Multiscale brain modelling.

A central difficulty of brain modelling is to span the range of spatio-temporal scales from synapses to the whole brain. This paper overviews results from a recent model of the generation of brain electrical activity that incorporates both basic microscopic neurophysiology and large-scale brain anatomy to predict brain electrical activity at scales from a few tenths of a millimetre to the whole brain. This model incorporates synaptic and dendritic dynamics, nonlinearity of the firing response, axonal propagation and corticocortical and corticothalamic pathways. Its relatively few parameters measure quantities such as synaptic strengths, corticothalamic delays, synaptic and dendritic time constants, and axonal ranges, and are all constrained by independent physiological measurements. It reproduces quantitative forms of electroencephalograms seen in various states of arousal, evoked response potentials, coherence functions, seizure dynamics and other phenomena. Fitting model predictions to experimental data enables underlying physiological parameters to be inferred, giving a new non-invasive window into brain function that complements slower, but finer-resolution, techniques such as fMRI. Because the parameters measure physiological quantities relating to multiple scales, and probe deep structures such as the thalamus, this will permit the testing of a range of hypotheses about vigilance, cognition, drug action and brain function. In addition, referencing to a standardized database of subjects adds strength and specificity to characterizations obtained.

Analysis of the electroencephalographic activity associated with thalamic tumors.

A physiologically based model of corticothalamic dynamics is used to investigate the electroencephalographic (EEG) activity associated with tumors of the thalamus. Tumor activity is modeled by introducing localized two-dimensional spatial non-uniformities into the model parameters, and calculating the resulting activity via the coupling of spatial eigenmodes. The model is able to reproduce various qualitative features typical of waking eyes-closed EEGs in the presence of a thalamic tumor, such as the appearance of abnormal peaks at theta ( approximately 3Hz) and spindle ( approximately 12Hz) frequencies, the attenuation of normal eyes-closed background rhythms, and the onset of epileptic activity, as well as the relatively normal EEGs often observed. The results indicate that the abnormal activity at theta and spindle frequencies arises when a small portion of the brain is forced into an over-inhibited state due to the tumor, in which there is an increase in the firing of (inhibitory) thalamic reticular neurons. The effect is heightened when there is a concurrent decrease in the firing of (excitatory) thalamic relay neurons, which are in any case inhibited by the reticular ones. This is likely due to a decrease in the responsiveness of the peritumoral region to cholinergic inputs from the brainstem, and a corresponding depolarization of thalamic reticular neurons, and hyperpolarization of thalamic relay neurons, similar to the mechanism active during slow-wave sleep. The results indicate that disruption of normal thalamic activity is essential to generate these spectral peaks. Furthermore, the present work indicates that high-voltage and epileptiform EEGs are caused by a tumor-induced local over-excitation of the thalamus, which propagates to the cortex. Experimental findings relating to local over-inhibition and over-excitation are discussed. It is also confirmed that increasing the size of the tumor leads to greater abnormalities in the observable EEG. The usefulness of EEG for localizing the tumor is investigated.

Unifying and interpreting the spectral wavenumber content of EEGs, ECoGs, and ERPs.

A biological model of corticothalamic dynamics is used to investigate the spatial power spectrum (wavenumber spectrum) of electrical activity in the brain. The model provides a single framework for unifying different aspects of activity. Comparisons of the predicted spectra with published electrocorticographic, electroencephalographic, and evoked response potential data enable physiology and anatomy to be inferred, producing results which are complementary to those obtained from comparisons in the frequency domain; the inferred quantities are consistent with, and complementary to, direct physiological and anatomical measurements. We also use the model to quantify the interdependence of the wavenumber and frequency domains, and deduce that further experiments that cover large wavenumber and frequency ranges simultaneously would greatly increase our knowledge of brain function. We conclude that both the frequency and wavenumber domains should be studied in order to build the fullest picture of brain dynamics: the two domains are both complementary and interdependent.

Spatially uniform and nonuniform analyses of electroencephalographic dynamics,with application to the topography of the alpha rhythm.

