Relation between regional functional MRI activation and vascular reactivity to carbon dioxide during normal aging.

Recent blood oxygenation level-dependent (BOLD) functional magnetic resonance imaging studies have shown a reduction of cerebral activation during aging, which may be associated with age-related changes of the cerebral vascular system. The authors used a global hypercapnic breath-holding challenge to define nonneuronal contributions to a significantly reduced activation in the primary sensorimotor cortex during finger tapping in a group of old (n = 6; mean age 65 years) compared with a group of young (n = 6; mean age 27 years) subjects. Within significantly activated voxels in both groups during finger tapping, the mean BOLD signal amplitudes were significantly smaller in the group of older subjects for both tasks. In those voxels showing significant activation only in young subjects during finger tapping, the response to hypercapnia was also greatly diminished in older subjects. The attenuated hypercapnic BOLD signal response in older subjects within this region suggests that age-dependent changes of the cerebral vasculature may alter the neuronal-vascular coupling. In older subjects, cerebral vessels may not react as effectively in response to a vasodilating stimulus, which will lead to differences in the number of voxels that pass a criterion threshold despite similar neuronal activation.     

Task demand modulation of steady-state functional connectivity to primary motor cortex

Correlations in blood oxygen level-dependent (BOLD) MRI signals from separate areas within the human brain have been used as a measure of functional connectivity. Steady-state measures of interregional correlations are particularly useful because they do not depend on the specific design of a task nor on subtracting conditions in a blocked design task. However, the conditions under which such correlations are measured may influence these indices of functional connectivity. The aim of this study was to investigate the influence of task demand on interregional correlations within the motor system. Specifically, tapping rates in audibly paced finger-tapping tasks were controlled and varied between runs in order to observe their effects on interregional correlations to contralateral primary motor cortex (PM). Regions of interest included the supplementary motor area, ipsilateral cerebellum, ipsilateral auditory cortex, and a control region. It was found that tapping rate was a significant factor in determining the mean correlation of some regions to PM, and that correlations measured during tapping in general increased relative to resting state. Furthermore, analysis of the percent of voxels in each region significantly correlated to PM suggested that changes in the mean correlation of that region to PM could be accounted for by changes in the fraction of significantly correlated voxels within a region. This provides insight into the manner in which steady-state correlations are modified in response to different task demands and further evidence that low-frequency fluctuations in BOLD signals reflect functional connectivity.     

A pilot study of somatotopic mapping after cortical infarct

BACKGROUND AND PURPOSE: Animal studies have described remodeling of sensory and motor representational maps after cortical infarct. These changes may contribute to return of function after stroke. METHODS: Functional MRI was used to compare sensory and motor maps obtained in 35 normal control subjects with results from 2 patients with good recovery 6 months after a cortical stroke. RESULTS: During finger tapping in controls, precentral gyrus activation exceeded or matched postcentral gyrus activation in 40 of 42 cases. Patient 1 had a small infarct limited to precentral gyrus. Finger tapping activated only postcentral gyrus, a pattern not seen in any control subject. During tactile stimulation of a finger or hand in controls, postcentral gyrus activation exceeded or matched precentral gyrus activation in 11 of 14 cases. Patient 2 had a small infarct limited to postcentral gyrus and superior parietal lobule. Tactile stimulation of the finger activated only precentral gyrus, a pattern not seen in any control. In both patients, activation during pectoralis contraction was medial to the site activated during finger tapping. CONCLUSIONS: Results during finger tapping (patient 1) and finger stimulation (patient 2) may reflect amplification of a preserved component of normal sensorimotor function, a shift in the cortical site of finger representation, or both. Cortical map reorganization along the infarct rim may be an important contributor to recovery of motor and sensory function after stroke. Functional MRI is useful for assessing motor and sensory representational maps.     

