Faculty Bibliography

Consciousness is hypothesized to be a process of sensorimotor transformations generated by coherent thalamocortical activity clusters oscillating at gamma-band (30-50 Hz) frequencies. This hypothesis predicts that higher amplitude gamma-band thalamocortical currents will correlate with shorter reaction times (RTs). We tested this prediction using whole-head 148-sensor MEG recordings during a simple RT task. Methods: 1 tactile stimulator under each middle finger, & 1 flat microswitch button under each index finger. Each trial had 1 finger tap, randomized across hands. Same-side responses for 400 trials, then opposite-side for 400 trials. 6 healthy subjects (4 age 20-40, 2 age 75-85). Results: In all subjects, the highest signal/noise ratio (SNR) independent component (IC_1) in somatosensory cortex indicated a large amplitude gamma-band current 30-80 ms post-stimulus. For each millisecond, we calculated correlations across trials between (a) IC_1 amplitude at that millisecond and (b) RT in that trial. Correlation minima ranged down to -0.6 and were synchronous with gamma-band amplitude maxima. Gamma-peaks and synchronous correlation minima occurred in both cortical hemispheres apprx50 ms in both response conditions, indicating that inter-hemispheric gamma-band currents correlate with faster RTs within and across hemispheres. Gamma-peaks and synchronous RT correlation-minima occurred in young and elderly subjects, but all elderly subjects exhibited lower gamma-band amplitudes, lower correlations, and longer RTs than young subjects. Conclusion: Early (apprx50) evoked 30-50 Hz activity within & across somatosensory cortices exhibits strong correlations with sensorimotor speed in individual reaction-time trials

Coordinated limb movements require the proper interaction between neuronal, muscular, and skeletal systems. The link between such systems may be addressed using mathematical models that simulate muscle contraction and that resulting joint rotations. A computer model for limb movement is presented that mimics muscle contraction and joint rotations as a function of motor neuron firing frequencies. The model generates angular changes in each joint with activation of a flexor-extensor muscle pair. The issue is that there are a large number of possible solutions to the generation of angular changes in a joint with muscle activation. This known as the over completeness problem We address it by proposing that in each joint only one of the muscles (the flexor or the extensor) is activated at a certain moment. The model considers the intersegmental joint angles, the lengths and masses of limb segments, the sites of muscle attachments, the force-length and force-frequency relationships of the muscles. The motor command for each muscle in each time interval is the firing rate of the muscle's motoneuron pool. This command generates angular motions in the joint. We apply the model to ankle muscle activities in two groups of swimming rats. One group spend 16 days in microgravity (flight) while the second group remained in the terrestrial environment. For both groups swimming was recorded on land. We computed firing rates of motoneuron pools to mimic joint angle changes that were recorded experimentally. The model predicts an increased firing rate for the muscles of the flight group. We propose that this is the result of the differences in motor control developed under different environmental conditions. The predicted higher firing rate is compatible with the observed higher flexions in the joints of the rats of the flight group

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

Calcium mobilization in cerebellar Purkinje cell (PC) of CD38 knockout mouse was imaged using two photon microscopy. CD38 is a homolog of ADP-ribosyl cyclase which activates Cyclic ADP-ribose, an endogenous Calcium Induced Calcium Release (CICR)regulator (Lee, 2001 ). In the CD38 knockout mouse (CD38(-/-)), which showed no phenotypic motor abnormalities, whole cerebellar cyclic ADP-ribose (cADPR) was reduced to a quarter of that in a wild control (CD38(+/+)). In addition caffeine treated CD38(-/-) PC dendrite showed a markedly reduced calcium response to a test depolarizing pulse most probably related to the reduced CICR. Cerebellar long-term depression (LTD) induced by the parallel fiber (PF) -climbing fiber (CF) conjunctional stimulation was absent in CD38(-/-) PC. However, during very prolonged direct depolarization of Purkinje cell somata, or when the test (PF) stimulation was quite close to the cell body during direct somatic depolarization, LTD could be induced in CD38(-/-) PC by the PF/depolarizing pulse conjunction. Overall, the CD38/cADPR system seems to be sensing/regulating intradendritic calcium levels. This seems to be an important modulator of the integrative properties of Purkinje cell activity. It seems clear that if (Ca)i becomes high enough to be deleterious to neuronal viability such system must be down regulated via LTD as a neuroprotective response to reduce further calcium increase. Immuno-staining study with a polyclonal CD38 antibody is presently in progress which is expected to find different levels of CD38 on the Purkinje cell soma, dendrites and spines of wild type mouse (CD38(+/+)) vs CD38 knockout cerebella

