Suboptimal Integration of Reward Magnitude and Prior Reward Likelihood in Categorical Decisions by Monkeys

Sensory decisions may be influenced by non-sensory information regarding reward magnitude or reward likelihood. Given identical sensory information, it is more optimal to choose an option if it is a priori more likely to be correct and hence rewarded (prior reward likelihood bias), or if it yields a larger reward, given that it is the correct choice (reward magnitude bias). Here, we investigated the ability of macaque monkeys to integrate reward magnitude and prior reward likelihood information into a categorical decision about stimuli with high signal strength but variable decision uncertainty. In the asymmetric reward magnitude condition, monkeys over-adjusted their decision criterion such that they chose the highly rewarded alternative far more often than was optimal; in contrast, monkeys did not adjust their decision criterion in response to asymmetric reward likelihood. This finding shows that in this setting, monkeys did not adjust their decision criterion based on the product of reward likelihood and reward magnitude as has been reported to be the case in value-based decisions that do not involve decision uncertainty due to stimulus categorization

Orienting of Attention to Gaze Direction Cues in Rhesus Macaques: Species-Specificity, and Effects of Cue Motion and Reward Predictiveness

Primates live in complex social groups and rely on social cues to direct their attention. For example, primates react faster to an unpredictable stimulus after seeing a conspecific looking in the direction of that stimulus. In the current study we tested the specificity of facial cues (gaze direction) for orienting attention and their interaction with other cues that are known to guide attention. In particular, we tested whether macaque monkeys only respond to gaze cues from conspecifics or if the effect generalizes across species. We found an attentional advantage of conspecific faces over human and cartoon faces. Because gaze cues are often conveyed by gesture, we also explored the effect of image motion (a simulated glance) on the orienting of attention in monkeys. We found that the simulated glance did not significantly enhance the speed of orienting for monkey-face stimuli, but had a significant effect for images of human faces. Finally, because gaze cues presumably guide attention toward relevant or rewarding stimuli, we explored whether orienting of attention was modulated by reward predictiveness. When the cue predicted reward location, face, and non-face cues were effective in speeding responses toward the cued location. This effect was strongest for conspecific faces. In sum, our results suggest that while conspecific gaze cues activate an intrinsic process that reflexively directs spatial attention, its effect is relatively small in comparison to other features including motion and reward predictiveness. It is possible that gaze cues are more important for decision-making and voluntary orienting than for reflexive orienting

Representation of Outcome Risk and Action in the Anterior Caudate Nucleus

The anterior caudate nucleus is essential for goal-directed behavior because it links outcome information to actions. It is well known that caudate neurons provide a variety of reward-related and action signals. However, it is still unclear how the two signals are integrated. We investigated whether and how outcome risk modulates spatial representation. We recorded neural activity in the anterior caudate nucleus while monkeys made saccades to multiple spatial targets, each associated with either fixed (safe) or variable (risky) amount of reward. We report that individual neurons combined the outcome reward signal with spatial information about the direction of saccades. These signals could be reliably read out from the populations of neurons. Moreover, the prospect of a risky outcome improved the quality of spatial information. These results provide direct evidence that global spatial representation in the caudate is modulated by outcome, which can be important for flexible control of behavior, particularly during learning and habit formation, when outcomes vary

Vector averaging for smoothpursuit eye movements initiated by two moving targets in monkeys.

The visual input for pursuit eye movements is represented in the cerebral cortex as the distributed activity of neurons that are tuned for both the direction and speed of target motion. To probe how the motor system uses this distributed code to compute a command for smooth eye movements, we have recorded the initiation of pursuit for 150 msec presentations of two spots moving at different speeds and/or in different directions. With equal probability, one of the two spots continued to move at the same speed and in the same direction and became the tracking target, whereas the other disappeared and served as a distractor. We measured eye acceleration in the interval from 110 to 206 msec after the onset of spot motion, within both the open-loop interval for pursuit and the interval during which eye motion was affected by the two spots. Our results demonstrate that weighted vector averaging is used to combine the responses to two moving spots. We found only a minute number of responses that were consistent with either vector summation or winner-take-all computations. In addition, our data show that it is difficult for the monkey to defeat vector averaging without extended training on the use of an explicit cue about which spot will become the target. We argue that our experiment reveals the computations done by the pursuit system in the absence of attentional bias and that vector averaging is normally used to read the distributed code of image motion when there is only one target

Long-Term Safety of Repeated Blood-Brain Barrier Opening via Focused Ultrasound with Microbubbles in Non-Human Primates Performing a Cognitive Task

Focused Ultrasound (FUS) coupled with intravenous administration of microbubbles (MB) is a non-invasive technique that has been shown to reliably open (increase the permeability of) the blood-brain barrier (BBB) in multiple in vivo models including non-human primates (NHP). This procedure has shown promise for clinical and basic science applications, yet the safety and potential neurological effects of long term application in NHP requires further investigation under parameters shown to be efficacious in that species (500kHz, 200–400 kPa, 4–5μm MB, 2 minute sonication). In this study, we repeatedly opened the BBB in the caudate and putamen regions of the basal ganglia of 4 NHP using FUS with systemically-administered MB over 4–20 months. We assessed the safety of the FUS with MB procedure using MRI to detect edema or hemorrhaging in the brain. Contrast enhanced T1-weighted MRI sequences showed a 98% success rate for openings in the targeted regions. T2-weighted and SWI sequences indicated a lack edema in the majority of the cases. We investigated potential neurological effects of the FUS with MB procedure through quantitative cognitive testing of’ visual, cognitive, motivational, and motor function using a random dot motion task with reward magnitude bias presented on a touchpanel display. Reaction times during the task significantly increased on the day of the FUS with MB procedure. This increase returned to baseline within 4–5 days after the procedure. Visual motion discrimination thresholds were unaffected. Our results indicate FUS with MB can be a safe method for repeated opening of the BBB at the basal ganglia in NHP for up to 20 months without any long-term negative physiological or neurological effects with the parameters used

