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1.  NMDA Receptors Subserve Persistent Neuronal Firing During Working Memory In Dorsolateral Prefrontal Cortex 
Neuron  2013;77(4):736-749.
Neurons in the primate dorsolateral prefrontal cortex (dlPFC) generate persistent firing in the absence of sensory stimulation, the foundation of mental representation. Persistent firing arises from recurrent excitation within a network of pyramidal Delay cells. Here, we examined glutamate receptor influences underlying persistent firing in primate dlPFC during a spatial working memory task. Computational models predicted dependence on NMDA receptor (NMDAR) NR2B stimulation, and Delay cell persistent firing was abolished by local NR2B NMDAR blockade or by systemic ketamine administration. AMPA receptors (AMPAR) contributed background depolarization to sustain network firing. In contrast, many Response cells -which likely predominate in rodent PFC- were sensitive to AMPAR blockade and increased firing following systemic ketamine, indicating that models of ketamine actions should be refined to reflect neuronal heterogeneity. The reliance of Delay cells on NMDAR may explain why insults to NMDARs in schizophrenia or Alzheimer’s Disease profoundly impair cognition.
PMCID: PMC3584418  PMID: 23439125
2.  Spatial attention, feature-based attention and saccades: Three sides of one coin? 
Biological psychiatry  2011;69(12):1147-1152.
The last three decades has seen a steady growth of neuroscience research aimed at understanding the functions and sources of top-down attentional modulation in the brain. This correlates with recognition that attention may be a necessary component of sensory systems to support natural behaviors in natural environments. Complexity and clutter are two of the most recognizable hallmarks of natural environments, which can simultaneously contain vitally important and completely irrelevant stimuli. Attention serves as an adaptive filter allowing each sensory modality preferential processing routes for important stimuli while suppressing responses to distracters, thus optimizing use of limited neural resources. In other words, “attention” is the family of mechanisms by which organisms are able to effectively and selectively allocate limited neural resources to achieve specific behavioral goals. This review provides some historical context for considering attentional frameworks and modern neurophysiological attention research, focusing on visual attention. A taxonomy of common attentional effects and neural mechanisms is provided, along with consideration of the specific relationship between attention and saccade planning. We examine the validity of premotor theories of attention, which posit that attention and saccade planning are one and the same. While there is strong evidence that attention and oculomotor planning are similar, with shared neural substrates, there is also evidence that these two functions are not synonymous. Finally, we examine neurophysiological explanations for dysfunction in Attention Deficit Hyperactivity Disorder (ADHD) and the hypothesis that social impairment in Autism Spectrum Disorders (ASD) is partially attributable to perturbations of attentional control circuitry.
PMCID: PMC3572732  PMID: 21529782
3.  Neuronal Basis of Age-Related Working Memory Decline 
Nature  2011;476(7359):210-213.
Many of the cognitive deficits of normal aging (forgetfulness, distractibility, inflexibility, and impaired executive functions) involve prefrontal cortical (PFC) dysfunction1–4. The PFC guides behavior and thought using working memory5, essential functions in the Information Age. Many PFC neurons hold information in working memory through excitatory networks that can maintain persistent neuronal firing in the absence of external stimulation6. This fragile process is highly dependent on the neurochemical environment7. For example, elevated cAMP signaling reduces persistent firing by opening HCN and KCNQ potassium channels8,9. It is not known if molecular changes associated with normal aging alter the physiological properties of PFC neurons during working memory, as there have been no in vivo recordings from PFC neurons of aged monkeys. Here we characterize the first recordings of this kind, revealing a marked loss of PFC persistent firing with advancing age that can be rescued by restoring an optimal neurochemical environment. Recordings showed an age-related decline in the firing rate of DELAY neurons, while the firing of CUE neurons remained unchanged with age. The memory-related firing of aged DELAY neurons was partially restored to more youthful levels by inhibiting cAMP signaling, or by blocking HCN or KCNQ channels. These findings reveal the cellular basis of age-related cognitive decline in dorsolateral PFC, and demonstrate that physiological integrity can be rescued by addressing the molecular needs of PFC circuits.
PMCID: PMC3193794  PMID: 21796118
prefrontal cortex; working memory; aging; cAMP signaling; HCN channels; KCNQ channels; α2A adrenoceptors
4.  Surround suppression and sparse coding in visual and barrel cortices 
During natural vision the entire retina is stimulated. Likewise, during natural tactile behaviors, spatially extensive regions of the somatosensory surface are co-activated. The large spatial extent of naturalistic stimulation means that surround suppression, a phenomenon whose neural mechanisms remain a matter of debate, must arise during natural behavior. To identify common neural motifs that might instantiate surround suppression across modalities, we review models of surround suppression and compare the evidence supporting the competing ideas that surround suppression has either cortical or sub-cortical origins in visual and barrel cortex. In the visual system there is general agreement lateral inhibitory mechanisms contribute to surround suppression, but little direct experimental evidence that intracortical inhibition plays a major role. Two intracellular recording studies of V1, one using naturalistic stimuli (Haider et al., 2010), the other sinusoidal gratings (Ozeki et al., 2009), sought to identify the causes of reduced activity in V1 with increasing stimulus size, a hallmark of surround suppression. The former attributed this effect to increased inhibition, the latter to largely balanced withdrawal of excitation and inhibition. In rodent primary somatosensory barrel cortex, multi-whisker responses are generally weaker than single whisker responses, suggesting multi-whisker stimulation engages similar surround suppressive mechanisms. The origins of suppression in S1 remain elusive: studies have implicated brainstem lateral/internuclear interactions and both thalamic and cortical inhibition. Although the anatomical organization and instantiation of surround suppression in the visual and somatosensory systems differ, we consider the idea that one common function of surround suppression, in both modalities, is to remove the statistical redundancies associated with natural stimuli by increasing the sparseness or selectivity of sensory responses.
