Kristen A. Ford

Inhibition and generation of saccades: Rapid event-related fMRI of prosaccades, antisaccades, and nogo trials

Flexible, adaptive behavior often requires the inhibition of automatic responses in favor of voluntary response generation. The antisaccade task requires active inhibition of the automatic saccade to a peripheral stimulus followed by generation of a voluntary antisaccade to the opposite location. Previous studies demonstrated greater functional magnetic resonance imaging (fMRI) activation for antisaccades than prosaccades in cortical saccade areas but did not distinguish the relative contributions of saccadic inhibition and generation. To address this question, we compared prosaccades, antisaccades, and nogo trials in a rapid event-related fMRI experiment with ten human subjects (6 female, 4 male). Trials were compound, containing a colored fixation point to cue trial type, followed by a 200-ms gap and then peripheral stimulus presentation and response. Required responses for prosaccade, antisaccade, and nogo trials, respectively, were to generate a saccade to the stimulus, look away from it, and inhibit the automatic saccade while maintaining central fixation. Frontal and supplementary eye fields, anterior cingulate cortex, intraparietal sulcus, and precuneus, exhibited surprisingly similar activation patterns for prosaccade and nogo responses, suggesting that BOLD signal in cortical saccade regions might predominantly reflect visual detection and attention processes rather than saccade generation or inhibition. These regions displayed greater activation for antisaccade responses versus prosaccade or nogo responses, possibly due to visuospatial remapping or increased attention levels in the antisaccade task. In right superior frontal sulcus, right supramarginal gyrus, and posterior cingulate sulcus, activation was greater for nogo compared to prosaccade responses, suggesting a role in active saccadic inhibition.

Hand-eye coordination for rapid pointing movements. Arm movement direction and distance are specified prior to saccade onset.

Visually guided arm movements such as reaching or pointing are accompanied by saccadic eye movements that typically begin prior to motion of the arm. In the past, some degree of coupling between the oculomotor and limb motor systems has been demonstrated by assessing the relative onset times of eye and arm movement, and by the demonstration of a gap effect for arm movement reaction times. However, measures of limb movement onset time based on kinematics are affected by factors such as the relatively high inertia of the limb and neuromechanical delays. The goal of the present study was thus to assess the relative timing of rapid eye and arm movements made to visual targets by examining electromyographic (EMG) activity of limb muscles in conjunction with eye and arm position measures. The observation of a positive correlation between eye and limb EMG onset latencies, and the presence of a gap effect for limb EMG onset times (a reduction in reaction time when a temporal gap is introduced between the disappearance of a central fixation point and the appearance of a new target) both support the idea that eye and arm movement initiation are linked. However, limb EMG onset in most cases precedes saccade onset, and the magnitude of EMG activity prior to eye movement is correlated with both the direction and amplitude of the upcoming arm movement. This suggests that, for the rapid movements studied here, arm movement direction and distance are specified prior to the onset of saccades.

BOLD fMRI activation for anti-saccades in nonhuman primates

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.

Neural Activity in Primate Caudate Nucleus Associated With Pro- and Antisaccades

The basal ganglia (BG) play a central role in movement and it has been demonstrated that the discharge rate of neurons in these structures are modulated by the behavioral context of a given task. Here we used the antisaccade task, in which a saccade toward a flashed visual stimulus must be inhibited in favor of a saccade to the opposite location, to investigate the role of the caudate nucleus, a major input structure of the BG, in flexible behavior. In this study, we recorded extracellular neuronal activity while monkeys performed pro- and antisaccade trials. We identified two populations of neurons: those that preferred contralateral saccades (CSNs) and those that preferred ipsilateral saccades (ISNs). CSNs increased their firing rates for prosaccades, but not for antisaccades, and ISNs increased their firing rates for antisaccades, but not for prosaccades. We propose a model in which CSNs project to the direct BG pathway, facilitating saccades, and ISNs project to the indirect pathway, suppressing saccades. This model suggests one possible mechanism by which these neuronal populations could be modulating activity in the superior colliculus.

Effect of stimulus probability on anti-saccade error rates

Abstract.Subjects sometimes fail to suppress a reflexive saccade towards the flashed stimulus in an anti-saccade task. Here, we studied how error rates in the anti-saccade task varied as a function of saccadic probability. Ten subjects performed 200 anti-saccade trials for each of three saccade-direction probability conditions (20%, 50%, and 80%). We found that as the likelihood of a saccade in a given direction increased, the percentage of pro-saccade errors also increased for stimulus presentations in this direction. These results provide support for the hypothesis that errors in the anti-saccade task are the result of an increased level of motor preparation.

