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Biomedical subjects

A D Mehta

Publications and source records attributed to A D Mehta.

At least 19 recordsLinked to original sources
PubMed2001

Determinants and mechanisms of attentional modulation of neural processing.

This review contrasts the most-studied variety of attention, visuospatial attention, with several types of nonspatial visual attention. We: 1) discuss the manner in which spatial and nonspatial varieties of attention are experimentally defined, and the ecological validity of the paradigms in which they are studied, 2) review and compare differing effects of spatial and nonspatial attention on neural processing, 3) discuss the manner in which attention operates within the framework of an anatomical visual hierarchy, as well as 4) how attention relates to the temporal dynamics of visual processing, 5) describe cellular circuits and physiological processes that appear to be involved in attention effects, 6) discuss the relationship of attentional physiology to the perceptual and cognitive effects of attention, and 7) consider the strengths and limitations of several current models of selective attention. Throughout, we attempt to integrate the findings of monkey and human studies whenever possible. We have three main conclusions. First, two models, the Neural Specificity Model of Harter and colleagues and the Feature Similarity Gain Model of Treue and colleagues best incorporate findings in relation to both spatial and nonspatial varieties of attention. Significantly, these models explicitly note that the specific neuronal components used in attentional modulation of processing are flexible and determined by task demands. Second, current evidence also provides strong bases for deriving testable hypotheses about the specific brain mechanisms utilized by attention. Cellular processes, brain circuits and neurotransmitter components can and should be incorporated into our models of attention. Finally, it is increasingly evident that we can and should analyze temporal patterns of attentional modulation, both within and across brain areas. These patterns provide critical information on the dynamics of attention.

Animals↗
PubMed2000

Negative hair-bundle stiffness betrays a mechanism for mechanical amplification by the hair cell.

Hearing and balance rely on the ability of hair cells in the inner ear to sense miniscule mechanical stimuli. In each cell, sound or acceleration deflects the mechanosensitive hair bundle, a tuft of rigid stereocilia protruding from the cell's apical surface. By altering the tension in gating springs linked to mechanically sensitive transduction channels, this deflection changes the channels' open probability and elicits an electrical response. To detect weak stimuli despite energy losses caused by viscous dissipation, a hair cell can use active hair-bundle movement to amplify its mechanical inputs. This amplificatory process also yields spontaneous bundle oscillations. Using a displacement-clamp system to measure the mechanical properties of individual hair bundles from the bullfrog's ear, we found that an oscillatory bundle displays negative slope stiffness at the heart of its region of mechanosensitivity. Offsetting the hair bundle's position activates an adaptation process that shifts the region of negative stiffness along the displacement axis. Modeling indicates that the interplay between negative bundle stiffness and the motor responsible for mechanical adaptation produces bundle oscillation similar to that observed. Just as the negative resistance of electrically excitable cells and of tunnel diodes can be embedded in a biasing circuit to amplify electrical signals, negative stiffness can be harnessed to amplify mechanical stimuli in the ear.

Animals↗
PubMed2000

Putting ion channels to work: mechanoelectrical transduction, adaptation, and amplification by hair cells.

As in other excitable cells, the ion channels of sensory receptors produce electrical signals that constitute the cellular response to stimulation. In photoreceptors, olfactory neurons, and some gustatory receptors, these channels essentially report the results of antecedent events in a cascade of chemical reactions. The mechanoelectrical transduction channels of hair cells, by contrast, are coupled directly to the stimulus. As a consequence, the mechanical properties of these channels shape our hearing process from the outset of transduction. Channel gating introduces nonlinearities prominent enough to be measured and even heard. Channels provide a feedback signal that controls the transducer's adaptation to large stimuli. Finally, transduction channels participate in an amplificatory process that sensitizes and sharpens hearing.

Adaptation, Physiological↗
PubMed2000

Myosin-V stepping kinetics: a molecular model for processivity.

Myosin-V is a molecular motor that moves processively along its actin track. We have used a feedback-enhanced optical trap to examine the stepping kinetics of this movement. By analyzing the distribution of time periods separating discrete approximately 36-nm mechanical steps, we characterize the number and duration of rate-limiting biochemical transitions preceding each such step. These data show that myosin-V is a tightly coupled motor whose cycle time is limited by ADP release. On the basis of these results, we propose a model for myosin-V processivity.

Actins↗
PubMed2000

In vitro assays of processive myosin motors.

Myosin V is an actin-based motor thought to be involved in vesicle transport. Since the properties of such a motor may be expected to differ from those of muscle myosin II, we have examined myosin V-driven movement using a combination of gliding filament and optical trap assays to observe single molecules with high resolution. The results clearly demonstrate that brain myosin V is a highly efficient processive motor. In vitro motility assays at low myosin V densities reveal apparent single-molecule supported movement. Processive stepping was also observed in optical trapping assays of myosin V-driven motion. Here the methods that were used to demonstrate the processivity of myosin V are described. These methods include density-dependent assays that eliminate the possibility of aggregation or chance colocalization of multiple motors being responsible for apparent single-molecule motility. Such assays will be useful tools for identifying other processive classes of myosins.

