Neural correlates of cognitively controlled vocalizations in a corvid songbird.

The neuronal basis of the songbird's song system is well understood. However, little is known about the neuronal correlates of the executive control of songbird vocalizations. Here, we record single-unit activity from the pallial endbrain region "nidopallium caudolaterale" (NCL) of crows that vocalize to the presentation of a visual go-cue but refrain from vocalizing during trials without a go-cue. We find that the preparatory activity of single vocalization-correlated neurons, but also of the entire population of NCL neurons, before vocal onset predicts whether or not the crows will produce an instructed vocalization. Fluctuations in baseline neuronal activity prior to the go-cue influence the premotor activity of such vocalization-correlated neurons and seemingly bias the crows' decision to vocalize. Neuronal response modulation significantly differs between volitional and task-unrelated vocalizations. This suggests that the NCL can take control over the vocal motor network during the production of volitional vocalizations in a corvid songbird.

Feature-based attention processes in primate prefrontal cortex do not rely on feature similarity.

Feature-based attention enables privileged processing of specific visual properties. During feature-based attention, neurons in visual cortices show "gain modulation" by enhancing neuronal responses to the features of attended stimuli due to top-down signals originating from prefrontal cortex (PFC). Attentional modulation in visual cortices requires "feature similarity:" neurons only increase their responses when the attended feature variable and the neurons' preferred feature coincide. However, whether gain modulation based on feature similarity is a general attentional mechanism is currently unknown. To address this issue, we record single-unit activity from PFC of macaques trained to switch attention between two conjunctive feature parameters. We find that PFC neurons experience gain modulation in response to attentional demands. However, this attentional gain modulation in PFC is independent of the feature-tuning preferences of neurons. These findings suggest that feature similarity is not a general mechanism in feature-based attention throughout the cortical processing hierarchy.

Blockage of NMDA- and GABA(A) Receptors Improves Working Memory Selectivity of Primate Prefrontal Neurons.

The ongoing activity of prefrontal neurons after a stimulus has disappeared is considered a neuronal correlate of working memory. It depends on the delicate but poorly understood interplay between excitatory glutamatergic and inhibitory GABAergic receptor effects. We administered the NMDA receptor antagonist MK-801 and the GABA(A) receptor antagonist bicuculline methiodide while recording cellular activity in PFC of male rhesus monkeys performing a delayed decision task requiring working memory. The blockade of GABA(A) receptors strongly improved the selectivity of the neurons' delay activity, causing an increase in signal-to-noise ratio during working memory periods as well as an enhancement of the neurons' coding selectivity. The blockade of NMDA receptors resulted in a slight enhancement of selectivity and encoding capacity of the neurons. Our findings emphasize the delicate and more complex than expected interplay of excitatory and inhibitory transmitter systems in modulating working memory coding in prefrontal circuits.SIGNIFICANCE STATEMENT Ongoing delay activity of prefrontal neurons constitutes a neuronal correlate of working memory. However, how this delay activity is generated by the delicate interplay of synaptic excitation and inhibition is unknown. We probed the effects of excitatory neurotransmitter glutamate and inhibitory neurotransmitter GABA in regulating delay activity in rhesus monkeys performing a delayed decision task requiring working memory. Surprisingly, the blockade of both glutamatergic NMDA and GABA(A) receptors improved neuronal selectivity of delay activity, causing an increase in neuronal signal-to-noise ratio. Moreover, individual neurons were similarly affected by blockade of both receptors. This emphasizes the delicate and more complex than expected interplay of excitatory and inhibitory transmitter systems in modulating working memory coding in prefrontal circuits.

Dopamine Gates Visual Signals in Monkey Prefrontal Cortex Neurons.

