Stress degrades working memory-related frontostriatal circuit function.

Goal-directed behavior is dependent on neuronal activity in the prefrontal cortex (PFC) and extended frontostriatal circuitry. Stress and stress-related disorders are associated with impaired frontostriatal-dependent cognition. Our understanding of the neural mechanisms that underlie stress-related cognitive impairment is limited, with the majority of prior research focused on the PFC. To date, the actions of stress across cognition-related frontostriatal circuitry are unknown. To address this gap, the current studies examined the effects of acute noise-stress on the spiking activity of neurons and local field potential oscillatory activity within the dorsomedial PFC (dmPFC) and dorsomedial striatum (dmSTR) in rats engaged in a test of spatial working memory. Stress robustly suppressed responses of both dmPFC and dmSTR neurons strongly tuned to key task events (delay, reward). Additionally, stress strongly suppressed delay-related, but not reward-related, theta and alpha spectral power within, and synchrony between, the dmPFC and dmSTR. These observations provide the first demonstration that stress disrupts the neural coding and functional connectivity of key task events, particularly delay, within cognition-supporting dorsomedial frontostriatal circuitry. These results suggest that stress-related degradation of neural coding within both the PFC and striatum likely contributes to the cognition-impairing effects of stress.

Changes in Endogenous Dopamine Induced by Methylphenidate Predict Functional Connectivity in Nonhuman Primates.

Dopamine (DA) levels in the striatum are increased by many therapeutic drugs, such as methylphenidate (MPH), which also alters behavioral and cognitive functions thought to be controlled by the PFC dose-dependently. We linked DA changes and functional connectivity (FC) using simultaneous [18F]fallypride PET and resting-state fMRI in awake male rhesus monkeys after oral administration of various doses of MPH. We found a negative correlation between [18F]fallypride nondisplaceable binding potential (BPND) and MPH dose in the head of the caudate (hCd), demonstrating increased extracellular DA resulting from MPH administration. The decreased BPND was negatively correlated with FC between the hCd and the PFC. Subsequent voxelwise analyses revealed negative correlations with FC between the hCd and the dorsolateral PFC, hippocampus, and precuneus. These results, showing that MPH-induced changes in DA levels in the hCd predict resting-state FC, shed light on a mechanism by which changes in striatal DA could influence function in the PFC.SIGNIFICANCE STATEMENT Dopamine transmission is thought to play an essential role in shaping large scale-neural networks that underlie cognitive functions. It is the target of therapeutic drugs, such as methylphenidate (Ritalin), which blocks the dopamine transporter, thereby increasing extracellular dopamine levels. Methylphenidate is used extensively to treat attention deficit hyperactivity disorder, even though its effects on cognitive functions and their underlying neural mechanisms are not well understood. To date, little is known about the link between changes in dopamine levels and changes in functional brain organization. Using simultaneous PET/MR imaging, we show that methylphenidate-induced changes in endogenous dopamine levels in the head of the caudate predict changes in resting-state functional connectivity between this structure and the prefrontal cortex, precuneus, and hippocampus.

Neural correlate of auditory spatial attention allocation in the superior colliculus.

This study is the physiological complement to previous behavioral work that demonstrated that rhesus monkeys are able to allocate attention about the surrounding space based on brief, broadband auditory cues. Single-unit recordings were taken from the intermediate layers of the superior colliculus (iSC) while the subjects oriented to visual and auditory targets in the context of a cuing task with their heads unrestrained. The results show a correlation between behavioral manifestations of attention allocation, attention capture and inhibition of return, and modulation of target-evoked responses in single iSC neurons. NEW & NOTEWORTHY These results show for the first time a neural correlate of attention capture and inhibition of return in response to auditory stimuli in the superior colliculus of the head-unrestrained monkey.

Decision making: effects of methylphenidate on temporal discounting in nonhuman primates.

