Erik E. Emeric

Influence of history on saccade countermanding performance in humans and macaque monkeys

The stop-signal or countermanding task probes the ability to control action by requiring subjects to withhold a planned movement in response to an infrequent stop signal which they do with variable success depending on the delay of the stop signal. We investigated whether performance of humans and macaque monkeys in a saccade countermanding task was influenced by stimulus and performance history. In spite of idiosyncrasies across subjects several trends were evident in both humans and monkeys. Response time decreased after successive trials with no stop signal. Response time increased after successive trials with a stop signal. However, post-error slowing was not observed. Increased response time was observed mainly or only after cancelled (signal inhibit) trials and not after noncancelled (signal respond) trials. These global trends were based on rapid adjustments of response time in response to momentary fluctuations in the fraction of stop signal trials. The effects of trial sequence on the probability of responding were weaker and more idiosyncratic across subjects when stop signal fraction was fixed. However, both response time and probability of responding were influenced strongly by variations in the fraction of stop signal trials. These results indicate that the race model of countermanding performance requires extension to account for these sequential dependencies and provide a basis for physiological studies of executive control of countermanding saccade performance.

Visual and Motor Connectivity and the Distribution of Calcium-Binding Proteins in Macaque Frontal Eye Field: Implications for Saccade Target Selection

The frontal eye field (FEF) contributes to directing visual attention and saccadic eye movement through intrinsic processing, interactions with extrastriate visual cortical areas (e.g., V4), and projections to subcortical structures (e.g., superior colliculus, SC). Several models have been proposed to describe the relationship between the allocation of visual attention and the production of saccades. We obtained anatomical information that might provide useful constraints on these models by evaluating two characteristics of FEF. First, we investigated the laminar distribution of efferent connections from FEF to visual areas V4 + TEO and to SC. Second, we examined the laminar distribution of different populations of GABAergic neurons in FEF. We found that the neurons in FEF that project to V4 + TEO are located predominantly in the supragranular layers, colocalized with the highest density of calbindin- and calretinin-immunoreactive inhibitory interneurons. In contrast, the cell bodies of neurons that project to SC are found only in layer 5 of FEF, colocalized primarily with parvalbumin inhibitory interneurons. None of the neurons in layer 5 that project to V4 + TEO also project to SC. These results provide useful constraints for cognitive models of visual attention and saccade production by indicating that different populations of neurons project to extrastriate visual cortical areas and to SC. This finding also suggests that FEF neurons projecting to visual cortex and SC are embedded in different patterns of intracortical circuitry.

Event-Related Potentials Elicited by Errors during the Stop-Signal Task. I. Macaque Monkeys

The error-related negativity (ERN) and positivity (Pe) are components of event-related potential (ERP) waveforms recorded from humans and are thought to reflect performance monitoring. Error-related signals have also been found in single-neuron responses and local-field potentials recorded in supplementary eye field and anterior cingulate cortex of macaque monkeys. However, the homology of these neural signals across species remains controversial. Here, we show that monkeys exhibit ERN and Pe components when they commit errors during a saccadic stop-signal task. The voltage distributions and current densities of these components were similar to those found in humans performing the same task. Subsequent analyses show that neither stimulus- nor response-related artifacts accounted for the error-ERPs. This demonstration of macaque homologues of the ERN and Pe forms a keystone in the bridge linking human and nonhuman primate studies on the neural basis of performance monitoring.

Performance Monitoring Local Field Potentials in the Medial Frontal Cortex of Primates: Supplementary Eye Field

We describe intracranial local field potentials (LFPs) recorded in the supplementary eye field (SEF) of macaque monkeys performing a saccade countermanding task. The most prominent feature at 90% of the sites was a negative-going polarization evoked by a contralateral visual target. At roughly 50% of sites a negative-going polarization was observed preceding saccades, but in stop signal trials this polarization was not modulated in a manner sufficient to control saccade initiation. When saccades were canceled in stop signal trials, LFP modulation increased with the inferred magnitude of response conflict derived from the coactivation of gaze-shifting and gaze-holding neurons. At 30% of sites, a pronounced negative-going polarization occurred after errors. This negative polarity did not appear in unrewarded correct trials. Variations of response time with trial history were not related to any features of the LFP. The results provide new evidence that error-related and conflict-related but not feedback-related signals are conveyed by the LFP in the macaque SEF and are important for identifying the generator of the error-related negativity.

