Ординатура / Офтальмология / Английские материалы / Eye Movements A Window on Mind and Brain_Van Gompel_2007

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Abstract

We used a blocked design experiment to localize functional brain areas as measured by fMRI. Subjects were instructed before stimulus onset either to look at the stimulus (pro-saccade) or to look away from the stimulus (anti-saccade). The cortical areas localized in the blocked design experiment comparing antiand pro-saccades were then used to examine activation during widely spaced event-related trial presentations. Eye movements were recorded and BOLD signal activation during the event-related experiment was grouped into correct anti-saccades and errors (saccades towards the stimulus on antisaccade trials). Correct anti-saccades were associated with significantly more activity in the right dorsolateral prefrontal cortex, the anterior cingulate cortex, and the supplementary eye fields compared with error anti-saccades, during the instruction period before stimulus appearance. Our findings suggest that rapidly presented trials in blocks elicit similar patterns of BOLD activation to widely spaced event-related trials, and confirm that activation of localized frontal cortical areas prior to stimulus presentation is associated with subjects’ performance in the anti-saccade task.

The cognitive control of action requires the ability to suppress automatic responses that may not be suitable in a given context and instead generate voluntary behaviours. The prefrontal cortex has been proposed to play a role in this process allowing human and animals to exercise behavioural flexibility and pursue long-term goals (Duncan, 2001; Miller, 2000; Miller & Cohen, 2001).

This flexible control of movement has been investigated using the anti-saccade task (Hallett, 1978) in which correct task performance requires subjects to look away from a flashed visual stimulus and to generate a saccade to the mirror opposite location (Everling and Fischer, 1998; Munoz and Everling, 2004). Correct anti-saccade task performance requires both the suppression of an automatic pro-saccade towards the stimulus and the generation of the anti-saccade away from the stimulus to an empty location in the visual field. Subjects sometimes fail to suppress a reflexive saccade towards the stimulus when instructed to generate an anti-saccade. These errors are especially frequent in young children and patients with certain neurological or psychiatric disorders that involve the frontal cortex and/or the basal ganglia (Everling and Fischer, 1998; Munoz and Everling, 2004). Therefore, it has been proposed that these areas provide top-down suppression signals during the preparation to execute an anti-saccade.

Differences between proand anti-saccade trials have been investigated using eventrelated functional magnetic resonance imaging (fMRI) studies in humans. These studies have demonstrated that a number of frontal areas including the dorsolateral prefrontal cortex (DLPFC) (Connolly, Goodale, Menon, & Munoz, 2002; Curtis and D’Esposito 2003; Desouza, Menon, & Everling, 2003; Ford, Goltz, Brown, & Everling, 2005), supplementary eye fields (SEF) (Curtis and D’Esposito, 2003; Ford et al., 2005), and frontal eye fields (FEF) (Connolly et al., 2002; Desouza et al., 2003; Ford et al., 2005) exhibit differences between proand anti-saccade trials during the preparatory period, lending support to the hypothesis that these areas provide top-down suppression signals during the preparation to execute an anti-saccade.

However, to more fully explore the role of these brain regions as potential sources of top-down suppression signals during the preparation to execute an anti-saccade, a direct comparison between correct and error anti-saccade trials has been investigated. If in fact the suppression of saccade neurons in FEF and superior colliculus is necessary for correct anti-saccade task performance as has been suggested by single neuron recordings in the monkey (Everling & Munoz, 2000; Everling, Dorris, & Munoz, 1998) and these frontal areas play a role in providing top-down suppression signals as has been suggested by single neuron recordings in SEF (Amador, Schlag-Rey, & Schlag, 2003; Schlag-Rey, Amador, Sanchez, & Schlag, 1997) and other studies of frontal area function (Gaymard, Ploner, Rivaud, Vermersch, & Pierrot-Deseilligny, 1998; Guitton, Buchtel, & Douglas, 1985; Pierrot-Deseilligny et al., 2003), then it can be hypothesized that frontal brain areas should show increased activation on trials in which the automatic pro-saccade is successfully suppressed (correct anti-saccade trial) as compared to trials in which the automatic pro-saccade is not suppressed (error anti-saccade trial).