Decisions are often made based on which option will result in the largest reward. When given a choice between a smaller but immediate reward and a larger delayed reward, however, humans and animals often choose the smaller, an effect known as temporal discounting. Dopamine (DA) neurotransmission is central to reward processing and encodes delayed reward value. Impulsivity, the tendency to act without forethought, is associated with excessive discounting of rewards, which has been documented in patients with attention deficit hyperactivity disorder (ADHD). Both impulsivity and temporal discounting are linked to the dopaminergic system. Methylphenidate (MPH), which blocks the DA transporter and increases extracellular levels of DA in the basal ganglia and prefrontal cortex, is a primary treatment for ADHD and, at low doses, ameliorates impulsivity in both humans and animals. This study tested the hypothesis that low doses of MPH would decrease the discounting rate of rhesus monkeys performing an intertemporal choice task, suggesting a reduction in impulsivity. The results support this hypothesis and provide further evidence for the role of DA in temporal discounting and impulsive behavior.

Coding of repetitive transients by auditory cortex on posterolateral superior temporal gyrus in humans: an intracranial electrophysiology study.

Evidence regarding the functional subdivisions of human auditory cortex has been slow to converge on a definite model. In part, this reflects inadequacies of current understanding of how the cortex represents temporal information in acoustic signals. To address this, we investigated spatiotemporal properties of auditory responses in human posterolateral superior temporal (PLST) gyrus to acoustic click-train stimuli using intracranial recordings from neurosurgical patients. Subjects were patients undergoing chronic invasive monitoring for refractory epilepsy. The subjects listened passively to acoustic click-train stimuli of varying durations (160 or 1,000 ms) and rates (4-200 Hz), delivered diotically via insert earphones. Multicontact subdural grids placed over the perisylvian cortex recorded intracranial electrocorticographic responses from PLST and surrounding areas. Analyses focused on averaged evoked potentials (AEPs) and high gamma (70-150 Hz) event-related band power (ERBP). Responses to click trains featured prominent AEP waveforms and increases in ERBP. The magnitude of AEPs and ERBP typically increased with click rate. Superimposed on the AEPs were frequency-following responses (FFRs), most prominent at 50-Hz click rates but still detectable at stimulus rates up to 200 Hz. Loci with the largest high gamma responses on PLST were often different from those sites that exhibited the strongest FFRs. The data indicate that responses of non-core auditory cortex of PLST represent temporal stimulus features in multiple ways. These include an isomorphic representation of periodicity (as measured by the FFR), a representation based on increases in non-phase-locked activity (as measured by high gamma ERBP), and spatially distributed patterns of activity.

Stress-induced impairment of a working memory task: role of spiking rate and spiking history predicted discharge.

Stress, pervasive in society, contributes to over half of all work place accidents a year and over time can contribute to a variety of psychiatric disorders including depression, schizophrenia, and post-traumatic stress disorder. Stress impairs higher cognitive processes, dependent on the prefrontal cortex (PFC) and that involve maintenance and integration of information over extended periods, including working memory and attention. Substantial evidence has demonstrated a relationship between patterns of PFC neuron spiking activity (action-potential discharge) and components of delayed-response tasks used to probe PFC-dependent cognitive function in rats and monkeys. During delay periods of these tasks, persistent spiking activity is posited to be essential for the maintenance of information for working memory and attention. However, the degree to which stress-induced impairment in PFC-dependent cognition involves changes in task-related spiking rates or the ability for PFC neurons to retain information over time remains unknown. In the current study, spiking activity was recorded from the medial PFC of rats performing a delayed-response task of working memory during acute noise stress (93 db). Spike history-predicted discharge (SHPD) for PFC neurons was quantified as a measure of the degree to which ongoing neuronal discharge can be predicted by past spiking activity and reflects the degree to which past information is retained by these neurons over time. We found that PFC neuron discharge is predicted by their past spiking patterns for nearly one second. Acute stress impaired SHPD, selectively during delay intervals of the task, and simultaneously impaired task performance. Despite the reduction in delay-related SHPD, stress increased delay-related spiking rates. These findings suggest that neural codes utilizing SHPD within PFC networks likely reflects an additional important neurophysiological mechanism for maintenance of past information over time. Stress-related impairment of this mechanism is posited to contribute to the cognition-impairing actions of stress.

Immediate neural impact and incomplete compensation after semantic hub disconnection.

