Kevin Johnston

Theta-Activity in anterior cingulate cortex predicts task rules and their adjustments following errors

Accomplishing even simple tasks depend on neuronal circuits to configure how incoming sensory stimuli map onto responses. Controlling these stimulus-response (SR) mapping rules relies on a cognitive control network comprising the anterior cingulate cortex (ACC). Single neurons within the ACC convey information about currently relevant SR mapping rules and signal unexpected action outcomes, which can be used to optimize behavioral choices. However, its functional significance and the mechanistic means of interaction with other nodes of the cognitive control network remain elusive and poorly understood. Here, we report that core aspects of cognitive control are encoded by rhythmic theta-band activity within neuronal circuits in the ACC. Throughout task performance, theta-activity predicted which of two SR mapping rules will be established before processing visual target information. Task-selective theta-activity emerged particularly early during those trials, which required the adjustment of SR rules following an erroneous rule representation in the preceding trial. These findings demonstrate a functional correlation of cognitive control processes and oscillatory theta-band activity in macaque ACC. Moreover, we report that spike output of a subset of cells in ACC is synchronized to predictive theta-activity, suggesting that the theta-cycle could serve as a temporal reference for coordinating local task selective computations across a larger network of frontal areas and the hippocampus to optimize and adjust the processing routes of sensory and motor circuits to achieve efficient sensory-motor control.

Monkey Dorsolateral Prefrontal Cortex Sends Task-Selective Signals Directly to the Superior Colliculus

The dorsolateral prefrontal cortex (DLPFC) has been implicated in the ability to perform complex behaviors requiring the implementation of cognitive control. A central supposition of models of prefrontal function is that the DLPFC engages control by selectively modulating the activity of target structures to which it is connected, but no studies in the primate have directly investigated DLPFC output signals. Here, we recorded the activity of DLPFC neurons identified as sending a direct projection to the superior colliculus, a midbrain oculomotor structure, while monkeys performed alternating blocks of trials in which they had to look toward a flashed peripheral stimulus (prosaccades) and trials in which they had to look away from the stimulus in the opposite direction (antisaccades). We report the first direct evidence that the primate DLPFC sends task-selective signals to a target structure. This supports the notion that the DLPFC orchestrates the activity of other brain areas in accordance with task requirements.

Neural Activity in Monkey Prefrontal Cortex Is Modulated by Task Context and Behavioral Instruction during Delayed-match-to-sample and Conditional Prosaccade---Antisaccade Tasks

Complex behavior often requires the formation of associations between environmental stimuli and motor responses appropriate to those stimuli. Moreover, the appropriate response to a given stimulus may vary depending on environmental context. Stimulus-response associations that are adaptive in one situation may not be in another. The prefrontal cortex (PFC) has been shown to be critical for stimulus-response mapping and the implementation of task context. To investigate the neural representation of sensory-motor associations and task context in the PFC, we recorded the activity of prefrontal neurons in two monkeys while they performed two tasks. The first task was a delayed-match-to-sample task in which monkeys were presented with a sample picture and rewarded for making a saccade to the test picture that matched the sample picture following a delay period. The second task was a conditional visuomotor task in which identical sample pictures were presented. In this task, animals were rewarded for performing either prosaccades or antisaccades following the delay period depending on sample picture identity. PFC neurons showed task selectivity, object selectivity, and combinations of task and object selectivity. These modulations of activity took the form of a reduction in stimulus and delay-related activity, and a pro/anti instruction-based grouping of delay activity in the conditional visuomotor task. These data show that activity in PFC neurons is modulated by experimental context, and that this activity represents the formal demands of the task currently being performed.

