Brian C. Coe

A neural correlate of response bias in monkey caudate nucleus

Primates are equipped with neural circuits in the prefrontal cortex, the parietal cortex and the basal ganglia that predict the availability of reward during the performance of behavioural tasks. It is not known, however, how reward value is incorporated in the control of action. Here we identify neurons in the monkey caudate nucleus that create a spatially selective response bias depending on the expected gain. In behavioural tasks, the monkey had to make a visually guided eye movement in every trial, but was rewarded for a correct response in only half of the trials. Reward availability was predictable on the basis of the spatial position of the visual target. We found that caudate neurons change their discharge rate systematically, even before the appearance of the visual target, and usually fire more when the contralateral position is associated with reward. Strong anticipatory activity of neurons with a contralateral preference is associated with decreased latency for eye movements in the contralateral direction. We conclude that this neuronal mechanism creates an advance bias that favours a spatial response when it is associated with a high reward value.

Feature-Based Anticipation of Cues that Predict Reward in Monkey Caudate Nucleus

A subset of caudate neurons fires before cues that instruct the monkey what he should do. To test the hypothesis that the anticipatory activity of such neurons depends on the context of stimulus-reward mapping, we examined their activity while the monkeys performed a memory-guided saccade task in which either the position or the color of a cue indicated presence or absence of reward. Some neurons showed anticipatory activity only when a particular position was associated with reward, while others fired selectively for color-reward associations. The functional segregation suggests that caudate neurons participate in feature-based anticipation of visual information that predicts reward. This neuronal code influences the general activity level in response to visual features without improving the quality of visual discrimination.

Alzheimer's Disease-Like Pathology Induced by Amyloid-β Oligomers in Nonhuman Primates

Alzheimers disease (AD) is a devastating neurodegenerative disorder and a major medical problem. Here, we have investigated the impact of amyloid-β (Aβ) oligomers, AD-related neurotoxins, in the brains of rats and adult nonhuman primates (cynomolgus macaques). Soluble Aβ oligomers are known to accumulate in the brains of AD patients and correlate with disease-associated cognitive dysfunction. When injected into the lateral ventricle of rats and macaques, Aβ oligomers diffused into the brain and accumulated in several regions associated with memory and cognitive functions. Cardinal features of AD pathology, including synapse loss, tau hyperphosphorylation, astrocyte and microglial activation, were observed in regions of the macaque brain where Aβ oligomers were abundantly detected. Most importantly, oligomer injections induced AD-type neurofibrillary tangle formation in the macaque brain. These outcomes were specifically associated with Aβ oligomers, as fibrillar amyloid deposits were not detected in oligomer-injected brains. Human and macaque brains share significant similarities in terms of overall architecture and functional networks. Thus, generation of a macaque model of AD that links Aβ oligomers to tau and synaptic pathology has the potential to greatly advance our understanding of mechanisms centrally implicated in AD pathogenesis. Furthermore, development of disease-modifying therapeutics for AD has been hampered by the difficulty in translating therapies that work in rodents to humans. This new approach may be a highly relevant nonhuman primate model for testing therapeutic interventions for AD.

Using eye movements to probe development and dysfunction

Publisher Summary Recording of saccadic eye movements has proved to be a valuable tool for investigation of brain function and dysfunction. Recent neurophysiological studies have revealed that the time from target appearance to saccade initiation can be modeled as an accumulator function in which both baseline and rate of rise of saccade-related activity contribute toward achieving threshold for movement initiation. The chapter reviews recent saccadic eye-movement studies designed to track abilities across development and in disorders of frontal cortex and basal ganglia. Studies can be designed to probe the ability to initiate automatic vs voluntary saccades or to suppress saccades. The accumulator model can be used to explain normal developmental changes in voluntary saccade control that are present in normal development as well as in attention deficit hyperactivity disorder (ADHD), Parkinsons disease (PD), and Tourette syndrome (TS).

Developmental improvements in voluntary control of behavior: Effect of preparation in the fronto-parietal network?

