Faculty Bibliography

Thalamic relay cells occupy a pivotal position in cerebral architecture, and characterizing the manner in which they integrate ascending and descending input is a requisite for understanding cortical function. It was demonstrated by McCormick and Huguenard in the early 1990's that the relay and low threshold burst modes of intrinsic response can be readily modeled using a single somatic compartment with an appropriate set of voltage and calcium concentration-gated currents. However, the study of synaptic integration in model cells requires simulations incorporating the dendritic tree. Destexhe, Huguenard and coworkers have decribed a relay cell model including a dendritic tree (Destexhe et al 1998) which concluded a predominantly distal T-channel density distribution, primarily constrained by recordings from acutely dissociated cells. There is however another intrinsic electrophysiological characteristic of relay cells which models have not yet accounted for: at holding potentials near spike threshold, relay cells produce a waxing and waning subthreshold oscillation observable at the soma (Pedroarena and Llinas 1996). Here we present the development of a new model of the thalamic relay cell, guided by the simultaneous constraints that it must produce the relay and low threshold burst modes which characterize these cells, as well as the ripple occurring at near-threshold holding potentials. We arrive at a model cell which is capable of the production isolated fast Ca2+ spikes in distal branch segments, driven by a rapidly inactivating high threshold channel. The model reproduces the low threshold spike behavior of the relay cell without requiring high T current density in the distal dendritic segments, and thus presents an alternative picture of the dendritic tree of relay cells, in which fast high threshold Ca2+ events occur distally, and slower T channel-driven spikes are primarily proximally driven. If borne out by direct experimental evidence, this model would have implications for the integration of descending and ascending inputs

One of the essential aspects of the neuronal organization in the global function of the brain is the rich thalamocortical interconnectivity and very particularly the reciprocal nature of this circuit. Also, the interaction between the systems specific thalamic and unspecific at cortical level suggests that the thalamus, more than a simple floodgate for the brain, represents an epicentre by means of which all the cortical areas can communicate to each other in isochronic way with independence of the transcortical distance. The objectives of this article are to explore: 1) the proposal that the temporary coincidence, to great scale, of the activity specific thalamic and unspecific generates the functional states that characterize the human knowledge; and 2) the possible relationship between the thalamocortical dysrhythmia and some neuropsychiatric illnesses

Individual evoked MEG or EEG responses typically exhibit low signal-to-noise ratios (SNRs) and high epoch variance across epochs; often hundreds of epochs are averaged to achieve adequate SNRs. High SNRs of gamma-band (20-50 Hz)activity were previously observed in the mean early (apprx50ms) evoked responses to brief tactile taps. However, SNRs are lower in evoked responses to pairs of stimuli presented near the subject's flicker-fusion threshold (apprx12 ms SOA) for pairs of identical tactile taps (or auditory clicks). At this threshold the gamma-band response to the first stimulus appears to be reset by the second stimulus, thus reducing SNRs. We attempted to increase SNRs in somatosensory evoked MEG responses to finger taps in 7 sighted and 7 blind subjects. Individual epochs were evaluated for frequency, phase, and amplitude similarities to the total average response during a window 20-90ms poststimulus. Epochs most similar to the total average were selected and averaged; the SNR of this response was compared to the SNR of the overall mean. ICA (Makeig, et al.) was also performed across all epochs and in conjunction with epoch selection. The two methods, applied separately or together, increased SNRs of the early evoked response. Detailed temporal structure of the evoked responses also became more evident, permitting increased resolution of the gamma-band reset near the subjects' psychophysical binding thresholds

Thalamocortical dysrhythmias (TCD) may underlie a variety of neurological and neuropsychiatric symptoms. (1,2) In TCD, pathological theta-range activity from thalamic deafferentation or disfacilitation is hypothesized to trigger thalamocortical (TC) domains to oscillate at low frequency, underlying negative symptoms, surrounded by areas of gamma-band activity, creating an 'edge effect' leading to some positive symptoms. TC connectivity and neuronal properties can distribute and sustain this pathological equilibrium. Spontaneous neuromagnetic activity was recorded from patients (n=5) with refractory OCD and from controls (n=4). Recordings were performed with whole-head MEG (4D Neuroimaging), for 5-10 min (0.1-508Hz) with subjects' eyes closed. Coherence, multitaper-based spectral and independent component analyses (ICA) were performed using Matlab (Mathworks) and in-house software. Power spectra from control recordings demonstrated typical alpha rhythms, while spectra from OCD subjects showed robust activity in the theta range and increased total power. In addition, cross-correlations of spectral amplitude from controls displayed activation of discrete frequencies; patterns from OCD subjects showed high coherence over a wider spectral range. Furthermore, ICA revealed components with theta-range spectral properties and dipolar positions consistent with aberrant resting cortical and basal ganglia oscillations. The conception of TCD may serve as a template for the study and treatment of neurological and psychiatric disorders. 1.Llinas,R et al (1999) PNAS 96:15222-7 2.Llinas,R et al (2001) Thal Rel Sys 1:237-44