Monkey Prefrontal Cortical Pyramidal and Putative Interneurons Exhibit Differential Patterns of Activity Between Prosaccade and Antisaccade Tasks

Previous studies have shown that prefrontal cortex (PFC) neurons carry task-related activity; however, it is largely unknown how this selectivity is implemented in PFC microcircuitry. Here, we exploited known differences in extracellular action potential waveforms, and antidromic identification, to classify PFC neurons as putative pyramidal or interneurons, and investigate their relative contributions to task-selectivity. We recorded the activity of prefrontal neurons while monkeys performed a blocked pro/antisaccade task in which they were required to look either toward or away from a peripheral visual stimulus. We found systematic differences in activity between neuron classes. Putative pyramidal neurons had higher stimulus-related activity on antisaccade trials, whereas putative interneurons exhibited greater activity for prosaccades. These findings suggest that task-selectivity in the PFC may be shaped by interactions between these neuronal classes. They are also consistent with the robust deficits in antisaccade performance frequently observed in disease states associated with PFC dysfunction.

Control of the superior colliculus by the lateral prefrontal cortex

Several decades of patient, functional imaging and neurophysiological studies have supported a model in which the lateral prefrontal cortex (PFC) acts to suppress unwanted saccades by inhibiting activity in the oculomotor system. However, recent results from combined PFC deactivation and neural recordings of the superior colliculus in monkeys demonstrate that the primary influence of the PFC on the oculomotor system is excitatory, and stands in direct contradiction to the inhibitory model of PFC function. Although erroneous saccades towards a visual stimulus are commonly labelled reflexive in patients with PFC damage or dysfunction, the latencies of most of these saccades are outside of the range of express saccades, which are triggered directly by the visual stimulus. Deactivation and pharmacological manipulation studies in monkeys suggest that response errors following PFC damage or dysfunction are not the result of a failure in response suppression but can best be understood in the context of a failure to maintain and implement the proper task set.

Microstimulation of monkey dorsolateral prefrontal cortex impairs antisaccade performance

The dorsolateral prefrontal cortex (DLPFC) has been implicated in various cognitive functions, including response suppression. This function is frequently probed with the antisaccade task, which requires suppression of the automatic tendency to look toward a flashed peripheral stimulus (prosaccade), and instead generate a voluntary saccade to the mirror location. To test whether activity in the DLPFC is causally linked to antisaccade performance, we applied electrical microstimulation to sites in the DLPFC of two monkeys, while they performed randomly interleaved pro- and antisaccade trials. Microstimulation resulted in significantly longer saccadic reaction times for ipsilaterally directed prosaccades and antisaccades, and increased the error rate on ipsilateral antisaccade trials. These findings provide causal evidence that activity in the DLPFC influences saccadic eye movements.

The Retinal Ganglion Cell Layer and Visual Acuity of the Camel

We examined the retinal ganglion cell layer of the dromedary camel, Camelus dromedarius. We have estimated that there are 8 million neurons in the ganglion cell layer of this large retina (mean area of 2,300 mm–2). However, only approximately 1 million are considered to be ganglion cells. The ganglion cells are arranged as two areas of high cell density, one in the temporal and one in the nasal retina. Densities of ganglion cells between these two high density regions is much lower, often less than 100 per mm–2. In between these two high density regions, on the nasal side of the optic nerve head, is a unique and dense vertical streak of mostly non-ganglion cells; the function of this specialization is unknown. On the basis of ganglion cell density we estimate that the peak acuity in the dromedary camel is about 10 and 9.5 cycles per degree in the temporal and nasal high density regions respectively and falls to 2–3 cycles per degree in the central retina. Behavioral acuity was estimated for one bactrian camel and was found to be approximately 10 cyc deg–1. The camel has a retina with a mean thickness of 104 µm, less than the 143 µm thickness that has previously been thought to be necessary for a retinal vasculature. Nevertheless, there is an extensive vitreal vasculature that does not appear to spare any retinal region.