The human brain extracts meaning using an extensive neural system for semantic knowledge. Whether broadly distributed systems depend on or can compensate after losing a highly interconnected hub is controversial. We report intracranial recordings from two patients during a speech prediction task, obtained minutes before and after neurosurgical treatment requiring disconnection of the left anterior temporal lobe (ATL), a candidate semantic knowledge hub. Informed by modern diaschisis and predictive coding frameworks, we tested hypotheses ranging from solely neural network disruption to complete compensation by the indirectly affected language-related and speech-processing sites. Immediately after ATL disconnection, we observed neurophysiological alterations in the recorded frontal and auditory sites, providing direct evidence for the importance of the ATL as a semantic hub. We also obtained evidence for rapid, albeit incomplete, attempts at neural network compensation, with neural impact largely in the forms stipulated by the predictive coding framework, in specificity, and the modern diaschisis framework, more generally. The overall results validate these frameworks and reveal an immediate impact and capability of the human brain to adjust after losing a brain hub.

Value encoding in single neurons in the human amygdala during decision making.

A growing consensus suggests that the brain makes simple choices by assigning values to the stimuli under consideration and then comparing these values to make a decision. However, the network involved in computing the values has not yet been fully characterized. Here, we investigated whether the human amygdala plays a role in the computation of stimulus values at the time of decision making. We recorded single neuron activity from the amygdala of awake patients while they made simple purchase decisions over food items. We found 16 amygdala neurons, located primarily in the basolateral nucleus that responded linearly to the values assigned to individual items.

Mapping effective connectivity of human amygdala subdivisions with intracranial stimulation.

The primate amygdala is a complex consisting of over a dozen nuclei that have been implicated in a host of cognitive functions, individual differences, and psychiatric illnesses. These functions are implemented through distinct connectivity profiles, which have been documented in animals but remain largely unknown in humans. Here we present results from 25 neurosurgical patients who had concurrent electrical stimulation of the amygdala with intracranial electroencephalography (electrical stimulation tract-tracing; es-TT), or fMRI (electrical stimulation fMRI; es-fMRI), methods providing strong inferences about effective connectivity of amygdala subdivisions with the rest of the brain. We quantified functional connectivity with medial and lateral amygdala, the temporal order of these connections on the timescale of milliseconds, and also detail second-order effective connectivity among the key nodes. These findings provide a uniquely detailed characterization of human amygdala functional connectivity that will inform functional neuroimaging studies in healthy and clinical populations.

Common fronto-temporal effective connectivity in humans and monkeys.

Human brain pathways supporting language and declarative memory are thought to have differentiated substantially during evolution. However, cross-species comparisons are missing on site-specific effective connectivity between regions important for cognition. We harnessed functional imaging to visualize the effects of direct electrical brain stimulation in macaque monkeys and human neurosurgery patients. We discovered comparable effective connectivity between caudal auditory cortex and both ventro-lateral prefrontal cortex (VLPFC, including area 44) and parahippocampal cortex in both species. Human-specific differences were clearest in the form of stronger hemispheric lateralization effects. In humans, electrical tractography revealed remarkably rapid evoked potentials in VLPFC following auditory cortex stimulation and speech sounds drove VLPFC, consistent with prior evidence in monkeys of direct auditory cortex projections to homologous vocalization-responsive regions. The results identify a common effective connectivity signature in human and nonhuman primates, which from auditory cortex appears equally direct to VLPFC and indirect to the hippocampus. VIDEO ABSTRACT.

The copula approach to characterizing dependence structure in neural populations.

The question as to the role that correlated activity plays in the coding of information in the brain continues to be one of the most important in neuroscience. One approach to understanding this role is to formally model the ensemble responses as multivariate probability distributions. We have previously introduced alternatives to linear assumptions of multivariate Gaussian dependence for spike timing in neural ensembles using the probabilistic copula approach. In probability theory the copula "couples" marginal distributions to form flexible multivariate distribution functions for characterizing ensemble behavior. The parametric copula can be factored out of the joint probability density, and as such is independent and isolated from the marginal densities. This greatly simplifies the analysis, and allows a direct examination of the shape of the dependence independent of the marginals. The shape of the copula function goes beyond describing the dependence with a single summarizing statistic. In this review, we illustrate the construction of the copula, and how it contributes to the analysis of information conveyed by populations of neurons.