Corticothalamic dynamics are investigated using a model in which spatial nonuniformities are incorporated via the coupling of spatial eigenmodes. Comparison of spectra generated using the nonuniform analysis with those generated using a uniform one demonstrates that, for most frequencies, local activity is only weakly dependent on activity elsewhere in the cortex; however, dispersion of low-wave-number activity ensures that distant dynamics influence local dynamics at low frequencies (below approximately 2 Hz ), and at the alpha frequency (approximately 10 Hz ), where propagating signals are inherently weakly damped, and wavelengths are large. When certain model parameters have similar spatial profiles, as is expected from physiology, the low-frequency discrepancies tend to cancel, and the uniform analysis with local parameter values is an adequate approximation to the full nonuniform one across the whole spectrum, at least for large-scale nonuniformities. After comparing the uniform and nonuniform analyses, we consider one possible application of the nonuniform analysis: studying the phenomenon of occipital alpha dominance, whereby the alpha frequency and power are greater at the back of the head (occipitally) than at the front. In order to infer realistic nonuniformities in the model parameters, the uniform version of the model is first fitted to data recorded from 98 normal subjects in a waking, eyes-closed state. This yields a set of parameters at each of five electrode sites along the midline. The inferred parameter nonuniformities are consistent with anatomical and physiological constraints. Introducing these spatial profiles into the full nonuniform model then quantitatively reproduces observed site-dependent variations in the alpha power and frequency. The results confirm that the frequency shift is mainly due to a decrease in the corticothalamic propagation delay, but indicate that the delay nonuniformity cannot account for the observed occipital increase in alpha power; the occipital alpha dominance is due to decreased cortical gains and increased thalamic gains in occipital regions compared to frontal ones.

Estimation of multiscale neurophysiologic parameters by electroencephalographic means.

It is shown that new model-based electroencephalographic (EEG) methods can quantify neurophysiologic parameters that underlie EEG generation in ways that are complementary to and consistent with standard physiologic techniques. This is done by isolating parameter ranges that give good matches between model predictions and a variety of experimental EEG-related phenomena simultaneously. Resulting constraints range from the submicrometer synaptic level to length scales of tens of centimeters, and from timescales of around 1 ms to 1 s or more, and are found to be consistent with independent physiologic and anatomic measures. In the process, a new method of obtaining model parameters from the data is developed, including a Monte Carlo implementation for use when not all input data are available. Overall, the approaches used are complementary to other methods, constraining allowable parameter ranges in different ways and leading to much tighter constraints overall. EEG methods often provide the most restrictive individual constraints. This approach opens a new, noninvasive window on quantitative brain analysis, with the ability to monitor temporal changes, and the potential to map spatial variations. Unlike traditional phenomenologic quantitative EEG measures, the methods proposed here are based explicitly on physiology and anatomy.

Neurophysical modeling of brain dynamics.

A recent neurophysical model of brain electrical activity is outlined and applied to EEG phenomena. It incorporates single-neuron physiology and the large-scale anatomy of corticocortical and corticothalamic pathways, including synaptic strengths, dendritic propagation, nonlinear firing responses, and axonal conduction. Small perturbations from steady states account for observed EEGs as functions of arousal. Evoked response potentials (ERPs), correlation, and coherence functions are also reproduced. Feedback via thalamic nuclei is critical in determining the forms of these quantities, the transition between sleep and waking, and stability against seizures. Many disorders correspond to significant changes in EEGs, which can potentially be quantified in terms of the underlying physiology using this theory. In the nonlinear regime, limit cycles are often seen, including a regime in which they have the characteristic petit mal 3 Hz spike-and-wave form.

Wave-number spectrum of electrocorticographic signals.

