francesco musso - Academia.edu (original) (raw)

Papers by francesco musso

Molecular Pain, 2010

Background Pain is a complex experience with sensory, emotional and cognitive aspects. Genetic an... more Background Pain is a complex experience with sensory, emotional and cognitive aspects. Genetic and environmental factors contribute to pain-related phenotypes such as chronic pain states. Genetic variations in the gene coding for catechol-O-methyltransferase (COMT) have been suggested to affect clinical and experimental pain-related phenotypes including regional μ-opioid system responses to painful stimulation as measured by ligand-PET (positron emission tomography). The functional val158met single nucleotide polymorphism has been most widely studied. However, apart from its impact on pain-induced opioid release the effect of this genetic variation on cerebral pain processing has not been studied with activation measures such as functional magnetic resonance imaging (fMRI), PET or electroencephalography. In the present fMRI study we therefore sought to investigate the impact of the COMT val158met polymorphism on the blood oxygen level-dependent (BOLD) response to painful laser stimulation. Results 57 subjects were studied. We found that subjects homozygous for the met158 allele exhibit a higher BOLD response in the anterior cingulate cortex (ACC), foremost in the mid-cingulate cortex, than carriers of the val158 allele. Conclusion This result is in line with previous studies that reported higher pain sensitivity in homozygous met carriers. It adds to the current literature in suggesting that this behavioral phenotype may be mediated by, or is at least associated with, increased ACC activity. More generally, apart from one report that focused on pain-induced opioid release, this is the first functional neuroimaging study showing an effect of the COMT val158met polymorphism on cerebral pain processing.

Journal of Cognitive Neuroscience

In a previous oddball task study, it was shown that the inclusion of electrophysiology (EEG), tha... more In a previous oddball task study, it was shown that the inclusion of electrophysiology (EEG), that is, single-trial P3 ERP parameters, in the analysis of fMRI responses can detect activation that is not apparent with conventional fMRI data modeling strategies [Warbrick, T., Mobascher, A., Brinkmeyer, J., Musso, F., Richter, N., Stoecker, T., et al. Single-trial P3 amplitude and latency informed event-related fMRI models yield different BOLD response patterns to a target detection task. Neuroimage, 47, 1532-1544, 2009]. Given that P3 is modulated by nicotine, including P3 parameters in the fMRI analysis might provide additional information about nicotine effects on brain function. A 1-mg nasal nicotine spray (0.5 mg each nostril) or placebo (pepper) spray was administered in a double-blind, placebo-controlled, within-subject, randomized, cross-over design. Simultaneous EEG-fMRI and behavioral data were recorded from 19 current smokers in response to an oddball-type visual choice RT task. Conventional general linear model analysis and single-trial P3 amplitude informed general linear model analysis of the fMRI data were performed. Comparing the nicotine with the placebo condition, reduced RTs in the nicotine condition were related to decreased BOLD responses in the conventional analysis encompassing the superior parietal lobule, the precuneus, and the lateral occipital cortex. On the other hand, reduced RTs were related to increased BOLD responses in the precentral and postcentral gyri, and ACC in the EEG-informed fMRI analysis. Our results show how integrated analyses of simultaneous EEG-fMRI data can be used to detect nicotine effects that would not have been revealed through conventional analysis of either measure in isolation. This emphasizes the significance of applying multimodal imaging methods to pharmacoimaging.

Human Brain Mapping, 2010

Previous studies on the spatio-temporal dynamics of cortical pain processing using electroencepha... more Previous studies on the spatio-temporal dynamics of cortical pain processing using electroencephalography (EEG), magnetoencephalography (MEG), or intracranial recordings point towards a high degree of parallelism, e.g. parallel instead of sequential activation of primary and secondary somatosensory areas or simultaneous activation of somatosensory areas and the mid-cingulate cortex. However, because of the inverse problem, EEG and MEG provide only limited spatial resolution and certainty about the generators of cortical pain-induced electromagnetic activity, especially when multiple sources are simultaneously active. On the other hand, intracranial recordings are invasive and do not provide whole-brain coverage. In this study, we thought to investigate the spatio-temporal dynamics of cortical pain processing in 10 healthy subjects using simultaneous EEG/functional magnetic resonance imaging (fMRI). Voltages of 20 ms segments of the EEG root mean square (a global, largely reference-free measure of event-related EEG activity) in a time window 0–400 ms poststimulus were used to model trial-to-trial fluctuations in the fMRI blood oxygen level dependent (BOLD) signal. EEG-derived regressors explained additional variance in the BOLD signal from 140 ms poststimulus onward. According to this analysis, the contralateral parietal operculum was the first cortical area to become activated upon painful laser stimulation. The activation pattern in BOLD analyses informed by subsequent EEG-time windows suggests largely parallel signal processing in the bilateral operculo-insular and mid-cingulate cortices. In that regard, our data are in line with previous reports. However, the approach presented here is noninvasive and bypasses the inverse problem using only temporal information from the EEG. Hum Brain Mapp, 2010. © 2010 Wiley-Liss, Inc.

International Journal of Psychophysiology, 2010

A painful experience is modified by processes like habituation/antinociception or sensitization. ... more A painful experience is modified by processes like habituation/antinociception or sensitization. Altered habituation may be one characteristic of chronic pain syndromes. In the present study we sought to investigate the functional magnetic resonance imaging (fMRI) blood oxygen level dependent (BOLD) correlate of rapid habituation to pain using simultaneous single trial electrodermal activity (EDA)/fMRI measurements. A total of N = 32 healthy subjects have been investigated. Subjects received painful laser stimulation of the left hand. The fMRI BOLD response was measured simultaneously with continuous EDA recordings. Single trial EDA responses to laser stimulation habituated over time with substantial subject-tosubject differences in the degree and speed of habituation. fMRI BOLD habituation was assessed by contrasting the first half of the experiment against the second half and was found in primary and secondary somatosensory cortices, the insula and the anterior cingulate cortex (ACC). We hypothesized that single trial EDA habituation would reflect BOLD habituation which was investigated separately in subjects with 'faster' (N = 15) and 'slower' (N = 14) EDA habituation. Significant habituation of the BOLD signal was only found in subjects with 'faster' EDA habituation that was accompanied by a signal increase in the rostral ACC and the periaqueductal grey. Furthermore, subjects with faster EDA habituation provided lower pain ratings. Therefore the EDA habituation profile to painful stimulation may constitute a pain-related (endo)phenotype and may be an informative additional endpoint measure in fMR-imaging of pain, especially when people suffering from chronic pain states in which pain processing is often altered are studied.