Methylphenidate affects task-switching and neural signaling in non-human primates.

RATIONALE: Low doses of psychostimulants such as methylphenidate (MPH), which increase extracellular dopamine and norepinephrine by inhibiting their reuptake, are the most commonly used treatment for attention deficit hyperactivity disorder (ADHD). Therapeutic doses of these drugs may improve focused attention at the expense of hindering other cognitive functions, including the ability to adapt behavior in response to changing circumstances-cognitive flexibility. Cognitive flexibility is thought to depend on proper operation of the prefrontal cortex (PFC) and is also linked to reward processing, which is dopamine-dependent. Additionally, reward outcome signals have been recorded from the PFC. OBJECTIVES: This study tested the hypothesis that therapeutic doses of MPH impair cognitive flexibility and that this impairment in performance resulted from interference in reward signals within the PFC. METHODS: Four rhesus monkeys were given therapeutically relevant doses of oral MPH (0, 3, and 6 mg/kg) while performing an oculomotor switching task to evaluate its effect on task performance. Single-unit recordings in the PFC of two monkeys were taken before and after MPH administration during task performance. RESULTS: The results show that MPH does hinder switching task performance, an effect that was correlated with a reduction in the amplitude of outcome signals found in the discharges of some neurons in the PFC. CONCLUSIONS: Methylphenidate impaired task-switching performance, which can be used as a measure of cognitive flexibility. This detriment may result from degraded outcome signaling within the PFC. This study has implications for the use of MPH in the treatment of ADHD.

Sparse Spectro-Temporal Receptive Fields Based on Multi-Unit and High-Gamma Responses in Human Auditory Cortex.

Spectro-Temporal Receptive Fields (STRFs) were estimated from both multi-unit sorted clusters and high-gamma power responses in human auditory cortex. Intracranial electrophysiological recordings were used to measure responses to a random chord sequence of Gammatone stimuli. Traditional methods for estimating STRFs from single-unit recordings, such as spike-triggered-averages, tend to be noisy and are less robust to other response signals such as local field potentials. We present an extension to recently advanced methods for estimating STRFs from generalized linear models (GLM). A new variant of regression using regularization that penalizes non-zero coefficients is described, which results in a sparse solution. The frequency-time structure of the STRF tends toward grouping in different areas of frequency-time and we demonstrate that group sparsity-inducing penalties applied to GLM estimates of STRFs reduces the background noise while preserving the complex internal structure. The contribution of local spiking activity to the high-gamma power signal was factored out of the STRF using the GLM method, and this contribution was significant in 85 percent of the cases. Although the GLM methods have been used to estimate STRFs in animals, this study examines the detailed structure directly from auditory cortex in the awake human brain. We used this approach to identify an abrupt change in the best frequency of estimated STRFs along posteromedial-to-anterolateral recording locations along the long axis of Heschl's gyrus. This change correlates well with a proposed transition from core to non-core auditory fields previously identified using the temporal response properties of Heschl's gyrus recordings elicited by click-train stimuli.

The effect of trajectory on the auditory motion aftereffect.

The auditory motion aftereffect (aMAE) can be induced in listeners after repeated presentation of a horizontally moving sound source. Aftereffects have also been found for the individual acoustic consequences of source motion such as amplitude or frequency modulations (AM, FM). No study, however, has investigated whether combining these changes would enhance the magnitude of the aMAE, which has appeared otherwise weak relative to its visual counterpart. AM, FM and binaural changes can occur simultaneously when sources move along common translational trajectories rather than the restricted rotational paths used in previous adaptation studies. This raises the question whether the observed weakness of the aMAE is due to the improper stimulation of units responsive to the entire macrostructure induced by translational motion. The hypothesis is tested here that if integrated motion detectors exist, then including lawful amplitude and frequency changes in adapting stimuli may enhance aftereffects. Though results indicate that interaurally moving stimuli in general induce an aMAE, the acoustic macrostructure of translational motion does not appear to increase the aftereffect. A simple cross-correlation model is used to illustrate that such acoustic modulations may allow brainstem auditory centers time to recover from adaptation to translational motion.