Long-Term Safety of Repeated Blood-Brain Barrier Opening via Focused Ultrasound with Microbubbles in Non-Human Primates Performing a Cognitive Task

Abstract Focused Ultrasound (FUS) coupled with intravenous administration of microbubbles (MB) is a non-invasive technique that has been shown to reliably open (increase the permeability of) the blood-brain barrier (BBB) in multiple in vivo models including non-human primates (NHP). This procedure has shown promise for clinical and basic science applications, yet the safety and potential neurological effects of long term application in NHP requires further investigation under parameters shown to be efficacious in that species (500kHz, 200-400 kPa, 4-5μm MB, 2 minute sonication). In this study, we repeatedly opened the BBB in the caudate and putamen regions of the basal ganglia of 4 NHP using FUS with systemicallyadministered MB over 4-20 months. We assessed the safety of the FUS with MB procedure using MRI to detect edema or hemorrhaging in the brain. Contrast enhanced T1-weighted MRI sequences showed a 98% success rate for openings in the targeted regions. T2-weighted and SWI sequences indicated a lack edema in the majority of the cases. We investigated potential neurological effects of the FUS with MB procedure through quantitative cognitive testing of' visual, cognitive, motivational, and motor function using a random dot motion task with reward magnitude bias presented on a touchpanel display. Reaction times during the task significantly increased on the day of the FUS with MB procedure. This increase returned to baseline within 4-5 days after the procedure. Visual motion discrimination thresholds were unaffected. Our results indicate FUS with MB can be a safe method for repeated opening of the BBB at the basal ganglia in NHP for up to 20 months without any long-term negative physiological or neurological effects with the parameters used

Characterizing Focused-Ultrasound Mediated Drug Delivery to the Heterogeneous Primate Brain In Vivo with Acoustic Monitoring

Focused ultrasound with microbubbles has been used to noninvasively and selectively deliver pharmacological agents across the blood-brain barrier (BBB) for treating brain diseases. Acoustic cavitation monitoring could serve as an on-line tool to assess and control the treatment. While it demonstrated a strong correlation in small animals, its translation to primates remains in question due to the anatomically different and highly heterogeneous brain structures with gray and white matteras well as dense vasculature. In addition, the drug delivery efficiency and the BBB opening volume have never been shown to be predictable through cavitation monitoring in primates. This study aimed at determining how cavitation activity is correlated with the amount and concentration of gadolinium delivered through the BBB and its associated delivery efficiency as well as the BBB opening volume in non-human primates. Another important finding entails the effect of heterogeneous brain anatomy and vasculature of a primate brain, i.e., presence of large cerebral vessels, gray and white matter that will also affect the cavitation activity associated with variation of BBB opening in different tissue types, which is not typically observed in small animals. Both these new findings are critical in the primate brain and provide essential information for clinical applications

Efficient Blood-Brain Barrier Opening in Primates with Neuronavigation-Guided Ultrasound and Real-Time Acoustic Mapping

Brain diseases including neurological disorders and tumors remain under treated due to the challenge to access the brain, and blood-brain barrier (BBB) restricting drug delivery which, also profoundly limits the development of pharmacological treatment. Focused ultrasound (FUS) with microbubbles is the sole method to open the BBB noninvasively, locally, and transiently and facilitate drug delivery, while translation to the clinic is challenging due to long procedure, targeting limitations, or invasiveness of current systems. In order to provide rapid, flexible yet precise applications, we have designed a noninvasive FUS and monitoring system with the protocol tested in monkeys (from in silico preplanning and simulation, real-time targeting and acoustic mapping, to post-treatment assessment). With a short procedure (30 min) similar to current clinical imaging duration or radiation therapy, the achieved targeting (both cerebral cortex and subcortical structures) and monitoring accuracy was close to the predicted 2-mm lower limit. This system would enable rapid clinical transcranial FUS applications outside of the MRI system without a stereotactic frame, thereby benefiting patients especially in the elderly population

Noninvasive, Transient and Selective Blood-Brain Barrier Opening in Non-Human Primates In Vivo

The blood-brain barrier (BBB) is a specialized vascular system that impedes entry of all large and the vast majority of small molecules including the most potent central nervous system (CNS) disease therapeutic agents from entering from the lumen into the brain parenchyma. Microbubble-enhanced, focused ultrasound (ME-FUS) has been previously shown to disrupt noninvasively, selectively, and transiently the BBB in small animals in vivo. For the first time, the feasibility of transcranial ME-FUS BBB opening in non-human primates is demonstrated with subsequent BBB recovery. Sonications were combined with two different types of microbubbles (customized 4–5 µm and Definity®). 3T MRI was used to confirm the BBB disruption and to assess brain damage