Psychopharmacology, 2007

Rationale There is abundant evidence from clinical and preclinical studies that acute administrat... more Rationale There is abundant evidence from clinical and preclinical studies that acute administration of nicotine has beneficial effects on attentional network function in the brain. In contrast, little is known about potentially neurotoxic effects on the attentional network during neurodevelopmentally critical periods, such as during adolescence and early adulthood. Methods Using event-related functional MRI (fMRI), we investigated prefrontal attentional network function in young adults (n=15 regular smokers and n=12 never-smokers; age: 22.6±1.5 years). Duration of smoking was 6.9±2.3 years (range of 2–10). Smokers were allowed to smoke ad libitum before the fMRI scanning was conducted. Results As expected from literature, prefrontal attentional network activity was significantly reduced in smokers compared to nonsmokers (Z=2.1; P=0.036). In smokers, we found that the history of smoking duration (years) is directly related to the extent of diminished attentional network activity (R=−0.67; P=0.012). Conclusions To our best knowledge, the relationship between the duration of smoking history and prefrontal attentional network function has not yet been reported. This finding might suggest that several years of chronic nicotine abuse may be sufficient to exert long-lasting effects on the brain function of adolescents and young adults.

Neuroimage, 2010

The brain is active even in the absence of explicit input or output as demonstrated from electrop... more The brain is active even in the absence of explicit input or output as demonstrated from electrophysiological as well as imaging studies. Using a combined approach we measured spontaneous fluctuations in the blood oxygen level dependent (BOLD) signal along with electroencephalography (EEG) in eleven healthy subjects during relaxed wakefulness (eyes closed). In contrast to other studies which used the EEG frequency information to guide the functional MRI (fMRI) analysis, we opted for transient EEG events, which identify and quantify brain electric microstates as time epochs with quasi-stable field topography. We then used this microstate information as regressors for the BOLD fluctuations. Single trial EEGs were segmented with a specific module of the LORETA (low resolution electromagnetic tomography) software package in which microstates are represented as normalized vectors constituted by scalp electric potentials, i.e., the related 3-dimensional distribution of cortical current density in the brain. Using the occurrence and the duration of each microstate, we modeled the hemodynamic response function (HRF) which revealed BOLD activation in all subjects. The BOLD activation patterns resembled well known resting-state networks (RSNs) such as the default mode network. Furthermore we "cross validated" the data performing a BOLD independent component analysis (ICA) and computing the correlation between each ICs and the EEG microstates across all subjects. This study shows for the first time that the information contained within EEG microstates on a millisecond timescale is able to elicit BOLD activation patterns consistent with well known RSNs, opening new avenues for multimodal imaging data processing.

Neuroimage, 2009

Using single-trial parameters as a regressor in the General Linear Model (GLM) is becoming an inc... more Using single-trial parameters as a regressor in the General Linear Model (GLM) is becoming an increasingly popular method for informing fMRI analysis. However, the parameter used to characterise or to differentiate brain regions involved in the response to a particular task varies across studies (e.g. ERP amplitude, ERP latency, reaction time). Furthermore, the way in which the single-trial information is used in the fMRI analysis is also important. For example, the single-trial parameters can be used as regressors in the GLM or to modify the duration of the events modelled in the GLM. The aim of this study was to investigate the BOLD response to a target detection task when including P3 amplitude, P3 latency and reaction time parameters in the GLM. Simultaneous EEG-fMRI was recorded from fifteen subjects in response to a visual choice reaction time task. Including P3 amplitude as a regressor in the GLM yielded activation in left central opercular cortex, left postcentral gyrus, left insula, left middle frontal gyrus, left insula and left parietal operculum. Using P3 latency and reaction time as an additional regressor yielded no additional activation in comparison with the conventional fMRI analysis. However, when P3 latency or reaction time was used to determine the duration of events at a single-trial level, additional activation was observed in the left postcentral gyrus, left precentral gyrus, anterior cingulate cortex and supramarginal gyrus. Our findings suggest that ERP amplitudes and latencies can yield different activation patterns when used to modify relevant aspects of the GLM.

Journal of Cognitive Neuroscience

Human brain lesion studies first investigated the biological roots of cognitive functions includi... more Human brain lesion studies first investigated the biological roots of cognitive functions including language in the late 1800s. Neuroimaging studies have reported correlation findings with general intelligence predominantly in fronto-parietal cortical areas. However, there is still little evidence about the relationship between verbal intelligence and structural properties of the brain. We predicted that verbal performance is related to language regions of Broca's and Wernicke's areas. Verbal intelligence quotient (vIQ) was assessed in 30 healthy young subjects. T1-weighted MRI and diffusion tensor imaging data sets were acquired. Voxel-wise regression analyses were used to correlate fractional anisotropy (FA) and mean diffusivity values with vIQ. Moreover, regression analyses of regional brain volume with vIQ were performed adopting voxel-based morphometry (VBM) and ROI methodology. Our analyses revealed a significant negative correlation between vIQ and FA and a significant positive correlation between vIQ and mean diffusivity in the left-hemispheric Broca's area. VBM regression analyses did not show significant results, whereas a subsequent ROI analysis of Broca's area FA peak cluster demonstrated a positive correlation of gray matter volume and vIQ. These findings suggest that cortical thickness in Broca's area contributes to verbal intelligence. Diffusion parameters predicted gray matter ratio in Broca's area more sensitive than VBM methodology.