Effects of anterior cingulate microstimulation on pro-and antisaccades in nonhuman primates

Numerous studies have established a role for the ACC in cognitive control. Current theories are at odds as to whether ACC itself directly engages or alternatively recruits other frontal cortical areas that implement control. The antisaccade task, in which subjects are required to make a saccade to the location opposite a suddenly appearing visual stimulus, is a simple oculomotor paradigm that has been used extensively to investigate flexible oculomotor control. Here, we tested a causal role of the dorsal ACC in cognitive control by applying electrical microstimulation during a preparatory period while monkeys performed alternating blocks of pro- and antisaccade trials. Microstimulation induced significant changes in saccadic RTs (SRTs) in both tasks. On prosaccade trials, SRTs were increased for saccades contralateral to and decreased for saccades ipsilateral to the stimulated hemisphere. In contrast, SRTs were decreased for both ipsi- and contralaterally directed antisaccades. These data show that microstimulation administered during response preparation facilitated the performance of antisaccades and are suggestive of a direct role of ACC in the implementation of cognitive control.

Bilateral saccadic deficits following large and reversible inactivation of unilateral frontal eye field

Inactivation permits direct assessment of the functional contribution of a given brain area to behavior. Previous inactivation studies of the frontal eye field (FEF) have either used large permanent ablations or reversible pharmacological techniques that only inactivate a small volume of tissue. Here we evaluated the impact of large, yet reversible, FEF inactivation on visually guided, delayed, and memory-guided saccades, using cryoloops implanted in the arcuate sulcus. While FEF inactivation produced the expected triad of contralateral saccadic deficits (increased reaction time, decreased accuracy and peak velocity) and performance errors (neglect or misdirected saccades), we also found consistent increases in reaction times of ipsiversive saccades in all three tasks. In addition, FEF inactivation did not increase the proportion of premature saccades to ipsilateral targets, as was predicted on the basis of pharmacological studies. Consistent with previous studies, greater deficits accompanied saccades toward extinguished visual cues. Our results attest to the functional contribution of the FEF to saccades in both directions. We speculate that the comparative effects of different inactivation techniques relate to the volume of inactivated tissue within the FEF. Larger inactivation volumes may reveal the functional contribution of more sparsely distributed neurons within the FEF, such as those related to ipsiversive saccades. Furthermore, while focal FEF inactivation may disinhibit the mirroring site in the other FEF, larger inactivation volumes may induce broad disinhibition in the other FEF that paradoxically prolongs oculomotor processing via increased competitive interactions.

Unilateral deactivation of macaque dorsolateral prefrontal cortex induces biases in stimulus selection

Following unilateral brain injury, patients are often unable to detect a stimulus presented in the contralesional field when another is presented simultaneously ipsilesionally. This phenomenon has been referred to as extinction and has been conceptualized as a deficit in selective attention. Although most commonly observed following damage to posterior parietal areas, extinction has been observed following lesions of prefrontal cortex (PFC) in both humans and nonhuman primates. To date, most studies in nonhuman primates have examined lesions of multiple PFC subregions, including the frontal eye fields (FEF). Theoretical accounts of attentional disturbances from human patients, however, also implicate other PFC areas, including the middle frontal gyrus. Here, we investigated the effects of deactivating PFC areas anterior to the FEF on stimulus selection using a free-choice task. Macaque monkeys were presented with two peripheral stimuli appearing either simultaneously, or at varying stimulus onset asynchronies, and their performance was evaluated during unilateral cryogenic deactivation of part of dorsolateral prefrontal cortex or the cortex lining the caudal principal sulcus, the likely homologue of the human middle frontal gyrus. A decreased proportion of saccades was made to stimuli presented in the hemifield contralateral to the deactivated PFC. We also observed increases in reaction times to contralateral stimuli and decreases for stimuli presented in the hemifield ipsilateral to the deactivated hemisphere. In both cases, these results were greatest when both PFC subregions were deactivated. These findings demonstrate that selection biases result from PFC deactivation and support a role of dorsolateral prefrontal subregions anterior to FEF in stimulus selection.