PMCID: PMC3389675  PMID: 22783169
inhibition; S1; somatosensory cortex; sparse coding; suppression; V1; vibrissae; visual cortex
5.  Robustness of the retinotopic attentional trace after eye movements 
Journal of vision  2010;10(3):19.1-1912.
With each eye movement, the image received by the visual system changes drastically. To maintain stable spatiotopic (world-centered) representations, the relevant retinotopic (eye-centered) coordinates must be continually updated. Although updating or remapping of visual scene representations can occur very rapidly, J. D. Golomb, M. M. Chun, and J. A. Mazer (2008) demonstrated that representations of sustained attention update more slowly than the remapping literature would predict; attentional benefits at previously attended retinotopic locations linger after completion of the saccade, even when this location is no longer behaviorally relevant. The present study explores the robustness of this “retinotopic attentional trace.” We report significant retinotopic facilitation despite attempts to eliminate or reduce it by enhancing spatiotopic reference frames with permanent visual cues in the stimulus display and by introducing a different task where the attended location is the saccade target itself. Our results support and extend our earlier model of native retinotopically organized salience maps that must be dynamically updated to reflect the task-relevant spatiotopic location with each saccade. Consistent with the idea that attentional facilitation arises from persistent, recurrent neural activity, it takes measurable time for this facilitation to decay, leaving behind a retinotopic attentional trace after the saccade has been executed, regardless of conflicting task demands.
PMCID: PMC3213860  PMID: 20377296
coordinate systems; spatial attention; saccades; reference frame; remapping
6.  Synaptic and Network Mechanisms of Sparse and Reliable Visual Cortical Activity during Nonclassical Receptive Field Stimulation 
Neuron  2010;65(1):107-121.
During natural vision, the entire visual field is stimulated by images rich in spatiotemporal structure. Although many visual system studies restrict stimuli to the classical receptive field (CRF), it is known that costimulation of the CRF and the surrounding nonclassical receptive field (nCRF) increases neuronal response sparseness. The cellular and network mechanisms underlying increased response sparseness remain largely unexplored. Here we show that combined CRF + nCRF stimulation increases the sparseness, reliability, and precision of spiking and membrane potential responses in classical regular spiking (RSC) pyramidal neurons of cat primary visual cortex. Conversely, fast-spiking interneurons exhibit increased activity and decreased selectivity during CRF + nCRF stimulation. The increased sparseness and reliability of RSC neuron spiking is associated with increased inhibitory barrages and narrower visually evoked synaptic potentials. Our experimental observations were replicated with a simple computational model, suggesting that network interactions among neuronal subtypes ultimately sharpen recurrent excitation, producing specific and reliable visual responses.
PMCID: PMC3110675  PMID: 20152117
7.  Attention doesn’t slide: spatiotopic updating after eye movements instantiates a new, discrete attentional locus 
During natural vision, eye movements can drastically alter the retinotopic (eye-centered) coordinates of locations and objects, yet the spatiotopic (world-centered) percept remains stable. Maintaining visuospatial attention in spatiotopic coordinates requires updating of attentional representations following each eye movement. However, this updating is not instantaneous; attentional facilitation temporarily lingers at the previous retinotopic location after a saccade, a phenomenon known as the retinotopic attentional trace. At various times after a saccade, we probed attention at an intermediate location between the retinotopic and spatiotopic locations to determine whether a single locus of attentional facilitation slides progressively from the previous retinotopic location to the appropriate spatiotopic location, or whether retinotopic facilitation decays while a new, independent spatiotopic locus concurrently becomes active. Facilitation at the intermediate location was not significant at any time, suggesting that top-down attention can result in enhancement of discrete retinotopic and spatiotopic locations without passing through intermediate locations.