Neuroimage, 2009

A painful experience is modified by processes like habituation/antinociception or sensitization. ... more A painful experience is modified by processes like habituation/antinociception or sensitization. Altered 25 habituation may be one characteristic of chronic pain syndromes. In the present study we sought to 26 investigate the functional magnetic resonance imaging (fMRI) blood oxygen level dependent (BOLD) 27 correlate of rapid habituation to pain using simultaneous single trial electrodermal activity (EDA)/fMRI 28 measurements. A total of N = 32 healthy subjects have been investigated. Subjects received painful laser 29 stimulation of the left hand. The fMRI BOLD response was measured simultaneously with continuous EDA 30 recordings. Single trial EDA responses to laser stimulation habituated over time with substantial subject-to-31 subject differences in the degree and speed of habituation. fMRI BOLD habituation was assessed by 32 contrasting the first half of the experiment against the second half and was found in primary and secondary 33 somatosensory cortices, the insula and the anterior cingulate cortex (ACC). We hypothesized that single trial 34 EDA habituation would reflect BOLD habituation which was investigated separately in subjects with 'faster' 35 (N = 15) and 'slower' (N = 14) EDA habituation. Significant habituation of the BOLD signal was only found in 36 subjects with 'faster' EDA habituation that was accompanied by a signal increase in the rostral ACC and the 37 periaqueductal grey. Furthermore, subjects with faster EDA habituation provided lower pain ratings. 38 Therefore the EDA habituation profile to painful stimulation may constitute a pain-related (endo)phenotype 39 and may be an informative additional endpoint measure in fMR-imaging of pain, especially when people 40 suffering from chronic pain states in which pain processing is often altered are studied. 41

Neuroimage, 2006

Human cortical information processing is thought to be dominated by distributed activity in vecto... more Human cortical information processing is thought to be dominated by distributed activity in vector state space (Churchland, P.S., Sejnowski, T.J., 1992. The Computational Brain. MIT Press, Cambridge.). In principle, it should be possible to quantify distributed brain activation with independent component analysis (ICA) through vector-based decomposition, i.e., through a separation of a mixture of sources. Using event-related functional magnetic resonance imaging (fMRI) during a selective attention-requiring task (visual oddball), we explored how the number of independent components within activated cortical areas is related to reaction time. Prior to ICA, the activated cortical areas were determined on the basis of a General linear model (GLM) voxel-by-voxel analysis of the target stimuli (checkerboard reversal). Two activated cortical areas (temporoparietal cortex, medial prefrontal cortex) were further investigated as these cortical regions are known to be the sites of simultaneously active electromagnetic generators which give rise to the compound event-related potential P300 during oddball task conditions. We found that the number of independent components more strongly predicted reaction time than the overall level of ''activation'' (GLM BOLD-response) in the left temporoparietal area whereas in the medial prefrontal cortex both ICA and GLM predicted reaction time equally well. Comparable correlations were not seen when principle components were used instead of independent components. These results indicate that the number of independently activated components, i.e., a high level of cortical activation complexity in cortical vector state space, may index particularly efficient information processing during selective attentionrequiring tasks. To our best knowledge, this is the first report describing a potential relationship between neuronal generators of cognitive processes, the associated electrophysiological evidence for the existence of distributed networks and BOLD fMRI signals using information from model order selection techniques.

Neuroimage, 2009

Pain is a complex experience with sensory, emotional and cognitive aspects. The cortical represen... more Pain is a complex experience with sensory, emotional and cognitive aspects. The cortical representation of painthe pain matrixconsists of a network of regions including the primary (S1) and secondary (S2) sensory cortex, insula, and anterior cingulate cortex (ACC). These structures interact with brain regions such as the prefrontal cortex and the amygdalae. Simultaneous EEG/fMRI (electroencephalography/functional magnetic resonance imaging) has recently been introduced as a method to study the spatiotemporal characteristics of cognitive processes with high spatial and high temporal resolution at the same time. The present study was conducted to clarify if single trial EEG-informed BOLD modeling supports the definition of functional compartments within the pain matrix and interconnected regions. Twenty healthy subjects received painful laser stimulation while EEG and the fMRI blood oxygen level dependent (BOLD) signal were recorded simultaneously. While the laser-evoked N2 potential provided no additional information for BOLD modeling, the regressor obtained from the single trial laser-evoked P2 potential explained additional variance in a network of cortical and subcortical structures that largely overlapped with the pain matrix. This modeling strategy yielded pronounced activation in the ACC, right amygdala and thalamus. Our results suggest that laser-evoked potential (LEP) informed fMRI can be used to visualize BOLD activation in the pain matrix with an emphasis on functional compartments (as defined by the temporal dynamics of the LEP) such as the medial pain system. Furthermore, our findings suggest a concerted effort of the ACC and the amygdala in the cognitive-emotional evaluation of pain.

American Journal of Psychiatry, 2006

Prefrontal dysfunction is considered a fundamental characteristic of schizophrenia. Recent electr... more Prefrontal dysfunction is considered a fundamental characteristic of schizophrenia. Recent electrophysiological evidence points to a major instability of signal processing in prefrontal cortical microcircuits because of reduced phase-synchronization (i.e., an increased stimulus-related variability [noise] of single-trial responses in the spatial and time domain). The authors used functional magnetic resonance imaging (fMRI) during a visual two-choice reaction task in order to measure, with higher topographic accuracy, signal stability in patients with schizophrenia and its relationship to more traditional measures of activation. Twelve clinically stable inpatients with schizophrenia and 16 matched comparison subjects were evaluated. Event-related blood-oxygen-level-dependent responses were subjected to an analysis of residual noise variance and to independent data dimension independent component analysis in the medial prefrontal cortex. In patients with schizophrenia, the authors found increased residual noise variance of the blood-oxygen-level-dependent response that predicted the level of prefrontal activation in these subjects. In the left hemisphere, residual noise variance strongly correlated with psychotic symptoms. Independent component analysis revealed a "fractionized" and unfocussed pattern of activation in patients. These findings suggest that unstable cortical signal processing underlies classic abnormal cortical activation patterns as well as psychosis in schizophrenia.

Human Molecular Genetics, 2007

Mutational analyses in xenopus oocyte and mice models indicate that the positive effect of nicoti... more Mutational analyses in xenopus oocyte and mice models indicate that the positive effect of nicotine on attention may be modulated by genetic variations within exon 5 of the alpha4 subunit of the nicotinergic acetylcholine receptor gene CHRNA4. The potential relevance of exon 5 is further emphasized by two recent family-based association studies of nicotine dependence because subgroups of nicotine-dependent subjects are thought to 'self-medicate' attentional deficits with nicotine. We investigated a synonymous single nucleotide polymorphisms (SNP): rs1044396, which has recently been associated with nicotinedependence, plus two adjacent synonymous SNPs rs1044394 and rs1044393 in exon 5 of n 5 47 unrelated healthy Caucasian subjects (age: 22.7 + + + + + 1.7 years; sex: n 5 23 males; regular smokers: n 5 19). Attentional network function was assessed in supplementary motor area/anterior cingulate (SMA/ACC) and parietal cortex with functional magnetic resonance imaging during an attention-requiring visual oddball task. SNP rs1044396 showed genotype effects on attentional network function both in the SMA/ACC and parietal cortex in the absence of overt behavioral effects. In the parietal cortex, a gene-dosage effect was seen. Comparable genotype effects were also found for the other two SNPs. This investigation provides first evidence that attentional network function may be modulated by genetic variations within CHRNA4 exon 5. If confirmed, future studies need to address what 'functional' polymorphisms are causative for the observed effects.

