateral or extratemporal abnormalities on EEG or MRI. [ABSTRACT FROM AUTHOR]

Objective: Tachykinins are neuropeptides present in sensory nerves in the lung. Aside from their role as neurotransmitters, these peptides exert pro-inflammatory and protective effects in the airways. Although tachykinins may be released from sensory nerves, there is increasing evidence that they are also produced by non-neuronal cells. The nett effect of tachykinins will likely result from relative changes in the levels of tachykinins, tachykinin receptors and tachykinin degrading enzymes. We investigated whether tachykinins might be produced locally in human airway epithelium in vivo, and whether mRNA levels for either tachykinins, their receptors, or for the tachykinin degrading enzyme neutral endopeptidase (NEP) were altered in subjects with chronic bronchitis compared to normals. Methodology: We used reverse transcription polymerase chain reaction analysis of brush biopsy samples to detect mRNAs of interest. We then developed a semi-quantitative approach to compare subject groups. Results: We detected a signal for preprotachykinin A (PPT-A) mRNA as well as for tachykinin receptors and NEP in patients with airways disease and normal subjects. We found a relative 10-fold increase in PPT-A mRNA in smokers with chronic bronchitis, along with similar increases in mRNA for the inflammatory markers intercellular adhesion molecule-1 and interleukin-8. In contrast, NEP and NK1 tachykinin receptor mRNA levels were not different between the groups. Conclusion: These findings imply that up-regulation of tachykinin production by cells present in the airway epithelium contributes to the pathophysiology of chronic bronchitis. [ABSTRACT FROM AUTHOR]

Highlights • Precise electrical source imaging (ESI) requires high density EEG, exact sensor positions and high-resolution individual head models constructed from the patient’s magnetic resonance image. • The HD-EEG allows whole head sampling, with sensors on the face and neck providing important measures particularly for temporal lobe seizures. • The individual head models include appropriate seven tissue conductivities and the lead field matrix with finite difference method. • Noninvasive ESI of oscillatory features at ictal onset using 256-channel HD-EEG and high-resolution individual head models can be implemented in an efficient and inexpensive workflow in presurgical evaluation. Abstract Surgical resection of the seizure onset zone (SOZ) requires that this region of the cortex is accurately localized. The onset of a seizure may be marked by transient discharges, but it also may be accompanied by oscillatory, sinusoidal electrographic activity, such as the EEG theta rhythm. However, because of the superposition of the seizure signal with other electrical signals, including noise artifacts and non-seizure brain activity, noninvasive Electrical Source Imaging (ESI) of the ictal EEG activity at seizure onset remains a challenging task for surgical planning. In the present study, we localize the SOZ from oscillatory features of the EEG at the ictal onset using 256-channel high density electroencephalography (HD-EEG), exact sensor positions, and individual electrical head models constructed from the patient’s T1 magnetic resonance image (MRI). Epileptic activities at the seizure onset were characterized with joint time-frequency analysis and source estimated by standardized low resolution electromagnetic tomography (sLORETA) inverse method. The consistency of this localization was examined across multiple seizures for individual patients. For validation, results were compared to three clinical criteria: (1) epileptogenic lesions, (2) seizure onset observed in intracranial EEG, and (3) successful surgical outcomes. In this set of 84 seizures, the onsets of 56 seizures could be localized. For the lateralization measure, the results from HD-EEG with interictal spikes (8/10) and with ictal onset (10/10) were more accurate than international 10–20 EEG for interictal spikes (5/10) and ictal onset (5/10). ESI from HD-EEG with ictal onset (9/10) had greater concordance to the clinical criteria than HD-EEG with interictal spikes (6/10). Noninvasive ESI of oscillatory features at ictal onset using 256-channel HD-EEG and high-resolution individual head models can make a useful contribution to the clinical localization of the SOZ in presurgical planning. [ABSTRACT FROM AUTHOR]

Adapting a 256 contact dense array system to perform multiday long-term EEG and video monitoring requires additional technical attention compared to standard long-term monitoring (LTM). Areas of concern are patient comfort, electrode maintenance, and increased time for record review. [ABSTRACT FROM AUTHOR]