A physiologically based continuum model of corticothalamic electrodynamics is generalized and used to derive the theoretical form of the electrocorticographic (ECoG) wave-number spectrum. A one-dimensional projection of the spectrum is derived, as is the azimuthally averaged two-dimensional spectrum for isotropic and anisotropic cortices. The predicted spectra are found to consist of a low-k plateau followed by three regions of power-law decrease, which result from filtering of the electrical activity through physical structures at different scales in the cortex. The magnitude of the maximum theoretical power-law exponent is larger for the two-dimensional (2D) spectrum than for its 1D counterpart. The predicted spectra agree well with experimental data obtained from 1D and 2D recording arrays on the cortical surface, enabling the structures in the brain that are important in determining spatial cortical dynamics to be identified. The cortical dispersion relation predicted by our model is also investigated, providing insight into the relationships between temporal and spatial brain dynamics.

Wave-number spectrum of electroencephalographic signals.

A recently developed, physiologically based continuum model of corticothalamic electrodynamics is used to derive the theoretical form of the electroencephalographic wave-number spectrum and its projection onto a one-dimensional recording array. The projected spectrum is found to consist of a plateau followed by regions of power-law decrease with various exponents, which are dependent on both model parameters and temporal frequency. The theoretical spectrum is compared with experimental results obtained in other studies, showing good agreement. The model provides a framework for understanding the nature of the spatial power spectrum by linking the underlying physiology with the large-scale dynamics of the brain.

Digitizing pediatric chest radiographs: comparison of low-cost, commercial off-the-shelf technologies.

OBJECTIVE: To compare low-cost, off-the-shelf technology for digitizing pediatric chest radiographs. MATERIALS AND METHODS: Forty pediatric chest radiographs (hard copy), each with a single abnormality, were digitized using a commercial film digitizer and two low-cost METHODS: a digital camera and a flatbed scanner. A stratified, randomized, block design was used where 20 readers evaluated 40 different images to determine the ability to accurately detect the abnormality. Readers then rated all 160 images (40 images x 4 methods) for conspicuity of the abnormality and overall image quality. RESULTS: Abnormalities were correctly identified on 82.3 % of hard copy images, 82.9 % of flatbed scanner images, 74.3 % of film digitizer images, and 69.7 % of digital camera images (p < 0.05) when compared to hard copy or flatbed scanner images. Lesion conspicuity was rated higher on hard copy (p < 0.05) than all digitized images. Conspicuity ratings were similar for flatbed scanner and film digitizer images, but lower in digital camera images (p < 0.05). For overall image quality, all were rated significantly different from each other (p < 0.05), with hard copy > flatbed scanner > film digitizer > digital camera images. CONCLUSION: A low-cost flatbed scanner yielded digital pediatric chest images which were significantly superior to digital camera images While flatbed scanner images were interpreted with the equivalent diagnostic accuracy of hard copy images, they were rated lower for image quality and lesion conspicuity.

Modal analysis of corticothalamic dynamics, electroencephalographic spectra, and evoked potentials.

The effects of cortical boundary conditions and resulting modal aspects of continuum corticothalamic electrodynamics are explored, including feedbacks. Dispersion relations, electroencephalographic spectra, and stimulus response functions are calculated from the underlying physiology, and the effects of discrete mode structure are determined. Conditions under which modal effects are important are obtained, along with estimates of the point at which modal series can be truncated, and the limit in which only a single globally uniform mode need be retained. It is found that for physiologically plausible parameters only the lowest cortical spatial eigenmode together with the set of next-lowest modes can produce distinct modal structure in spectra and response functions, and then only at frequencies where corticothalamic resonances reduce dissipation to the point where the spatial eigenmodes are weakly damped. The continuum limit is found to be a good approximation, except at very low frequencies and, under some circumstances, near the alpha resonance. It is argued that the major electroencephalographic rhythms result from corticothalamic feedback resonances, but that cortical modal effects can contribute to weak substructure in the alpha resonance. This mechanism is compared and contrasted with purely cortical and pacemaker-based alternatives and testable predictions are formulated to enable experimental discrimination between these possibilities.

Individual sympathetic varicosities possess different sensitivities to alpha 2 and P2 receptor agonists and antagonists in mouse vas deferens.