Neuropsychobiology, 2009

Reaction time (RT) is a frequently used measure of information processing speed, but the underlyi... more Reaction time (RT) is a frequently used measure of information processing speed, but the underlying physiological and anatomical conditions are not yet fully understood. A correlation between measures of white matter (WM) ultrastructural properties and RT is expected--particularly for those WM tracts that are involved in the attentional system of the brain. Diffusion tensor imaging data were acquired in 43 unrelated healthy subjects (age: 22.7 +/- 1.8 years), and RT was measured during an attention-requiring visual oddball task in the same scanning session. Voxel-by-voxel and region of interest analyses were performed for the large association tracts. A linear regression model was used to correlate fractional anisotropy (FA) and mean diffusivity (MD) values with mean RT. Our analyses revealed significant positive correlations between RT and MD in several WM association tracts, predominantly in the right hemisphere. To a lesser extent, significant negative correlations were found between RT and FA in right temporal WM. These findings suggest that subcortical ultrastructural properties of the dorsal and ventral visual stream are relevant with regard to information processing speed. Furthermore, MD appears to be more sensitive than FA in detecting functionally relevant ultrastructural variations in WM tracts.

Journal of Cognitive Neuroscience, 2012

Human brain lesion studies first investigated the biological roots of cognitive functions includi... more Human brain lesion studies first investigated the biological roots of cognitive functions including language in the late 1800s. Neuroimaging studies have reported correlation findings with general intelligence predominantly in fronto-parietal cortical areas. However, there is still little evidence about the relationship between verbal intelligence and structural properties of the brain. We predicted that verbal performance is related to language regions of Broca's and Wernicke's areas. Verbal intelligence quotient (vIQ) was assessed in 30 healthy young subjects. T1-weighted MRI and diffusion tensor imaging data sets were acquired. Voxel-wise regression analyses were used to correlate fractional anisotropy (FA) and mean diffusivity values with vIQ. Moreover, regression analyses of regional brain volume with vIQ were performed adopting voxel-based morphometry (VBM) and ROI methodology. Our analyses revealed a significant negative correlation between vIQ and FA and a significant positive correlation between vIQ and mean diffusivity in the left-hemispheric Broca's area. VBM regression analyses did not show significant results, whereas a subsequent ROI analysis of Broca's area FA peak cluster demonstrated a positive correlation of gray matter volume and vIQ. These findings suggest that cortical thickness in Broca's area contributes to verbal intelligence. Diffusion parameters predicted gray matter ratio in Broca's area more sensitive than VBM methodology.

Neuroimage, 2009

HE Hulst, SD Roosendaal, MM Schoonheim, YD van der Werf,

Human Brain Mapping, 2007

Functional magnetic resonance imaging (fMRI) depends on the coupling of cerebral blood flow, ener... more Functional magnetic resonance imaging (fMRI) depends on the coupling of cerebral blood flow, energy demand, and neural activity. The precise nature of this interaction, however, is poorly understood. A positive correlation between BOLD-response and cortically generated local field potentials, which reflect the weighted average of synchronized dentrosomatic components of pyramidal synaptic signals, has been demonstrated. Likewise, positive BOLD-responses have been reported in conjunction with scalp-recorded synchronized electromagnetic activity by a number of groups. However, it is not yet clear how the opposite electromagnetic pattern, i.e. cortical desynchronization, is related to the BOLD signal. To address this question, we conducted a combined event-related fMRI and 275 sensor whole-head MEG study during identical visual two-choice reaction time task conditions in 10 human subjects. We found complex sequences of MEG-synchronization and desynchronization across a wide frequency range in the visual and motor area in close correspondence with “locales” of positive BOLD-responses. These results indicate that a correspondence of positive BOLD-responses is not exclusively found for cortical synchronization but also for desynchronization, suggesting that the relationship between BOLD signals and electromagnetic activity might be more complex than previously thought. Hum Brain Mapp 2006. © 2006 Wiley-Liss, Inc.

Neuroimage, 2006

Objective: Prefrontal dopamine (DA) is catabolized by the COMT (catechol-O-methyltransferase) enz... more Objective: Prefrontal dopamine (DA) is catabolized by the COMT (catechol-O-methyltransferase) enzyme. Literature suggests that the Val/Met single nucleotide polymorphism (SNP) in the COMT gene predicts executive cognition in humans with Val carriers showing poorer performance due to less available synaptic DA. Recent fMRI studies are thought to agree with these studies having demonstrated prefrontal hyperactivation during n-back and attention-requiring tasks. This was interpreted as "less efficient" processing due to impaired signal-to-noise ratio (SNR) of neuronal activity. However, electrophysiological studies of neuronal SNR in primates and humans imply that prefrontal cortex should show a diminished prefrontal BOLD response in Val carriers. In the present study, we addressed the question of whether the prefrontal SNR of the BOLD response is decreased in Val carriers using a visual oddball task and an approach to analysis of fMRI data that maximizes noise characterization. Methods: We investigated N = 17 homozygous Met carriers compared with N = 24 Val carriers matched for age, sex, education, IQ, reaction time (variability) and head motion. Event-related fMRI was conducted presenting 160 visual stimuli (40 targets, checkerboard reversal). Subjects had to respond as quickly as possible to targets by button press. In the fMRI GLM [y(t) = β * x(t) +c + e(t)] analysis, voxel-byvoxel 'activation' [y(t)] as well as residual noise variance [e(t) = σ 2 ] were calculated using a conservative full-width half maximum (FWHM = 6 mm). Results: As compared to Val carriers, we observed a stronger and more extended BOLD responses in homozygous Met carriers in left supplementary motor area (SMA) extending to ACC and dorsolateral prefrontal cortex. Vice versa, increased levels of noise were seen in Val carriers surrounding the peak activation maximum. Discussion: In line with our expectations from prior electrophysiological studies, we observed a diminished BOLD response and increased noise in Val carriers. This suggests that the DA stabilizes cortical microcircuits by sharpening the signal and suppressing surrounding noise.

