gebieden in de hersenen. Met functionele MRI kan deze activiteit worden bestudeerd. Uit voorgaand... more gebieden in de hersenen. Met functionele MRI kan deze activiteit worden bestudeerd. Uit voorgaand onderzoek is gebleken dat tinnituspatiënten exces- sieve hersenactivatie vertonen in respons op geluid. Een dergelijke overactivatie is in goede overeen- stemming met de hypothese dat tinnitus wordt ver- oorzaakt door een verhoogd niveau van spontane activiteit in het centrale auditieve systeem. Bij pa- tiënten die hun
In this paper, we review studies that have investigated brain morphology in chronic tinnitus in o... more In this paper, we review studies that have investigated brain morphology in chronic tinnitus in order to better understand the underlying pathophysiology of the disorder. Current consensus is that tinnitus is a disorder involving a distributed network of peripheral and central pathways in the nervous system. However, the precise mechanism remains elusive and it is unclear which structures are involved. Given that brain structure and function are highly related, identification of anatomical differences may shed light upon the mechanism of tinnitus generation and maintenance. We discuss anatomical changes in the auditory cortex, the limbic system, and prefrontal cortex, among others. Specifically, we discuss the gating mechanism of tinnitus and evaluate the evidence in support of the model from studies of brain anatomy. Although individual studies claim significant effects related to tinnitus, outcomes are divergent and even contradictory across studies. Moreover, results are often confounded by the presence of hearing loss. We conclude that, at present, the overall evidence for structural abnormalities specifically related to tinnitus is poor. As this area of research is expanding, we identify some key considerations for research design and propose strategies for future research.
Although a consensus is emerging in the literature regarding the tonotopic organisation of audito... more Although a consensus is emerging in the literature regarding the tonotopic organisation of auditory cortex in humans, previous studies employed a vast array of different neuroimaging protocols. In the present functional magnetic resonance imaging (fMRI) study, we made a systematic comparison between stimulus protocols involving jittered tone sequences with either a narrowband, broadband, or sweep character in order to evaluate their suitability for the purpose of tonotopic mapping. Data-driven analysis techniques were used to identify cortical maps related to sound-evoked activation and tonotopic frequency tuning. Principal component analysis (PCA) was used to extract the dominant response patterns in each of the three protocols separately, and generalised canonical correlation analysis (CCA) to assess the commonalities between protocols. Generally speaking, all three types of stimuli evoked similarly distributed response patterns and resulted in qualitatively similar tonotopic maps. However, quantitatively, we found that broadband stimuli are most efficient at evoking responses in auditory cortex, whereas narrowband and sweep stimuli offer the best sensitivity to differences in frequency tuning. Based on these results, we make several recommendations regarding optimal stimulus protocols, and conclude that an experimental design based on narrowband stimuli provides the best sensitivity to frequency-dependent responses to determine tonotopic maps. We forward that the resulting protocol is suitable to act as a localiser of tonotopic cortical fields in individuals, or to make quantitative comparisons between maps in dedicated tonotopic mapping studies.
Tinnitus is a percept of sound that is not related to an acoustic source outside the body. For ma... more Tinnitus is a percept of sound that is not related to an acoustic source outside the body. For many forms of tinnitus, mechanisms in the central nervous system are believed to play a role in the pathology. In this work we specifically assessed possible neural correlates of unilateral tinnitus. Functional magnetic resonance imaging (fMRI) was used to investigate differences in sound-evoked neural activity between controls, subjects with left-sided tinnitus, and subjects with right-sided tinnitus. We assessed connectivity patterns between auditory nuclei and the lateralization of the sound-evoked responses. Interestingly, these response characteristics did not relate to the laterality of tinnitus. The lateralization for left-or right ear stimuli, as expressed in a lateralization index, was considerably smaller in subjects with tinnitus compared to that in controls, reaching significance in the right primary auditory cortex (PAC) and the right inferior colliculus (IC). Reduced functional connectivity between the brainstem and the cortex was observed in subjects with tinnitus. These differences are consistent with two existing models that relate tinnitus to i) changes in the corticothalamic feedback loops or ii) reduced inhibitory effectiveness between the limbic system and the thalamus. The vermis of the cerebellum also responded to monaural sound in subjects with unilateral tinnitus. In contrast, no cerebellar response was observed in control subjects. This suggests the involvement of the vermis of the cerebellum in unilateral tinnitus.
