SUMMARY Discrimination tasks require processing, interpreting, and linking sensory information to the appropriate motor response. We report that neurons in prefrontal cortex represent visual motion with precision comparable to cortical neurons at early stages of motion processing and readily adapt this representation to behavioral context. We found that direction selectivity, recorded while the monkeys discriminated directions, decreased when they judged motion speed and ignored its direction. This decrease was more pronounced in neurons classified as narrow-spiking (NS) putative inter-neurons, than in broad-spiking (BS) putative pyramidal neurons. However, during passive fixation when the link between motion and its behavioral relevance was removed, both cell types showed a severe selectivity loss. Our results show that flexible sensory representation during active discrimination tasks is achieved in the PFC by a specialized neuronal network of NS neurons readily adjusting their selectivity to behavioral context, and BS neurons capable of maintaining relatively stable sensory representation.

During motion discrimination tasks, many prefrontal cortex (PFC) neurons are strongly modulated by the behavioral context, suggesting their involvement in sensory discriminations. Recent studies suggest that trial-to-trial variability of spiking activity characteristic of cortical neurons could be a source of information about the state of neurons and their participation in behavioral tasks. We tested this hypothesis by examining the variability of putative pyramidal PFC neurons, a likely source of top-down influences. The variability of these neurons was calculated as a ratio of spike count variance to its mean (fano factor, FF), while monkeys compared the directions of two moving stimuli, sample and test, separated by a delay. We found that the FF tracked consecutive components of the task, dropping rapidly with the onset of stimuli being discriminated and declining more slowly before each salient event of the trial: The sample, the test, and the response. These time-dependent signals were less consistent in direction selective neurons and were largely absent during passive fixation. Furthermore, neurons with test responses that reflected the remembered sample decreased their FF well before the test, revealing the predictive nature of response variability, an effect present only during the active task. The FF was also sensitive to behavioral performance, exhibiting different temporal dynamics on error trials. These changes did not depend on firing rates and were often the only metric correlated with task demands. Our results demonstrate that trial-to-trial variability provides a sensitive measure of the engagement of putative pyramidal PFC neurons in circuits subserving discrimination tasks. direction discrimination | direction selectivity | macaque monkey | working memory N eurons in the prefrontal cortex (PFC) are thought to play a key role in cognitive control and to exert top-down influences on sensory cortical regions with which they are reciprocally connected (1, 2). Recent recordings from the PFC during motion discrimination tasks revealed direction-selective (DS) responses that depended on behavioral context, shedding light on the nature of the top-down signals PFC is likely to provide (3, 4). These and other studies (e.g., ref. 5) demonstrating the involvement of the PFC in visual discrimination tasks based their conclusions on the analysis of average firing rates over repeated trial conditions. Indeed, the average rate of action potentials has proven to be a remarkably useful measure of neural activity that not only encodes a broad range of stimulus and response dimensions but also correlates with more cognitive aspects of behavior, such as memory storage, anticipation, reward, and decision.However, there is mounting evidence that the mean firing rate is not the only measure of how neurons are affected by external events. Recent theoretical and experimental studies provide evidence that trial-by-trial variability in activity characteristic of cortical neurons (6) may also be a source of information a...

Comparing two stimuli that occur at different times demands the coordination of bottom-up and top-down processes. It has been hypothesized that the dorsolateral prefrontal (PFC) cortex, the likely source of top-down cortical influences, plays a key role in such tasks, contributing to both maintenance and sensory comparisons. We examined this hypothesis by recording from the PFC of monkeys comparing directions of two moving stimuli, S1 and S2, separated by a memory delay. We determined the contribution of the two principal cell types to these processes, by classifying neurons into broad-spiking (BS) putative pyramidal cells and narrow-spiking (NS) putative local interneurons. During the delay, BS cells were more likely to exhibit anticipatory modulation and to represent the remembered direction. While this representation was transient, appearing at different times in different neurons, it weakened when direction was not task-relevant, suggesting its utility. During S2, both putative cell types showed comparison-related activity modulations. These modulations were of two types, each carried by different neurons, which either preferred trials with stimuli moving in the same direction or trials with stimuli of different directions. These comparison effects were strongly correlated with choice, suggesting their role in circuitry underlying decision-making. These results provide the first demonstration of distinct contributions made by principal cell types to memory-guided perceptual decisions. During sensory stimulation both cell types represent behaviorally relevant stimulus features, contributing to comparison and decision-related activity. However in the absence of sensory stimulation, putative pyramidal cells dominated, carrying information about the elapsed time and the preceding direction.

When a monkey needs to decide whether motion direction of one stimulus is the same or different as that of another held in working memory, neurons in dorsolateral prefrontal cortex (DLPFC) faithfully represent the motion directions being evaluated and contribute to their comparison. Here, we examined whether DLPFC neurons are more generally involved in other types of sensory comparisons. Such involvement would support the existence of generalized sensory comparison mechanisms within DLPFC, shedding light on top-down influences this region is likely to provide to the upstream sensory neurons during comparison tasks. We recorded activity of individual neurons in the DLPFC while monkeys performed a memory-guided decision task in which the important dimension was the speed of two sequentially presented moving random-dot stimuli. We found that many neurons, both narrow-spiking putative local interneurons and broad-spiking putative pyramidal output cells, were speed-selective, with tuning reminiscent of that observed in the motion processing middle temporal (MT) cortical area. Throughout the delay, broad-spiking neurons were more active, showing anticipatory rate modulation and transient periods of speed selectivity. During the comparison stimulus, responses of both cell types were modulated by the speed of the first stimulus, and their activity was highly predictive of the animals’ behavioral report. These results are similar to those found for comparisons of motion direction, suggesting the existence of generalized neural mechanisms in the DLPFC subserving the comparison of sensory signals.

Objective:To estimate the relative frequency of acute medication overuse (AMO) among people with episodic migraine (EM) and chronic migraine (CM), to characterize the types of acute medications overused for migraine, and to identify factors associated with AMO.Methods:We analyzed data from the Chronic Migraine Epidemiology and Outcomes (CaMEO) Study (ClinicalTrials.gov, NCT01648530), a cross-sectional and longitudinal Internet study that included a systematic sampling of the US population. From September 2012 to November 2013, the CaMEO Study respondents participated in different modules to collect data on the clinical course of migraine, family burden, barriers to care, endophenotypes, and comorbidities. Among people who met criteria for migraine consistent with the International Classification of Headache Disorders, 3rd edition (ICHD-3), we evaluated types and frequency of medications used for headache/migraine, selected comorbidities, and emergency department (ED) and urgent care (UC) use. AMO was defined by days/month of medication use as specified by ICHD-3 criteria for medication overuse headache (MOH) without the requirement for ≥15 monthly headache days (MHDs). Nested, multivariable binary logistic regression modeling was used to identify factors associated with increased risk of AMO.Results:Of 16,789 CaMEO respondents with migraine, 2,975 (17.7%) met AMO criteria. Approximately 67.9% (2,021/2,975) of AMO respondents reported <15 MHDs. Simple analgesics, combination analgesics, and opioids were the medication classes most commonly overused. Factors associated with AMO in the final multivariable logistic regression model included ≥15 MHDs, moderate to severe disability, severe migraine interictal burden, use of preventive medication, and an ED/UC visit for headache within 6 months.Conclusions:Approximately two-thirds of respondents with AMO reported <15 MHDs and therefore did not meet criteria for MOH. Those with AMO had greater disease burden and increased ED/UC utilization relative to people with migraine but not AMO.