Pyramidal cells of layers 2 and 3 comprise one of the principal cell classes in the neocortex, but because of their small size the electrophysiological properties of their dendritic tree have only recently been accessible to direct measurement (Waters et al 2001). We have generated a detailed compartment model of layer 2/3 pyramidal cells based on recent data and used it to predict the response of these cells to synaptic inputs arriving at different regions of the dendritic tree. Distributions of dendritic Na+, K+ and Ca2+ conductances were constrained by the requirement that model electrophysiology fit the measured responses. For such distributions we found that simulated layer 1 synaptic input to the apical tuft was surprisingly ineffective in triggering somatic firing. This was because active propagation of excitation from the tuft inward to the soma rarely occurred in the model, consistent with our experimental findings. In contrast, the model showed that somatic firing was readily driven by input to the basal arbor. These predicted layer 2/3 pyramid input/output characteristics differ from those of layer 5 pyramidal cell models (Rhodes and Llinas 2001). In simulations, tuft input is more effective in layer 5 pyramids than layer 2/3 pyramids, whereas layer 2/3 pyramids are more responsive to feedforward synaptic input impinging upon the proximal arbor. We propose that feedforward and feedback streams of information in cortex may have complementary effects upon the microcircuitry of the column

Voltage-sensitive dye imaging of mouse thalamocortical slices demonstrated that electrical stimulation of the centrolateral intralaminar thalamic nucleus (CL) resulted in the specific activation of thalamic reticular nucleus, striatum/putamen, and cortical layers 5, 6, and 1. By contrast, ventrobasal (VB) thalamic stimulation, while activating the reticular and basal ganglia nuclei, also activated directly layers 4 and deep 5 of the cortex. Conjoined stimulation of the VB and CL nuclei resulted in supralinear summation of the two inputs at cortical output layer 5, demonstrating coincidence detection along the apical dendrites. This supralinear summation was also noticed at gamma band stimulus frequency ( approximately 40 Hz). Direct stimulation of cortical layer 1, after a radial section of the cortex that spared only that layer, was shown to sum supralinearly with the cortical activation triggered by VB stimulation, providing a second demonstration for coincidence detection. Coincidence detection by coactivation of the specific (VB) and nonspecific (CL) thalamic nuclei has been proposed as the basis for the temporal conjunction that supports cognitive binding in the brain

Spatiotemporal profiles of ensemble subthreshold neuronal oscillation were studied in brainstem slices using high-speed voltage-sensitive dye imaging. After local electrical stimuli, the overall voltage profile demonstrated coherent oscillatory waves that spread over the inferior olive (IO). These oscillations were also observed in concurrently obtained intracellular recordings from IO neurons. Over the first few seconds after the stimuli, the optically recorded oscillations clustered into coherent groups comprising hundreds of neurons. Statistical analysis of the spatial profiles of these clusters revealed size fluctuation around stable core regions that were surrounded by a rim the diameter of which varied in time during the oscillation period. The neuronal ensemble oscillations were calcium derived and had an average frequency range of 1-7 Hz. This rhythmic response demonstrated a different spatiotemporal distribution in the presence of picrotoxin, which induced the merging of neuronal clusters into larger areas of coherent activity. The possibility that such clustering is a consequence of intrinsic oscillations in ensembles of coupled neurons was tested using mathematical modeling

OBJECTIVE: To minimize the risks associated with treating cortical cerebral arteriovenous malformations (AVMs), we developed a technique combining functional imaging and cerebral angiography. The functional loci obtained by performing magnetoencephalography (MEG) are projected onto stereoscopic pairs of a stereotactically derived digital subtraction angiogram. The result is a simultaneous three-dimensional perspective of the angioarchitecture of an AVM and its relationship to the sensorimotor cortex. METHODS: Eight patients underwent multimodality brain imaging, including magnetic resonance imaging, functional mapping via MEG, and stereotactic angiography using a modified Compass fiducial system (Compass International, Rochester, MN). The coordinates derived by performing MEG were superimposed onto stereotactic, stereoscopic, angiographic pairs using custom-made distortion correction and coordinate transfer software. RESULTS: The magnetoencephalographic angiogram allowed simultaneous viewing of the angioarchitecture of the AVM nidus, the feeding vessels, and the draining veins and their relationship to the normal cerebral vasculature and functional cortex. This imaging technique was particularly valuable in identifying en passant vessels that supplied functional cortex and was used during the treatment of these lesions. CONCLUSION: The techniques of MEG and cerebral angiography were combined to provide simultaneous viewing of both modalities in a three-dimensional perspective. This technique can aid in risk stratification in the management of patients with cerebral AVMs. In addition, this technique can facilitate the selective targeting of vessels, thus potentially reducing the risks associated with embolization of these formidable lesions