High signal intensity on magnetic resonance imaging as a predictor of neurobehavioral performance of workers exposed to manganese

INTRODUCTION: Using previously obtained cross-sectional data from a nationwide survey on workers exposed to manganese (Mn), we assessed the relation of high signal intensity with neurobehavioral effects, and reevaluated the preexisting cross-sectional data to get additional findings on the relation of high signals with other Mn-exposure indices. SUBJECTS AND METHODS: Subjects were the same as those in the previous study. The exposure status was reassessed based on similar exposure groups. The signal intensity of the globus pallidus (GP) relative to frontal white matter was subjectively evaluated as either with or without increased signals, and the increased signals were further graded into three categories. For quantitative evaluation of signal intensities of the GP we also calculated the pallidal index (PI). Neurobehavioral function was assessed using the World Health Organization Neurobehavioral Core Test Battery. In addition, computerized finger tapping speed was included to assess motor speed. RESULTS: The mean blood Mn for those with grade III was significantly greater than those without increased signals and those with grade I. Airborne Mn and PI also showed similar findings. PI paralleled subjective MRI gradings. The proportion of workers with increased signals increased with all the Mn-exposure variables, airborne and blood Mn, the duration of work, and cumulative exposure. The PI was significantly associated with a correct score of pursuit aiming II tests and finger tapping of the dominant hand after control of age and educational level among neurobehavioral performances. DISCUSSION: The present findings showed that signal index on T1-weighted MRI showed a dose-response relationship with all the Mn-exposure variables. The two neurobehavioral tests reflecting fine motor function were significantly decreased above 107.1 of PI, the cutoff point between those with and without increased signals. Hence, signal intensity on MRI is an effective predictor of the neurobehavioral performance of Mn exposed workers.     

Spatial nonuniformity of the resting CBF and BOLD responses to sevoflurane: in vivo study of normal human subjects with magnetic resonance imaging

Pulsed arterial spin labeling magnetic resonance imaging (MRI) was performed to investigate the local coupling between resting regional cerebral blood flow (rCBF) and BOLD (blood oxygen level dependent) signal changes in 22 normal human subjects during the administration of 0.25 MAC (minimum alveolar concentration) sevoflurane. Two states were compared with subjects at rest: anesthesia and no-anesthesia. Regions of both significantly increased and decreased resting-state rCBF were observed. Increases were limited primarily to subcortical structures and insula, whereas, decreases were observed primarily in neocortical regions. No significant change was found in global CBF (gCBF). By simultaneously measuring rCBF and BOLD, region-specific anesthetic effects on the coupling between rCBF and BOLD were identified. Multiple comparisons of the agent-induced rCBF and BOLD changes demonstrated significant (P < 0.05) spatial variability in rCBF-BOLD coupling. The slope of the linear regression line for AC, where rCBF was increased by sevoflurane, was markedly smaller than the slope for those ROIs where rCBF was decreased by sevoflurane, indicating a bigger change in BOLD per unit change in rCBF in regions where rCBF was increased by sevoflurane. These results suggest that it would be inaccurate to use a global quantitative model to describe coupling across all brain regions and in all anesthesia conditions. The observed spatial nonuniformity of rCBF and BOLD signal changes suggests that any interpretation of BOLD fMRI data in the presence of an anesthetic requires consideration of these insights.     

The influence of external timing cues upon the rhythm of voluntary movements in Parkinson''s disease.

The ability of patients with Parkinson's disease (PD) and healthy subjects to synchronise finger tapping, produced by rhythmic wrist movements, with auditory signals of target frequencies (range 1-5 Hz) and to sustain such rhythms following sudden withdrawal of auditory cues was studied. Healthy subjects were able, in the presence of auditory cues, to duplicate target frequencies accurately over the range investigated both in terms of mean tapping rate and in regularity of tapping. PD patients were less accurate under these conditions and on average tended to tap too rapidly at the lower (1-3 Hz) target frequencies and too slowly at the highest (5 Hz) target frequency. In addition, the variability of their tapping rhythms was generally greater. Healthy subjects were able to sustain tapping rhythms well following suppression of auditory signals. By contrast, withdrawal of external timing cues resulted in marked impairment of the patients' rhythm generation. At lower frequency targets (1-3 Hz) patients' tapping rates increased over rates which were already elevated in the presence of external cues. Conversely, at higher target frequencies (4-5 Hz), the average tapping rate tended to decline further from previously depressed levels. The accuracy of almost all patients fell outside the normal range. Two patterns of tapping errors were found. The first was hastening of tapping which was most evident at intermediate target frequencies. The second was faltering which occurred mainly at the higher target frequencies. These forms of behaviour may result from inherent abnormalities of internal rhythm generation since they occurred both in the presence and absence of external timing signals. Overall, our findings are consistent with the view that the basal ganglia have a role in the internal cueing of repetitive voluntary movements.     