The present functional magnetic resonance imaging (fMRI) study presents data challenging the trad... more The present functional magnetic resonance imaging (fMRI) study presents data challenging the traditional view that sound is processed almost exclusively in the classical auditory pathway unless imbued with behavioral significance. In a first experiment, subjects were presented with broadband noise in on/off fashion as they performed an unrelated visual task. A conventional analysis assuming predictable sound-evoked responses demonstrated a typical activation pattern that was confined to classical auditory centers. In contrast, spatial independent component analysis (sICA) disclosed multiple networks of acoustically responsive brain centers. One network comprised classical auditory centers, but four others included nominally "nonauditory" areas: cingulo-insular cortex, mediotemporal limbic lobe, basal ganglia, and posterior orbitofrontal cortex, respectively. Functional connectivity analyses confirmed the sICA results by demonstrating coordinated activity between the involv...
Tinnitus is a phantom sound percept that can be severely disabling. Its pathophysiology is poorly... more Tinnitus is a phantom sound percept that can be severely disabling. Its pathophysiology is poorly understood, partly due to the inability to objectively measure neural correlates of tinnitus. Gaze-evoked tinnitus (GET) is a rare form of tinnitus that may arise after vestibular schwannoma removal. Subjects typically describe tinnitus in the deaf ear on the side of the surgery that can be modulated by peripheral eye gaze. This phenomenon offers a unique opportunity to study the relation between tinnitus and brain activity. We used functional magnetic resonance imaging in humans to show that in normal-hearing control subjects, peripheral gaze results in inhibition of the auditory cortex, but no detectable response in the medial geniculate body (MGB) and inferior colliculus (IC).
Although it is known that responses in the auditory cortex are evoked predominantly contralateral... more Although it is known that responses in the auditory cortex are evoked predominantly contralateral to the side of stimulation, the lateralization of responses at lower levels in the human central auditory system has hardly been studied. Furthermore, little is known on the functional interactions between the involved processing centers. In this study, functional MRI was performed using sound stimuli of varying left and right intensities. In normal hearing subjects, contralateral activation was consistently detected in the temporal lobe, thalamus and midbrain. Connectivity analyses showed that auditory information crosses to the contralateral side in the lower brainstem followed by ipsilateral signal conduction towards the auditory cortex, similar to the flow of auditory signals in other mammals. In unilaterally deaf subjects, activation was more symmetrical for the cortices but remained contralateral in the midbrain and thalamus. Input connection strengths were different only at cortical levels, and there was no evidence for plastic reorganization at subcortical levels. D
Evoked responses in functional magnetic resonance imaging (fMRI) are affected by the presence of ... more Evoked responses in functional magnetic resonance imaging (fMRI) are affected by the presence of acoustic scanner noise (ASN). Particularly, stimulus-related activation of the auditory system and deactivation of the default mode network have repeatedly been shown to diminish. In contrast, little is known about the influence of ASN on the spontaneous fluctuations in brain activity that are crucial for network-related neuroimaging methods like independent component analysis (ICA) or functional and effective connectivity analysis (ECA). The present study assessed the robustness of intrinsic connectivity networks in the human brain to the presence of ASN by comparing 'silent' (sparse) and 'noisy' (continuous) acquisition schemes, both during task performance and during rest. In agreement with existing literature, ASN strongly diminished conventional evoked response levels. In contrast, ICA and ECA robustly identified similar functional networks regardless of the scanning method. ASN affected the strength of only few independent components, and effective connectivity was hardly sensitive to ASN overall. However, unexpectedly, ICA revealed notable differences in the underlying neurodynamics. In particular, low-frequency network oscillations dominated in the commonly used continuous scanning environment, but signal spectra were significantly flatter during the less noisy sparse scanning runs. We tentatively attribute these differences to the ubiquitous influence of ASN on alertness and arousal.
