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1.  Prefrontal cortex neurons reflect categorical decisions about ambiguous stimuli 
Journal of cognitive neuroscience  2014;26(6):1283-1291.
We examined whether prefrontal cortex (PFC) neuron activity reflects categorical decisions in monkeys categorizing ambiguous stimuli. A morphing system was used to systematically vary stimulus shape and precisely define category boundaries. Ambiguous stimuli were centered on a category boundary, i.e., they were a mix of 50% of two prototypes and therefore had no category information, so monkeys guessed at their category membership. We found that the monkey's trial-by-trial decision about the category membership of an ambiguous image was reflected in PFC activity. Activity to the same ambiguous image differed significantly depending on which category the monkey had assigned it to. This effect only occurred when that scheme was behaviorally relevant. These indicate that PFC activity reflects categorical decisions.
doi:10.1162/jocn_a_00568
PMCID: PMC4034266  PMID: 24405188
prefrontal cortex; categorization; monkey; flexibility; goal directed; object vision
2.  Prefrontal cortex activity during flexible categorization 
Items are categorized differently depending on the behavioral context. For instance, a lion can be an African animal or a type of cat. We recorded lateral prefrontal cortex (PFC) neural activity while monkeys switched between categorizing the same image set along two different category schemes with orthogonal boundaries. We found that each category scheme was largely represented by independent PFC neuronal populations and that activity reflecting a category distinction was weaker, but not absent, when that category was irrelevant. We suggest that the PFC represents competing category representations independently to reduce interference between them.
doi:10.1523/JNEUROSCI.4837-09.2010
PMCID: PMC3709835  PMID: 20573899
prefrontal cortex; categorization; monkey; flexibility; goal directed; object vision
3.  Rapid Association Learning in the Primate Prefrontal Cortex in the Absence of Behavioral Reversals 
Journal of Cognitive Neuroscience  2010;23(7):1823-1828.
The PFC plays a central role in our ability to learn arbitrary rules, such as “green means go.” Previous experiments from our laboratory have used conditional association learning to show that slow, gradual changes in PFC neural activity mirror monkeys’ slow acquisition of associations. These previous experiments required monkeys to repeatedly reverse the cue–saccade associations, an ability known to be PFC-dependent. We aimed to test whether the relationship between PFC neural activity and behavior was due to the reversal requirement, so monkeys were trained to learn several new conditional cue–saccade associations without reversing them. Learning-related changes in PFC activity now appeared earlier and more suddenly in correspondence with similar changes in behavioral improvement. This suggests that learning of conditional associations is linked to PFC activity regardless of whether reversals are required. However, when previous learning does not need to be suppressed, PFC acquires associations more rapidly.
doi:10.1162/jocn.2010.21555
PMCID: PMC3260045  PMID: 20666598
4.  Task-Dependent Changes in Short-Term Memory in the Prefrontal Cortex 
The prefrontal cortex (PFC) is important for flexible, context-dependent behavioral control. It also plays a critical role in short-term memory maintenance. Though many studies have investigated these functions independently, it is unclear how these two very different processes are realized by a single brain area. To address this we trained two monkeys on two variants of an object sequence memory task. These tasks had the same memory requirements but differed in how information was read out and used. For the “Recognition” task the monkeys had to remember two sequentially presented objects and then release a bar when a matching sequence was recognized. For the “Recall” task, the monkeys had to remember the same sequence of objects but were instead required to recall the sequence and reproduce it with saccadic eye movements when presented with an array of objects. After training we recorded the activity of PFC neurons during task performance. We recorded 222 neurons during the Recognition task, 177 neurons during the Recall task, and 248 neurons during the Switching task (interleaved blocks of Recognition and Recall). Task context had a profound influence on neural selectivity for objects. During the Recall task, the first object was encoded more strongly than the second object, while during the Recognition task the second object was encoded more strongly. In addition, most of the neurons encoded both the task and the objects, evidence for a single population responsible for these two critical prefrontal functions.
doi:10.1523/JNEUROSCI.1569-10.2010
PMCID: PMC3082458  PMID: 21106819
prefrontal; monkey; memory; sequence; multi-item; delay activity
5.  INCREASES IN FUNCTIONAL CONNECTIVITY BETWEEN PREFRONTAL CORTEX AND STRIATUM DURING CATEGORY LEARNING 
Neuron  2014;83(1):216-225.