Abstract: Neural mechanisms of conscious attention require thalamic control of widespread cortical networks. Absence spells involve a momentary loss of voluntary control of attention, during which the person is inactive and unresponsive. The spike–wave seizure discharges of these spells rapidly engage both cerebral hemispheres in the classic sign of a “generalized” seizure. Animal evidence suggests that spike–wave seizures are caused by a disruption of thalamic circuitry, with extensive spread to cortex through thalamocortical propagation. We applied advanced methods of electrical source analysis to dense array (256-channel) electroencephalographic recordings of spike–wave discharges of absence spells. Neither the onset nor the spread of these seizures is generalized. Rather, the slow waves of the discharges are restricted to frontotemporal networks, and the spikes represent a highly localized and stereotyped progression of electrophysiological activity in ventromedial frontal networks. Given the current knowledge of the neurophysiology of absence seizures, this specificity of the frontal cortical discharges suggests the hypothesis that absence spells are associated with pathology in a circuit comprising ventromedial frontal cortex, rostral thalamic reticular nucleus, and limbic nuclei of the thalamus. Disrupted in absence, this circuit appears to regulate important aspects of the voluntary control of conscious attention. [Copyright &y& Elsevier]

Purpose: Patients with psychogenic nonepileptic seizures (PNES) and those with epileptic seizures (ES) purportedly have roughly equal neurocognitive deficits. However, recent findings suggest that patients with somatoform disorders exhibit more variable effort on neurocognitive testing than do controls. We reexamined neurocognitive function in patients with ESs and PNES by using symptom validity testing to control for variability in effort. Methods: Patients referred for video-EEG monitoring were administered the Word Memory Test (WMT), a measure of symptom validity, as part of neuropsychological evaluation. Patients classified with ictal video-EEG recordings as having ES (n = 41) or PNES (n = 43) were compared on neurocognitive and WMT performance and demographic, psychiatric, and medical variables. Results: Striking rates of WMT failure were observed in the PNES (51.2%) group, but not in the ES (8.1%) group (p = <0.001) after controlling for false-positive errors. Although the PNES and ES groups reported equivalent neurologic histories, the PNES group exhibited less objective evidence of impairment as measured by valid neuropsychological testing, MRI of the brain, and video-EEG monitoring. Conclusions: Many patients with PNES do not put forth maximal effort during neuropsychological assessment. When patients with PNES put forth valid effort, they demonstrate less objective evidence of neuropathologic injury or disease than do patients with ES. The cognitive impairment reported by this group appears to be more a function of motivational (although not necessarily intentional) factors than of verifiable neuropathology. [ABSTRACT FROM AUTHOR]

Summary: Matrix metalloproteinases (MMPs) are essential for extracellular matrix (ECM) breakdown and repair, and have been implicated in the development of metastases. TIMP-3 was initially identified as a potent inhibitor of MMPs, however it also has several properties that are unique and not related to its ability to abrogate MMPs. We studied the effects of overexpression of tissue inhibitor of metalloproteinases-3 (TIMP-3) on lung cancer cells and explored the mechanisms involved in apoptosis-induction in susceptible cells and subsequently, the therapeutic effect in vivo. Overexpression of TIMP-3 resulted in apoptosis of A549 lung cancer cells and AdCMVTIMP3 up-regulated the expression of p53, Fas ligand, TNFR1 and TNFR2 on these cells. Adenoviral delivery of TIMP-3 gene inhibited the growth of pre-established A549 tumours in Balb/c nude mice, and was associated with a greater therapeutic effect than either TIMP-1 or -2 gene delivery. There was no evidence of increased hepatic toxicity following the delivery of TIMP-3 either from intra-tumoural or intravenous injection. Thus, at least in cells showing in vitro susceptibility, TIMP-3 gene therapy offers a therapeutic advantage over TIMPs 1 and 2. These findings establish the potential of adenoviral gene delivery of TIMP3 as a therapeutic agent for selected lung cancers. [Copyright &y& Elsevier]

