The ability to promptly respond to behaviourally relevant events depends on both general alertness and phasic changes in attentional state driven by temporal expectations. Using a variable foreperiod simple reaction time (RT) task in four adult male rhesus macaques, we investigated the role of the cholinergic system in alertness and temporal expectation. Foreperiod effects on RT reflect temporal expectation, while alertness is quantified as overall response speed. We measured these RT parameters under vehicle treatment and systemic administration of the muscarinic receptor antagonist scopolamine. We also investigated whether and to what extent the effects of scopolamine were reversed by donepezil, a cholinesterase inhibitor widely used for the treatment of dementia. In the control condition, RT showed a continuous decrease as the foreperiod duration increased, which clearly indicated the effect of temporal expectation on RT. This foreperiod effect was mainly detectable on the faster tail of the RT distribution and was eliminated by scopolamine. Furthermore, scopolamine treatment slowed down the average RT. Donepezil treatment was efficient on the slower tail of the RT distribution and improved scopolamine‐induced impairments only on the average RT reflecting a general beneficial effect on alertness without any improvement in temporal expectation. The present results highlight the role of the cholinergic system in temporal expectation and alertness in primates and help delineate the efficacy and scope of donepezil and other cholinomimetic agents as cognitive enhancers in present and future clinical practice.

Cholinergic neuromodulation is known to play a key role in visual working memory (VWM) - keeping relevant stimulus representations available for cognitive processes for short time periods (up to a few minutes). Despite the growing body of evidence on how the neural and cognitive mechanisms of VWM dynamically change over retention time, there is mixed evidence available on cholinergic effects as a function of VWM delay period in non-human primates. Using the delayed matching to sample VWM task in rhesus macaques (N = 6), we aimed to characterize VWM maintenance in terms of performance changes as a function of delay duration (across a wide range of delays from 1 to 76 s). Then, we studied how cholinergic neuromodulation influences VWM maintenance using the muscarinic receptor antagonist scopolamine administered alone as transient amnestic treatment, and in combination with two doses of the acetylcholinesterase inhibitor donepezil, a widely used Alzheimer's medication probing for the reversal of scopolamine-induced impairments. Results indicate that scopolamine-induced impairments of VWM maintenance are delay-dependent and specifically affect the 15-33 s time range, suggesting that scopolamine worsens the normal decay of VWM with the passage of time. Donepezil partially rescued the observed scopolamine-induced impairments of VWM performance. These results provide strong behavioral evidence for the role of increased cholinergic tone and muscarinic neuromodulation in the maintenance of VWM beyond a few seconds, in line with our current knowledge on the role of muscarinic acetylcholine receptors in sustained neural activity during VWM delay periods.

Cortical excitability (CE) is commonly assessed via motor evoked potentials (MEPs) elicited by single-pulse transcranial magnetic stimulation (sp-TMS). While the motor threshold (MT) remains the most widely used measure of CE, it provides a limited, one-dimensional measure based on a fixed MEP amplitude criterion. In contrast, the recruitment curve (RC) offers a more comprehensive characterization of corticospinal recruitment dynamics. To date, the few available preclinical TMS studies measuring RC in non-human primates have been conducted under anaesthesia with limited translational relevance. Hence, we characterised CE in 20 sessions of 4 awake rhesus macaques by recording RCs at nine stimulation intensity levels and parametrising them using exponentiated sigmoid functions. The traditional 100 µV MEP MT criterion level (SI_100µV) aligned most closely with the inflection point of the RC sigmoid fit and was consistent with relative frequency-based traditional MT (tradMT) measured in separate sessions. The onset of the logarithmic recruitment phase of the sigmoid (lower ankle point) was found at 0.9 × SI_100µV/tradMT. Well-formed MEPs were measured below the SI_100µV/tradMT, but not below the lower ankle point, which is a physiologically relevant response threshold. Thus, in rhesus macaques the 100-µV criterion may be suitable to approximate the RC inflection point, but not the physiological motor threshold. The overall RC shape was consistent with previous human data, however, plateau MEP amplitudes were substantially smaller than those reported in humans. These results lay the groundwork for the adaptation of TMS protocols and CE metrics to non-human primates that is necessary for translationally valid research.