Functional changes of the cortical motor system in hereditary spastic paraparesis

Background – Hereditary spastic paraparesis (HSP) is a heterogeneous group of disorders characterized by progressive bilateral lower limb spasticity. Functional imaging studies in patients with corticospinal tract involvement have shown reorganization of motor circuitry. Our study investigates functional changes in sensorimotor brain areas in patients with HSP. Methods – Twelve subjects with HSP and 12 healthy subjects were studied. Functional magnetic resonance imaging (fMRI) was used to measure brain activation during right‐hand finger tapping. Image analysis was performed using general linear model and regions of interest (ROI)‐based approach. Weighted laterality indices (wLI) and anterior/posterior indicies (wAI and wPI) were calculated for predefined ROIs. Results and discussion – Comparing patients and controls at the same finger‐tapping rate (1.8 Hz), there was increased fMRI activation in patients’ bilateral posterior parietal cortex and left primary sensorimotor cortex. No differences were found when comparing patients and controls at 80% of their individual maximum tapping rates. wLI of the primary sensorimotor cortex was significantly lower in patients. Subjects with HSP also showed a relative increase in the activation of the posterior parietal and premotor areas compared with that of the primary sensorimotor cortex. Our findings demonstrate an altered pattern of cortical activation in subjects with HSP during motor task. The increased activation probably reflects reorganization of the cortical motor system.     

Functional magnetic resonance imaging in schizophrenia: cortical response to motor stimulation

Previous functional magnetic resonance imaging (fMRI) studies suggest that motor system abnormalities are present in schizophrenia. However, these studies have often produced conflicting or ambiguous findings. The purpose of this study was to ascertain whether activation differences could be identified in stable schizophrenic patients on the basis of BOLD measures in two motor regions, the primary motor cortex, Brodmann area 4 (BA4) and the premotor and supplementary motor area, Brodmann area 6 (BA6). Twenty-one schizophrenic patients and 21 healthy control subjects were studied with BOLD fMRI methods during a sequential finger tapping task. Statistical parametric maps were generated for each subject, and anatomic regions were automatically defined using an anatomic atlas. Compared with controls, the schizophrenic patients showed a significant reduction in contralateral activation for both BA4 and BA6 (P<0.001), and in ipsilateral activation in BA4 (P=0.007) and BA6 (P=0.002). In healthy controls, the coactivation in the ipsilateral cortex is reduced in comparison with the contralateral cortex for right and left handed tasks. In BA4, this reduction is significant for right (P=0.007) and left (P=0.003) finger tapping. Similar results were obtained for BA6. Further analyses are necessary to evaluate the activation in other motor system regions.     

Cortical correlates of neuromotor development in healthy children.

OBJECTIVE: To examine the relationship between acquisition of fine motor skills in childhood and development of the motor cortex. METHODS: We measured finger tapping speed and mirror movements in 43 healthy right-handed subjects (6-26 years of age). While recording surface electromyographic activity from right and left first dorsal interosseus, we delivered focal transcranial magnetic stimulation (TMS) over the hand areas of each motor cortex. We measured motor evoked potential (MEP) threshold, and ipsilateral (iSP) and contralateral (CSP) silent periods. RESULTS: As children got older, finger speeds got faster, MEP threshold decreased, iSP duration increased and latency decreased. Finger tapping speed got faster as motor thresholds and iSP latency decreased, but was unrelated to CSP duration. In all subjects right hemisphere MEP thresholds were higher than those on the left and duration of right hemisphere CSP was longer than that on the left. Children under 10 years of age had higher left hand mirror movement scores, and fewer left hemisphere iSPs which were of longer duration. CONCLUSIONS: Maturation of finger tapping skills is closely related to developmental changes in the motor threshold and iSP latency. Studies are warranted to explore the relationship between these measures and other neuromotor skills in children with motor disorders. SIGNIFICANCE: TMS can provide important insights into certain functional aspects of neurodevelopment in children.     

受病变累及的运动中枢fMR表现

目的观察正常及受病变累及的运动中枢的脑功能核磁共振成像(fMR)表现.方法通过双手对指运动使运动中枢功能活跃,然后对14例正常志愿者和36例运动中枢受累的病人进行运动功能区血氧水平依赖法(BOLD)fMR成像.结果通过双手对指运动使运动中枢功能活跃,正常志愿者和病人脑内产生了相应的功能信号,表现为功能区信号增高.在正常志愿者中,双侧半球运动功能区的位置基本对称,但大部分志愿者左侧半球功能信号稍强于对侧半球.在累及运动中枢病变的病人中,病变侧功能信号全部位于病变外或病变边缘,病变内未见功能信号.病侧功能区主要表现为功能信号降低、移位.结论BOLD法fMR可以很好的显示正常和病变的运动中枢,是评价运动中枢的有效方法.     

