Elsevier

NeuroImage

Volume 45, Issue 2, 1 April 2009, Pages 470-476
NeuroImage

BOLD fMRI activation for anti-saccades in nonhuman primates

https://doi.org/10.1016/j.neuroimage.2008.12.009Get rights and content

Abstract

Most of our knowledge about the functional organization of the nonhuman primate brain has come from single neuron recordings, whereas functional magnetic resonance imaging (fMRI) has rapidly become the method of choice for the study of the human brain. In some cases these two methods have resulted in conflicting models of frontal lobe function. Based on the finding that the frontal eye fields (FEF) exhibit a higher blood-oxygenation-level dependent (BOLD) activation for anti-saccades compared with pro-saccades, it has been proposed that this area is more involved in voluntary than automatic saccade generation. This model has been questioned by the finding of decreased single neuron activity in FEF for anti-compared with pro-saccades in monkeys. To reconcile these findings, we employed fMRI to compare BOLD activation between anti-saccades and pro-saccades in monkeys. FEF and a number of other cortical and subcortical areas showed an increased activation for anti-saccades. The results indicate that previous contrary findings between single neuron recordings and fMRI were due to differences between these techniques and were not related to differences between the two primate species.

Introduction

For several decades trained monkeys have played a major role as surrogates for the study of human brain function. Single neuron recording techniques in these animals have provided vital insights into the organization of sensory, motor and cognitive systems. Although these techniques provide excellent spatial and temporal resolution, their invasive nature limits their application to specific groups of human patients. Within the last decade, non-invasive functional magnetic resonance imaging (fMRI) has become the method of choice for investigating the functional organization of the human brain. Single unit recording studies in monkeys and fMRI studies in humans have often provided valuable complimentary data. Investigation of the neural circuitry underlying the anti-saccade task (Hallett, 1978), a popular task in the study of voluntary, goal-driven eye movements is one such example. This task requires subjects to suppress the automatic response to look toward a visual stimulus (pro-saccade) and instead generate a voluntary saccade away from it (Everling and Fischer, 1998, Munoz and Everling, 2004).

Several brain regions have been found to play a role in anti-saccade task performance. Single neuron recordings in monkeys have shown that neurons in the lateral intraparietal sulcus (area LIP) play a role in vector inversion (Zhang and Barash, 2000) and show an enhanced response to cues that trigger an anti-saccade (Gottlieb and Goldberg, 1999). The role of area LIP in anti-saccade task performance has been supported by human fMRI studies (Brown et al., 2006, Brown et al., 2007, Curtis and Connolly, 2008, Ettinger et al., 2008, Ford et al., 2005, Matsuda et al., 2004, Medendorp et al., 2005) Similarly, the role of the anterior cingulate cortex (ACC) has been investigated in anti-saccade performance utilizing both single neuron recordings in monkeys (Johnston et al., 2007) and human imaging studies (Brown et al., 2007, Curtis et al., 2005, Ford et al., 2005, Matsuda et al., 2004, Polli et al., 2005), yielding complementary findings. In addition, single neuron recording studies have shown that prefrontal neurons exhibit differential preparatory activity between pro- and anti-saccade trials (Everling and Desouza, 2005, Johnston and Everling, 2006b, Johnston et al., 2007). Human fMRI studies have also found higher activations in prefrontal areas for anti-saccades than pro-saccades (Brown et al., 2007, Desouza et al., 2003, Dyckman et al., 2007, Ettinger et al., 2008, Ford et al., 2005). Finally, both electrophysiological recordings in monkeys (Yoshida and Tanaka, 2008) and human fMRI (Raemaekers et al., 2002, Raemaekers et al., 2006) have revealed higher activation in the basal ganglia during anti-saccades compared with pro-saccades.

However, monkey single neuron recordings and human fMRI have also yielded one notably divergent finding regarding the role of frontal cortex in the control of anti-saccades. Single neuron recordings in monkeys have shown that anti-saccade trials are associated with a marked reduction in the activity of saccade-related neurons in the frontal eye field (FEF) (Everling and Munoz, 2000), while fMRI studies in humans have consistently shown increased activation in FEF for anti-saccade trials compared with pro-saccade trials (Brown et al., 2006, Brown et al., 2007, Connolly et al., 2000, Connolly et al., 2002, Connolly et al., 2005, Curtis and D'Esposito, 2003, Desouza et al., 2003, Ford et al., 2005, Kimmig et al., 2001).

There are two possible explanations for these conflicting results. First, although monkeys are widely used as models for human frontal lobe function, there exist substantial differences between the frontal lobes of these two primate species in relative and absolute size, convolution and neuronal specialization (Petrides and Pandya, 1999, Petrides and Pandya, 2002, Semendeferi et al., 2002, Watson et al., 2006). A likely consequence of these differences is the dramatically longer training requirement for monkeys than for humans on the anti-saccade task. Therefore, different neural processes may underlie similar task performance in the two primate species. A second possibility is that differences between the techniques have resulted in these contrary findings. Single neuron recordings have a bias towards sampling the activity of large pyramidal neurons, whereas it has been suggested that fMRI activation may be more reflective of the input to a given area and the processing of interneurons (Logothetis et al., 2001).

To investigate these possibilities, we measured BOLD fMRI while monkeys performed blocks of pro- and anti-saccade trials.

Section snippets

Methods

Data was obtained from two male rhesus monkeys (Macaca mulatta, 6 and 7 kg) over 23 individual functional imaging sessions (10 sessions from monkey G and 13 sessions from monkey C). All training, surgical, and experimental procedures were in accordance with the Canadian Council of Animal Care policy on the use of laboratory animals and approved by the Animal Use Subcommittee of the University of Western Ontario Council on Animal Care.

Standard surgical procedures were used to prepare both

Behaviour

Monkeys performed blocks of pro- and anti-saccades as illustrated in Fig. 1. Each block contained 5 individual trials. Fig. 2A shows horizontal eye position traces aligned to the onset of the fixation target while monkey C performed pro- and anti-saccades in the MR scanner during functional data acquisition.

Fig. 2B shows cumulative distribution plots of saccadic reaction times (SRT) separately for monkey C and monkey G for all correct pro-saccades and anti-saccades recorded during functional

Discussion

Neural correlates for response inhibition and the voluntary generation of movement have been extensively studied using the anti-saccade task in both human and nonhuman primates (Munoz and Everling, 2004). These studies have found conflicting results regarding the role of the frontal eye fields (FEF) in anti-saccade task performance. Single neuron recordings in monkeys have demonstrated decreased activity of saccade-related neurons during anti-saccade trials as compared with pro-saccade trials (

Acknowledgments

This work was supported by a grant from the Canadian Institutes of Health Research (CIHR) and the EJLB Foundation to SE and a scholarship from the Natural Science and Engineering Research Council (NSERC) to KAF. We thank K. Johnston for helpful comments.

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