The ability to prepare for an action improves the speed and accuracy of its performance. While many studies indicate that behavior performance continues to improve throughout childhood and adolescence, it remains unclear whether or how preparatory processes change with development. Here, we used a rapid event-related fMRI design in three age groups (8-12, 13-17, 18-25years) who were instructed to execute either a prosaccade (look toward peripheral target) or an antisaccade (look away from target) task. We compared brain activity within the core fronto-parietal network involved in saccade control at two epochs of saccade generation: saccade preparation related to task instruction versus saccade execution related to target appearance. The inclusion of catch trials containing only task instruction and no target or saccade response allowed us to isolate saccade preparation from saccade execution. Five regions of interest were selected: the frontal, supplementary, parietal eye fields which are consistently recruited during saccade generation, and two regions involved in top down executive control: the dorsolateral prefrontal and anterior cingulate cortices. Our results showed strong evidence that developmental improvements in saccade performance were related to better saccade preparation rather than saccade execution. These developmental differences were mostly attributable to children who showed reduced fronto-parietal activity during prosaccade and antisaccade preparation, along with longer saccade reaction times and more incorrect responses, compared to adolescents and adults. The dorsolateral prefrontal cortex was engaged similarly across age groups, suggesting a general role in maintaining task instructions through the whole experiment. Overall, these findings suggest that developmental improvements in behavioral control are supported by improvements in effectively presetting goal-appropriate brain systems.

Role of the basal ganglia in switching a planned response

The ability to perform an appropriate response in the presence of competing alternatives is a critical facet of human behavioral control. This is especially important if a response is prepared for execution but then has to be changed suddenly. A popular hypothesis of basal ganglia (BG) function suggests that its direct and indirect pathways could provide a neural mechanism to rapidly switch from one planned response to an alternative. However, if one response is more dominant or ‘automatic’ than the other, the BG might have a different role depending on switch direction. We built upon the pro‐ and antisaccade tasks, two models of automatic and voluntary behavior, respectively, and investigated whether the BG are important for switching any planned response in general, or if they are more important for switching from a more automatic response to a response that is more difficult to perform. Subjects prepared either a pro‐ or antisaccade but then had to switch it unexpectedly on a subset of trials. The results revealed increased striatal activation for switching from a pro‐ to an antisaccade but this did not occur for switching from an anti‐ to a prosaccade. This activation pattern depended on the relative difficulty in switching, and it was distinct from frontal eye fields, an area shown to be more active for antisaccade trials than for prosaccade trials. This suggests that the BG are important for compensating for differences in response difficulty, facilitating the rapid switching of one response for another.

Preparatory neural networks are impaired in adults with attention-deficit/hyperactivity disorder during the antisaccade task

Adults with attention-deficit/hyperactivity disorder (ADHD) often display executive function impairments, particularly in inhibitory control. The antisaccade task, which measures inhibitory control, requires one to suppress an automatic prosaccade toward a salient visual stimulus and voluntarily make an antisaccade in the opposite direction. ADHD patients not only have longer saccadic reaction times, but also make more direction errors (i.e., a prosaccade was executed toward the stimulus) during antisaccade trials. These deficits may stem from pathology in several brain areas that are important for executive control. Using functional MRI with a rapid event-related design, adults with combined subtype of ADHD (coexistence of attention and hyperactivity problems), who abstained from taking stimulant medication 20 h prior to experiment onset, and age-match controls performed pro- and antisaccade trials that were interleaved with pro- and anti-catch trials (i.e., instruction was presented but no target appeared, requiring no response). This method allowed us to examine brain activation patterns when participants either prepared (during instruction) or executed (after target appearance) correct pro or antisaccades. Behaviorally, ADHD adults displayed several antisaccade deficits, including longer and more variable reaction times and more direction errors, but saccade metrics (i.e., duration, velocity, and amplitude) were normal. When preparing to execute an antisaccade, ADHD adults showed less activation in frontal, supplementary, and parietal eye fields, compared to controls. However, activation in these areas was normal in the ADHD group during the execution of a correct antisaccade. Interestingly, unlike controls, adults with ADHD produced greater activation than controls in dorsolateral prefrontal cortex during antisaccade execution, perhaps as part of compensatory mechanisms to optimize antisaccade production. Overall, these data suggest that the saccade deficits observed in adults with ADHD do not result from an inability to execute a correct antisaccade but rather the failure to properly prepare (i.e., form the appropriate task set) for the antisaccade trial. The data support the view that the executive impairments, including inhibitory control, in ADHD adults are related to poor response preparation.