Ongoing studies indicate that the conjunction of spontaneous thalamocortical activity, at low-(theta; 4-8Hz) and high-(gamma; 25-50Hz) frequencies serves as the physiological basis for a set of disorders we have termed the thalamocortical dysrhythmia syndromes (TCD). Elements in this set are proposed to include Parkinson's disease, tinnitus, central pain, OCD, depression and schizoaffective (SA) disorder. The common denominator is a prominent theta-range oscillation underlying negative symptoms, in temporal coherence with gamma band activity relating to positive symptoms. Results demonstrate that localization of TCD activity is possible and add a more direct functional dimension to results obtained with other imaging techniques.Continuous neuromagnetic activity was recorded with whole-head MEG (4D Neuroimaging) from 6 subjects with SA disorder and 8 healthy controls. Multitaper spectral estimation was used to calculate frequency spectra, and independent components (ICs) were derived with EEGlab software. Selected ICs were localized in a probabilistic sourcespace. A recursive weighted minimum norm algorithm was used to calculate solutions for current density localization.Power spectra from controls demonstrated typical occipital alpha rhythm, while spectra from SA subjects showed an increase in theta power localized in mediofrontal supraorbital and temporal areas. These results support a model in which deinactivation of thalamic T-type Ca++ currents leads to localized oscillatory changes. The presence of both frontal and temporal activity in individual ICs suggests functional synchronization between these areas in SA disorder and corroborates findings of low-frequency oscillation with metabolic hypofrontality in PET studies.It is concluded that ICA may identify and localize abnormal TC dynamics in SA disorder and that MEG represents an important tool in the investigation of TCD patients

The sources of the neuromagnetic fields recorded in Magnetoencephalography (MEG) are distributed compactly as sparse clusters of high current density in functionally interactive cortical and subcortical neural networks. Recursive minimum norm algorithms (e.g., FOCUSS) iteratively sharpen and eventually prune an initial distributed solution by down-weighting the contribution of low-amplitude dipoles. Most nonzero variables are not needed to explain the data and can be eliminated by iteratively adding a null space vector to the previous solution that minimizes a diversity measure and guarantees feasibility. Computer simulations with randomly selected source configurations of increasing order and with sparse extended sources were carried out to quantify the spatial resolution of recursive minimum-norm algorithms with several spatial error metrics. Different a priori weights and diversity measures were tested. Results demonstrate that stable super-resolution for high-order source models can only be achieved by using an optimal a priori weight matrix (full column normalization), followed by a sequence of iterations which minimize an optimal p-norm-like diversity measure (p=0.9-1). Further improvement is achieved by directly minimizing a cost of diversity and discrepancy at each iteration with a nonlinear 1-dimensional search of the optimal null vector length, and by simultaneously solving multiple measurement vectors from a time interval. Simulations with non-gaussian activation functions show that Independent Component Analysis (ICA) and the new FOCUSS-learning algorithms can dramatically increase the number of recovered sources. Finally, visually evoked and spontaneous signals are analyzed with these algorithms. Results demonstrate the importance of cortico-thalamo-cortical loops in global brain function

Intracellular recording and in vitro high-speed voltage-sensitive dye imaging were combined to investigate the role of electrotonic coupling in the generation and distribution of subthreshold oscillations in the inferior olivary (IO) nucleus. Brainstem slices from 2-3 week old rats were stained with a voltage-sensitive fluorescence dye RH-414 (Molecular Probes) and imaged with a fast CCD camera (Fujix HRDeltaron 1700; 128 x 128 pixels of spatial resolution and 4.8 ms of temporal resolution). Comparison of spatio-temporal profiles of subthreshold IO oscillations in control conditions and in the presence a specific gap junctional blocker (18-beta glycyrrhetinic acid) was implemented. In control conditions, spontaneous IO oscillations emanated from multiple clusters of coherently oscillating neurons. Addition of 18-beta glycyrrhetinic acid had a blocking effect such clusters. However, single-cell oscillations were still observed in concurrently obtained intracellular recordings from individual IO cells. Small but significant differences in the amplitude and frequency of the 'uncoupled' and control neuronal oscillations were detected. In addition, the cells had higher resistance (10-20% increase) and lower capacitance (20-30% decrease) in the presence of the blocker. We conclude that gap junctions are not necessary for generating subthreshold IO oscillations but are required for oscillatory synchronization and the clustering of coherent oscillatory activity in the inferior olivary nucleus

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