Several recent fMRI studies have examined differences in preparatory activation between correct and error anti-saccades. One study by Curtis and D’Esposito (2003) utilized a region of interest (ROI) analysis. However, previous research indicates that a large network of brain areas are differentially modulated during the execution of proand anti-saccades, and this limited ROI analysis may not have captured all potentially modulated areas. A recent study from our group examined differences between pro-saccades, correct anti-saccades and error anti-saccades during the preparatory and saccade periods utilizing an event-related trial design and whole brain general linear model (GLM) analysis (Ford, Goltz, Brown, & Everling, 2005). Results from this study indicated that a number of areas exhibited increased activation during the preparatory period for correct anti-saccades as compared with errors, including right DLPFC, anterior cingulate cortex (ACC) and pre-SEF. In addition, one area in the superior frontal sulcus (SFS) showed the opposite pattern of activation, with increased activation for errors compared to correct anti-saccades. However, this analysis left several questions unanswered. First, we wished to directly compare cortical activation patterns elicited by rapid blocked trial presentations to those elicited by slow event-related trial presentations. A number of recent fMRI studies have utilized long preparatory periods in an effort to dissociate temporal processing within individual trials (Connolly et al., 2002; Curtis and D’Esposito, 2003; Desouza et al., 2003; Ford et al., 2005). By combining our new blocked experimental data with our event-related data previously analyzed, we investigated the validity of attributing differences exhibited in blocked design experiments to differences demonstrated in slow event-related design experiments. Second, by localizing functional areas using our new blocked design experiment, we were able to perform a new analysis of our event-related data. This new analysis makes no assumptions about the particular temporal waveform shape of the BOLD signal response, therefore allowing for greater sensitivity in our analysis and allowing us to further examine this data for potentially significant differences.

To address these questions subjects performed blocks of proand anti-saccade trials, which were analyzed using a whole brain analysis. We then compared these activations to those we previously localized using our slow event-related design, and examined the brain areas shown to be differently modulated using event-related trials with long preparatory periods.

1. Methods

1.1. Subjects

Ten subjects (Seven male, three female, mean age of 28 years) provided informed consent and participated in this study. All were right handed, could see clearly at arms length without glasses and reported no history of head injury, epilepsy, neurological or psychiatric disorder. The experiments were approved by the University of Western Ontario Review

Board for Health Sciences Research Involving Human Subjects and are in accordance with the 1964 Declaration of Helsinki.

1.2. Experimental task

1.2.1. Blocked design experiment

Blocks of proand anti-saccades were alternated with blocks of fixation, with a fixation control block at the beginning of each scan (Figure 1a). A change in the colour of the white fixation cross-conveyed the instruction to generate a proor anti-saccade upon stimulus presentation. The colours (red, green, or blue) used as the proor anti-saccade instruction were kept constant across functional scans within subjects and were randomized across subjects. Each proor anti-saccade block (see Figure 1a) began with the fixation cross changing color from white to either a red, green or blue. After 1 s, the central fixation cross-disappeared, and 0.2 s of darkness (gap period) were introduced before a peripheral stimulus (white circle, 2 ) was flashed for 0.5 s, either 10 to the left or 10 to the right of the initial fixation cross. Subjects were required to maintain fixation on the central cross during the fixation blocks, the instruction period and the gap period. Subjects were instructed to look towards the stimulus on pro-saccade trials and to look away from the stimulus to its mirror position in the opposite hemifield on anti-saccade trials. The white central fixation cross then reappeared for 0.5 s before the start of the next trial, and subjects were instructed to return gaze to center and fixate the white cross after executing each saccade. Eight saccades (either proor anti-saccades) were executed within each 20 s block. Each block was repeated 8 times (four blocks each of proand anti-saccades) in each functional scan. Each subject performed threeor four-blocked design functional scans. Each scan was 5.33 min. long.

1.2.2. Event-related Experiment

Figure 1b shows the timing of event-related trials. For a detailed description of the event-related trial design refer to our previously published work which also examined this functional data (Ford et al., 2005).

