Faculty Bibliography

The article considers the problem of dividing the encephalography data into two time series, that generated by the brain and that generated by other electrical sources located in the human head. The magnetic encephalograms and magnetic resonance images of the head were recorded in the Center for Neuromagnetism at NYU Grossman School of Medicine. Data obtained at McGill University and Montreal University were also used. Recordings were made in a magnetically shielded room and the gradiometers were designed to suppress external noise, making it possible to eliminate them from the data analysis. Magnetic encephalograms were analyzed by the method of functional tomography, based on the Fourier transform and on the solution of inverse problem for all frequencies. In this method, one spatial position is assigned to each frequency component. Magnetic resonance images of the head were evaluated to annotate the space to be included in the analysis. The included space was divided into two parts: «brain» and «non-brain». The frequency components were classified by the feature of their inclusion in one or the other part. The set of frequencies, designated as «brain», represented the partial spectrum of the brain signal, while the set of frequencies designated as «non-brain», represented the partial spectrum of the physiological noise produced by the head. Both partial spectra shared the same frequency band. From the partial spectra, a time series of the «brain» area signal and «non-brain» area head noise were reconstructed. Summary spectral power of the signal was found to be ten times greater than the noise. The proposed method makes it possible to analyze in detail both the signal and the noise components of the encephalogram and to filter the magnetic encephalogram.

A spectroscopic paradigm has been developed that allows the magnetic field emissions generated by the electrical activity in the human body to be imaged in real time. The growing significance of imaging modalities in biology is evident by the almost exponential increase of their use in research, from the molecular to the ecological level. The method of analysis described here allows totally noninvasive imaging of muscular activity (heart, somatic musculature). Such imaging can be obtained without additional methodological steps such as the use of contrast media.

1-octanol is a therapeutic candidate for disorders involving the abnormal activation of the T-type calcium current since it blocks this current specifically. Such disorders include essential tremor and a group of neurological and psychiatric disorders resulting from thalamocortical dysrhythmia (TCD). For example, clinically, the observable phenotype in essential tremor is the tremor itself. The differential diagnostic of TCD is not based only on clinical signs and symptoms. Rather, TCD incorporates an electromagnetic biomarker, the presence of abnormal thalamocortical low frequency brain oscillations. The effect of 1-octanol on brain activity has not been tested. As a preliminary step to such a TCD study, we examined the short-term effects of a single dose of 1-octanol on resting brain activity in 32 healthy adults using magnetoencephalograpy. Visual inspection of baseline power spectra revealed that the subjects fell into those with strong low frequency activity (set 2, n = 11) and those without such activity, but dominated by an alpha peak (set 1, n = 22). Cross-validated linear discriminant analysis, using mean spectral density (MSD) in nine frequency bands as predictors, found overall that 82.5% of the subjects were classified as determined by visual inspection. The effect of 1-octanol on the MSD in narrow frequency bands differed between the two subject groups. In set 1 subjects the MSD increased in the 4.5-6.5Hz and 6.5-8.5 Hz bands. This was consistent with a widening of the alpha peak toward lower frequencies. In the set two subjects the MSD decrease in the 2.5-4.5 Hz and 4.5-6.5 Hz bands. This decreased power is consistent with the blocking effect of 1-octanol on T-type calcium channels. The subjects reported no adverse effects of the 1-octanol. Since stronger low frequency activity is characteristic of patients with TCD, 1-octanol and other T-type calcium channel blockers are good candidates for treatment of this group of disorders following a placebo-controlled study.

A new method for the analysis and localization of brain activity has been developed, based on multichannel magnetic field recordings, over minutes, superimposed on the MRI of the individual. Here, a high resolution Fourier Transform is obtained over the entire recording period, leading to a detailed multi-frequency spectrum. Further analysis implements a total decomposition of the frequency components into functionally invariant entities, each having an invariant field pattern localizable in recording space. The method, addressed as functional tomography, makes it possible to find the distribution of magnetic field sources in space. Here, the method is applied to the analysis of simulated data, to oscillating signals activating a physical current dipoles phantom, and to recordings of spontaneous brain activity in 10 healthy adults. In the analysis of simulated data, 61 dipoles are localized with 0.7 mm precision. Concerning the physical phantom the method is able to localize three simultaneously activated current dipoles with 1 mm precision. Spatial resolution 3 mm was attained when localizing spontaneous alpha rhythm activity in 10 healthy adults, where the alpha peak was specified for each subject individually. Co-registration of the functional tomograms with each subject's head MRI localized alpha range activity to the occipital and/or posterior parietal brain region. This is the first application of this new functional tomography to human brain activity. The method successfully provides an overall view of brain electrical activity, a detailed spectral description and, combined with MRI, the localization of sources in anatomical brain space.