Molecular Pain, 2010

Background Pain is a complex experience with sensory, emotional and cognitive aspects. Genetic an... more Background Pain is a complex experience with sensory, emotional and cognitive aspects. Genetic and environmental factors contribute to pain-related phenotypes such as chronic pain states. Genetic variations in the gene coding for catechol-O-methyltransferase (COMT) have been suggested to affect clinical and experimental pain-related phenotypes including regional μ-opioid system responses to painful stimulation as measured by ligand-PET (positron emission tomography). The functional val158met single nucleotide polymorphism has been most widely studied. However, apart from its impact on pain-induced opioid release the effect of this genetic variation on cerebral pain processing has not been studied with activation measures such as functional magnetic resonance imaging (fMRI), PET or electroencephalography. In the present fMRI study we therefore sought to investigate the impact of the COMT val158met polymorphism on the blood oxygen level-dependent (BOLD) response to painful laser stimulation. Results 57 subjects were studied. We found that subjects homozygous for the met158 allele exhibit a higher BOLD response in the anterior cingulate cortex (ACC), foremost in the mid-cingulate cortex, than carriers of the val158 allele. Conclusion This result is in line with previous studies that reported higher pain sensitivity in homozygous met carriers. It adds to the current literature in suggesting that this behavioral phenotype may be mediated by, or is at least associated with, increased ACC activity. More generally, apart from one report that focused on pain-induced opioid release, this is the first functional neuroimaging study showing an effect of the COMT val158met polymorphism on cerebral pain processing.

Journal of Cognitive Neuroscience

In a previous oddball task study, it was shown that the inclusion of electrophysiology (EEG), tha... more In a previous oddball task study, it was shown that the inclusion of electrophysiology (EEG), that is, single-trial P3 ERP parameters, in the analysis of fMRI responses can detect activation that is not apparent with conventional fMRI data modeling strategies [Warbrick, T., Mobascher, A., Brinkmeyer, J., Musso, F., Richter, N., Stoecker, T., et al. Single-trial P3 amplitude and latency informed event-related fMRI models yield different BOLD response patterns to a target detection task. Neuroimage, 47, 1532-1544, 2009]. Given that P3 is modulated by nicotine, including P3 parameters in the fMRI analysis might provide additional information about nicotine effects on brain function. A 1-mg nasal nicotine spray (0.5 mg each nostril) or placebo (pepper) spray was administered in a double-blind, placebo-controlled, within-subject, randomized, cross-over design. Simultaneous EEG-fMRI and behavioral data were recorded from 19 current smokers in response to an oddball-type visual choice RT task. Conventional general linear model analysis and single-trial P3 amplitude informed general linear model analysis of the fMRI data were performed. Comparing the nicotine with the placebo condition, reduced RTs in the nicotine condition were related to decreased BOLD responses in the conventional analysis encompassing the superior parietal lobule, the precuneus, and the lateral occipital cortex. On the other hand, reduced RTs were related to increased BOLD responses in the precentral and postcentral gyri, and ACC in the EEG-informed fMRI analysis. Our results show how integrated analyses of simultaneous EEG-fMRI data can be used to detect nicotine effects that would not have been revealed through conventional analysis of either measure in isolation. This emphasizes the significance of applying multimodal imaging methods to pharmacoimaging.

Human Brain Mapping, 2010

Previous studies on the spatio-temporal dynamics of cortical pain processing using electroencepha... more Previous studies on the spatio-temporal dynamics of cortical pain processing using electroencephalography (EEG), magnetoencephalography (MEG), or intracranial recordings point towards a high degree of parallelism, e.g. parallel instead of sequential activation of primary and secondary somatosensory areas or simultaneous activation of somatosensory areas and the mid-cingulate cortex. However, because of the inverse problem, EEG and MEG provide only limited spatial resolution and certainty about the generators of cortical pain-induced electromagnetic activity, especially when multiple sources are simultaneously active. On the other hand, intracranial recordings are invasive and do not provide whole-brain coverage. In this study, we thought to investigate the spatio-temporal dynamics of cortical pain processing in 10 healthy subjects using simultaneous EEG/functional magnetic resonance imaging (fMRI). Voltages of 20 ms segments of the EEG root mean square (a global, largely reference-free measure of event-related EEG activity) in a time window 0–400 ms poststimulus were used to model trial-to-trial fluctuations in the fMRI blood oxygen level dependent (BOLD) signal. EEG-derived regressors explained additional variance in the BOLD signal from 140 ms poststimulus onward. According to this analysis, the contralateral parietal operculum was the first cortical area to become activated upon painful laser stimulation. The activation pattern in BOLD analyses informed by subsequent EEG-time windows suggests largely parallel signal processing in the bilateral operculo-insular and mid-cingulate cortices. In that regard, our data are in line with previous reports. However, the approach presented here is noninvasive and bypasses the inverse problem using only temporal information from the EEG. Hum Brain Mapp, 2010. © 2010 Wiley-Liss, Inc.

International Journal of Psychophysiology, 2010

A painful experience is modified by processes like habituation/antinociception or sensitization. ... more A painful experience is modified by processes like habituation/antinociception or sensitization. Altered habituation may be one characteristic of chronic pain syndromes. In the present study we sought to investigate the functional magnetic resonance imaging (fMRI) blood oxygen level dependent (BOLD) correlate of rapid habituation to pain using simultaneous single trial electrodermal activity (EDA)/fMRI measurements. A total of N = 32 healthy subjects have been investigated. Subjects received painful laser stimulation of the left hand. The fMRI BOLD response was measured simultaneously with continuous EDA recordings. Single trial EDA responses to laser stimulation habituated over time with substantial subject-tosubject differences in the degree and speed of habituation. fMRI BOLD habituation was assessed by contrasting the first half of the experiment against the second half and was found in primary and secondary somatosensory cortices, the insula and the anterior cingulate cortex (ACC). We hypothesized that single trial EDA habituation would reflect BOLD habituation which was investigated separately in subjects with 'faster' (N = 15) and 'slower' (N = 14) EDA habituation. Significant habituation of the BOLD signal was only found in subjects with 'faster' EDA habituation that was accompanied by a signal increase in the rostral ACC and the periaqueductal grey. Furthermore, subjects with faster EDA habituation provided lower pain ratings. Therefore the EDA habituation profile to painful stimulation may constitute a pain-related (endo)phenotype and may be an informative additional endpoint measure in fMR-imaging of pain, especially when people suffering from chronic pain states in which pain processing is often altered are studied.