Functional magnetic resonance imaging in schizophrenia: cortical response to motor stimulation

Previous functional magnetic resonance imaging (fMRI) studies suggest that motor system abnormalities are present in schizophrenia. However, these studies have often produced conflicting or ambiguous findings. The purpose of this study was to ascertain whether activation differences could be identified in stable schizophrenic patients on the basis of BOLD measures in two motor regions, the primary motor cortex, Brodmann area 4 (BA4) and the premotor and supplementary motor area, Brodmann area 6 (BA6). Twenty-one schizophrenic patients and 21 healthy control subjects were studied with BOLD fMRI methods during a sequential finger tapping task. Statistical parametric maps were generated for each subject, and anatomic regions were automatically defined using an anatomic atlas. Compared with controls, the schizophrenic patients showed a significant reduction in contralateral activation for both BA4 and BA6 (P<0.001), and in ipsilateral activation in BA4 (P=0.007) and BA6 (P=0.002). In healthy controls, the coactivation in the ipsilateral cortex is reduced in comparison with the contralateral cortex for right and left handed tasks. In BA4, this reduction is significant for right (P=0.007) and left (P=0.003) finger tapping. Similar results were obtained for BA6. Further analyses are necessary to evaluate the activation in other motor system regions.     

Mechanical flutter stimulation induces a lasting response in the sensorimotor cortex as revealed with BOLD fMRI

It has been recently shown that 20 min of mechanical flutter stimulation induces lasting motor cortical excitability changes, as assessed by transcranial magnetic stimulation in relaxed hand muscles. The present functional magnetic resonance imaging (fMRI) study aims to examine if such neuromodulatory changes are reflected in the BOLD signal during a motor test. Therefore, two groups were recruited: one group receiving whole‐hand flutter stimulation with a frequency of 25 Hz (FSTIM group, n = 22) and a second group receiving no stimulation (NOSTIM group, n = 22). As motor test finger‐to‐thumb tapping was performed to activate a wide sensorimotor network during the fMRI measurements. Three fMRI measurements were obtained with this test: before stimulation (PRE), after stimulation (POST1), and 1 h after stimulation (POST2). Three regions of interest (ROIs) were defined: primary motor area (M1), primary somatosensory area (S1), and supplementary motor area. In the absence of baseline differences between both groups, the FSTIM group showed increased movement‐related brain activations compared with the NOSTIM group, both at POST1 and POST2. ROI analysis revealed increased blood‐oxygenation‐level‐dependent (BOLD) responses within contralateral S1 (+20%) and M1 (+25%) at POST1, which lasted until POST2. These poststimulatory effects within S1 and M1 obviously reflect neuroplastic changes associated with augmented cortical excitability. These findings are of high clinical relevance, for example, to improve the treatment of stroke patients. Hum Brain Mapp 34:2767–2774, 2013. © 2012 Wiley Periodicals, Inc.     

BOLD fMRI signal increases with age in selected brain regions in children

To determine whether the BOLD signal used in fMRI is age dependent in childhood, 332 healthy children (age 4.9-18.9 years) performed tasks in a periodic block design during 3 T fMRI: (1) a verb generation task interleaved with a finger tapping task; (2) a word-picture matching task interleaved with an image discrimination task. Significant correlations between percent signal change in BOLD effect and age occurred in left Broca's, middle frontal, Wernicke's, and inferior parietal regions, and anterior cingulate during the verb generation task; in precentral, postcentral, middle frontal, supplementary motor, and precuneus regions during the finger tapping task; and in bilateral lingula gyri during the word-picture matching task. Thus, BOLD effect increases with age in children during sensorimotor and language tasks.     