Superfusion of the squid giant synapse with artificial seawater (ASW) based on isotonic saline containing oxygen nanobubbles (RNS60 ASW) generates an enhancement of synaptic transmission. This was determined by examining the postsynaptic response to single and repetitive presynaptic spike activation, spontaneous transmitter release, and presynaptic voltage clamp studies. In the presence of RNS60 ASW single presynaptic stimulation elicited larger postsynaptic potentials (PSP) and more robust recovery from high frequency stimulation than in control ASW. Analysis of postsynaptic noise revealed an increase in spontaneous transmitter release with modified noise kinetics in RNS60 ASW. Presynaptic voltage clamp demonstrated an increased EPSP, without an increase in presynaptic ICa(++) amplitude during RNS60 ASW superfusion. Synaptic release enhancement reached stable maxima within 5-10 min of RNS60 ASW superfusion and was maintained for the entire recording time, up to 1 h. Electronmicroscopic morphometry indicated a decrease in synaptic vesicle density and the number at active zones with an increase in the number of clathrin-coated vesicles (CCV) and large endosome-like vesicles near junctional sites. Block of mitochondrial ATP synthesis by presynaptic injection of oligomycin reduced spontaneous release and prevented the synaptic noise increase seen in RNS60 ASW. After ATP block the number of vesicles at the active zone and CCV was reduced, with an increase in large vesicles. The possibility that RNS60 ASW acts by increasing mitochondrial ATP synthesis was tested by direct determination of ATP levels in both presynaptic and postsynaptic structures. This was implemented using luciferin/luciferase photon emission, which demonstrated a marked increase in ATP synthesis following RNS60 administration. It is concluded that RNS60 positively modulates synaptic transmission by up-regulating ATP synthesis, thus leading to synaptic transmission enhancement.

BACKGROUND: Care for patients with advanced heart failure (HF) has traditionally focused on managing HF alone; however, little is known about the prevalence and contribution of comorbidity to mortality among this population. We compared the impact of comorbidity on mortality in older adults with HF with high mortality risk and those with lower mortality risk, as defined by presence or absence of a prior hospitalization for HF, respectively. METHODS: This was a retrospective cohort study (2002-2006) of 18,322 age-matched and gender-matched Medicare beneficiaries. We used the baseline year of 2002 to ascertain HF hospitalization history, in order to identify beneficiaries at either high or low risk of future HF mortality. We calculated the prevalence of 19 comorbidities and overall comorbidity burden, defined as a count of conditions, among both high and low risk beneficiaries, in 2002. Proportional hazards regressions were used to determine the effect of individual comorbidity and comorbidity burden on mortality between 2002 and 2006 among both groups. RESULTS: Most comorbidities were significantly more prevalent among hospitalized versus non-hospitalized beneficiaries; myocardial infarction, atrial fibrillation, kidney disease (CKD), chronic obstructive pulmonary disease (COPD), and hip fracture were more than twice as prevalent in the hospitalized group. Among hospitalized beneficiaries, myocardial infarction, diabetes, COPD, CKD, dementia, depression, hip fracture, stroke, colorectal cancer and lung cancer were each significantly associated with increased hazard of dying (hazard ratios [HRs]: 1.16-1.93), adjusting for age, gender and race. The mortality risk associated with most comorbidities was higher among non-hospitalized beneficiaries (HRs: 1.32-3.78). CONCLUSIONS: Comorbidity confers a significantly increased mortality risk even among older adults with an overall high mortality risk due to HF. Clinicians who routinely care for this population should consider the impact of comorbidity on outcomes in their overall management of HF. Such information may also be useful when considering the risks and benefits of aggressive, high-intensity life-prolonging interventions.

Abnormal brain activity dynamics, in the sense of a thalamocortical dysrhythmia (TCD), has been proposed as the underlying mechanism for a subset of disorders that bridge the traditional delineations of neurology and neuropsychiatry. In order to test this proposal from a psychiatric perspective, a study using magnetoencephalography (MEG) was implemented in subjects with schizophrenic spectrum disorder (n = 14), obsessive-compulsive disorder (n = 10), or depressive disorder (n = 5) and in control individuals (n = 18). Detailed CNS electrophysiological analysis of these patients, using MEG, revealed the presence of abnormal theta range spectral power with typical TCD characteristics, in all cases. The use of independent component analysis and minimum-norm-based methods localized such TCD to ventromedial prefrontal and temporal cortices. The observed mode of oscillation was spectrally equivalent but spatially distinct from that of TCD observed in other related disorders, including Parkinson's disease, central tinnitus, neuropathic pain, and autism. The present results indicate that the functional basis for much of these pathologies may relate most fundamentally to the category of calcium channelopathies and serve as a model for the cellular substrate for low-frequency oscillations present in these psychiatric disorders, providing a basis for therapeutic strategies

Complex Regional Pain Syndrome (CRPS) is a neuropathic disease that presents a continuing challenge in terms of pathophysiology, diagnosis, and treatment. Recent studies of neuropathic pain, in both animals and patients, have established a direct relationship between abnormal thalamic rhythmicity related to Thalamo-cortical Dysrhythmia (TCD) and the occurrence of central pain. Here, this relationship has been examined using magneto-encephalographic (MEG) imaging in CRPS Type I, characterized by the absence of nerve lesions. The study addresses spontaneous MEG activity from 13 awake, adult patients (2 men, 11 women; age 15-62), with CRPS Type I of one extremity (duration range: 3months to 10years) and from 13 control subjects. All CRPS I patients demonstrated peaks in power spectrum in the delta (<4Hz) and/or theta (4-9Hz) frequency ranges resulting in a characteristically increased spectral power in those ranges when compared to control subjects. The localization of such abnormal activity, implemented using independent component analysis (ICA) of the sensor data, showed delta and/or theta range activity localized to the somatosensory cortex corresponding to the pain localization, and to orbitofrontal-temporal cortices related to the affective pain perception. Indeed, CRPS Type I patients presented abnormal brain activity typical of TCD, which has both diagnostic value indicating a central origin for this ailment and a potential treatment interest involving pharmacological and electrical stimulation therapies