SUMMARY
Functional connectivity between the prefrontal cortex (PFC) and striatum (STR) is thought critical for cognition, and has been linked to conditions like autism and schizophrenia. We recorded from multiple electrodes in PFC and STR while monkeys acquired new categories. Category learning was accompanied by an increase in beta-band synchronization of LFPs between, but not within, the PFC and STR. After learning, different pairs of PFC-STR electrodes showed stronger synchrony for one or the other category, suggesting category-specific functional circuits. This category-specific synchrony was also seen between PFC spikes and STR LFPs, but not the reverse, reflecting the direct monosynaptic connections from the PFC to STR. However, causal connectivity analyses suggested that the polysynaptic connections from STR to the PFC exerted a stronger overall influence. This supports models positing that the basal ganglia “train” the PFC. Category learning may depend on the formation of functional circuits between the PFC and STR.
doi:10.1016/j.neuron.2014.05.005
PMCID: PMC4098789  PMID: 24930701
6.  Task Dependence of Visual and Category Representations in Prefrontal and Inferior Temporal Cortices 
The Journal of Neuroscience  2014;34(48):16065-16075.
Visual categorization is an essential perceptual and cognitive process for assigning behavioral significance to incoming stimuli. Categorization depends on sensory processing of stimulus features as well as flexible cognitive processing for classifying stimuli according to the current behavioral context. Neurophysiological studies suggest that the prefrontal cortex (PFC) and the inferior temporal cortex (ITC) are involved in visual shape categorization. However, their precise roles in the perceptual and cognitive aspects of the categorization process are unclear, as the two areas have not been directly compared during changing task contexts. To address this, we examined the impact of task relevance on categorization-related activity in PFC and ITC by recording from both areas as monkeys alternated between a shape categorization and passive viewing tasks. As monkeys viewed the same stimuli in both tasks, the impact of task relevance on encoding in each area could be compared. While both areas showed task-dependent modulations of neuronal activity, the patterns of results differed markedly. PFC, but not ITC, neurons showed a modest increase in firing rates when stimuli were task relevant. PFC also showed significantly stronger category selectivity during the task compared with passive viewing, while task-dependent modulations of category selectivity in ITC were weak and occurred with a long latency. Finally, both areas showed an enhancement of stimulus selectivity during the task compared with passive viewing. Together, this suggests that the ITC and PFC show differing degrees of task-dependent flexibility and are preferentially involved in the perceptual and cognitive aspects of the categorization process, respectively.
doi:10.1523/JNEUROSCI.1660-14.2014
PMCID: PMC4244472  PMID: 25429147
categorization; inferior temporal cortex; neurophysiology; object recognition; prefrontal cortex; vision
7.  The importance of mixed selectivity in complex cognitive tasks 
Nature  2013;497(7451):585-590.
Single-neuron activity in prefrontal cortex (PFC) is tuned to mixtures of multiple task-related aspects. Such mixed selectivity is highly heterogeneous, seemingly disordered and therefore difficult to interpret. We analysed the neural activity recorded in monkeys during an object sequence memory task to identify a role of mixed selectivity in subserving the cognitive functions ascribed to PFC. We show that mixed selectivity neurons encode distributed information about all task-relevant aspects. Each aspect can be decoded from the population of neurons even when single-cell selectivity to that aspect is eliminated. Moreover, mixed selectivity offers a significant computational advantage over specialized responses in terms of the repertoire of input-output functions implementable by readout neurons. This advantage originates from the highly diverse non-linear selectivity to mixtures of task-relevant variables, a signature of high-dimensional neural representations. Crucially, this dimensionality is predictive of animal behaviour as it collapses in error trials. Our findings suggest to move the focus of attention from neurons that exhibit easily interpretable response tuning to the widely observed, but rarely analysed, mixed selectivity neurons.
doi:10.1038/nature12160
PMCID: PMC4412347  PMID: 23685452
9.  Limber Neurons for a Nimble Mind 
Neuron  2013;78(2):211-213.