The neurotransmitter dopamine, which acts via the D1-like receptor (D1R) and D2-like receptor (D2R) family, may play an important role in gating sensory information to the prefrontal cortex (PFC). We tested this hypothesis in awake macaques and recorded visual motion-direction tuning functions of single PFC neurons. Using micro-iontophoretic drug application combined with single-unit recordings, we simulated receptor-specific dopaminergic input to the PFC and explored cellular gating mechanisms. We find that stimulating D1Rs, and particularly D2Rs, enhances the single-neuron and population coding quality in PFC neurons. D2R stimulation causes a clear increase of the neurons' responses to the preferred motion direction and a decrease to the non-preferred motion direction, thus enhancing neuronal signal-to-noise ratio. Neither D1R nor D2R stimulation had any impact on the neurons' tuning sharpness. These results elucidate the mechanisms of how receptor-specific dopamine effects can act as a gating signal that enables privileged access of sensory information to PFC circuits.

Feature-specific prediction errors and surprise across macaque fronto-striatal circuits.

To adjust expectations efficiently, prediction errors need to be associated with the precise features that gave rise to the unexpected outcome, but this credit assignment may be problematic if stimuli differ on multiple dimensions and it is ambiguous which feature dimension caused the outcome. Here, we report a potential solution: neurons in four recorded areas of the anterior fronto-striatal networks encode prediction errors that are specific to feature values of different dimensions of attended multidimensional stimuli. The most ubiquitous prediction error occurred for the reward-relevant dimension. Feature-specific prediction error signals a) emerge on average shortly after non-specific prediction error signals, b) arise earliest in the anterior cingulate cortex and later in dorsolateral prefrontal cortex, caudate and ventral striatum, and c) contribute to feature-based stimulus selection after learning. Thus, a widely-distributed feature-specific eligibility trace may be used to update synaptic weights for improved feature-based attention.

Dopamine Receptors Influence Internally Generated Oscillations during Rule Processing in Primate Prefrontal Cortex.

Neural oscillations in distinct frequency bands in the prefrontal cortex (pFC) are associated with specialized roles during cognitive control. How dopamine modulates oscillations to structure pFC functions remains unknown. We trained macaques to switch between two numerical rules and recorded local field potentials from pFC while applying dopamine receptor targeting drugs using microiontophoresis. We show that the D1 and D2 family receptors (D1Rs and D2Rs, respectively) specifically altered internally generated prefrontal oscillations, whereas sensory-evoked potentials remained unchanged. Blocking D1Rs or stimulating D2Rs increased low-frequency theta and alpha oscillations known to be involved in learning and memory. In contrast, only D1R inhibition enhanced high-frequency beta oscillations, whereas only D2R stimulation increased gamma oscillations linked to top-down and bottom-up attentional processing. These findings suggest that dopamine alters neural oscillations relevant for executive functioning through dissociable actions at the receptor level.

Prefrontal and anterior cingulate cortex neurons encode attentional targets even when they do not apparently bias behavior.

Neurons in anterior cingulate and prefrontal cortex (ACC/PFC) carry information about behaviorally relevant target stimuli. This information is believed to affect behavior by exerting a top-down attentional bias on stimulus selection. However, attention information may not necessarily be a biasing signal but could be a corollary signal that is not directly related to ongoing behavioral success, or it could reflect the monitoring of targets similar to an eligibility trace useful for later attentional adjustment. To test this suggestion we quantified how attention information relates to behavioral success in neurons recorded in multiple subfields in macaque ACC/PFC during a cued attention task. We found that attention cues activated three separable neuronal groups that encoded spatial attention information but were differently linked to behavioral success. A first group encoded attention targets on correct and error trials. This group spread across ACC/PFC and represented targets transiently after cue onset, irrespective of behavior. A second group encoded attention targets on correct trials only, closely predicting behavior. These neurons were not only prevalent in lateral prefrontal but also in anterior cingulate cortex. A third group encoded target locations only on error trials. This group was evident in ACC and PFC and was activated in error trials "as if" attention was shifted to the target location but without evidence for such behavior. These results show that only a portion of neuronaly available information about attention targets biases behavior. We speculate that additionally a unique neural subnetwork encodes counterfactual attention information.

Interareal Spike-Train Correlations of Anterior Cingulate and Dorsal Prefrontal Cortex during Attention Shifts.