The power of spectral density analysis for mapping endogenous BOLD signal fluctuations

FMRI has revealed the presence of correlated low-frequency cerebro-vascular oscillations within functional brain systems, which are thought to reflect an intrinsic feature of large-scale neural activity. The spatial correlations shown by these fluctuations has been their identifying feature, distinguishing them from fluctuations associated with other processes. Major analysis methods characterize these correlations, identifying networks and their interactions with various factors. However, other analysis approaches are required to fully characterize the regional signal dynamics contributing to these correlations between regions. In this study we show that analysis of the power spectral density (PSD) of regional signals can identify changes in oscillatory dynamics across conditions, and is able to characterize the nature and spatial extent of signal changes underlying changes in measures of connectivity. We analyzed spectral density changes in sessions consisting of both resting-state scans and scans recording 2 min blocks of continuous unilateral finger tapping and rest. We assessed the relationship of PSD and connectivity measures by additionally tracking correlations between selected motor regions. Spectral density gradually increased in gray and white matter during the experiment. Finger tapping produced widespread decreases in low-frequency spectral density. This change was symmetric across the cortex, and extended beyond both the lateralized task-related signal increases, and the established "resting-state" motor network. Correlations between motor regions also reduced with task performance. In conclusion, analysis of PSD is a sensitive method for detecting and characterizing BOLD signal oscillations that can enhance the analysis of network connectivity.     

Cerebral blood flow and BOLD fMRI responses to hypoxia in awake and anesthetized rats

This study investigated the functional MRI responses to graded hypoxia in awake/restrained and anesthetized animals by measuring cerebral blood flow (CBF) and blood oxygenation (BOLD) changes and estimating changes in cerebral metabolic rate of oxygen (CMRO2). Hypoxia in isoflurane anesthetized rats reduced blood pressure but did not change heart rate and respiration rate. In contrast, hypoxia in awake animals showed compensatory responses by sustaining blood pressure, increasing heart rate and respiration rate. Basal CBF was higher under isoflurane anesthesia than awake state because isoflurane is a vasodilator. Graded hypoxia decreased BOLD signals. Surprisingly, hypoxia also decreased CBF likely because hypoxia induced hypocapnia. Hypoxia-induced CBF and BOLD decreases were smaller in awake, relative to anesthetized, rats at low pO2, but similar at high pO2. CBF leveled off with decreasing hypoxia-induced pCO2 in awake rats, but monotonically decreased in anesthetized rats. CMRO2 estimated using a biophysical BOLD model did not change under mild hypoxia but was reduced under severe hypoxia relative to baseline. These results showed that isoflurane attenuated autonomic responses to hypoxia, hypoxia-induced hypocapnia dominated CBF changes, tissues in awake conditions appeared better oxygenated, and severe hypoxia reduced oxygen metabolism. This study underscored the marked differences in BOLD and CBF MRI responses to hypoxia in vivo between awake and anesthetized conditions and has implications for functional MRI studies of hypoxia in anesthetized animal models.     

High-resolution CMR(O2) mapping in rat cortex: a multiparametric approach to calibration of BOLD image contrast at 7 Tesla.

The blood oxygenation level-dependent (BOLD) functional magnetic resonance imaging (fMRI) method, which is sensitive to vascular paramagnetic deoxyhemoglobin, is dependent on regional values of cerebral metabolic rate of oxygen utilization (CMR(O2)), blood flow (CBF), and volume (CBV). Induced changes in deoxyhemoglobin function as an endogenous contrast agent, which in turn affects the transverse relaxation rates of tissue water that can be measured by gradient-echo and spin-echo sequences in BOLD fMRI. The purpose here was to define the quantitative relation between BOLD signal change and underlying physiologic parameters. To this end, magnetic resonance imaging and spectroscopy methods were used to measure CBF, CMR(O2), CBV, and relaxation rates (with gradient-echo and spin-echo sequences) at 7 Tesla in rat sensorimotor cortex, where cerebral activity was altered pharmacologically within the autoregulatory range. The changes in tissue transverse relaxation rates were negatively and linearly correlated with changes in CBF, CMR(O2), and CBV. The multiparametric measurements revealed that CBF and CMR(O2) are the dominant physiologic parameters that modulate the BOLD fMRI signal, where the ratios of (deltaCMR(O2)/CMR(O2)/(deltaCBF/ CBF) and (deltaCBV/CBV)/(deltaCBF/CBF) were 0.86 +/- 0.02 and 0.03 +/- 0.02, respectively. The calibrated BOLD signals (spatial resolution of 48 microL) from gradient-echo and spin-echo sequences were used to predict changes in CMR(O2) using measured changes in CBF, CBV, and transverse relaxation rates. The excellent agreement between measured and predicted values for changes in CMR(O2) provides experimental support of the current theory of the BOLD phenomenon. In gradient-echo sequences, BOLD contrast is affected by reversible processes such as static inhomogeneities and slow diffusion, whereas in spin-echo sequences these effects are refocused and are mainly altered by extravascular spin diffusion. This study provides steps by which multiparametric MRI measurements can be used to obtain high-spatial resolution CMR(O2) maps.     