Stokes et al demonstrate that cortical neurons that adapt their properties with task demands form patterns reflecting the shifting mental states needed to solve the task. Adaptive neurons may be critical to hallmarks of cognition: behavioral complexity and flexibility.
doi:10.1016/j.neuron.2013.04.007
PMCID: PMC3657130  PMID: 23622059
10.  Cortical Circuits for the Control of Attention 
Current opinion in neurobiology  2012;23(2):216-222.
How are some thoughts favored over others? A wealth of data at the level of single neurons has yielded candidate brain areas and mechanisms for our best understood model: visual attention. Recent work has naturally evolved toward efforts at a more integrative, network, understanding. It suggests that focusing attention arises from interactions between widespread cortical and subcortical networks that may be regulated via their rhythmic synchronization.
doi:10.1016/j.conb.2012.11.011
PMCID: PMC3709832  PMID: 23265963
11.  Synchronous Oscillatory Neural Ensembles for Rules in the Prefrontal Cortex 
Neuron  2012;76(4):838-846.
SUMMARY
Intelligent behavior requires acquiring and following rules. Rules define how our behavior should fit different situations. To understand its neural mechanisms, we simultaneously recorded from multiple electrodes in dorsolateral prefrontal cortex (PFC) while monkeys switched between two rules (respond to color versus orientation). We found evidence that oscillatory synchronization of local field potentials (LFPs) formed neural ensembles representing the rules: there were rule-specific increases in synchrony at “beta” (19–40 Hz) frequencies between electrodes. In addition, individual PFC neurons synchronized to the LFP ensemble corresponding to the current rule (color versus orientation). Furthermore, the ensemble encoding the behaviorally dominant orientation rule showed increased “alpha” (6–16 Hz) synchrony when preparing to apply the alternative (weaker) color rule. This suggests that beta-frequency synchrony selects the relevant rule ensemble, while alpha-frequency synchrony deselects a stronger, but currently irrelevant, ensemble. Synchrony may act to dynamically shape task-relevant neural ensembles out of larger, overlapping circuits.
doi:10.1016/j.neuron.2012.09.029
PMCID: PMC3907768  PMID: 23177967
12.  The “working” of working memory 
This review examines the evidence for a neurobiological explanation of executive functions of working memory. We suggest that executive control stems from information about task rules acquired by mixed selective, adaptive coding, multifunctional neurons in the prefrontal cortex. The output of these neurons dynamically links the cortex-wide networks needed to complete the task. The linking may occur via synchronizing of neural rhythms, which may explain why we have a limited capacity for simultaneous thought.
PMCID: PMC3898679  PMID: 24459408
basal ganglia; cognition; executive function; oscillation; prefrontal cortex; synchrony; working memory
13.  The Role of Prefrontal Dopamine D1 Receptors in the Neural Mechanisms of Associative Learning 
Neuron  2012;74(5):10.1016/j.neuron.2012.04.018.
Summary
Dopamine is thought to play a major role in learning. However, while dopamine D1 receptors (D1Rs) in the prefrontal cortex (PFC) have been shown to modulate working memory-related neural activity, their role in the cellular basis of learning is unknown. We recorded activity from multiple electrodes while injecting the D1R antagonist SCH23390 in the lateral PFC as monkeys learned visuomotor associations. Blocking D1Rs impaired learning of novel associations and decreased cognitive flexibility, but spared performance of already familiar associations. This suggests a greater role for prefrontal D1Rs in learning new, than performing familiar, associations. There was a corresponding greater decrease in neural selectivity and increase in alpha and beta oscillations in local field potentials for novel than familiar associations. Our results suggest that weak stimulation of D1Rs observed in aging and psychiatric disorders may impair learning and PFC function by reducing neural selectivity and exacerbating neural oscillations associated with inattention and cognitive deficits.
doi:10.1016/j.neuron.2012.04.018
PMCID: PMC3819197  PMID: 22681691
14.  Category Learning in the Brain 
Annual review of neuroscience  2010;33:203-219.
