Mathijs Raemaekers

Function of striatum beyond inhibition and execution of motor responses.

We used functional magnetic resonance imaging (fMRI) to study the role of the striatum in inhibitory motor control. Subjects had to refrain from responding to designated items (STOP trials) within a similar series of motor stimuli. Striatal activation was increased significantly compared to that when responding to all targets within a series of motor stimuli, indicating that the striatum is more active when inhibitory motor control over responses is required. The likelihood of a STOP trial was varied parametrically by varying the number of GO trials before a STOP trial. We could thus measure the effect of expecting a STOP trial on the fMRI response in the striatum. We show for the first time in humans that the striatum becomes more active when the likelihood of inhibiting a planned motor response increases. Our findings suggest that the striatum is critically involved in inhibitory motor control, most likely by controlling the execution of planned motor responses. Hum Brain Mapp, 2005.

Test-retest reliability of fMRI activation during prosaccades and antisaccades

Various studies have investigated reproducibility of fMRI results. Whereas group results can be highly reproducible, individual activity maps tend to vary across sessions. Individual reliability is of importance for the application of fMRI in endophenotype research, where brain activity is linked to genetic polymorphisms. In this study, the test-retest reliability of activation maps during the antisaccade paradigm was assessed for individual and group results. Functional MRI images were acquired during two sessions of prosaccades and antisaccades in twelve healthy subjects using an event-related fMRI design. Reliability was assessed for both individual and group-wise results. In addition, the reliability of differences between subjects was established in predefined regions of interest. The reliability of group activation maps was high for prosaccades and antisaccades, but only moderate for antisaccades vs. prosaccades, probably as a result of low statistical power of individual results. Reproducibility of individual subject maps was highly variable, indicating that reliable results can be obtained in some but not all subjects. Reliability of individual activity maps was largely explained by individual differences in the global temporal signal to noise ratio (SNR). As the global SNR was stable over sessions, it explained a large portion of the differences between subjects in regional brain activation. A low SNR in some subjects may be dealt with either by improving the statistical sensitivity of the fMRI procedure or by subject exclusion. Differences in the global SNR between subjects should be addressed before using regional brain activation as phenotype in genetic studies.

Striatal dysfunction in schizophrenia and unaffected relatives.

BACKGROUND Schizophrenia has been frequently associated with impaired inhibitory control. Such control is known to involve the striatum. Here, we investigate whether impaired inhibitory control is associated with abnormal striatal activation in schizophrenia. First-degree relatives of patients were also tested to examine whether striatal abnormality is associated with schizophrenia, or with the risk for the illness. METHODS Both functional MRI and behavioral data were acquired during a task designed to invoke inhibitory control in 21 patients, 15 unaffected siblings, and 36 matched controls. Subjects must refrain from responding to designated stop cues occurring within a series of motor cues. Subjects could anticipate the occurrence of stop cues as the likelihood of these cues increased in a linear fashion throughout the task. RESULTS Control subjects showed striatal activation while responding to motor cues. This activation increased in a linear fashion when the likelihood of having to inhibit the response was increased. Both patients siblings did not show anticipation-related increase in either striatal activation. However, only patients showed behavioral impairments. CONCLUSIONS Striatal abnormalities occur in schizophrenia patients and unaffected siblings. Thus striatal abnormalities may be related to an increased (genetic) risk to develop schizophrenia.

Within-subject variation in BOLD-fMRI signal changes across repeated measurements: Quantification and implications for sample size

Functional magnetic resonance imaging (fMRI) can be used to detect experimental effects on brain activity across measurements. The success of such studies depends on the size of the experimental effect, the reliability of the measurements, and the number of subjects. Here, we report on the stability of fMRI measurements and provide sample size estimations needed for repeated measurement studies. Stability was quantified in terms of the within-subject standard deviation (sigma(w)) of BOLD signal changes across measurements. In contrast to correlation measures of stability, this statistic does not depend on the between-subjects variance in the sampled group. Sample sizes required for repeated measurements of the same subjects were calculated using this sigma(w). Ten healthy subjects performed a motor task on three occasions, separated by one week, while being scanned. In order to exclude training effects on fMRI stability, all subjects were trained extensively on the task. Task performance, spatial activation pattern, and group-wise BOLD signal changes were highly stable over sessions. In contrast, we found substantial fluctuations (up to half the size of the group mean activation level) in individual activation levels, both in ROIs and in voxels. Given this large degree of instability over sessions, and the fact that the amount of within-subject variation plays a crucial role in determining the success of an fMRI study with repeated measurements, improving stability is essential. In order to guide future studies, sample sizes are provided for a range of experimental effects and levels of stability. Obtaining estimates of these latter two variables is essential for selecting an appropriate number of subjects.