Conflict in Cingulate Cortex Function between Humans and Macaque Monkeys: More Apparent than Real

A recent review in Trends in Neuroscience by Cole, Yeung, Freiwald and Botvinick identified a potential fundamental difference in functional properties of the anterior cingulate cortex (ACC) of humans and macaque monkeys [Cole et al., 2009]. The key function in question is monitoring of conflict in response preparation. The conflict hypothesis, defended by the senior authors of the review as a general theory of ACC function, states that when a task calls for multiple competing responses, then executive control is required to resolve the conflict. It is supposed to explain the origin and purpose of event-related potential components such as the error-related negativity (ERN) that occurs after response errors [reviewed by Taylor et al., 2007] and a body of functional brain imaging data. The ERN can be generated by a dipole in the ACC; however, uncertainties in the localization of this dipole as well as other neuroimaging and lesion data demonstrate that more dorsal areas of medial frontal cortex including preSMA also contribute to performance monitoring [e.g. Garavan et al., 2003]. The ERN can also be identified with a reward prediction error originating from the dopamine system [Taylor et al., 2007]. An active literature has developed evaluating these and other alternative hypotheses using human subjects. The relative merits of these alternative hypotheses are not the focus of this commentary. Over the last decade this literature derived from human studies has been supplemented by neurophysiological data from macaque monkeys. In monkeys performing an eye movement stop signal task, neurons are found in the supplementary eye field that signal when errors are produced, when reward is delivered and when conflict occurs [Stuphorn et al., 2000]. In contrast, multiple neurophysiological studies of the macaque monkey ACC have reported error and reward signals but an absence of a conflict signal in tasks that should engender such response conflict [Ito et al., 2003; Nakamura et al., 2005; Emeric et al., 2008]. Cole et al. [2009] argue that the lack of a single neuron conflict signal in macaque monkeys in contrast to humans is a manifestation of a fundamental species difference and a greater sensitivity of functional brain imaging methods to weak conflict signals. We will argue that simpler alternative interpretations have not been ruled out. To account for the apparent incommensurability of results in monkeys and humans, Cole et al. [2009] emphasize species differences. We suggest that effector differences should be considered first. The monkey studies that sparked their review were based on data obtained in tasks requiring monkeys to produce or inhibit saccadic eye movements. The human studies used to describe conflict (as well as error and feedback) signals typically employ forelimb movements. Although the motor control of the eyes and of the hands may share common features centrally, they are substantially different peripherally. Eye movements entail fewer degrees of freedom (basically just 2) and need not be concerned about gravity. Natural arm movements entail more degrees of freedom (as many as 7 not counting the fingers) and usually must contend with gravity. Furthermore, and possibly crucially for this review, being an extension of the body, the limbs can get into kinds of trouble that the eyes cannot, e.g. colliding with other objects in the world. Specific neuroanatomical differences should also be highlighted. First, the neurons in the cortex that contribute to eye movement generation do not form synapses on the motor neurons innervating the muscles of the eyes, but the neurons in the cortex that contribute to forelimb movement generation form synapses directly on the motor neurons innervating the muscles of the limbs. Second, parts of cingulate cortex project to motor cortex and the spinal cord [Dum and Strick 2002], and body movements can be evoked by electrical stimulation of these regions, but such connectivity and excitability for saccades is considerably weaker. Indeed, eye movements are evoked only rarely by stimulation of the ACC of most monkeys. Finally, in many of the studies that report conflict signals with manual movements the alternative responses could be generated together, e.g. press buttons with both hands. In contrast, only one saccadic eye movement can be produced at a time. Why are neuronal responses related to error and reward but not response conflict consistently observed in the ACC? We suggest that conflict signals may not be observed because the oculomotor representation of the macaque ACC does not support enough connections to influence gaze. However, the presence of a conflict signal in supplementary eye fields can perform the same function for the eyes that such a signal in the ACC can perform for the limbs. Cole et al. [2009] also suggest that the conflict-sensitive portion of the human ACC has no homologue in macaque monkeys. However, it is not clear that this view is consistent with the most current anatomical descriptions. While the sulcal pattern in humans with the parasplenial lobules is more complex than that in macaques, the cytoarchitecture of the cingulofrontal transitional cortex identified as area 32 is shared by humans and macaques [Vogt et al., 1995, 2005]. In other words, cortex with cytoarchitecture of area 32 is not absent in macaques, just smaller area. In fact, the caudal part of human area 32ac has been identified as a homolog of macaque area 24c, making it part of the cingulate motor areas [Ongur et al., 2003]. The cingulate motor areas in the caudal anterior cingulate are in a unique position to monitor response conflict and exert control on the skeletal motor system through connections with motor cortical areas and the spinal cord [Dum and Strick 2002]. Meta-analyses of cingulate activation have demonstrated that a somatotopic map corresponding to the cingu- late motor areas in monkeys [Picard and Strick, 2001] overlaps with the foci of conflict-related activation across studies within the region labeled area 32′ [e.g. Hester et al., 2004]. Although we heartily endorse distinguishing illusory from actual cross-species differences, drawing categorical conclusions from nuanced and often ambiguous data is premature. Fundamentally, it is not clear why the general conflict model should not apply to macaques who exhibit complex, extended responses to ambiguous stimuli with uncertain payoffs. If macaque monkeys are not equipped to monitor conflict, then specifically what should they not be able to do?

Contents Vol. 75, 2010

309 30th Annual Meeting of the J.B. Johnston Club and 22nd Annual Karger Workshop San Diego, Calif., November 11–12, 2010 317 Author Index Vol. 75, 2010 318 Subject Index Vol. 75, 2010