The ability to group items and events into functional categories is a fundamental characteristic of sophisticated thought. It is subserved by plasticity in many neural systems, including neocortical regions (sensory, prefrontal, parietal, and motor cortex), the medial temporal lobe, the basal ganglia, and midbrain dopaminergic systems. These systems interact during category learning. Corticostriatal loops may mediate recursive, bootstrapping interactions between fast reward-gated plasticity in the basal ganglia and slow reward-shaded plasticity in the cortex. This can provide a balance between acquisition of details of experiences and generalization across them. Interactions between the corticostriatal loops can integrate perceptual, response, and feedback-related aspects of the task and mediate the shift from novice to skilled performance. The basal ganglia and medial temporal lobe interact competitively or cooperatively, depending on the demands of the learning task.
doi:10.1146/annurev.neuro.051508.135546
PMCID: PMC3709834  PMID: 20572771
classification; concept learning; memory systems
15.  Representation of Multiple, Independent Categories in the Primate Prefrontal Cortex 
Neuron  2010;66(5):796-807.
Summary
Neural correlates of visual categories have been previously identified in the prefrontal cortex (PFC). However, whether individual neurons can represent multiple categories is unknown. Varying degrees of generalization vs. specialization of neurons in the PFC have been theorized. We recorded from lateral PFC neural activity while monkeys switched between two different and independent categorical distinctions (Cats vs. Dogs, Sports Cars vs. Sedans). We found that many PFC neurons reflected both categorical distinctions. In fact, these multitasking neurons had the strongest category effects. This stands in contrast to our lab’s recent report that monkeys switching between competing categorical distinctions (applied to the same stimulus set) showed independent representations. We suggest that cognitive demands determine whether PFC neurons function as category “multi-taskers”.
doi:10.1016/j.neuron.2010.05.005
PMCID: PMC2909642  PMID: 20547135
16.  Serial, Covert, Shifts of Attention during Visual Search are Reflected by the Frontal Eye Fields and Correlated with Population Oscillations 
Neuron  2009;63(3):386-396.
Attention regulates the flood of sensory information into a manageable stream, and so understanding how attention is controlled is central to understanding cognition. Competing theories suggest visual search involves serial and/or parallel allocation of attention, but there is little direct, neural, evidence for either mechanism. Two monkeys were trained to covertly search an array for a target stimulus under visual search (endogenous) and pop-out (exogenous) conditions. Here we present neural evidence in the frontal eye fields (FEF) for serial, covert shifts of attention during search but not pop-out. Furthermore, attention shifts reflected in FEF spiking activity were correlated with 18–34 Hz oscillations in the local field potential, suggesting a ‘clocking’ signal. This provides direct neural evidence that primates can spontaneously adopt a serial search strategy and that these serial covert shifts of attention are directed by the FEF. It also suggests that neuron population oscillations may regulate the timing of cognitive processing.
doi:10.1016/j.neuron.2009.06.020
PMCID: PMC2758537  PMID: 19679077
17.  Learning substrates in the primate prefrontal cortex and striatum: sustained activity related to successful actions 
Neuron  2009;63(2):244-253.
Summary
Learning from experience requires knowing whether a past action resulted in a desired outcome. The prefrontal cortex and basal ganglia are thought to play key roles in such learning of arbitrary stimulus-response associations. Previous studies have found neural activity in these areas, similar to dopaminergic neuron signals that transiently reflect whether a response is correct or incorrect. However, it is unclear how this transient activity, which fades in under a second, influences actions that occur much later. Here we report sustained outcome-related responses in single neurons of both areas, which last for several seconds until the next trial. Moreover, the outcome on a single trial influences the neural activity and behavior on the next trial: behavioral responses are more often correct and single neurons more accurately discriminate between the possible responses when the previous trial was correct. These long-lasting signals about trial outcome provide a way to link one action to the next, and may allow reward signals to be combined over time to implement successful learning.
doi:10.1016/j.neuron.2009.06.019
PMCID: PMC2874751  PMID: 19640482
18.  A Neural Circuit Model of Flexible Sensori-motor Mapping: Learning and Forgetting on Multiple Timescales 
Neuron  2007;54(2):319-333.