Brain Activation During Antisaccades in Unaffected Relatives of Schizophrenic Patients

BACKGROUND Schizophrenia patients have difficulty inhibiting automatic saccades. Many studies have failed to resolve whether healthy first-degree relatives share the same deficit. Measures of brain activity may be more sensitive than behavioral measures. In patients, the saccadic inhibition deficit has been related to impaired frontostriatal functioning. This study attempts to establish whether this abnormality is also present in unaffected relatives of patients. METHODS Functional brain images were acquired during prosaccades and antisaccades in 16 control subjects and 16 unaffected siblings of schizophrenia patients using an event-related functional magnetic resonance imaging design. Eye movements were measured during scanning. RESULTS The task activated a network of regions corresponding to the oculomotor system. Siblings and control subjects did not differ during execution of prosaccades. During antisaccades, siblings did not activate the caudate nucleus. Siblings and control subjects did not differ on the percentage of antisaccade errors. CONCLUSIONS Siblings did not appropriately activate the striatum during antisaccades, similar to what has been reported in patients. Siblings, however, did not make significantly more errors during antisaccades, indicating that they were able to compensate for the inactive caudate. Future research is needed to assess the potential of this striatal deficit as (genetic) risk factor for schizophrenia.

Effects of Aging on BOLD fMRI during Prosaccades and Antisaccades

Age affects the ability to inhibit saccadic eye movements. According to current theories, this may be associated with age-induced neurophysiological changes in the brain and with compensatory activation in frontal brain areas. In the present study, the effects of aging are assessed on brain systems that subserve generation and inhibition of saccadic eye movements. For this purpose, an event-related functional magnetic resonance imaging design was used in adults covering three age ranges (1830, 3055, and 5572 years). Group differences were controlled for task performance. Activity associated with saccadic inhibition was represented by the contrast between prosaccade and antisaccade activation. The tasks activated well-documented networks of regions known to be involved in generation and inhibition of saccadic eye movements. There was an age-related shift in activity from posterior to frontal brain regions after young adulthood. In addition, old adults demonstrated an overall reduction in the blood oxygenation level dependent (BOLD) signal in the visual and oculomotor system. Age, however, did not affect saccade inhibition activity. Mid and old adults appear to increase frontal activation to maintain performance even during simple prosaccades. The global reduction of the BOLD response in old adults could reflect a reduction in neural activity, as well as changes in the neuronal-vascular coupling. Future research should address the impact of altered vascular dynamics on neural activation and the BOLD signal.

Cortical and subcortical contributions to saccade latency in the human brain

An important property of our motor system is the ability to either perform or inhibit an automatic goal‐directed reaction. Imagine, for example, how easily we can catch a ball, while at the same time we would never grasp a stinging insect approaching us. The oculomotor system provides a good model to study this ability. Monkey midbrain superior colliculus neurons are responsible for automatic visually evoked saccades, whereas the frontal eye fields can prevent reflexive glances. Little is known about human superior colliculus or the competition between the midbrain and frontal areas controlling saccades. In the present functional magnetic resonance study we used the gap paradigm, where a stimulus fixated with the eyes is removed 200 ms prior to saccade target onset. Subjects were required to either look at the target or prevent an eye movement. From what is known from non‐human primate neurophysiology, it is expected that the gap will result in enlarged neuronal activity in the human superior colliculus, disinhibiting the oculomotor system and enhancing automatic reactions. Importantly, we demonstrate that the human superior colliculus homologue is indeed activated by the removal of a fixation target, in either task. The frontal eye fields show a reverse pattern when saccades were suppressed. Furthermore, magnitude of responses in the superior colliculus correlated negatively with saccade latency, and in the frontal eye fields positively. These findings confirm for the first time that the human superior colliculus generates automatic goal‐directed saccades, whereas the frontal eye fields can exert volitional control over automatic orienting.