Psychopharmacology, 2007

Rationale There is abundant evidence from clinical and preclinical studies that acute administrat... more Rationale There is abundant evidence from clinical and preclinical studies that acute administration of nicotine has beneficial effects on attentional network function in the brain. In contrast, little is known about potentially neurotoxic effects on the attentional network during neurodevelopmentally critical periods, such as during adolescence and early adulthood. Methods Using event-related functional MRI (fMRI), we investigated prefrontal attentional network function in young adults (n=15 regular smokers and n=12 never-smokers; age: 22.6±1.5 years). Duration of smoking was 6.9±2.3 years (range of 2–10). Smokers were allowed to smoke ad libitum before the fMRI scanning was conducted. Results As expected from literature, prefrontal attentional network activity was significantly reduced in smokers compared to nonsmokers (Z=2.1; P=0.036). In smokers, we found that the history of smoking duration (years) is directly related to the extent of diminished attentional network activity (R=−0.67; P=0.012). Conclusions To our best knowledge, the relationship between the duration of smoking history and prefrontal attentional network function has not yet been reported. This finding might suggest that several years of chronic nicotine abuse may be sufficient to exert long-lasting effects on the brain function of adolescents and young adults.

Neuroimage, 2010

The brain is active even in the absence of explicit input or output as demonstrated from electrop... more The brain is active even in the absence of explicit input or output as demonstrated from electrophysiological as well as imaging studies. Using a combined approach we measured spontaneous fluctuations in the blood oxygen level dependent (BOLD) signal along with electroencephalography (EEG) in eleven healthy subjects during relaxed wakefulness (eyes closed). In contrast to other studies which used the EEG frequency information to guide the functional MRI (fMRI) analysis, we opted for transient EEG events, which identify and quantify brain electric microstates as time epochs with quasi-stable field topography. We then used this microstate information as regressors for the BOLD fluctuations. Single trial EEGs were segmented with a specific module of the LORETA (low resolution electromagnetic tomography) software package in which microstates are represented as normalized vectors constituted by scalp electric potentials, i.e., the related 3-dimensional distribution of cortical current density in the brain. Using the occurrence and the duration of each microstate, we modeled the hemodynamic response function (HRF) which revealed BOLD activation in all subjects. The BOLD activation patterns resembled well known resting-state networks (RSNs) such as the default mode network. Furthermore we "cross validated" the data performing a BOLD independent component analysis (ICA) and computing the correlation between each ICs and the EEG microstates across all subjects. This study shows for the first time that the information contained within EEG microstates on a millisecond timescale is able to elicit BOLD activation patterns consistent with well known RSNs, opening new avenues for multimodal imaging data processing.

Neuroimage, 2009

Using single-trial parameters as a regressor in the General Linear Model (GLM) is becoming an inc... more Using single-trial parameters as a regressor in the General Linear Model (GLM) is becoming an increasingly popular method for informing fMRI analysis. However, the parameter used to characterise or to differentiate brain regions involved in the response to a particular task varies across studies (e.g. ERP amplitude, ERP latency, reaction time). Furthermore, the way in which the single-trial information is used in the fMRI analysis is also important. For example, the single-trial parameters can be used as regressors in the GLM or to modify the duration of the events modelled in the GLM. The aim of this study was to investigate the BOLD response to a target detection task when including P3 amplitude, P3 latency and reaction time parameters in the GLM. Simultaneous EEG-fMRI was recorded from fifteen subjects in response to a visual choice reaction time task. Including P3 amplitude as a regressor in the GLM yielded activation in left central opercular cortex, left postcentral gyrus, left insula, left middle frontal gyrus, left insula and left parietal operculum. Using P3 latency and reaction time as an additional regressor yielded no additional activation in comparison with the conventional fMRI analysis. However, when P3 latency or reaction time was used to determine the duration of events at a single-trial level, additional activation was observed in the left postcentral gyrus, left precentral gyrus, anterior cingulate cortex and supramarginal gyrus. Our findings suggest that ERP amplitudes and latencies can yield different activation patterns when used to modify relevant aspects of the GLM.

Journal of Cognitive Neuroscience

Human brain lesion studies first investigated the biological roots of cognitive functions includi... more Human brain lesion studies first investigated the biological roots of cognitive functions including language in the late 1800s. Neuroimaging studies have reported correlation findings with general intelligence predominantly in fronto-parietal cortical areas. However, there is still little evidence about the relationship between verbal intelligence and structural properties of the brain. We predicted that verbal performance is related to language regions of Broca's and Wernicke's areas. Verbal intelligence quotient (vIQ) was assessed in 30 healthy young subjects. T1-weighted MRI and diffusion tensor imaging data sets were acquired. Voxel-wise regression analyses were used to correlate fractional anisotropy (FA) and mean diffusivity values with vIQ. Moreover, regression analyses of regional brain volume with vIQ were performed adopting voxel-based morphometry (VBM) and ROI methodology. Our analyses revealed a significant negative correlation between vIQ and FA and a significant positive correlation between vIQ and mean diffusivity in the left-hemispheric Broca's area. VBM regression analyses did not show significant results, whereas a subsequent ROI analysis of Broca's area FA peak cluster demonstrated a positive correlation of gray matter volume and vIQ. These findings suggest that cortical thickness in Broca's area contributes to verbal intelligence. Diffusion parameters predicted gray matter ratio in Broca's area more sensitive than VBM methodology.