Summary
Volitional behavior relies on the brain’s ability to remap sensory flow to motor programs whenever demanded by a changed behavioral context. To investigate the circuit basis of such flexible behavior, we have developed a biophysically-based decision-making network model of spiking neurons for arbitrary sensorimotor mapping. The model quantitatively reproduces behavioral and prefrontal single-cell data from an experiment in which monkeys learn visuo-motor associations that are reversed unpredictably from time to time. We show that when synaptic modifications occur on multiple timescales, the model behavior becomes flexible only when needed: slow components of learning usually dominate the decision process. However, if behavioral contexts change frequently enough, fast components of plasticity take over, and the behavior exhibits a quick forget-and-learn pattern. This model prediction is confirmed by monkey data. Therefore, our work reveals a scenario for conditional associative learning that is distinct from instant switching between sets of well established sensorimotor associations.
doi:10.1016/j.neuron.2007.03.017
PMCID: PMC2833020  PMID: 17442251
19.  Shifting the Spotlight of Attention: Evidence for Discrete Computations in Cognition 
Our thoughts have a limited bandwidth; we can only fully process a few items in mind simultaneously. To compensate, the brain developed attention, the ability to select information relevant to the current task, while filtering out the rest. Therefore, by understanding the neural mechanisms of attention we hope to understand a core component of cognition. Here, we review our recent investigations of the neural mechanisms underlying the control of visual attention in frontal and parietal cortex. This includes the observation that the neural mechanisms that shift attention were synchronized to 25 Hz oscillatory brain rhythms, with each shift in attention falling within a single cycle of the oscillation. We generalize these findings to present a hypothesis that cognition relies on neural mechanisms that operate in discrete, periodic computations, as reflected in ongoing oscillations. We discuss the advantages of the model, experimental support, and make several testable hypotheses.
doi:10.3389/fnhum.2010.00194
PMCID: PMC2990535  PMID: 21119775
attention; cognition; synchrony; oscillations
20.  Microstimulation of Frontal Cortex Can Reorder a Remembered Spatial Sequence 
PLoS Biology  2006;4(5):e134.
Complex goal-directed behaviors extend over time and thus depend on the ability to serially order memories and assemble compound, temporally coordinated movements. Theories of sequential processing range from simple associative chaining to hierarchical models in which order is encoded explicitly and separately from sequence components. To examine how short-term memory and planning for sequences might be coded, we used microstimulation to perturb neural activity in the supplementary eye field (SEF) while animals held a sequence of two cued locations in memory over a short delay. We found that stimulation affected the order in which animals saccaded to the locations, but not the memory for which locations were cued. These results imply that memory for sequential order can be dissociated from that of its components. Furthermore, stimulation of the SEF appeared to bias sequence endpoints to converge toward a location in contralateral space, suggesting that this area encodes sequences in terms of their endpoints rather than their individual components.
Errors induced by microstimulation of the supplementary eye fields while monkeys performed a remembered series of saccadic eye movements give insight into the nature of sequence coding in this cortical area.
doi:10.1371/journal.pbio.0040134
PMCID: PMC1440931  PMID: 16620152
21.  The prefrontal cortex: categories, concepts and cognition. 
The ability to generalize behaviour-guiding principles and concepts from experience is key to intelligent, goal-directed behaviour. It allows us to deal efficiently with a complex world and to adapt readily to novel situations. We review evidence that the prefrontal cortex-the cortical area that reaches its greatest elaboration in primates-plays a central part in acquiring and representing this information. The prefrontal cortex receives highly processed information from all major forebrain systems, and neurophysiological studies suggest that it synthesizes this into representations of learned task contingencies, concepts and task rules. In short, the prefrontal cortex seems to underlie our internal representations of the 'rules of the game'. This may provide the necessary foundation for the complex behaviour of primates, in whom this structure is most elaborate.
doi:10.1098/rstb.2002.1099
PMCID: PMC1693009  PMID: 12217179

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