The interaction of physical and numerical size has been investigated and repeatedly demonstrated in the numerical Stroop task, in which participants compare digits of different physical sizes. It is, however, not entirely clear yet what psychological processes contribute to this interaction. The aim of the present study is to investigate the role of inhibition in the interaction of physical and numerical size, by introducing a novel paradigm that is suitable to elicit inhibition-related event-related potential components. To this end, we combined the go/nogo paradigm with the numerical Stroop task while measuring EEG and reaction times. Participants were presented with Arabic number pairs and had to press a button if the number on one side was numerically larger and they had to refrain from responding if the number on the other side was numerically larger. The physical size of the number pairs was also manipulated, in order to create congruent, neutral, and incongruent trials. Behavioural results confirmed the well-established numerical distance and numerical Stroop effects. Analysis of electrophysiological data revealed the classical go/nogo electrophysiological effects with numerical stimuli, and showed that peak amplitudes were larger for nogo than for go trials on the N2, as well as on the P3 component, on frontal and midline electrodes. When analysing the congruency effects, the peak amplitude of N2 was larger in incongruent trials than in neutral and congruent trials, while there was no evidence of a congruency effect on the P3 component peaks. Further analysis of the electrophysiological data revealed an additional facilitatory effect in the go trials, as well as an additional interference effect in the nogo trials. Taken together, it seems that interference effects are probably resolved by inhibitory processes and that facilitatory effects are affected by different cognitive control processes required by go versus nogo trials.

The ability to promptly respond to behaviourally relevant events depends on both general alertness and phasic changes in attentional state driven by temporal expectations. Using a variable foreperiod simple reaction time (RT) task in four adult male rhesus macaques, we investigated the role of the cholinergic system in alertness and temporal expectation. Foreperiod-effects on RT reflect temporal expectation, while alertness is quantified as overall response speed. We measured these RT parameters under vehicle treatment and systemic administration of the muscarinic receptor antagonist scopolamine. We also investigated whether and to what extent the effects of scopolamine were reversed by donepezil, a cholinesterase inhibitor widely used for the treatment of dementia. In the control condition, RT showed a continuous decrease as the foreperiod duration increased, which clearly indicated the effect of temporal expectation on RT. This foreperiod effect was mainly detectable on the faster tail of the RT distribution and was eliminated by scopolamine. Furthermore, scopolamine treatment slowed down the average RT. Donepezil treatment was efficient on the slower tail of the RT distribution and improved scopolamine-induced impairments only on the average RT reflecting a general beneficial effect on alertness without any improvement in temporal expectation. The present results highlight the role of the cholinergic system in temporal expectation and alertness in primates and help delineate the efficacy and scope of donepezil and other cholinomimetic agents as cognitive enhancers in present and future clinical practice.

Behaviours that are regulated with future goals and drive states in mind are regarded as cornerstones of human cognition. One key phenomenon through which future-orientation can be studied is the delay of gratification, quantified by the waiting time for which an individual withstands the consumption of an immediate reward to achieve a larger reward available after a certain delay. The delays used in animal delayed gratification paradigms are rather short to be considered relevant for studying human-like future-orientation. Here, for the first time, we show that rhesus macaques exhibit human-relevant future-orientation downregulating their operant food consumption in anticipation of a nutritionally equivalent but more palatable food with an unprecedentedly long delay of approx. 2.5 hours. This behaviour was not learnt gradually through conditioning but was readily displayed after a single exposure to a two-session “worse-now & better-later” food schedule. Importantly, no food choice was directly imposed by the experiment itself, but the animals intrinsically adjusted their behaviour to their satiation dynamics across the sessions, demonstrating their superior ability to anticipate future drive states. Our results have a strong implication that the cognitive time horizon of primates, when faced with ecologically valid foraging-like experimental situations, extends much further into the future than previously considered. In agreement with past observations from the broader perspective of animal foresight and planning, the present findings open new avenues that up till now have been opaque for translational biomedical research.