Neuroimage, 2009

A painful experience is modified by processes like habituation/antinociception or sensitization. ... more A painful experience is modified by processes like habituation/antinociception or sensitization. Altered 25 habituation may be one characteristic of chronic pain syndromes. In the present study we sought to 26 investigate the functional magnetic resonance imaging (fMRI) blood oxygen level dependent (BOLD) 27 correlate of rapid habituation to pain using simultaneous single trial electrodermal activity (EDA)/fMRI 28 measurements. A total of N = 32 healthy subjects have been investigated. Subjects received painful laser 29 stimulation of the left hand. The fMRI BOLD response was measured simultaneously with continuous EDA 30 recordings. Single trial EDA responses to laser stimulation habituated over time with substantial subject-to-31 subject differences in the degree and speed of habituation. fMRI BOLD habituation was assessed by 32 contrasting the first half of the experiment against the second half and was found in primary and secondary 33 somatosensory cortices, the insula and the anterior cingulate cortex (ACC). We hypothesized that single trial 34 EDA habituation would reflect BOLD habituation which was investigated separately in subjects with 'faster' 35 (N = 15) and 'slower' (N = 14) EDA habituation. Significant habituation of the BOLD signal was only found in 36 subjects with 'faster' EDA habituation that was accompanied by a signal increase in the rostral ACC and the 37 periaqueductal grey. Furthermore, subjects with faster EDA habituation provided lower pain ratings. 38 Therefore the EDA habituation profile to painful stimulation may constitute a pain-related (endo)phenotype 39 and may be an informative additional endpoint measure in fMR-imaging of pain, especially when people 40 suffering from chronic pain states in which pain processing is often altered are studied. 41

Neuroimage, 2006

Human cortical information processing is thought to be dominated by distributed activity in vecto... more Human cortical information processing is thought to be dominated by distributed activity in vector state space (Churchland, P.S., Sejnowski, T.J., 1992. The Computational Brain. MIT Press, Cambridge.). In principle, it should be possible to quantify distributed brain activation with independent component analysis (ICA) through vector-based decomposition, i.e., through a separation of a mixture of sources. Using event-related functional magnetic resonance imaging (fMRI) during a selective attention-requiring task (visual oddball), we explored how the number of independent components within activated cortical areas is related to reaction time. Prior to ICA, the activated cortical areas were determined on the basis of a General linear model (GLM) voxel-by-voxel analysis of the target stimuli (checkerboard reversal). Two activated cortical areas (temporoparietal cortex, medial prefrontal cortex) were further investigated as these cortical regions are known to be the sites of simultaneously active electromagnetic generators which give rise to the compound event-related potential P300 during oddball task conditions. We found that the number of independent components more strongly predicted reaction time than the overall level of ''activation'' (GLM BOLD-response) in the left temporoparietal area whereas in the medial prefrontal cortex both ICA and GLM predicted reaction time equally well. Comparable correlations were not seen when principle components were used instead of independent components. These results indicate that the number of independently activated components, i.e., a high level of cortical activation complexity in cortical vector state space, may index particularly efficient information processing during selective attentionrequiring tasks. To our best knowledge, this is the first report describing a potential relationship between neuronal generators of cognitive processes, the associated electrophysiological evidence for the existence of distributed networks and BOLD fMRI signals using information from model order selection techniques.

Neuroimage, 2009

Pain is a complex experience with sensory, emotional and cognitive aspects. The cortical represen... more Pain is a complex experience with sensory, emotional and cognitive aspects. The cortical representation of painthe pain matrixconsists of a network of regions including the primary (S1) and secondary (S2) sensory cortex, insula, and anterior cingulate cortex (ACC). These structures interact with brain regions such as the prefrontal cortex and the amygdalae. Simultaneous EEG/fMRI (electroencephalography/functional magnetic resonance imaging) has recently been introduced as a method to study the spatiotemporal characteristics of cognitive processes with high spatial and high temporal resolution at the same time. The present study was conducted to clarify if single trial EEG-informed BOLD modeling supports the definition of functional compartments within the pain matrix and interconnected regions. Twenty healthy subjects received painful laser stimulation while EEG and the fMRI blood oxygen level dependent (BOLD) signal were recorded simultaneously. While the laser-evoked N2 potential provided no additional information for BOLD modeling, the regressor obtained from the single trial laser-evoked P2 potential explained additional variance in a network of cortical and subcortical structures that largely overlapped with the pain matrix. This modeling strategy yielded pronounced activation in the ACC, right amygdala and thalamus. Our results suggest that laser-evoked potential (LEP) informed fMRI can be used to visualize BOLD activation in the pain matrix with an emphasis on functional compartments (as defined by the temporal dynamics of the LEP) such as the medial pain system. Furthermore, our findings suggest a concerted effort of the ACC and the amygdala in the cognitive-emotional evaluation of pain.

American Journal of Psychiatry, 2006

Prefrontal dysfunction is considered a fundamental characteristic of schizophrenia. Recent electr... more Prefrontal dysfunction is considered a fundamental characteristic of schizophrenia. Recent electrophysiological evidence points to a major instability of signal processing in prefrontal cortical microcircuits because of reduced phase-synchronization (i.e., an increased stimulus-related variability [noise] of single-trial responses in the spatial and time domain). The authors used functional magnetic resonance imaging (fMRI) during a visual two-choice reaction task in order to measure, with higher topographic accuracy, signal stability in patients with schizophrenia and its relationship to more traditional measures of activation. Twelve clinically stable inpatients with schizophrenia and 16 matched comparison subjects were evaluated. Event-related blood-oxygen-level-dependent responses were subjected to an analysis of residual noise variance and to independent data dimension independent component analysis in the medial prefrontal cortex. In patients with schizophrenia, the authors found increased residual noise variance of the blood-oxygen-level-dependent response that predicted the level of prefrontal activation in these subjects. In the left hemisphere, residual noise variance strongly correlated with psychotic symptoms. Independent component analysis revealed a "fractionized" and unfocussed pattern of activation in patients. These findings suggest that unstable cortical signal processing underlies classic abnormal cortical activation patterns as well as psychosis in schizophrenia.

Human Molecular Genetics, 2007

Mutational analyses in xenopus oocyte and mice models indicate that the positive effect of nicoti... more Mutational analyses in xenopus oocyte and mice models indicate that the positive effect of nicotine on attention may be modulated by genetic variations within exon 5 of the alpha4 subunit of the nicotinergic acetylcholine receptor gene CHRNA4. The potential relevance of exon 5 is further emphasized by two recent family-based association studies of nicotine dependence because subgroups of nicotine-dependent subjects are thought to 'self-medicate' attentional deficits with nicotine. We investigated a synonymous single nucleotide polymorphisms (SNP): rs1044396, which has recently been associated with nicotinedependence, plus two adjacent synonymous SNPs rs1044394 and rs1044393 in exon 5 of n 5 47 unrelated healthy Caucasian subjects (age: 22.7 + + + + + 1.7 years; sex: n 5 23 males; regular smokers: n 5 19). Attentional network function was assessed in supplementary motor area/anterior cingulate (SMA/ACC) and parietal cortex with functional magnetic resonance imaging during an attention-requiring visual oddball task. SNP rs1044396 showed genotype effects on attentional network function both in the SMA/ACC and parietal cortex in the absence of overt behavioral effects. In the parietal cortex, a gene-dosage effect was seen. Comparable genotype effects were also found for the other two SNPs. This investigation provides first evidence that attentional network function may be modulated by genetic variations within CHRNA4 exon 5. If confirmed, future studies need to address what 'functional' polymorphisms are causative for the observed effects.

