microstimulation of monkey dorsolateral prefrontal cortex impairs antisaccade performance

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  • Exp Brain Res (2008) 190:463473DOI 10.1007/s00221-008-1488-4RESEARCH ARTICLE

    Microstimulation of monkey dorsolateral prefrontal cortex impairs antisaccade performance

    Stephen P. Wegener Kevin Johnston Stefan Everling

    Received: 15 April 2008 / Accepted: 2 July 2008 / Published online: 19 July 2008 Springer-Verlag 2008

    Abstract The dorsolateral prefrontal cortex (DLPFC) hasbeen implicated in various cognitive functions, includingresponse suppression. This function is frequently probedwith the antisaccade task, which requires suppression of theautomatic tendency to look toward a Xashed peripheralstimulus (prosaccade), and instead generate a voluntarysaccade to the mirror location. To test whether activity inthe DLPFC is causally linked to antisaccade performance,we applied electrical microstimulation to sites in theDLPFC of two monkeys, while they performed randomlyinterleaved pro- and antisaccade trials. Microstimulationresulted in signiWcantly longer saccadic reaction times foripsilaterally directed prosaccades and antisaccades, andincreased the error rate on ipsilateral antisaccade trials.These Wndings provide causal evidence that activity in theDLPFC inXuences saccadic eye movements.

    Keywords Antisaccade Inhibition Prefrontal cortex Saccade Attention

    Introduction

    Top-down control in both humans and monkeys has beenextensively investigated using the antisaccade task (Hallett1978; Everling and Fischer 1998; Munoz and Everling2004). Correct performance of this task requires that the

    subject suppress the automatic tendency to look toward aXashed peripheral stimulus (prosaccade), and instead usethe stimulus information to program and execute a saccadeto the diametrically opposite location. The antisaccade tasktests the subjects ability to suppress a congruent in favor ofan incongruent stimulus-response mapping, and as such,provides an ideal paradigm to investigate executivefunction.

    Evidence for a role of the DLPFC in the performanceof the antisaccade task has come from lesion (Pierrot-Deseilligny et al. 1991; Walker et al. 1998; Gaymard et al.2003; Ploner et al. 2005) and functional imaging studies inhumans (Sweeney et al. 1996; Doricchi et al. 1997; McDowellet al. 2002; Curtis and DEsposito 2003; Desouza et al.2003; Ford et al. 2005; Brown et al. 2007), as well as singleneuron recordings in non-human primates (Funahashi et al.1993; Everling and Desouza 2005; Johnston and Everling2006b; Johnston and Everling 2006a). Recently, werecorded from DLPFC neurons that project directly to thesuperior colliculus (SC) (Johnston and Everling 2006a).These corticotectal neurons demonstrated an increasedlevel of pre-stimulus activity, and higher contralateral stim-ulus-related responses, on antisaccade trials in comparisonto prosaccade trials. We also found that corticotectal pre-stimulus activity and saccadic reaction times werenegatively correlated for antisaccade trials. Based on theseWndings, we proposed that the DLPFC provides top-downsignals to saccade-related brain areas that suppress contra-lateral automatic saccades. Support for such a conceptuali-zation is provided by the observation that patients withDLPFC lesions make performance errors in the antisaccadetask consistent with a failure of automatic saccade inhibi-tion (Pierrot-Deseilligny et al. 1991; Walker et al. 1998;Gaymard et al. 2003; Ploner et al. 2005). However, a directcausal relationship between DLPFC activity and antisaccade

    S. P. Wegener K. Johnston S. EverlingDepartment of Physiology and Pharmacology, University of Western Ontario, London, ON, Canada

    S. Everling (&)The Centre for Brain and Mind, Robarts Research Institute, 100 Perth Drive, London, ON N6A 5K8, Canadae-mail: severlin@uwo.ca123

  • 464 Exp Brain Res (2008) 190:463473performance remains to be established, as the notion thatthe DLPFC is involved in suppression of automatic sac-cades was based on diVerences in activity between pro andantisaccades and on a correlation between corticotectal pre-stimulus activity and antisaccade reaction time (Johnstonand Everling 2006a). In fact, a recent neurophysiologicalstudy that employed chemical deactivation of the prefrontalcortex in monkeys found eVects on anti-saccades for ven-trolateral but not for dorsolateral muscimol injections(Condy et al. 2007).

    To further investigate the role of the DLPFC in antisaccadetask performance, we applied electrical microstimulation tothe DLPFC of two monkeys while they performed a taskcomposed of randomly interleaved pro and antisaccade trials.Based on our previous Wndings (Johnston and Everling2006a), we hypothesized that microstimulation of the DLPFCat the time of stimulus presentation would enhance suppres-sion of reXexive saccades, and therefore improve the animalsperformance for antisaccades when the stimulus appears onthe contralateral side (i.e., ipsilateral antisaccades).