The aim of this fMRI study was to relate cortical fMRI responses to both physical and perceptual ... more The aim of this fMRI study was to relate cortical fMRI responses to both physical and perceptual sound level characteristics. Besides subjects with normal hearing, subjects with high-frequency sensorineural hearing loss were included, as distortion of loudness perception is a characteristic of such impairment. Cortical responses in both subject groups were analyzed as a function of the physical intensity and the perceived loudness of low and high-frequency stimuli. For the low-frequency stimuli, intensity levels ranged from 0 to 70 dB SL; for the highfrequency stimuli, intensity levels were set such that the corresponding loudness levels matched those of the low-frequency stimuli. Responses were found to increase significantly and predominantly linearly with intensity level and with loudness level. Response saturation at the highest levels was not apparent, but activation exhibited a steep rise between 0 and 10 dB for the low-frequency stimuli. The activation in the subjects with hearing loss increased significantly more strongly with stimulus intensity than that in the normally hearing subjects. This reflects loudness recruitment, characterized by a disproportionate increase in loudness with stimulus intensity. In contrast, the rate of activation increase as a function of loudness level did not differ between both subject groups. This demonstrates that fMRI activation at the level of the auditory cortex is more closely related to the percept of a stimulus (i.e., loudness) rather than to its physical characteristics (i.e., intensity).
Associative emotional learning, which is important for the social emotional functioning of indivi... more Associative emotional learning, which is important for the social emotional functioning of individuals and is often impaired in psychiatric illnesses, is in part mediated by dopamine and glutamate pathways in the brain. The protein DARPP-32 is involved in the regulation of dopaminergic and glutaminergic signaling. Consequently, it has been suggested that the haplotypic variants of the gene PPP1R1B that encodes DARPP-32 are associated with working memory and emotion processing. We hypothesized that PPP1R1B should have a significant influence on the network of brain regions involved in associative emotional learning that are rich in DARPP-32, namely the striatum, prefrontal cortex (comprising the medial frontal gyrus and inferior frontal gyrus (IFG)), amygdala and parahippocampal gyrus (PHG). Dynamic causal models were applied to functional MRI data to investigate how brain connectivity during an associative emotional learning task is affected by different single-nucleotide polymorphisms (SNPs) of PPP1R1B: rs879606, rs907094 and rs3764352. Compared to heterozygotes, homozygotes with GTA alleles displayed increased intrinsic connectivity between the IFG and PHG, as well as increased excitability of the PHG for negative emotional stimuli. We have also elucidated the directionality of these genetic influences. Our data suggest that homozygotes with GTA alleles involve stronger functional connections between brain areas in order to maintain activation of these regions. Homozygotes might engage a greater degree of motivational learning and integration of information to perform the emotional learning task correctly. We conclude that PPP1R1B is associated with the neural network involved in associative emotional learning.
Functional MRI was performed to investigate differences in the basic functional organization of t... more Functional MRI was performed to investigate differences in the basic functional organization of the primary and secondary auditory cortex regarding preferred stimulus lateralization and frequency. A modified sparse acquisition scheme was used to spatially map the characteristics of the auditory cortex at the level of individual voxels. In the regions of Heschl's gyrus and sulcus that correspond with the primary auditory cortex, activation was systematically strongest in response to contralateral stimulation. Contrarily, in the surrounding secondary active regions including the planum polare and the planum temporale, largescale preferences with respect to stimulus lateralization were absent. Regarding optimal stimulus frequency, low-to high-frequency spatial gradients were discernable along the Heschl's gyrus and sulcus in anterolateral to posteromedial direction, especially in the right hemisphere, consistent with the presence of a tonotopic organization in these primary areas. However, in the surrounding activated secondary areas frequency preferences were erratic. Lateralization preferences did not depend on stimulus frequency, and frequency preferences did not depend on stimulus lateralization. While the primary auditory cortex is topographically organized with respect to physical stimulus properties (i.e., lateralization and frequency), such organizational principles are no longer obvious in secondary and higher areas. This suggests a neural re-encoding of sound signals in the transition from primary to secondary areas, possibly in relation to auditory scene analysis and the processing of auditory objects.