Neuropsychobiology, 2009

Reaction time (RT) is a frequently used measure of information processing speed, but the underlyi... more Reaction time (RT) is a frequently used measure of information processing speed, but the underlying physiological and anatomical conditions are not yet fully understood. A correlation between measures of white matter (WM) ultrastructural properties and RT is expected--particularly for those WM tracts that are involved in the attentional system of the brain. Diffusion tensor imaging data were acquired in 43 unrelated healthy subjects (age: 22.7 +/- 1.8 years), and RT was measured during an attention-requiring visual oddball task in the same scanning session. Voxel-by-voxel and region of interest analyses were performed for the large association tracts. A linear regression model was used to correlate fractional anisotropy (FA) and mean diffusivity (MD) values with mean RT. Our analyses revealed significant positive correlations between RT and MD in several WM association tracts, predominantly in the right hemisphere. To a lesser extent, significant negative correlations were found between RT and FA in right temporal WM. These findings suggest that subcortical ultrastructural properties of the dorsal and ventral visual stream are relevant with regard to information processing speed. Furthermore, MD appears to be more sensitive than FA in detecting functionally relevant ultrastructural variations in WM tracts.

Journal of Cognitive Neuroscience, 2012

Human brain lesion studies first investigated the biological roots of cognitive functions includi... more Human brain lesion studies first investigated the biological roots of cognitive functions including language in the late 1800s. Neuroimaging studies have reported correlation findings with general intelligence predominantly in fronto-parietal cortical areas. However, there is still little evidence about the relationship between verbal intelligence and structural properties of the brain. We predicted that verbal performance is related to language regions of Broca's and Wernicke's areas. Verbal intelligence quotient (vIQ) was assessed in 30 healthy young subjects. T1-weighted MRI and diffusion tensor imaging data sets were acquired. Voxel-wise regression analyses were used to correlate fractional anisotropy (FA) and mean diffusivity values with vIQ. Moreover, regression analyses of regional brain volume with vIQ were performed adopting voxel-based morphometry (VBM) and ROI methodology. Our analyses revealed a significant negative correlation between vIQ and FA and a significant positive correlation between vIQ and mean diffusivity in the left-hemispheric Broca's area. VBM regression analyses did not show significant results, whereas a subsequent ROI analysis of Broca's area FA peak cluster demonstrated a positive correlation of gray matter volume and vIQ. These findings suggest that cortical thickness in Broca's area contributes to verbal intelligence. Diffusion parameters predicted gray matter ratio in Broca's area more sensitive than VBM methodology.

Neuroimage, 2009

HE Hulst, SD Roosendaal, MM Schoonheim, YD van der Werf,

Human Brain Mapping, 2007

Functional magnetic resonance imaging (fMRI) depends on the coupling of cerebral blood flow, ener... more Functional magnetic resonance imaging (fMRI) depends on the coupling of cerebral blood flow, energy demand, and neural activity. The precise nature of this interaction, however, is poorly understood. A positive correlation between BOLD-response and cortically generated local field potentials, which reflect the weighted average of synchronized dentrosomatic components of pyramidal synaptic signals, has been demonstrated. Likewise, positive BOLD-responses have been reported in conjunction with scalp-recorded synchronized electromagnetic activity by a number of groups. However, it is not yet clear how the opposite electromagnetic pattern, i.e. cortical desynchronization, is related to the BOLD signal. To address this question, we conducted a combined event-related fMRI and 275 sensor whole-head MEG study during identical visual two-choice reaction time task conditions in 10 human subjects. We found complex sequences of MEG-synchronization and desynchronization across a wide frequency range in the visual and motor area in close correspondence with “locales” of positive BOLD-responses. These results indicate that a correspondence of positive BOLD-responses is not exclusively found for cortical synchronization but also for desynchronization, suggesting that the relationship between BOLD signals and electromagnetic activity might be more complex than previously thought. Hum Brain Mapp 2006. © 2006 Wiley-Liss, Inc.

Neuroimage, 2006

Objective: Prefrontal dopamine (DA) is catabolized by the COMT (catechol-O-methyltransferase) enz... more Objective: Prefrontal dopamine (DA) is catabolized by the COMT (catechol-O-methyltransferase) enzyme. Literature suggests that the Val/Met single nucleotide polymorphism (SNP) in the COMT gene predicts executive cognition in humans with Val carriers showing poorer performance due to less available synaptic DA. Recent fMRI studies are thought to agree with these studies having demonstrated prefrontal hyperactivation during n-back and attention-requiring tasks. This was interpreted as "less efficient" processing due to impaired signal-to-noise ratio (SNR) of neuronal activity. However, electrophysiological studies of neuronal SNR in primates and humans imply that prefrontal cortex should show a diminished prefrontal BOLD response in Val carriers. In the present study, we addressed the question of whether the prefrontal SNR of the BOLD response is decreased in Val carriers using a visual oddball task and an approach to analysis of fMRI data that maximizes noise characterization. Methods: We investigated N = 17 homozygous Met carriers compared with N = 24 Val carriers matched for age, sex, education, IQ, reaction time (variability) and head motion. Event-related fMRI was conducted presenting 160 visual stimuli (40 targets, checkerboard reversal). Subjects had to respond as quickly as possible to targets by button press. In the fMRI GLM [y(t) = β * x(t) +c + e(t)] analysis, voxel-byvoxel 'activation' [y(t)] as well as residual noise variance [e(t) = σ 2 ] were calculated using a conservative full-width half maximum (FWHM = 6 mm). Results: As compared to Val carriers, we observed a stronger and more extended BOLD responses in homozygous Met carriers in left supplementary motor area (SMA) extending to ACC and dorsolateral prefrontal cortex. Vice versa, increased levels of noise were seen in Val carriers surrounding the peak activation maximum. Discussion: In line with our expectations from prior electrophysiological studies, we observed a diminished BOLD response and increased noise in Val carriers. This suggests that the DA stabilizes cortical microcircuits by sharpening the signal and suppressing surrounding noise.