1. The diversity of alpha(2) and purinergic autoreceptor actions on action potential evoked calcium transients in single varicosities has been investigated using the calcium indicator Oregon Green 488 BAPTA-1. 2. During long trains of impulses (10 Hz for 30 s), the change in calcium concentration in varicosities from its resting level (Delta[Ca(2+)](v)) increased in many varicosities during the first 3 s of stimulation before reaching a plateau. 3. The alpha(2) adrenoceptor agonist clonidine (1 microM) decreased Delta[Ca(2+)](v) by over 40% during short trains (five impulses at 5 Hz) in most varicosities, although some were unaffected. The alpha(2) adrenoceptor antagonist idazoxan (2 microM) increased the Delta[Ca(2+)](v) plateau following long trains in most varicosities. Hence, most varicosities possess alpha(2) adrenoceptors which are activated when noradrenaline accumulates extracellularly. 4. During long trains of impulses, the P(2y)-purinergic receptor agonist 2-methyl-thio-ATP (100 microM) decreased Delta[Ca(2+)](v) plateau by about 50% in most varicosities; alpha,beta-methylene ATP (100 microM) decreased it by about 50% in a minority of varicosities; adenosine (200 microM) had no significant effect. Suramin (100 microM) increased the Delta[Ca(2+)](v) during all stimulus protocols in most varicosities, suggesting that ambient ATP modulates Delta[Ca(2+)](v) responses. The P(2y) receptor antagonist reactive blue (100 microM) affected a minority of varicosities. Given that most varicosities respond to suramin, other P(2) receptor subtypes are probably present. 5. The ATP ectoenzyme antagonist ARL67157 (50 microM) decreased the plateau Delta[Ca(2+)](v) during long trains in complete strings of varicosities but not in others. 6. The present technique indicates that varicosities have diverse autoreceptor utilization.

Meckel's diverticulum: demonstration of heterotopic gastric mucosa with technetium-99m-pertechnetate SPECT.

Demonstration of functioning heterotopic gastric mucosa with 99mTc-pertechnetate SPECT is reported. Abnormal tracer uptake was shown conclusively with SPECT but not with planar imaging. When a Meckel's diverticulum is suspected, we suggest SPECT be performed if the results of planar scintigraphy are equivocal and that it be considered if there is a high clinical suspicion and planar imaging is normal.

Fewer metabolites of dietary choline reach the blood of rats after treatment with lithium.

Choline is an important precursor for the biosynthesis of acetylcholine, phosphatidylcholine and sphingomyelin. It is also a major source of labile methyl groups. Lithium is an important component of the treatment of bipolar affective illness, and it inhibits choline transport across membranes. We studied the effect of lithium treatment upon the appearance in blood, liver and intestine of metabolites formed from dietary choline. Rats were treated for 9 days with 2 mEq/kg lithium carbonate or water. Animals were fasted overnight, and on the 10th day were fed with a solution containing radiolabeled choline chloride. The lithium-treated groups also received 2.0 mEq/kg lithium as part of this solution. After an oral dose of 1 ml of a 1 mM choline solution, the lithium-treated animals had significantly lower levels of choline-derived radiolabel in blood than did controls at 30, 60, 120, and 180 minutes (47% (+/- 5%; SEM), 51% (+/- 7%), 59% (+/- 4%) and 74% (+/- 9%), respectively). We observed similar decreases of the accumulation in blood, at 180 minutes after the dose, of choline-derived radiolabel when choline was administered at lower or higher concentrations. After an oral treatment containing 0.1, 1 or 10 mM choline, lithium treated animals accumulated 69% (+/- 6%; SEM), 66% (+/- 11%) and 72% (+/- 7%) as much radiolabel in serum as did controls. Most of the radiolabel found in blood at 180 minutes was in metabolites of choline which are formed within liver (betaine and phosphatidylcholine). The diminished accumulation of radiolabel in serum after lithium treatment was not due to increased accumulation of label by erythrocytes, liver or gut wall. We suggest that lithium influences the release by liver of betaine and phosphatidylcholine.