Functional MRI was used to investigate the characteristics of the human cerebral response to dyna... more Functional MRI was used to investigate the characteristics of the human cerebral response to dynamic ripples. Dynamic ripples are sound stimuli containing regular spectrotemporal modulations, which are of major importance in speech processing; however, in contrast to speech, dynamic ripples can be characterized fully by a limited number of parameters. Extensive activation consisting of multiple separate regions was found bilaterally in the auditory cortex, particularly along the Heschl's gyri. This agrees with the presence of a structural cortical subdivision into functional fields. The level and the extent of activation were measured and correlated highly (R 2 ϭ 0.97). Both measures depended strongly on the spectral density, temporal frequency, and amplitude of the modulations and matched the perceptual discernibility of the spectrotemporal modulations. The largest responses occurred for parameter values near the optimal human sensitivity. The drift direction of the modulations did not influence the activation. No quantitative differences were found between the two hemispheres. Average brain activation levels proved to be separable with regard to the spectral density and temporal frequency of the modulations. Topographic mappings of the modulation density and frequency onto the cortical surface were shown, approximately in posterolateral-to-anteromedial and lateral-to-medial directions, respectively. Posterolateral regions were most sensitive to spectrotemporal features at a scale similar to phonemes. Anteromedial regions, however, were also relatively sensitive to smaller scale acoustic features. This spatially dependent sensitivity suggests a functional topographic and hierarchical organization of the auditory cortex.
Due to a typesetting error, the index under "min" in Eq. is incorrect. The index should read i ≥ ... more Due to a typesetting error, the index under "min" in Eq. is incorrect. The index should read i ≥ j instead of i ≤ j. For the reader's convenience, the entire correct Eq. (5) appears here.
In the context of neuroimaging experiments, it is essential to account for the multiple compariso... more In the context of neuroimaging experiments, it is essential to account for the multiple comparisons problem when thresholding statistical mappings. Various methods are in use to deal with this issue, but they differ in their signal detection power for small-and large-scale effects. In this paper, we comprehensively describe a new method that is based on control of the false discovery rate (FDR). Our method increases sensitivity by exploiting the spatially clustered nature of neuroimaging effects. This is achieved by using a sliding window technique, in which FDR-control is first applied at a regional level. Thus, a new statistical map that is related to the regionally achieved FDR is derived from the available voxelwise P-values. On the basis of receiver operating characteristic (ROC) curves, thresholding based on this map is demonstrated to have better discriminatory power than conventional thresholding based on P-values. Secondly, it is shown that the resulting maps can be thresholded at a level that results in control of the global FDR. By means of statistical arguments and numerical simulations under widely varying conditions, our method is validated, characterized, and compared to some other common voxel-based methods (uncorrected thresholding, Bonferroni correction, and conventional FDR-control). It is found that our method shows considerably higher sensitivity as compared to conventional FDR-control, while still controlling the achieved FDR at the same level or better. Finally, our method is applied to two diverse neuroimaging experiments to assess its practical merits, resulting in substantial improvements as compared to the other methods.
In this study, the application of factor analytic (FA) rotation methods in the context of neuroim... more In this study, the application of factor analytic (FA) rotation methods in the context of neuroimaging data analysis was explored. Three FA algorithms (ProMax, QuartiMax, and VariMax) were employed to carry out blind source separation in a functional magnetic resonance imaging (fMRI) experiment that involved a basic audiovisual stimulus paradigm. The outcomes were compared with those from three common independent component analysis (ICA) methods (FastICA, InfoMax, and Jade). When applied in the spatial domain (sFA), all three FA methods performed satisfactorily and comparably to the ICA methods. The QuartiMax and VariMax methods resulted in highly similar outcomes, while the ProMax results more closely resembled those from the FastICA and InfoMax ICA analyses. All methods were able to identify multiple distinct contributing factors of neural origin, including e.g. the central auditory system, the mediotemporal limbic lobe, the basal ganglia, and the motor system. In addition, various contributions from artifacts could be observed, but these constituted different factors that were well separated from those with neural effects. When applied in the temporal domain (tFA), the factor analytic methods performed drastically worse, in the sense that the spatial activation maps revealed activation much more diffusely throughout the brain and the corresponding time courses were less pronouncedly related to the employed stimulus paradigm. Temporal ICA performed better than tFA, with the possible exception of the Jade method, but still did worse than any of the spatial FA or ICA methods. In conclusion, the present findings suggest that sFA forms a viable and useful alternative to ICA in the context of fMRI data analyses, and indicate that sFA methods complement the range of blind source separation methods that are currently in use in fMRI already.