Caffeine attenuates practice effects in word stem completion as measured by fMRI BOLD signal

Caffeine ingestion results in increased brain cell metabolism (Nehlig et al. [1992] Brain Res Brain Res Rev 17:139-170) and decreased cerebral blood flow (Field et al. [2003] Radiology 227:129-135; Mulderink et al. [2002] Neuroimage 15:37-44). The current study investigated the effect of caffeine in a word stem completion task using only novel word stems (no repeated stimuli). Resting perfusion was measured with arterial spin labeled perfusion MRI, along with blood oxygenation level-dependent (BOLD) signal before and after ingestion of regular coffee, decaffeinated coffee, and water. Based on previous research (Laurienti et al. [2002] Neuroimage 17:751-757; Mulderink et al. [2002] Neuroimage 15:37-44), we hypothesized that caffeine would result in increased BOLD signal intensity and extent of BOLD activation. As expected, caffeine resulted in a significant decrease in cerebral perfusion. However, both the control and caffeine groups showed an increase in BOLD signal amplitude across two sets of novel word stems. Additionally, the control group showed a 50% reduction in the extent of BOLD activation, while the caffeine group showed no change in activation extent. Neither group showed changes in BOLD baseline signal over time, which had been suggested to mediate caffeine-related BOLD signal changes. The results suggest that caffeine may attenuate general task practice effects that have been described in recent functional MRI studies of word stem completion (Buckner et al. [2000] Brain 123:620-640).     

Dextroamphetamine causes a change in regional brain activity in vivo during cognitive tasks: a functional magnetic resonance imaging study of blood oxygen level-dependent response.

BACKGROUND: Dextroamphetamine is known to have profound effects on both subjective and physiologic measurements, but it is unclear to what extent these behavioral changes are a direct result of altered regional brain activation. One method to measure this is to use functional magnetic resonance imaging (fMRI). METHODS: In the present study, fMRI was used to measure both the spatial extent of changes (the number of pixels activated) and the magnitude of the blood oxygen level-dependent (BOLD) response. We examined the effects of motor, verbal, memory, and spatial attention task during fMRI in 18 healthy volunteers. Functional MRI measurements were obtained at baseline and again 75 min after an oral dose of 25 mg dextroamphetamine. RESULTS: Dextroamphetamine caused a decrease in the number of activated pixels and the magnitude of the BOLD response during the three cognitive tasks tested but not during the motor task. These changes were region and task specific. CONCLUSIONS: This is the first study to examine the effect of dextroamphetamine on the number of activated pixels and the BOLD response during the performance of a range of cognitive and motor tasks. Our results suggest that dextroamphetamine causes measurable decreases in brain activity in a variety of regions during cognitive tasks. These changes might be linked to behavioral changes observed after dextroamphetamine administration and could possibly be mediated by alterations in dopaminergic activation.     

Tapping movements according to regular and irregular visual timing signals investigated with fMRI

Whole-head functional MR images were acquired while 10 subjects were asked to tap with their right index finger in synchrony with a visual stimulus appearing regularly with a frequency of 1.5 Hz, or irregularly with a mean frequency of 1.5 Hz. Performance data show that during regular tapping most taps were close to stimulus onset. However, when the subjects paced their tapping according to the irregular stimuli, most taps appeared about 300 ms after the onset of the pacing stimuli. Comparing the brain activations resulting from regular tapping with those from irregular tapping, we found increased activation in left precuneus only. Comparing irregular versus regular tapping shows increased activity in right cerebellar nuclei and vermis, left ventrolateral thalamus, left sensorimotor cortex, left and right pre-SMA and left SMA proper. These results show that during irregular pacing the motor areas are more strongly activated than during regular pacing. In addition, further neural systems are involved in the motor control during irregular pacing: cerebellar vermis and a cerebello-thalamo-cortical system. The latter is supposedly involved in error correction in the context of visually guided movements.