Actin Cytoskeleton↗
PubMed2000

Intermodal selective attention in monkeys. I: distribution and timing of effects across visual areas.

This study quantified the magnitude and timing of selective attention effects across areas of the macaque visual system, including the lateral geniculate nucleus (LGN), lower cortical areas V1 and V2, and multiple higher visual areas in the dorsal and ventral processing streams. We used one stimulus configuration and behavioral paradigm, with simultaneous recordings from different areas to allow direct comparison of the distribution and timing of attention effects across the system. Streams of interdigitated auditory and visual stimuli were presented at a high rate with an irregular interstimulus interval (mean of 4/s). Attention to visual stimuli was manipulated by requiring subjects to make discriminative behavioral responses to stimuli in one sensory modality, ignoring all stimuli in the other. The attended modality was alternated across trial blocks, and difficulty of discrimination was equated across modalities. Stimulus presentation was gated, so that no stimuli were presented unless the subject gazed at the center of the visual stimulus display. Visual stimuli were diffuse light flashes differing in intensity or color and subtending 12 degrees centered at the point of gaze. Laminar event-related potential (ERP) and current source density (CSD) response profiles were sampled during multiple paired penetrations in multiple visual areas with linear array multicontact electrodes. Attention effects were assessed by comparing responses to specific visual stimuli when attended versus when visual stimuli were looked at the same way, but ignored. Effects were quantified by computing a modulation index (MI), a ratio of the differential CSD response produced by attention to the sum responses to attended and ignored visual stimuli. The average MI increased up levels of the lower visual pathways from none in the LGN to 0.0278 in V1 to 0.101 in V2 to 0.170 in V4. Above the V2 level, attention effects were larger in ventral stream areas (MI = 0. 152) than in dorsal stream areas (MI = 0.052). Although onset latencies were shortest in dorsal stream areas, attentional modulation of the early response was small relative to the stimulus-evoked response. Higher ventral stream areas showed substantial attention effects at the earliest poststimulus time points, followed by the lower visual areas V2 and V1. In all areas, attentional modulation lagged the onset of the stimulus-evoked response, and attention effects grew over the time course of the neuronal response. The most powerful, consistent, and earliest attention effects were those found to occur in area V4, during the 100-300 ms poststimulus interval. Smaller effects occurred in V2 over the same interval, and the bulk of attention effects in V1 were later. In the accompanying paper, we describe the physiology of attention effects in V1, V2 and V4.

Animals↗
PubMed2000

Intermodal selective attention in monkeys. II: physiological mechanisms of modulation.

Of all areas studied in the accompanying study, attention effects were most consistent and well resolved in V4. In this study, to define some of the anatomical circuits and neural processes underlying the influence of attention, we examined the laminar distribution and physiology of attention effects in V4 and in two lower areas, V1 and V2. Laminar event-related potential (ERP), current source density (CSD) and multiunit activity (MUA) profiles allowed identification of processes occurring in the local ensembles, as well as their sequence and laminar distribution. These methods also permitted us to analyze the brain processes reflected in attention-sensitive components of the surface ERP. As outlined in the previous study, the first robust modulation by attention occurred in V4 during the 100-300 ms poststimulus interval. This is the time frame of the net refractoriness which follows the net local excitatory response to luminance increment. Over this interval, attention reduced CSD amplitudes and increased action potential firing rates, findings consistent with disinhibition as a mechanism for attention in V4. Similar effects were observed during the 100-300 ms time frame in V2. In V4, attention had no effect on the initial excitatory response at the depth of lamina 4, but it did produce large modulations in supragranular and deep laminae, origins of both feedforward and feedback projections. Attentional modulation in V2 was later than in V4 and concentrated in extragranular laminae, with no modulation of the initial layer 4 response. Attentional modulation in V1 was smaller and still later than that in V2 and was focused in the supragranular laminae. In this paradigm, attention did not modulate either the response in lateral geniculate nucleus (LGN) or the initial excitation in lamina 4C of V1. The timing of effects across areas and the laminar distribution of effects within areas indicate that attention effects are mediated by feedback projections. Moreover, our findings suggest that attention may increase the perceptual salience of stimuli by reducing stimulus-evoked refractoriness and/or inhibition in cortical ensembles. Finally, attentional modulation of transmembrane current flow in V4 produced a sustained negative deflection in the laminar ERP profile, that was manifested in the ERP over the occipital surface. This posits a mechanism for the 'selection negativity', a scalp ERP effect noted under similar experimental conditions in human subjects.