Cognitive Deterioration and Functional Compensation in ALS Measured with fMRI Using an Inhibitory Task

Amyotrophic lateral sclerosis (ALS) is characterized by degeneration of upper and lower motor neurons, resulting in progressive weakness and muscle atrophy. Recent studies suggest that nondemented ALS patients can show selective cognitive impairments, predominantly executive dysfunction, but little is known about the neural basis of these impairments. Oculomotor studies in ALS have described deficits in antisaccade execution, which requires the implementation of a task set that includes inhibition of automatic responses followed by generation of a voluntary action. It has been suggested that the dorsolateral prefrontal cortex (DLPFC) contributes in this process. Thus, we investigated whether deterioration of executive functions in ALS patients, such as the ability to implement flexible behavior during the antisaccade task, is related to DLPFC dysfunction. While undergoing an fMRI scan, 12 ALS patients and 12 age-matched controls performed an antisaccade task with concurrent eye tracking. We hypothesized that DLPFC deficits would appear during the antisaccade preparation stage, when the task set is being established. ALS patients made more antisaccade direction errors and showed significant reductions in DLPFC activation. In contrast, regions, such as supplementary eye fields and frontal eye fields, showed increased activation that was anticorrelated with the number of errors. The ALS group also showed reduced saccadic latencies that correlated with increased activation across the oculomotor saccade system. These findings suggest that ALS results in deficits in the inhibition of automatic responses that are related to impaired DLPFC activation. However, they also suggest that ALS patients undergo functional changes that partially compensate the neurological impairment.

Brain structures involved in visual search in the presence and absence of color singletons

It is still debated to what degree top–down and bottom–up driven attentional control processes are subserved by shared or by separate mechanisms. Interactions between these attentional control forms were investigated using a rapid event-related fMRI design, using an attentional search task. Following a prestimulus mask, target stimuli (consisting of a letter C or a mirror image of the C, enclosed in a diamond outline) were presented either at one unique location among three nontarget items (consisting of a random letter, enclosed in a circle outline; 50% probability), or at all four possible target locations (also 50% probability). On half the trials, irrelevant color singletons were presented, consisting of a color change of one of the four prestimulus masks, just prior to target appearance. Participants were required to search for a target letter inside the diamond and report its orientation. Results indicate that, in addition to a common network of parietal areas, medial frontal cortex is uniquely involved in top–down orienting, whereas bottom–up control is mainly subserved by a network of occipital and parietal areas. Additionally, we found that participants who were better able to suppress orienting to the color singleton showed middle frontal gyrus activation, and that the degree of top–down control correlated with insular activity. We conclude that, in addition to a common set of parietal areas, separate brain areas are involved in top–down and bottom–up driven attentional control, and that frontal areas play a role in the suppression of attentional capture by an irrelevant color singleton.

Mechanisms of saccade suppression revealed in the anti-saccade task

The anti-saccade task has emerged as an important tool for investigating the complex nature of voluntary behaviour. In this task, participants are instructed to suppress the natural response to look at a peripheral visual stimulus and look in the opposite direction instead. Analysis of saccadic reaction times (SRT: the time from stimulus appearance to the first saccade) and the frequency of direction errors (i.e. looking toward the stimulus) provide insight into saccade suppression mechanisms in the brain. Some direction errors are reflexive responses with very short SRTs (express latency saccades), while other direction errors are driven by automated responses and have longer SRTs. These different types of errors reveal that the anti-saccade task requires different forms of suppression, and neurophysiological experiments in macaques have revealed several potential mechanisms. At the start of an anti-saccade trial, pre-emptive top-down inhibition of saccade generating neurons in the frontal eye fields and superior colliculus must be present before the stimulus appears to prevent express latency direction errors. After the stimulus appears, voluntary anti-saccade commands must compete with, and override, automated visually initiated saccade commands to prevent longer latency direction errors. The frequencies of these types of direction errors, as well as SRTs, change throughout the lifespan and reveal time courses for development, maturation, and ageing. Additionally, patients diagnosed with a variety of neurological and/or psychiatric disorders affecting the frontal lobes and/or basal ganglia produce markedly different SRT distributions and types of direction errors, which highlight specific deficits in saccade suppression and inhibitory control. The anti-saccade task therefore provides valuable insight into the neural mechanisms of saccade suppression and is a valuable tool in a clinical setting. This article is part of the themed issue ‘Movement suppression: brain mechanisms for stopping and stillness’.