Routing states transition during oscillatory bursts and attentional selection.

Brain-wide information routing relies on the spatio-temporal dynamics of neural activity, but it remains unclear how routing states emerge at fast spiking timescales and relate to slower activity dynamics during cognitive processes. Here, we show that localized spiking events participate in directional routing states with spiking activity in distant brain areas that dynamically switch or amplify states during oscillatory bursts, attentional selection, and decision-making. Modeling and neural recordings from lateral prefrontal cortex (LPFC), anterior cingulate cortex (ACC), and striatum of nonhuman primates revealed that cross-regional routing states arise within 20 ms following individual neuron spikes, with LPFC spikes leading the activity in ACC and striatum. The baseline routing state amplified during LPFC beta bursts between LPFC and striatum and switched direction during ACC theta/alpha bursts between ACC and LPFC. Selective attention amplified theta-/alpha-band-specific lead ensembles in ACC, while decision-making increased the lead of ACC and LPFC spikes to the striatum.

Dose-Dependent Dissociation of Pro-cognitive Effects of Donepezil on Attention and Cognitive Flexibility in Rhesus Monkeys.

Background: Donepezil exerts pro-cognitive effects by nonselectively enhancing acetylcholine (ACh) across multiple brain systems. Two brain systems that mediate pro-cognitive effects of attentional control and cognitive flexibility are the prefrontal cortex and the anterior striatum, which have different pharmacokinetic sensitivities to ACh modulation. We speculated that these area-specific ACh profiles lead to distinct optimal dose ranges for donepezil to enhance the cognitive domains of attention and flexible learning. Methods: To test for dose-specific effects of donepezil on different cognitive domains, we devised a multitask paradigm for nonhuman primates that assessed attention and cognitive flexibility. The nonhuman primates received either vehicle or variable doses of donepezil before task performance. We measured intracerebral donepezil and its strength in preventing the breakdown of ACh within the prefrontal cortex and anterior striatum using solid phase microextraction neurochemistry. Results: The highest administered donepezil dose improved attention and made the subjects more robust against distractor interference, but it did not improve flexible learning. In contrast, only a lower dose range of donepezil improved flexible learning and reduced perseveration, but without distractor-dependent attentional improvement. Neurochemical measurements confirmed a dose-dependent increase of extracellular donepezil and decreases in choline within the prefrontal cortex and the striatum. Conclusions: The donepezil dose for maximally improving attention differed from the dose range that enhanced cognitive flexibility despite the availability of the drug in two major brain systems supporting these functions. These results suggest that in our cohort of adult monkeys, donepezil traded improvements in attention for improvements in cognitive flexibility at a given dose range.

Anterior cingulate cortex causally supports flexible learning under motivationally challenging and cognitively demanding conditions.

Anterior cingulate cortex (ACC) and striatum (STR) contain neurons encoding not only the expected values of actions, but also the value of stimulus features irrespective of actions. Values about stimulus features in ACC or STR might contribute to adaptive behavior by guiding fixational information sampling and biasing choices toward relevant objects, but they might also have indirect motivational functions by enabling subjects to estimate the value of putting effort into choosing objects. Here, we tested these possibilities by modulating neuronal activity in ACC and STR of nonhuman primates using transcranial ultrasound stimulation while subjects learned the relevance of objects in situations with varying motivational and cognitive demands. Motivational demand was indexed by varying gains and losses during learning, while cognitive demand was varied by increasing the uncertainty about which object features could be relevant during learning. We found that ultrasound stimulation of the ACC, but not the STR, reduced learning efficiency and prolonged information sampling when the task required averting losses and motivational demands were high. Reduced learning efficiency was particularly evident at higher cognitive demands and when subjects experienced loss of already attained tokens. These results suggest that the ACC supports flexible learning of feature values when loss experiences impose a motivational challenge and when uncertainty about the relevance of objects is high. Taken together, these findings provide causal evidence that the ACC facilitates resource allocation and improves visual information sampling during adaptive behavior.

A Kiosk Station for the Assessment of Multiple Cognitive Domains and Cognitive Enrichment of Monkeys.