Task and task‐free FMRI reproducibility comparison for motor network identification

Test‐retest reliability of individual functional magnetic resonance imaging (fMRI) results is of importance in clinical practice and longitudinal experiments. While several studies have investigated reliability of task‐induced motor network activation, less is known about the reliability of the task‐free motor network. Here, we investigate the reproducibility of task‐free fMRI, and compare it to motor task activity. Sixteen healthy subjects participated in this study with a test‐retest interval of seven weeks. The task‐free motor network was assessed with a univariate, seed‐voxel‐based correlation analysis. Reproducibility was tested by means of intraclass correlation (ICC) values and ratio of overlap. Higher ICC values and a better overlap were found for task fMRI as compared to task‐free fMRI. Furthermore, ratio of overlap improved for task fMRI at higher thresholds, while it decreased for task‐free fMRI, suggesting a less focal spatial pattern of the motor network during resting state. However, for both techniques the most active voxels were located in the primary motor cortex. This indicates that, just like task fMRI, task‐free fMRI can properly identify critical brain areas for motor task performance. Although both fMRI techniques are able to detect the motor network, resting‐state fMRI is less reliable than task fMRI. Hum Brain Mapp 35:340–352, 2014.

Patterns of resting state connectivity in human primary visual cortical areas: A 7T fMRI study

The nature and origin of fMRI resting state fluctuations and connectivity are still not fully known. More detailed knowledge on the relationship between resting state patterns and brain function may help to elucidate this matter. We therefore performed an in depth study of how resting state fluctuations map to the well known architecture of the visual system. We investigated resting state connectivity at both a fine and large scale within and across visual areas V1, V2 and V3 in ten human subjects using a 7Tesla scanner. We found evidence for several coexisting and overlapping connectivity structures at different spatial scales. At the fine-scale level we found enhanced connectivity between the same topographic locations in the fieldmaps of V1, V2 and V3, enhanced connectivity to the contralateral functional homologue, and to a lesser extent enhanced connectivity between iso-eccentric locations within the same visual area. However, by far the largest proportion of the resting state fluctuations occurred within large-scale bilateral networks. These large-scale networks mapped to some extent onto the architecture of the visual system and could thereby obscure fine-scale connectivity. In fact, most of the fine-scale connectivity only became apparent after the large-scale network fluctuations were filtered from the timeseries. We conclude that fMRI resting state fluctuations in the visual cortex may in fact be a composite signal of different overlapping sources. Isolating the different sources could enhance correlations between BOLD and electrophysiological correlates of resting state activity.

Test-retest variability underlying fMRI measurements

INTRODUCTION A high test-retest reliability is of pivotal importance for many disciplines in fMRI research. To assess the current limits of fMRI reliability, we estimated the variability in true underlying Blood Oxygen Level Dependent (BOLD) activation, with which we mean the variability that would be found in the theoretical case when we could obtain an unlimited number of scans in each measurement. METHODS In this test-retest study, subjects were scanned twice with one week apart, while performing a visual and a motor inhibition task. We addressed the nature of the variability in the underlying BOLD signal, by separating for each brain area and each subject the between-session differences in the spatial pattern of BOLD activation, and the global (whole brain) changes in the amplitude of the spatial pattern of BOLD activation. RESULTS We found evidence for changes in the true underlying spatial pattern of BOLD activation for both tasks across the two sessions. The sizes of these changes in pattern activation were approximately 16% of the total activation within the pattern, irrespective of brain area and task. After spatial smoothing, this variability was greatly reduced, which suggests it takes place at a small spatial scale. The mean between-session differences in the amplitude of activation across the whole brain were 13.8% for the visual task and 23.4% for the motor inhibition task. CONCLUSIONS Between-session changes in the true underlying spatial pattern of BOLD activation are always present, but occur at a scale that is consistent with partial voluming effects or spatial distortions. We found no evidence that the reliability of the spatial pattern of activation differs systematically between brain areas. Consequently, between-session changes in the amplitude of activation are probably due to global effects. The observed variability in amplitude across sessions warrants caution when interpreting fMRI estimates of height of brain activation. A Matlab implementation of the used algorithm is available for download at www.ni-utrecht.nl/downloads/ura.