The anterior cingulate cortex (ACC) and prefrontal cortex (PFC) are believed to coactivate during goal-directed behavior to identify, select, and monitor relevant sensory information. Here, we tested whether coactivation of neurons across macaque ACC and PFC would be evident at the level of pairwise neuronal correlations during stimulus selection in a spatial attention task. We found that firing correlations emerged shortly after an attention cue, were evident for 50-200 ms time windows, were strongest for neuron pairs in area 24 (ACC) and areas 8 and 9 (dorsal PFC), and were independent of overall firing rate modulations. For a subset of cell pairs from ACC and dorsal PFC, the observed functional spike-train connectivity carried information about the direction of the attention shift. Reliable firing correlations were evident across area boundaries for neurons with broad spike waveforms (putative excitatory neurons) as well as for pairs of putative excitatory neurons and neurons with narrow spike waveforms (putative interneurons). These findings reveal that stimulus selection is accompanied by slow time scale firing correlations across those ACC/PFC subfields implicated to control and monitor attention. This functional coupling was informative about which stimulus was selected and thus indexed possibly the exchange of task-relevant information. We speculate that interareal, transient firing correlations reflect the transient coordination of larger, reciprocally interacting brain networks at a characteristic 50-200 ms time scale. Significance statement: Our manuscript identifies interareal spike-train correlations between primate anterior cingulate and dorsal prefrontal cortex during a period where attentional stimulus selection is likely controlled by these very same circuits. Interareal correlations emerged during the covert attention shift to one of two peripheral stimuli, proceeded on a slow 50-200 ms time scale, and occurred between putative pyramidal and putative interneurons. Spike-train correlations emerged particularly for cell pairs tuned to similar contralateral target locations, thus indexing the interareal coordination of attention-relevant information. These findings characterize a possible way by which prefrontal and anterior cingulate cortex circuits implement their control functions through coordinated firing when macaque monkeys select and monitor relevant stimuli for goal-directed behaviors.

Inferior-frontal cortex phase synchronizes with the temporal-parietal junction prior to successful change detection.

The inferior frontal gyrus (IFG) and the temporo-parietal junction (TPJ) are believed to be core structures of human brain networks that activate when sensory top-down expectancies guide goal directed behavior and attentive perception. But it is unclear how activity in IFG and TPJ coordinates during attention demanding tasks and whether functional interactions between both structures are related to successful attentional performance. Here, we tested these questions in electrocorticographic (ECoG) recordings in human subjects using a visual detection task that required sustained attentional expectancy in order to detect non-salient, near-threshold visual events. We found that during sustained attention the successful visual detection was predicted by increased phase synchronization of band-limited 15-30 Hz beta band activity that was absent prior to misses. Increased beta-band phase alignment during attentional engagement early during the task was restricted to inferior and lateral prefrontal cortex, but with sustained attention it extended to long-range IFG-TPJ phase synchronization and included superior prefrontal areas. In addition to beta, a widely distributed network of brain areas comprising the occipital cortex showed enhanced and reduced alpha band phase synchronization before correct detections. These findings identify long-range phase synchrony in the 15-30 Hz beta band as the mesoscale brain signal that predicts the successful deployment of attentional expectancy of sensory events. We speculate that localized beta coherent states in prefrontal cortex index 'top-down' sensory expectancy whose coupling with TPJ subregions facilitates the gating of relevant visual information.

Asymmetric generalization in adaptation to target displacement errors in humans and in a neural network model.

Different error signals can induce sensorimotor adaptation during visually guided reaching, possibly evoking different neural adaptation mechanisms. Here we investigate reach adaptation induced by visual target errors without perturbing the actual or sensed hand position. We analyzed the spatial generalization of adaptation to target error to compare it with other known generalization patterns and simulated our results with a neural network model trained to minimize target error independent of prediction errors. Subjects reached to different peripheral visual targets and had to adapt to a sudden fixed-amplitude displacement ("jump") consistently occurring for only one of the reach targets. Subjects simultaneously had to perform contralateral unperturbed saccades, which rendered the reach target jump unnoticeable. As a result, subjects adapted by gradually decreasing reach errors and showed negative aftereffects for the perturbed reach target. Reach errors generalized to unperturbed targets according to a translational rather than rotational generalization pattern, but locally, not globally. More importantly, reach errors generalized asymmetrically with a skewed generalization function in the direction of the target jump. Our neural network model reproduced the skewed generalization after adaptation to target jump without having been explicitly trained to produce a specific generalization pattern. Our combined psychophysical and simulation results suggest that target jump adaptation in reaching can be explained by gradual updating of spatial motor goal representations in sensorimotor association networks, independent of learning induced by a prediction-error about the hand position. The simulations make testable predictions about the underlying changes in the tuning of sensorimotor neurons during target jump adaptation.