Background: Lung transplant tolerance depends on effective control of T-cell proliferation and activation. Commonly used immunosuppressive agents promote peripheral blood-derived lymphocyte apoptosis and inhibit production of cytokines involved in lymphocyte proliferation and survival. However, there have been no studies of the effectiveness of immunosuppressive treatments on apoptosis of T cells derived from the airways of lung transplant recipients. Our main aim was to compare apoptosis of T cells derived from peripheral blood and bronchoalveolar lavage (BAL) from lung transplant recipients, with no evidence of chronic or acute cellular rejection, and healthy volunteers. Lung transplantation may also be associated with increased apoptosis of airway epithelial cells. To investigate this possibility, we also examined apoptosis of epithelial cells derived from bronchial brushing. Methods: BAL, blood, and bronchial brushings were obtained from lung transplant recipients (n = 9) and age-matched controls (n = 15). T cell and epithelial cell apoptosis, Fas, Bax, Bcl-2, and p53 were evaluated by flow cytometry. Results: Increased apoptosis of peripheral blood T cells and decreased Bcl-2 were observed in the transplant patients. In contrast, there was no significant change in apoptosis of airway T cells or apoptosis-related proteins. Increased apoptosis and increased p53 were observed in the airway epithelial cells from the transplant recipients, possibly as a result of ineffective control of infiltrating cytotoxic T cells. Conclusions: Immunosuppressive agents may not be as effective in inducing apoptosis of airway-derived T cells as peripheral blood-derived T cells after lung transplantation. These findings may have implications on the outcome of the immune response in the airways after immunosuppressive therapy and may be particularly relevant to lung allograft rejection. [Copyright &y& Elsevier]

Objective: Tachykinins are mediators of airway hyper-reactivity and inflammation. There is in vitro evidence that ovine responses to tachykinins correlate closely to human responses. This study was designed to characterize the effect of intravenously administered tachykinins on sheep lung resistance in vivo to determine the effect of dose timing on reproducibility of responses and the induction of tachyphylaxis. We then used this information to help further characterize the response with several pharmacological agents. Methodology: Substance P (SP) was administered by infusion to conscious merino ewes and lung resistance (RL) was measured. Infusions were given at 30, 60, 120 min and 24 h intervals. The effect of various agents on the response to SP was then assessed. Results: Substance P led to a transient increase in RL, mean (± SEM) 754.8 (± 139)% of baseline, with marked tachyphylaxis at 30, 60 and 120 min. Phosphoramidon increased the peak response to 1151.5 ± 196%. Atropine and CP 96 345 abolished the response to SP, while indomethacin, sodium cromoglycate and pyrilamine had no significant effect. Substance P had a greater effect on RL than did neurokinin A. Conclusions: Substance P increases RL in sheep via a cholinergic mechanism which is mediated by NK-1 receptors, and is subject to tachyphylaxis. These findings have implications for the design of studies using the ovine model in the evaluation of tachykinin antagonists as potential therapeutic agents. [ABSTRACT FROM AUTHOR]

Summary: Purpose: Several EEG-based studies suggest that epileptiform activity originates from the left more than the right hemisphere. In contrast, other pathophysiologies such as stroke lateralize relatively symmetrically. Study of focal slowing and other EEG abnormalities allows assessment of favoring as well as referral and interpretation bias. Methods: The 1,331 consecutive adult EEG reports were reviewed for epileptiform discharges (EDs) and nonepileptiform focal slowing. Side of slowing or EDs, interpreting electoencephalographer, and whether the patient was undergoing long-term monitoring or routine EEG were tallied. Results were statistically analyzed. Results: Focal slowing occurred symmetrically; EDs favored the left hemisphere (p < 0.01). Conclusions: The left hemisphere may be more prone to epileptiform abnormalities in adults, but not to the nonspecific pathophysiologic processes that cause slowing. These findings suggest that potential interpretation bias does not influence left hemispheric favoring of EDs and instead may implicate a biologic etiology. [ABSTRACT FROM AUTHOR]