PMCID: PMC3097429  PMID: 21258903
Retinotopic; Remapping; Eye-centered; Reference frame; Coordinate systems; Saccades
8.  Attentional facilitation throughout human visual cortex lingers in retinotopic coordinates after eye movements 
With each eye movement, the image of the world received by the visual system changes dramatically. To maintain stable spatiotopic (world-centered) visual representations, the retinotopic (eye-centered) coordinates of visual stimuli are continually remapped, even before the eye movement is completed. Recent psychophysical work has suggested that updating of attended locations occurs as well, although on a slower time scale, such that sustained attention lingers in retinotopic coordinates for several hundred milliseconds after each saccade. To explore where and when this “retinotopic attentional trace” resides in the cortical visual processing hierarchy, we conducted complementary fMRI and ERP experiments using a novel gaze-contingent task. Human subjects executed visually guided saccades while covertly monitoring a fixed spatiotopic target location. Although subjects responded only to stimuli appearing at the attended spatiotopic location, blood oxygen level dependent (BOLD) responses to stimuli appearing after the eye movement at the previously, but no longer, attended retinotopic location were enhanced in area V4 and throughout visual cortex. This retinotopic attentional trace was also detectable with higher temporal resolution in the anterior N1 component of the ERP data, a well-established signature of attentional modulation. Taken together, these results demonstrate that when top-down spatiotopic signals act to redirect visuo-spatial attention to new retinotopic locations after eye movements, facilitation transiently persists in the cortical regions representing the previously relevant retinotopic location.
PMCID: PMC2925081  PMID: 20685992
spatial attention; eye-centered; spatiotopic; fMRI; ERP; retinotopic attentional trace
9.  Attention to stimulus features shifts spectral tuning of V4 neurons during natural vision 
Neuron  2008;59(3):509-521.
Most current neurophysiological data indicate that selective attention can alter the baseline response level or response gain of neurons in extrastriate visual areas but that it cannot change neuronal tuning. Current models of attention therefore assume that neurons in visual cortex transmit a veridical representation of the natural world, via labeled lines, to central areas responsible for executive processes and decision-making. However, some theoretical studies have suggested that attention might modify neuronal tuning in visual cortex and thus change the neural representation of stimuli. To test this hypothesis experimentally, we measured orientation and spatial frequency tuning of area V4 neurons during two distinct natural visual search tasks, one that required fixation and one that allowed free-viewing during search. We find that spatial attention modulates response baseline and/or gain but does not alter tuning, consistent with previous reports. In contrast, attention directed toward particular visual features often shifts neuronal tuning. These tuning shifts are inconsistent with the labeled line model, and tend to enhance responses to stimulus features that distinguish the search target. Our data suggest that V4 neurons behave as matched filters that are dynamically tuned to optimize visual search.
PMCID: PMC2948549  PMID: 18701075
10.  The native coordinate system of spatial attention is retinotopic 
Visual processing can be facilitated by covert attention at behaviorally relevant locations. If the eyes move while a location in the visual field is facilitated, what happens to the internal representation of the attended location? With each eye movement, the retinotopic (eye-centered) coordinates of the attended location change while the spatiotopic (world-centered) coordinates remain stable. To investigate whether the neural substrates of spatial attention reside in retinotopically- and/or spatiotopically-organized maps, we utilized a novel gaze-contingent behavioral paradigm that probed spatial attention at various times after eye movements. When task demands required maintaining a spatiotopic representation after the eye movement, we found facilitation at the retinotopic location of the spatial cue for 100-200ms following the saccade, although this location had no behavioral significance. This task-irrelevant retinotopic representation dominated immediately after the saccade, whereas at later delays the task-relevant spatiotopic representation prevailed. On the other hand, when task demands required maintaining the cue in retinotopic coordinates, a strong retinotopic benefit persisted long after the saccade, and there was no evidence of spatiotopic facilitation. These data suggest that the cortical and sub-cortical substrates of spatial attention primarily reside in retinotopically-organized maps that must be dynamically updated to compensate for eye movements when behavioral demands require a spatiotopic representation of attention. Our conclusion is that the visual system’s native or low-level representation of endogenously maintained spatial attention is retinotopic, and remapping of attention to spatiotopic coordinates occurs slowly and only when behaviorally necessary.
PMCID: PMC2601623  PMID: 18923041
spatial attention; coordinate systems; saccades; eye movements; retinotopic; remapping
11.  Detection of Large Interaural Delays and Its Implication for Models of Binaural Interaction  
The interaural time difference (ITD) is a major cue to sound localization along the horizontal plane. The maximum natural ITD occurs when a sound source is positioned opposite to one ear. We examined the ability of owls and humans to detect large ITDs in sounds presented through headphones. Stimuli consisted of either broad or narrow bands of Gaussian noise, 100 ms in duration. Using headphones allowed presentation of ITDs that are greater than the maximum natural ITD. Owls were able to discriminate a sound leading to the left ear from one leading to the right ear, for ITDs that are 5 times the maximum natural delay. Neural recordings from optic-tectum neurons, however, show that best ITDs are usually well within the natural range and are never as large as ITDs that are behaviorally discriminable. A model of binaural cross-correlation with short delay lines is shown to explain behavioral detection of large ITDs. The model uses curved trajectories of a cross-correlation pattern as the basis for detection. These trajectories represent side peaks of neural ITD-tuning curves and successfully predict localization reversals by both owls and human subjects.
PMCID: PMC3202365  PMID: 12083726
interaural; binaural; owl; ITD

Results 1-11 (11)