Anterior Cingulate Cortex Cells Identify Process-Specific Errors of Attentional Control Prior to Transient Prefrontal-Cingulate Inhibition.

Errors indicate the need to adjust attention for improved future performance. Detecting errors is thus a fundamental step to adjust and control attention. These functions have been associated with the dorsal anterior cingulate cortex (dACC), predicting that dACC cells should track the specific processing states giving rise to errors in order to identify which processing aspects need readjustment. Here, we tested this prediction by recording cells in the dACC and lateral prefrontal cortex (latPFC) of macaques performing an attention task that dissociated 3 processing stages. We found that, across prefrontal subareas, the dACC contained the largest cell populations encoding errors indicating (1) failures of inhibitory control of the attentional focus, (2) failures to prevent bottom-up distraction, and (3) lapses when implementing a choice. Error-locked firing in the dACC showed the earliest latencies across the PFC, emerged earlier than reward omission signals, and involved a significant proportion of putative inhibitory interneurons. Moreover, early onset error-locked response enhancement in the dACC was followed by transient prefrontal-cingulate inhibition, possibly reflecting active disengagement from task processing. These results suggest a functional specialization of the dACC to track and identify the actual processes that give rise to erroneous task outcomes, emphasizing its role to control attentional performance.

Beta coherence within human ventromedial prefrontal cortex precedes affective value choices.

Ventromedial prefrontal cortex (vmPFC) forms a core region of larger brain circuits that assign value to sensory inputs and interfaces motivational and cognitive dominated brain processes. This network function of the vmPFC could be realized by synchronizing local activity at time scales that are shared by connected brain areas, but it is unknown whether vmPFC circuitry engages in functionally specific synchronization. Here, we recorded in human subcallosal vmPFC while subjects engaged in an emotion tracking task that required the assignment of positive or negative affective value to ambiguous (happy-sad) facial expressions. We found that vmPFC engages in low beta-band (15-20 Hz) coherent activation just before subjects subjectively judged ambiguous facial expressions as conveying negative valence ('sad') information, but not before positive valence ('happy') judgments. The predictive beta coherence emerged particularly for conflicting rather than pure emotional facial cues and dissipated slowly after the choice was made. These results suggest that 15-20 Hz coherent activity within vmPFC marks a functional signature of a valuation process that informs categorical affective choices. We hypothesize that coherent beta band activation signifies functional interactions to anatomical vmPFC projection targets, raising the possibility that dysfunctional biases in affective valuation and an enhanced decision conflict in clinical depression could be indexed by alterations of beta coherent network activation.

Choosing goals, not rules: deciding among rule-based action plans.

In natural situations, movements are often directed toward locations different from that of the evoking sensory stimulus. Movement goals must then be inferred from the sensory cue based on rules. When there is uncertainty about the rule that applies for a given cue, planning a movement involves both choosing the relevant rule and computing the movement goal based on that rule. Under these conditions, it is not clear whether primates compute multiple movement goals based on all possible rules before choosing an action, or whether they first choose a rule and then only represent the movement goal associated with that rule. Supporting the former hypothesis, we show that neurons in the frontoparietal reach areas of monkeys simultaneously represent two different rule-based movement goals, which are biased by the monkeys' choice preferences. Apparently, primates choose between multiple behavioral options by weighing against each other the movement goals associated with each option.

What is 'anti' about anti-reaches? Reference frames selectively affect reaction times and endpoint variability.