Nonhuman primates (NHP's) are self-motivated to perform cognitive tasks on touchscreens in their animal housing setting. To leverage this ability, fully integrated hardware and software solutions are needed that work within housing and husbandry routines while also spanning cognitive task constructs of the Research Domain Criteria (RDoC). Here, we detail such an integrated robust hardware and software solution for running cognitive tasks in cage-housed NHP's with a cage-mounted Kiosk Station (KS-1). KS-1 consists of a frame for mounting flexibly on housing cages, a touchscreen animal interface with mounts for receptables, reward pumps, and cameras, and a compact computer cabinet with an interface for controlling behavior. Behavioral control is achieved with a Unity3D program that is virtual-reality capable, allowing semi-naturalistic visual tasks to assess multiple cognitive domains.KS-1 is fully integrated into the regular housing routines of monkeys. A single person can operate multiple KS-1's. Monkeys engage with KS-1 at high motivation and cognitive performance levels at high intra-individual consistency. KS-1 is optimized for flexible mounting onto standard apartment cage systems and provides a new design variation complementing existing cage-mounted touchscreen systems. KS-1 has a robust animal interface with options for gaze/reach monitoring. It has an integrated user interface for controlling multiple cognitive tasks using a common naturalistic object space designed to enhance task engagement. All custom KS-1 components are open-sourced.In summary, KS-1 is a versatile new tool for cognitive profiling and cognitive enrichment of cage-housed monkeys. It reliably measures multiple cognitive domains which promises to advance our understanding of animal cognition, inter-individual differences, and underlying neurobiology in refined, ethologically meaningful behavioral foraging contexts.

Interneuron-specific gamma synchronization indexes cue uncertainty and prediction errors in lateral prefrontal and anterior cingulate cortex.

Inhibitory interneurons are believed to realize critical gating functions in cortical circuits, but it has been difficult to ascertain the content of gated information for well-characterized interneurons in primate cortex. Here, we address this question by characterizing putative interneurons in primate prefrontal and anterior cingulate cortex while monkeys engaged in attention demanding reversal learning. We find that subclasses of narrow spiking neurons have a relative suppressive effect on the local circuit indicating they are inhibitory interneurons. One of these interneuron subclasses showed prominent firing rate modulations and (35-45 Hz) gamma synchronous spiking during periods of uncertainty in both, lateral prefrontal cortex (LPFC) and anterior cingulate cortex (ACC). In LPFC, this interneuron subclass activated when the uncertainty of attention cues was resolved during flexible learning, whereas in ACC it fired and gamma-synchronized when outcomes were uncertain and prediction errors were high during learning. Computational modeling of this interneuron-specific gamma band activity in simple circuit motifs suggests it could reflect a soft winner-take-all gating of information having high degree of uncertainty. Together, these findings elucidate an electrophysiologically characterized interneuron subclass in the primate, that forms gamma synchronous networks in two different areas when resolving uncertainty during adaptive goal-directed behavior.

Fast spiking interneuron activity in primate striatum tracks learning of attention cues.

Cognitive flexibility depends on a fast neural learning mechanism for enhancing momentary relevant over irrelevant information. A possible neural mechanism realizing this enhancement uses fast spiking interneurons (FSIs) in the striatum to train striatal projection neurons to gate relevant and suppress distracting cortical inputs. We found support for such a mechanism in nonhuman primates during the flexible adjustment of visual attention in a reversal learning task. FSI activity was modulated by visual attention cues during feature-based learning. One FSI subpopulation showed stronger activation during learning, while another FSI subpopulation showed response suppression after learning, which could indicate a disinhibitory effect on the local circuit. Additionally, FSIs that showed response suppression to learned attention cues were activated by salient distractor events, suggesting they contribute to suppressing bottom-up distraction. These findings suggest that striatal fast spiking interneurons play an important role when cues are learned that redirect attention away from previously relevant to newly relevant visual information. This cue-specific activity was independent of motor-related activity and thus tracked specifically the learning of reward predictive visual features.

Adaptive spike-artifact removal from local field potentials uncovers prominent beta and gamma band neuronal synchronization.

BACKGROUND: Many neurons synchronize their action potentials to the phase of local field potential (LFP) fluctuations in one or more frequency bands. Analyzing this spike-to-LFP synchronization is challenging, however, when neural spikes and LFP are generated in the same local circuit, because the spike's action potential waveform leak into the LFP and distort phase synchrony estimates. Existing approaches to address this spike bleed-through artifact relied on removing the average action potential waveforms of neurons, but this leaves artifacts in the LFP and distorts synchrony estimates. NEW METHOD: We describe a spike-removal method that surpasses these limitations by decomposing individual action potentials into their frequency components before their removal from the LFP. The adaptively estimated frequency components allow for variable spread, strength and temporal variation of the spike artifact. RESULTS: This adaptive approach effectively removes spike bleed-through artifacts in synthetic data with known ground truth, and in single neuron and LFP recordings in nonhuman primate striatum. For a large population of neurons with both narrow and broad action potential waveforms, the use of adaptive artifact removal uncovered 20-35 Hz beta and 35-45 Hz gamma band spike-LFP synchronization that would have remained contaminated otherwise. COMPARISON WITH EXISTING METHODS: We demonstrate that adaptive spike-artifact removal cleans LFP data that remained contaminated when applying existing Bayesian and non-Bayesian methods of average spike-artifact removal. CONCLUSIONS: Applying adaptive spike-removal from field potentials allows to estimate the phase at which neurons synchronize and the consistency of their phase-locked firing for both beta and low gamma frequencies. These metrics may prove essential to understand cell-to-circuit neuronal interactions in multiple brain systems.