Animals↗
PubMed1999

Myosin-V is a processive actin-based motor.

Class-V myosins, one of 15 known classes of actin-based molecular motors, have been implicated in several forms of organelle transport, perhaps working with microtubule-based motors such as kinesin. Such movements may require a motor with mechanochemical properties distinct from those of myosin-II, which operates in large ensembles to drive high-speed motility as in muscle contraction. Based on its function and biochemistry, it has been suggested that myosin-V may be a processive motor like kinesin. Processivity means that the motor undergoes multiple catalytic cycles and coupled mechanical advances for each diffusional encounter with its track. This allows single motors to support movement of an organelle along its track. Here we provide direct evidence that myosin-V is indeed a processive actin-based motor that can move in large steps approximating the 36-nm pseudo-repeat of the actin filament.

Actins↗
PubMed1999

Single-molecule biomechanics with optical methods.

Single-molecule observation and manipulation have come of age. With the advent of optical tweezers and other methods for probing and imaging single molecules, investigators have circumvented the model-dependent extrapolation from ensemble assays that has been the hallmark of classical biochemistry and biophysics. In recent years, there have been important advances in the understanding of how motor proteins work. The range of these technologies has also started to expand into areas such as DNA transcription and protein folding. Here, recent experiments with rotary motors, linear motors, RNA polymerase, and titin are described.

Biomechanical Phenomena↗
PubMed1998

Single molecule biochemistry using optical tweezers.

The use of optical trapping to create extremely compliant mechanical probes has ushered in a new field of biological inquiry, the mechanical and kinetic study of proteins at the single molecule level. This review focuses on three examples of such study and includes methods of extracting parameters of interest from the raw data such experiments generate.

Biochemistry↗
PubMed1997

Detection of single-molecule interactions using correlated thermal diffusion.

Observation of discrete, single-molecule binding events allows one to bypass assumptions required to infer single-molecule properties from studies of ensembles of molecules. Optically trapped beads and glass microneedles have been applied to detect single-molecule binding events, but it remains difficult to identify signs of binding events given the large displacements induced by thermal forces. Here, we exploit thermal diffusion by using correlation between motion of optically trapped beads attached to both ends of a single actin filament to track binding events of individual myosin molecules. We use correlated diffusion to measure the stiffness of a single myosin molecule and estimate its thermal fluctuation in a poststroke state as comparable in amplitude to the measured stroke distance. The use of correlated diffusion to measure kinetics of single-molecule interactions and the stiffness of the interacting moieties should be applicable to any pair of interacting molecules, and not limited to biological motors.

Actins↗
PubMed1997

N-methyl-D-aspartate enhancement of phasic responses in primate neocortex.

In area 17 of the awake macaque, disinhibition by blockade of GABA(A) receptors results in a marked elevation in neuronal excitability, with a particular focus in the supragranular laminae. We examined the possibility that the excitatory supragranular response is N-methyl-D-aspartate (NMDA)-mediated. Laminar activity profiles consisting of flash-evoked field potential, current source density (CSD) and multiunit activity (MUA) measures were obtained during striate cortex penetrations using multicontact electrodes that incorporated single or double microinjection cannulae. Profiles were recorded before and at successive time points after bicuculline induction of disinhibition. Both the noncompetitive NMDA antagonist MK-801 and the competitive antagonist APV reversed bicuculline effects, producing a normal laminar activity profile. NMDA-mediated enhancement of excitatory responses in the supragranular laminae of neocortex is believed to play a role in normal signal processing, as well as in epileptic manifestations.

Animals↗
PubMed1995

Characterization of single actin-myosin interactions.

The feedback-enhanced laser trap assay (Finer et al., 1994) allows the measurement of force and displacement produced by single myosin molecules interacting with an actin filament suspended in solution by two laser traps. The average displacement of 11 nm at low load and the average force of 4 pN near isometric conditions are consistent with the conventional swinging cross-bridge model of muscle contraction (Huxley, 1969). The durations of single actin-myosin interactions at low load, 3-7 ms, suggest a relatively small duty ratio. Event durations can be increased either by reducing the ATP concentration until ATP binding is rate-limiting or by lowering the temperature. For sufficiently long interactions near isometric conditions, low frequency force fluctuations were observed within the time frame of a single event. Single myosin events can be measured at ionic strengths that disrupt weak binding actomyosin interactions, supporting the postulate of distinct weak and strong binding states. Myosin-generated force and displacement were measured simultaneously against several different loads to generate a force-displacement curve. The linear appearance of this curve suggests that the myosin powerstroke is driven by the release of a strained linear elastic element with a stiffness of approximately 0.4 pN nm-1.

Actins↗