In functional MRI experiments on the central auditory system, activation caused by acoustic scann... more In functional MRI experiments on the central auditory system, activation caused by acoustic scanner noise is a dominating factor that partially masks the hemodynamic response signals to sound stimuli of interest. In this study, the nonlinear interaction between auditory responses to single scans and those to tone stimuli was investigated. By using irregular acquisition repetition times and quasi-random stimulus timings, the brain responses to pure tone stimuli were analyzed, as well as their interaction with scanner noise. The tone frequencies were chosen to match either the fundamental frequency of the scanner noise (730 Hz) or a region with little spectral power (4.70 kHz). The hemodynamic responses could be characterized by amplitudes of 1.3% and a time-to-peak of 4.0 -4.5 sec in the absence of scanner noise. Interaction effects due to a single previous scan typically decreased the response magnitudes to 0.9%. The functional shape of the interaction was analyzed and could be described by a highly separable, dominantly symmetric interaction function that fairly agreed with a low-order Volterra expansion of a simple nonlinear model. Interactions were stronger and more complex in shape when the spectral content of the tone stimulus and the scanner noise were more similar. Magn Reson Med 53:49 -60, 2005.
Although orderly representations of sound frequency in the brain play a guiding role in the inves... more Although orderly representations of sound frequency in the brain play a guiding role in the investigation of auditory processing, a rigorous statistical evaluation of cortical tonotopic maps has so far hardly been attempted. In this report, the group-level significance of local tonotopic gradients was assessed using mass-multivariate statistics. The existence of multiple fields on the superior surface of the temporal lobe in both hemispheres was shown. These fields were distinguishable on the basis of tonotopic gradient direction and may likely be identified with the human homologues of the core areas AI and R in primates. Moreover, an objective comparison was made between the usage of volumetric and surface-based registration methods. Although the surface-based method resulted in a better registration across subjects of the grey matter segment as a whole, the alignment of functional subdivisions within the cortical sheet did not appear to improve over volumetric methods. This suggests that the variable relationship between the structural and the functional characteristics of auditory cortex is a limiting factor that cannot be overcome by morphology-based registration techniques alone. Finally, to illustrate how the proposed approach may be used in clinical practice, the method was used to test for focal differences regarding the tonotopic arrangements in healthy controls and tinnitus patients. No significant differences were observed, suggesting that tinnitus does not necessarily require tonotopic reorganisation to occur. Hum Brain Mapp 00:000-000, Published online in Wiley Online Library (wileyonlinelibrary. com). V C 2013 Wiley Periodicals, Inc. r Langers r r 2 r r Langers r r 14 r r Langers r r 16 r r 2D and 3D Assessment of Tonotopic Organisation r r 17 r
This report presents and validates a method for the group-level statistical assessment of indepen... more This report presents and validates a method for the group-level statistical assessment of independent component analysis (ICA) outcomes. The method is based on a matching of individual component maps to corresponding aggregate maps that are obtained from concatenated data. Group-level statistics are derived that include an explicit correction for selection bias. Outcomes were validated by means of calculations with artificial null data. Although statistical inferences were found to be incorrect if bias was neglected, the use of the proposed bias correction sufficed to obtain valid results. This was further confirmed by extensive calculations with artificial data that contained known effects of interest. While uncorrected statistical assessments systematically violated the imposed confidence level thresholds, the corrected method was never observed to exceed the allowed false positive rate. Yet, bias correction was found to result in a reduced sensitivity and a moderate decrease in discriminatory power. The method was also applied to analyze actual fMRI data. Various effects of interest that were detectable in the aggregate data were similarly revealed by the retrospective matching method. In particular, stimulus-related responses were extensive. Nevertheless, differences were observed regarding their spatial distribution. The presented findings indicate that the proposed method is suitable for neuroimaging analyses. Finally, a number of generalizations are discussed. It is concluded that the proposed method provides a framework that may supplement many of the currently available group ICA methods with validated unbiased group inferences. Hum Brain Mapp 31:727-742,