    Methods

    Two male rhesus monkeys (Macaca mulatta) weighing 8and 11 kg were subjects in the present experiment. Allexperimental methods described were performed in accor-dance with the guidelines of the Canadian Council on Ani-mal Care policy on the care and use of experimentalanimals, and an ethics protocol approved by the AnimalUsers Subcommittee of the University of Western OntarioCouncil on Animal Care.

    Details of the surgical procedures have been describedpreviously (Desouza and Everling 2004). BrieXy, bothmonkeys were prepared for chronic electrophysiologicalexperiments by undergoing a surgical procedure to place animplant, containing both a recording chamber and a headpost, on the skull. The recording chamber was placed over a19 mm diameter craniotomy located above the principalsulcus of the right hemisphere. A preformed eye coil wasimplanted into one eye behind the conjunctiva (Judge et al.1980). The correct placement of the recording chamber wasveriWed after surgery by a high-resolution T2-weightedmagnetic resonance image (MRI) obtained in a 4 TMR-scanner.

    Behavioral task

    Monkeys performed an experimental task of randomlyinterleaved prosaccade and antisaccade trials (Everlinget al. 1999). Prosaccade trials required the monkeys to looktowards a Xashed peripheral stimulus, and antisaccade trialsrequired the monkeys to look away from the stimulus in a

    direction opposite the stimulus (Fig. 1a). Each trial beganwith the presentation of a white Wxation point at the centerof a 21-inch CRT monitor at a viewing distance of 42 cm infront of the animals. Monkeys were required to Wxate onthis white center point within a 3 3 window for a periodof 500 ms. Following this, the central Wxation pointchanged color, either to red or green, to provide the taskinstruction. For Monkey W a red Wxation point instructed aprosaccade, and a green Wxation point instructed an antisac-cade. The color of the instructional cues was reversed forMonkey R. Monkeys were required to continue Wxation onthe colored Wxation point within a 3 3 window for aperiod of 500 ms, after which the Wxation point disap-peared. A 200 ms gap period followed Wxation point oVsetin which the monkey was required to maintain central Wxa-tion. The 200-ms gap was included because it is known todecrease the Wxation-related activity and increase the sac-cade-related activity in the superior colliculus (Dorris et al.1997; Everling et al. 1999), resulting in a larger proportionof erroneous prosaccade responses on antisaccade trials(Fischer and Weber 1992; Forbes and Klein 1996; Bellet al. 2000). After the gap period, a 0.15 visual stimuluswas presented pseudorandomly with equal probabilityeither 8 to the left or right of Wxation along the horizontalplane. The visual stimulus was red for Monkey W andgreen for Monkey R. Saccade endpoints were required tofall within a 8 6 window centered at the saccade targetlocation. This large target window was necessary becausemonkey R generated very hypometric antisaccades towardthe right side (

  • Exp Brain Res (2008) 190:463473 465manually controlled hydraulic microdrive (Narashige, TypeMO-95, Tokyo, Japan) while multiunit extracellular activ-ity was monitored using the Plexon MAP system (Plexon

    Inc., Dallas, TX, USA). Once strong single- or multi-unitactivity was observed and stable recordings were obtained,the electrode was disconnected from the recording systemand connected to a microstimulator with a photoelectricstimulus isolation unit (Grass S88 with PSIU6 photoelectricstimulus isolation unit, Astro-Med, RI, USA) and the para-digm commenced. Microstimulation was applied randomlyon 50% of the trials and consisted of a 200 ms pulse train(0.3 ms biphasic pulses, 200 Hz, 50 A) that began coinci-dent with the time of peripheral stimulus presentation(Fig. 1b). The stimulation parameters were chosen based onseveral initial sessions in which modiWcations were made toduration (range 50200 ms), frequency (range 100300 Hz)and current (range 50200 A) in order to determinethreshold parameters for obtaining behavioral eVects. Theseparameters are similar to those recently used for obtainedbehavioral eVects in other frontal cortical areas (presupple-mentary motor area 0.2 ms, 200 Hz, 6080 A (Isoda andHikosaka 2007); supplementary eye Weld: 0.2 ms, 250 Hz,50120 A area (Histed and Miller 2006)). Microstimula-tion currents of up to 200 A did not evoke saccades at anyof the stimulation sites (200 ms, 300 Hz, 0.3 ms biphasicpulses). The eVects of microstimulation on saccadic reac-tion times (SRTs) of pro- and anti-saccades were monitoredon-line during the stimulation session. If no eVect on SRTswas observed after 22 trials per condition (t-tests, P > 0.05for all conditions) at this stimulation site, the electrode wasmoved by at least 500 m and a second data Wle was col-lected for a second stimulation site (same penetration, butdiVerent depth). Data from all sites (those with and withouton-line signiWcant eVects) we

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