Faculty Bibliography

The human visual system is hypothesized to code motion in discrete time quanta, given that at a certain threshold, motion is perceived in the reverse direction (wagon wheel illusion). To investigate the neurobiological correlates of quantal motion perception, we developed a reduced approach using local apparent motion stimuli with increasing stimulus onset asynchrony (SOA). Using a whole-head 148-channel MEG system (4D-Neuroimaging), subjects were recorded while stimulated with two bars of light separated by 1degree, flashed for 3ms, with SOAs of 0, 3,... , to 27ms. After each trial set subjects reported whether they perceived apparent motion, and its direction. Neuromagnetic responses were selectively averaged, bandpass filtered (3-40, 20-50, and 15-100Hz), and analyzed by the time-dependent FFT. A high resolution 3D cortical surface was reconstructed from the MRI. The lead field matrix was computed for a reduced set of vertices with dipole orientations normal to that surface. The Moore-Penrose pseudoinverse was computed, and used for minimum-norm estimates of the current distribution. Results indicate that subjects perceived apparent motion in the correct direction for SOAs longer than 12-15 ms. For shorter SOAs the two lights were perceived as simultaneous. Near threshold, motion was ocassionally perceived, but in the reverse direction. With SOAs above threshold magnetic waveforms showed a second overlapping peak near 75-100 ms. The time-dependent FFT showed gamma-band activity at the posterior channels. Current distribution estimates indicated that striate and extrastiate areas were activated recurrently at 75, 125, 175, 225, 275ms. MT was maximally activated at latencies of 125 and 175 ms, and was more active when motion was perceived. In conclusion, apparent motion is processed in quanta of 12-15 ms, and correlates with gamma-band activity in the visual system

Synchronous gamma-band neural activity has been proposed as a mechanism for 'binding' sensory stimuli into unitary conscious representations. Previous auditory and somatosensory experiments indicate covariance between gamma-band activity and subjects' thresholds for identifying one vs two sensory stimuli. Using a 148-channel whole-head MEG system (4-D Neuroimaging), we investigated whether similar covariance between perceptual thresholds and gamma-band activity is evident when human subjects identify stimuli that separately activate cortical hemispheres. Subjects were stimulated with taps of 2 ms duration from 2 piezoelectric stimulators, each held between the thumb and index finger of each hand. Both hands were stimulated synchronously with one tap each, or the left hand tap preceded the right hand tap by 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, or 24 ms. After each trial, subjects indicated whether the taps overlapped in time (perceived as one event) or were consecutive (perceived as two events). Evoked magnetic responses were averaged, analyzed by FFT, Principal Component Analysis, and filtered in several frequency ranges (1-400, 15-100, and 20-50 Hz). Results indicate a psychophysical threshold of apprx12 ms. For stimuli perceived as simultaneous, a single 20-50 Hz response occurred in each hemisphere. For taps perceived as sequential, a second gamma-band response was most evident in the hemisphere contralateral to the first stimulus. This suggests that somatosensory stimuli are bound across cortical hemispheres with a time-course similar to that of stimuli bound within a hemisphere, thus supporting the hypothesis that gamma-band activity is a neurophysiological correlate of perceptual binding

The GTPase dynamin I is required for synaptic vesicle (SV) endocytosis. Our observation that dynamin binds to the SV protein synaptophysin in a Ca2+-dependent fashion suggested the possibility that a dynamin/synaptophysin complex functions in SV recycling. Here we show that disruption of the dynamin/synaptophysin interaction by peptide injection into the squid giant synapse preterminal results in a decrease in transmitter release during high-frequency stimulation, indicating an inhibition of SV recycling. Electron microscopy of these synapses reveals a depletion of SVs, demonstrating a block of vesicle retrieval after fusion. In addition, we observed an increase in clathrin-coated vesicles, indicating that the peptide does not block clathrin-dependent endocytosis. We conclude that the dynamin/synaptophysin complex functions in a clathrin-independent mechanism of SV endocytosis that is activated by the high Ca2+ concentration at SV release sites

P.A. Rhodes1,2* and R. Llinas2, 1MRB, NIDDK, NIH, Bethesda, MD 20814; 2Dept. Physiology and Neuroscience, NYU Medical School, New York, NY 10016. The complexities of mammalian 6-layered neocortex make elucidation of its basic functions a daunting challenge. One seeks a model system which reflects its fundamental neural operations but with a simpler set of elements. We offer here an analysis supporting the conjecture that the cortex of the turtle pseudomys scripta provides a suitable model system. Principal cell dendritic morphology, intrinsic firing properties, spine form and distribution, feedforward inhibitory physiology, ACh and NE innervation, the laminar organization of corticocortical association, and many other features are common between turtle and mammalian neocortex, along with piriform cortex and dentate gyrus. One implication of the proposed homology concerns the nature of layer 1 input. In turtle cortex layer 1 conveys the feedforward relay, both from sensory thalamus and the corticocortical feedforward projection (Desan 1984). In mammalian piriform cortex and dentate gyrus layer 1 also conveys the feedforward relay of sensory information. In mammalian neocortex, however, layer 1 conveys inputs from higher to lower cortical areas, and so has heretofore been considered a secondary projection, modulating rather than driving cortical activity. The analogy with turtle cortex suggests an alternative view: neocortical layer 1, which appears to be quite effective in triggering layer 5 cell firing (Cauller and Connors 1992; Rhodes and Llinas 1999), may be a direct driver of cortical activity, with a role analogous to sensory input

