Microstimulation of monkey dorsolateral prefrontal cortex impairs antisaccade performance

Download Microstimulation of monkey dorsolateral prefrontal cortex impairs antisaccade performance

Post on 10-Jul-2016

214 views

Category:

Documents

1 download

TRANSCRIPT

<ul><li><p>Exp Brain Res (2008) 190:463473DOI 10.1007/s00221-008-1488-4RESEARCH ARTICLE</p><p>Microstimulation of monkey dorsolateral prefrontal cortex impairs antisaccade performance</p><p>Stephen P. Wegener Kevin Johnston Stefan Everling </p><p>Received: 15 April 2008 / Accepted: 2 July 2008 / Published online: 19 July 2008 Springer-Verlag 2008</p><p>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.</p><p>Keywords Antisaccade Inhibition Prefrontal cortex Saccade Attention</p><p>Introduction</p><p>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</p><p>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.</p><p>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</p><p>S. P. Wegener K. Johnston S. EverlingDepartment of Physiology and Pharmacology, University of Western Ontario, London, ON, Canada</p><p>S. Everling (&amp;)The Centre for Brain and Mind, Robarts Research Institute, 100 Perth Drive, London, ON N6A 5K8, Canadae-mail: severlin@uwo.ca123</p></li><li><p>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).</p><p>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).</p><p>Methods</p><p>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.</p><p>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.</p><p>Behavioral task</p><p>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</p><p>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 (</p></li><li><p>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</p><p>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 &gt; 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) were included in the data analy-sis. We later realized that many of the SRTs had non-nor-mal distributions and we therefore replaced the parametrict-test with non-parametric tests in the oV-line data analysis.Monkeys performed between 22 and 65 trials per condition(176520 trials).</p><p>Fig. 1 Behavioral task and timing of microstimulation. a Monkeyswere required to generate either a saccade to a peripheral stimulus (pro-saccade) or to its diametrically opposite location (antisaccade) depend-ing on Wxation point coloring, either red or green. The paradigmincluded a gap period, i.e., the Wxation point extinguished 200 ms priorto peripheral stimulus onset. b Electrical microstimulation (200 ms,200 Hz, 0.3 ms biphasic pulses, 50 A) was applied at the time ofperipheral stimulus presentation. Eh horizontal eye trace; Stim appliedmicrostimulation; VS peripheral target; FP Wxation point</p><p>Table 1 Percentage of exclud-ed trials (n = 56) Control Microstimulation P value(Wilcoxon)</p><p>Contralateral prosaccadesAnticipation (SRT &lt; 80 ms) 2.4 0.59 2.4 0.62 0.94No response (SRT &gt; 500 ms) 0.0 0.0 0.1 0.51 1.00</p><p>Ipsilateral prosaccadesAnticipation (SRT &lt; 80 ms) 6.3 0.99 7.1 1.15 0.30No response (SRT &gt; 500 ms) 0.2 0.15 0.0 0.0 1.00</p><p>Contralateral antisaccadesAnticipation (SRT &lt; 80 ms) 7.1 0.86 5.5 0.61 0.07No response (SRT &gt; 500 ms) 0.2 1.02 0.1 0.08 1.00</p><p>Ipsilateral antisaccadesAnticipations (SRT &lt; 80 ms) 4.0 0.67 4.2 0.74 0.63No response (SRT &gt; 500 ms) 0.0 0.0 0.1 0.09 1.00123</p></li><li><p>466 Exp Brain Res (2008) 190:463473Data analysis</p><p>In an oV-line analysis, saccade onsets were automaticallyidentiWed by a custom-written computer program usingMATLAB 7.3 (The Mathworks Inc., Natick, MA, USA).</p><p>Saccade onset was deWned as the time when horizontaleye velocity Wrst exceeded 30/s following stimulus presen-tation, while saccade oVset was identiWed as the time, aftersaccade onset, when horizontal eye velocity fell below 30/s.Trials were visually inspected to ensure accurate markingof saccade onset and oVset. Trials with saccadic reactiontimes (SRTs) less than 80 ms or greater than 500 ms wereexcluded as anticipations or no-response trials, respectively(Table 1). Trials with incorrect or broken Wxation were alsoexcluded.</p><p>For each stimulation site, non-parametric Wilcoxon ranksum tests were used to compare SRTs between stimulationand control trials for each of the four task conditions (leftprosaccades, right prosaccades, left antisaccades, right anti-saccades). A site was deWned as signiWcant if the P value ofthis test reached 0.05, n = 38), and black cir-cles those locations which dem-onstrated a signiWcant stimulated change in ipsilateral antisaccadic reaction time (P &lt; 0.05; n = 18). PS principal sulcus; iAS inferior arcuate sulcus; A Anterior; P posterior; M medial; L lateral123</p></li><li><p>Exp Brain Res (2008) 190:463473 467Fig. 3a, bottom panel). This eVect was also consistentacross all eight signiWcant sites (four from Monkey R; fourfrom Monkey W). When mean SRTs were determined fromonly the signiWcant sites, monkey W demonstrated anincrease from 136.0 2.9 ms on control trials to161.3 4.2 ms on microstimulation trials (P &lt; 0.001).Similarly, monkey R showed an increase in mean SRTfrom 179.0 3.5 ms on control trials to 204.3 3.6 ms onmicrostimulation trials.</p><p>Next, we investigated the SRT for contralateral antisac-cades (i.e., stimulus on the ipsilateral side). We found thatthe mean SRT during stimulation trials (176.9 4.1 ms)did not signiWcantly diVer from that during control trials(177.1 3.7 ms; p &gt; 0.90; Figure 3b, top panel).</p><p>For ipsilateral antisaccade trials (i.e., stimulus on the con-tralateral side), DLPFC microstimulation resulted in a sig-niWcant increase in SRT (microstimulation: 188.9 5.4 ms;control: 176.8 4.3 ms; P &lt; 0.001; Fig. 3b, bottom panel).SigniWcant diVerences between microstimulation and con-trol trials were found for 18 sites (10 from Monkey R; 8from Monkey W). Microstimulation at each of these sitesprolonged the SRTs of ipsilateral antisaccades. In monkeyW, SRTs increased from 157.1 1.8 ms on control trials to</p><p>177.4 2.2 ms on microstimulation trials. Similarly, inmonkey R, SRTs increased from 210.6 2.3 ms to237.9 2.6 ms on microstimulation trials.</p><p>These Wndings demonstrate that microstimulation of theright DLPFC increases SRTs for ipsilateral prosaccadesand antisaccades. This eVect was stronger for antisaccadesthan prosaccades when all 56 sites from both monkeys werecompared (P &lt; 0.01; Wilcoxon Sign Rank test) but onlymonkey R showed a signiWcant diVerence (P &lt; 0.05;Wilcoxon Sign Rank test).</p><p>Figure 4 shows the cumulative distribution of SRTsobtained from the two monkeys for the contralateral anti-saccade condition during the experiments in which weobtained signiWcant eVects between microstimulation andcontrol trials in this task condition. Correct antisaccades onmicrostimulation trials (thick dashed lines) had longerSRTs that correct antisaccades on control trials (thick solidlines). Direction errors (thin lines), i.e., prosaccadestowards the stimulus, had shorter SRTs than correct anti-saccades (thick lines). For these sites, it also appears thatdirection errors had short...</p></li></ul>

Recommended

View more >