Directional influence between the human amygdala and orbitofrontal cortex at the time of decision-making.

There is a growing consensus that the brain makes simple choices, such as choosing between an apple and an orange, by assigning value to the options under consideration, and comparing those values to make a choice. There is also a consensus that value signals computed in orbitofrontal cortex (OFC) and amygdala play a critical role in the choice process. However, the nature of the flow of information between OFC and amygdala at the time of decision is still unknown. In order to study this question, simultaneous local field potentials were recorded from OFC and amygdala in human patients while they performed a simple food choice task. Although the interaction of these circuits has been studied in animals, this study examines the effective connectivity directly in the human brain on a moment-by-moment basis. A spectral conditional Granger causality analysis was performed in order to test if the modulation of activity goes mainly from OFC-to-amygdala, from amygdala-to-OFC, or if it is bi-directional. Influence from amygdala-to-OFC was dominant prior to the revealed choice, with a small but significant OFC influence on the amygdala earlier in the trial. Alpha oscillation amplitudes analyzed with the Hilbert-Huang transform revealed differences in choice valence coincident with temporally specific amygdala influence on the OFC.

Two systems drive attention to rewards.

How options are framed can dramatically influence choice preference. While salience of information plays a central role in this effect, precisely how it is mediated by attentional processes remains unknown. Current models assume a simple relationship between attention and choice, according to which preference should be uniformly biased towards the attended item over the whole time-course of a decision between similarly valued items. To test this prediction we considered how framing alters the orienting of gaze during a simple choice between two options, using eye movements as a sensitive online measure of attention. In one condition participants selected the less preferred item to discard and in the other, the more preferred item to keep. We found that gaze gravitates towards the item ultimately selected, but did not observe the effect to be uniform over time. Instead, we found evidence for distinct early and late processes that guide attention according to preference in the first case and task demands in the second. We conclude that multiple time-dependent processes govern attention during choice, and that these may contribute to framing effects in different ways.

Real-time contrast enhancement to improve speech recognition.

An algorithm that operates in real-time to enhance the salient features of speech is described and its efficacy is evaluated. The Contrast Enhancement (CE) algorithm implements dynamic compressive gain and lateral inhibitory sidebands across channels in a modified winner-take-all circuit, which together produce a form of suppression that sharpens the dynamic spectrum. Normal-hearing listeners identified spectrally smeared consonants (VCVs) and vowels (hVds) in quiet and in noise. Consonant and vowel identification, especially in noise, were improved by the processing. The amount of improvement did not depend on the degree of spectral smearing or talker characteristics. For consonants, when results were analyzed according to phonetic feature, the most consistent improvement was for place of articulation. This is encouraging for hearing aid applications because confusions between consonants differing in place are a persistent problem for listeners with sensorineural hearing loss.

Likelihood approaches to sensory coding in auditory cortex.

Likelihood methods began their evolution in the early 1920s with R A Fisher, and have developed into a rich framework for inferential statistics. This framework offers tools for the analysis of the differential geometry of the full likelihood function based on observed data. We examine likelihood functions derived from inverse Gaussian (IG) probability density models of cortical ensemble responses of single units. Specifically, we investigate the problem of sound localization from the observation of an ensemble of neural responses recorded from the primary (Al) field of the auditory cortex. The problem is framed as a probabilistic inverse problem with multiple sources of ambiguity. Observed and expected Fisher information are defined for the IG cortical ensemble likelihood functions. Receptive field functions of multiple acoustic parameters are constructed and linked to the IG density. The impact of estimating multiple acoustic parameters related to the direction of a sound is discussed, and the implications of eliminating nuisance parameters are considered. We examine the degree of acuity afforded by a small ensemble of cortical neurons for locating sounds in space, and show the predicted patterns of estimation errors, which tend to follow psychophysical performance.