1.2.3. Visual display and eye-tracking

Visual stimuli were generated using SuperLab Pro 2.0 software (Cedrus, San Padro, CA) and presented using fiber optics housed in dual stalks that are placed in front of a subject’s eyes, allowing binocular presentation of visual stimuli (SMI iView-fMRI Eye™ tracking (SensoMotoric Instruments, Needham/Boston, MA) and Silent Vision™ SV-40 21 (Avotec, Stuart, FL)). Eye-tracking was identical for event-related and blocked experiments. For further details of eye-tracking refer to previously published work by Ford and colleagues (2005).

Correct anti-saccades

10°

Errors

5 s

(c)

Figure 1. (a) Visual presentation sequence of blocked design experiment. Each experimental run consisted of 8 saccade blocks (4 pro-saccade, 4 anti-saccade) separated by 20 s blocks of fixation. Eight saccades were executed within each 20-s saccade block. FIX, fixation block; PRO, pro-saccade block; ANTI, anti-saccade block; (b) Visual presentation sequence of the event-related experiment for anti-saccade trials. Each experimental run consisted of 8 anti-saccade trials and 4 pro-saccade trials in a pseudo-random order. ITI, inter-trial interval; PREP, 10s preparatory period; STIM, stimulus presentation; (c) Horizontal eye-position traces from a single subject’s scanning session during functional data acquisition, showing correct anti-saccade eye position traces (black) and error anti-saccades (grey). Note that the subject maintained fixation during the inter-trial period and preparatory period and anti-saccade errors were corrected.

1.2.4. Imaging and data analysis

All imaging data were acquired on a 4-Tesla whole body MRI system (Varian, Palo Alto, CA; Siemens, Erlangen, Germany). Imaging parameters were identical for event-related and blocked experiments and have been previously described (Ford et al., 2005). Analyses

were conducted using BrainVoyager 2000 version 4.8 (Brain Innovation, Maastricht, The Netherlands). Functional runs were scaled to the Talairach standard (Talairach and Tournoux, 1988) and superimposed on anatomical scans for each subject. All functional images underwent motion correction, temporal filtering (linear trend removal, high-pass filter in Fourier domain with cut-off of 6 cycles/run for the event-related experiments and 4 cycles/run for the blocked design experiments, Gaussian filter in time domain with full width at half-maximum (FWHM) of 2.8 s), and spatial filtering (Gaussian filter in spatial domain with FWHM of 4.00 mm). For the blocked design experiments all eye movements were included in the analysis. For the event-related experiment, each trial was analyzed offline using the time-locked eye position traces recorded in the MR scanner, as previously described (Ford et al., 2005).

1.2.5. Statistical analysis of blocked experiment

Functional data from the blocked design experiment were statistically analyzed using the GLM framework with separate boxcar predictor functions for blocks of pro-saccades and anti-saccades. We then convolved these two predictors with the hemodynamic response function as implemented by the BrainVoyager software package. This convolution involves modelling the hemodynamic response function as a gamma curve after Boynton, Engel, Glover, & Heeger (1996) using the parameters tau = 1 25 and delta = 2 5. Data from left and right saccadic eye movements were combined. The GLM analysis resulted in statistical contrast activation maps for the comparison of pro-saccade blocks and anti-saccade blocks (Figure 2) (p < 0 01, corrected for multiple comparisons; and a cluster threshold size of >50 voxels). The functionally mapped brain regions which were shown to exhibit statistically significant differences in BOLD signal intensity between blocks of proand anti-saccades were then used to directly examine the BOLD signal differences between the preparatory periods of correct anti-saccades and error anti-saccades from each subject’s event-related experiments.

1.2.6. New statistical analysis of event-related experiment

Mean BOLD signal time courses for each region identified in the blocked design experiment were then computed for each subject (Figure 3a, C). Raw data from each trial were transformed into % signal change values ((signal – baseline) 100/baseline), where baseline was defined as the average signal over the first 2 s of the trial on a trial-by-trial basis. Ten “within subject” mean activation curves were computed for each of correct anti-saccade and error anti-saccade tasks. Then, “between subjects” mean curves were computed by taking the mean across all 10 subjects for each of the two trial types. To examine the preparatory period we shifted our time series for statistical analysis 2 s forward in time and excluded the first data point to accommodate the hemodynamic response function. Our time series for statistical comparison of the 10 s preparatory period was