Medial Prefrontal and Anterior Insular Connectivity in Early Schizophrenia and Major Depressive Disorder: A Resting Functional MRI Evaluation of Large-Scale Brain Network Models

Anomalies in the medial prefrontal cortex, anterior insulae, and large-scale brain networks associated with them have been proposed to underlie the pathophysiology of schizophrenia and major depressive disorder (MDD). In this study, we examined the connectivity of the medial prefrontal cortices and anterior insulae in 24 healthy controls, 24 patients with schizophrenia, and 24 patients with MDD early in illness with seed-based resting state functional magnetic resonance imaging analysis using Statistical Probability Mapping. As hypothesized, reduced connectivity was found between the medial prefrontal cortex and the dorsal anterior cingulate cortex and other nodes associated with directed effort in patients with schizophrenia compared to controls while patients with MDD had reduced connectivity between the medial prefrontal cortex and ventral prefrontal emotional encoding regions compared to controls. Reduced connectivity was found between the anterior insulae and the medial prefrontal cortex in schizophrenia compared to controls, but contrary to some models emotion processing regions failed to demonstrate increased connectivity with the medial prefrontal cortex in MDD compared to controls. Although, not statistically significant after correction for multiple comparisons, patients with schizophrenia tended to demonstrate decreased connectivity between basal ganglia-thalamocortical regions and the medial prefrontal cortex compared to patients with MDD, which might be expected as these regions effect action. Results were interpreted to support anomalies in nodes associated with directed effort in schizophrenia and nodes associated with emotional encoding network in MDD compared to healthy controls.

Correlation of brain default mode network activation with bipolarity index in youth with mood disorders

BACKGROUND Major Depressive Disorder (MDD) and Bipolar Disorder (BD) can be difficult to differentiate, as both feature depressive episodes. Here we have utilized fMRI and a measure of trait bipolarity to examine resting-state functional connectivity of brain activation in the default mode network in youth with MDD and BD to isolate trait-specific patterns. METHODS We collected resting-state fMRI scans from thirty youth (15 MDD; 15 BD, Type 1). The Bipolarity Index (BI) was completed by each patients treating psychiatrist. Independent components analysis was used to extract a default mode network component from each participant, and then multiple regression was used to identify correlations between bipolarity and network activation. RESULTS Activation in putamen/claustrum/insula correlated positively with BI; activation in the postcentral gyrus/posterior cingulate gyrus correlated negatively with BI. These correlations did not appear to be driven by movement in the scanner, state depression, gender or lithium use. LIMITATIONS There were group differences in state depression and sex that needed to be statistically covaried; differences in medication use existed between the groups; sample size was not large. CONCLUSIONS The identification of the putamen/claustrum in our positive correlation may indicate a potential trait marker for the psychomotor activation unique to bipolar mania. The negative correlation in the postcentral gyrus/posterior cingulate suggests that this functional inactivation is more specific to MDD and is consistent with previous research. Ultimately, this approach may help to develop techniques to minimize the current clinical dilemma by facilitating the classification between BD and MDD.

Unique functional abnormalities in youth with combined marijuana use and depression: an FMRI study.

Prior research has shown a relationship between early onset marijuana (MJ) use and depression; however, this relationship is complex and poorly understood. Here, we utilized passive music listening and fMRI to examine functional brain activation to a rewarding stimulus in 75 participants [healthy controls (HC), patients with major depressive disorder (MDD), frequent MJ users, and the combination of MDD and MJ (MDD + MJ)]. For each participant, a preferred and neutral piece of instrumental music was determined (utilizing ratings on a standardized scale), and each completed two 6-min fMRI scans of a passive music listening task. Data underwent pre-processing and 61 participants were carried forward for analysis (17 HC, 15 MDD, 15 MJ, 14 MDD + MJ). Two statistical analyses were performed using SPM8, an analysis of covariance with two factors (group × music type) and a whole brain, multiple regression analysis incorporating two predictors of interest [MJ use in past 28 days; and Beck Depression Inventory (BDI) score]. We identified a significant group × music type interaction. Post hoc comparisons showed that the preferred music had significantly greater activation in the MDD + MJ group in areas including the right middle and inferior frontal gyri extending into the claustrum and putamen and the anterior cingulate. No significant differences were identified in MDD, MJ, or HC groups. Multiple regression analysis showed that activation in medial frontal cortex was positively correlated with amount of MJ use, and activation in areas including the insula was negatively correlated with BDI score. Results showed modulation in brain activation during passive music listening specific to MDD, frequent MJ users. This supports the suggestion that frequent MJ use, when combined with MDD, is associated with changes in neurocircuitry involved in reward processing in ways that are absent with either frequent MJ use or MDD alone. This could help inform clinical recommendations for youth with MDD.

Anti-saccade task performance is dependent upon bold activation prior to stimulus presentation: An FMRI study in human subjects

Publisher Summary This chapter discusses a blocked design experiment to localize functional brain areas as measured by Functional Magnetic Resonance Imaging (FMRI). Subjects were instructed before stimulus onset either to look at the stimulus or to look away from the stimulus. The cortical areas localized in the blocked design experiment comparing anti- and 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. 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. The 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.