Reach movement planning involves the representation of spatial target information in different reference frames. Neurons at parietal and premotor stages of the cortical sensorimotor system represent target information in eye- or hand-centered reference frames, respectively. How the different neuronal representations affect behavioral parameters of motor planning and control, i.e. which stage of neural representation is relevant for which aspect of behavior, is not obvious from the physiology. Here, we test with a behavioral experiment if different kinematic movement parameters are affected to a different degree by either an eye- or hand-reference frame. We used a generalized anti-reach task to test the influence of stimulus-response compatibility (SRC) in eye- and hand-reference frames on reach reaction times, movement times, and endpoint variability. While in a standard anti-reach task, the SRC is identical in the eye- and hand-reference frames, we could separate SRC for the two reference frames. We found that reaction times were influenced by the SRC in eye- and hand-reference frame. In contrast, movement times were only influenced by the SRC in hand-reference frame, and endpoint variability was only influenced by the SRC in eye-reference frame. Since movement time and endpoint variability are the result of planning and control processes, while reaction times are consequences of only the planning process, we suggest that SRC effects on reaction times are highly suited to investigate reference frames of movement planning, and that eye- and hand-reference frames have distinct effects on different phases of motor action and different kinematic movement parameters.

Acquisition of myoelectric signals to control a hand prosthesis with implantable epimysial electrodes.

The acquisition of myoelectric signals from the Musculus deltoideus of a rhesus monkey is described. Such signals are aimed to be used as control signal for an active myoelectric hand prosthesis. For recording, implantable flexible, polyimide-based multi-site microelectrodes were placed epimysially on the muscle. EMG signals were recorded during voluntary goal-directed movements of the arm, and analyzed with respect to signal amplitude and frequency.

The cortical timeline for deciding on reach motor goals.

Flexible sensorimotor planning is the basis for goal-directed behavior. We investigated the integration of visuospatial information with context-specific transformation rules during reach planning. We were especially interested in the relative timing of motor-goal decisions in monkey dorsal premotor cortex (PMd) and parietal reach region (PRR). We used a rule-based mapping task with different cueing conditions to compare task-dependent motor-goal latencies. The task allowed us a separation of cue-related from motor-related activity, and a separation of activity related to motor planning from activity related to motor initiation or execution. The results show that selectivity for the visuospatial goal of a pending movement occurred earlier in PMd than PRR whenever the task required spatial remapping. Such remapping was needed if the spatial representation of a cue or of a default motor plan had to be transformed into a spatially incongruent representation of the motor goal. In contrast, we did not find frontoparietal latency differences if the spatial representation of the cue or the default plan was spatially congruent with the motor goal. The fact that frontoparietal latency differences occurred only in conditions with spatial remapping was independent of the subjects' partial a priori knowledge about the pending goal. Importantly, frontoparietal latency differences existed for motor-goal representations during movement planning, without immediate motor execution. We interpret our findings as being in support of the hypothesis that latency differences reflect a dynamic reorganization of network activity in PRR, and suggest that the reorganization is contingent on frontoparietal projections from PMd.

Implementation of spatial transformation rules for goal-directed reaching via gain modulation in monkey parietal and premotor cortex.

Planning goal-directed movements requires the combination of visuospatial with abstract contextual information. Our sensory environment constrains possible movements to a certain extent. However, contextual information guides proper choice of action in a given situation and allows flexible mapping of sensory instruction cues onto different motor actions. We used anti-reach tasks to test the hypothesis that spatial motor-goal representations in cortical sensorimotor areas are gain modulated by the behavioral context to achieve flexible remapping of spatial cue information onto arbitrary motor goals. We found that gain modulation of neuronal reach goal representations is commonly induced by the behavioral context in individual neurons of both, the parietal reach region (PRR) and the dorsal premotor cortex (PMd). In addition, PRR showed stronger directional selectivity during the planning of a reach toward a directly cued goal (pro-reach) compared with an inferred target (anti-reach). PMd, however, showed stronger overall activity during reaches toward inferred targets compared with directly cued targets. Based on our experimental evidence, we suggest that gain modulation is the computational mechanism underlying the integration of spatial and contextual information for flexible, rule-driven stimulus-response mapping, and thereby forms an important basis of goal-directed behavior. Complementary contextual effects in PRR versus PMd are consistent with the idea that posterior parietal cortex preferentially represents sensory-driven, "automatic" motor goals, whereas frontal sensorimotor areas are stronger engaged in the representation of rule-based, "inferred" motor goals.