Thalamocortical dysrhythmia (TCD) is a pathophysiological event postulated to underlie a range of neuropsychiatric disorders, including neurogenic pain (NP), tinnitus, Parkinson's disease, major depression, OCD and some forms of epilepsy. Patients suffering from this syndrome exhibit chronic and excessive theta (4-8 Hz) rhythmicity and increased coherence between high- and low-frequency thalamocortical oscillations. (Llinas et al, PNAS 1999) To determine the possibility of distinguishing between pain symptoms which emanate from TCD and those which derive from nociceptive activation, MEG was used to record 5 minutes of spontaneous brain activity from patients obtaining relief from epidural spinal cord stimulation (SCS), patients who failed SCS, patients with mild NP not requiring SCS and normal controls at baseline and during thermal (cold) pain stimulation. Analysis of patients who failed SCS showed significant increases in theta/alpha (8-12 Hz) power ratios and spectral amplitudes, together with abnormal levels of coherence between amplitudes at different frequencies. In contrast, there were no significant differences in spectral properties or coherence between controls and remaining patients or between baseline and thermal pain states in controls. These findings indicate that chronic pain may be generated either by TCD or via continuous nociceptive input, and that each has distinct mechanisms for its generation and responds to different therapeutic interventions. Thus, SCS is successful in peripheral pain but fails in NP

Spontaneous magnetoencephalographic activity was recorded in awake, healthy human controls and in patients suffering from neurogenic pain, tinnitus, Parkinson's disease, or depression. Compared with controls, patients showed increased low-frequency theta rhythmicity, in conjunction with a widespread and marked increase of coherence among high- and low-frequency oscillations. These data indicate the presence of a thalamocortical dysrhythmia, which we propose is responsible for all the above mentioned conditions. This coherent theta activity, the result of a resonant interaction between thalamus and cortex, is due to the generation of low-threshold calcium spike bursts by thalamic cells. The presence of these bursts is directly related to thalamic cell hyperpolarization, brought about by either excess inhibition or disfacilitation. The emergence of positive clinical symptoms is viewed as resulting from ectopic gamma-band activation, which we refer to as the 'edge effect.' This effect is observable as increased coherence between low- and high-frequency oscillations, probably resulting from inhibitory asymmetry between high- and low-frequency thalamocortical modules at the cortical level

Bath application of compound T-588, a neuroprotective agent, reduced paired-pulse and repetitive-pulse facilitation at mammalian and crustacean neuromuscular junctions. In addition, it reduced voltage-gated sodium and potassium currents in a use-dependent fashion, but had only a small effect on the presynaptic Ca(2+) conductance. By contrast, it blocked FM 1-43 vesicular uptake but not its release, in both species. Postsynaptically, T-588 reduced acetylcholine currents at the mammalian junction in a voltage-independent manner, but had no effect on the crayfish glutamate junction. All of these effects were rapidly reversible and were observed at concentrations close to the compound's acute protective level. We propose that this set of mechanisms, which reduces high-frequency synaptic transmission, is an important contributory factor in the neuroprotective action of T-588

A woman (LR), unconscious for 20 years, spontaneously produces infrequent, isolated words unrelated to any environmental context. Fluorodeoxy-glucose-positron emission tomography (FDG-PET) imaging coregistered with magnetic resonance imaging (MRI) revealed a mean brain metabolism equivalent to deep anesthesia. Nevertheless, PET imaging demonstrated islands of modestly higher metabolism that included Broca's and Wernicke's areas. Functional brain imaging with magnetoencephalographic (MEG) imaging, a technique providing a temporal resolution of better than 1 msec, identified preserved dynamic patterns of spontaneous and evoked brain activity in response to sensory stimulation. Specifically, we examined spontaneous gamma-band activity (near 40 Hz) and its reset or modification during early auditory processing, a measure that correlated with human perception of sensory stimuli (Joliot, Ribary, & Llinas, 1994). Evidence of abnormal and incomplete gamma-band responses appeared in the left hemisphere only in response to auditory or somatosensory stimulation. MEG single-dipole reconstructions localized to the auditory cortex in the left hemisphere and overlapped with metabolically active regions identified by FDG-PET. The observation demonstrates that isolated neuronal groups may express well-defined fragments of activity in a severely damaged, unconscious brain. The motor fixed-action pattern character of her expressed words supports the notion of brain modularity in word generation