gebieden in de hersenen. Met functionele MRI kan deze activiteit worden bestudeerd. Uit voorgaand... more gebieden in de hersenen. Met functionele MRI kan deze activiteit worden bestudeerd. Uit voorgaand onderzoek is gebleken dat tinnituspatiënten exces- sieve hersenactivatie vertonen in respons op geluid. Een dergelijke overactivatie is in goede overeen- stemming met de hypothese dat tinnitus wordt ver- oorzaakt door een verhoogd niveau van spontane activiteit in het centrale auditieve systeem. Bij pa- tiënten die hun
In this paper, we review studies that have investigated brain morphology in chronic tinnitus in o... more In this paper, we review studies that have investigated brain morphology in chronic tinnitus in order to better understand the underlying pathophysiology of the disorder. Current consensus is that tinnitus is a disorder involving a distributed network of peripheral and central pathways in the nervous system. However, the precise mechanism remains elusive and it is unclear which structures are involved. Given that brain structure and function are highly related, identification of anatomical differences may shed light upon the mechanism of tinnitus generation and maintenance. We discuss anatomical changes in the auditory cortex, the limbic system, and prefrontal cortex, among others. Specifically, we discuss the gating mechanism of tinnitus and evaluate the evidence in support of the model from studies of brain anatomy. Although individual studies claim significant effects related to tinnitus, outcomes are divergent and even contradictory across studies. Moreover, results are often confounded by the presence of hearing loss. We conclude that, at present, the overall evidence for structural abnormalities specifically related to tinnitus is poor. As this area of research is expanding, we identify some key considerations for research design and propose strategies for future research.
Although a consensus is emerging in the literature regarding the tonotopic organisation of audito... more Although a consensus is emerging in the literature regarding the tonotopic organisation of auditory cortex in humans, previous studies employed a vast array of different neuroimaging protocols. In the present functional magnetic resonance imaging (fMRI) study, we made a systematic comparison between stimulus protocols involving jittered tone sequences with either a narrowband, broadband, or sweep character in order to evaluate their suitability for the purpose of tonotopic mapping. Data-driven analysis techniques were used to identify cortical maps related to sound-evoked activation and tonotopic frequency tuning. Principal component analysis (PCA) was used to extract the dominant response patterns in each of the three protocols separately, and generalised canonical correlation analysis (CCA) to assess the commonalities between protocols. Generally speaking, all three types of stimuli evoked similarly distributed response patterns and resulted in qualitatively similar tonotopic maps. However, quantitatively, we found that broadband stimuli are most efficient at evoking responses in auditory cortex, whereas narrowband and sweep stimuli offer the best sensitivity to differences in frequency tuning. Based on these results, we make several recommendations regarding optimal stimulus protocols, and conclude that an experimental design based on narrowband stimuli provides the best sensitivity to frequency-dependent responses to determine tonotopic maps. We forward that the resulting protocol is suitable to act as a localiser of tonotopic cortical fields in individuals, or to make quantitative comparisons between maps in dedicated tonotopic mapping studies.
Tinnitus is a percept of sound that is not related to an acoustic source outside the body. For ma... more Tinnitus is a percept of sound that is not related to an acoustic source outside the body. For many forms of tinnitus, mechanisms in the central nervous system are believed to play a role in the pathology. In this work we specifically assessed possible neural correlates of unilateral tinnitus. Functional magnetic resonance imaging (fMRI) was used to investigate differences in sound-evoked neural activity between controls, subjects with left-sided tinnitus, and subjects with right-sided tinnitus. We assessed connectivity patterns between auditory nuclei and the lateralization of the sound-evoked responses. Interestingly, these response characteristics did not relate to the laterality of tinnitus. The lateralization for left-or right ear stimuli, as expressed in a lateralization index, was considerably smaller in subjects with tinnitus compared to that in controls, reaching significance in the right primary auditory cortex (PAC) and the right inferior colliculus (IC). Reduced functional connectivity between the brainstem and the cortex was observed in subjects with tinnitus. These differences are consistent with two existing models that relate tinnitus to i) changes in the corticothalamic feedback loops or ii) reduced inhibitory effectiveness between the limbic system and the thalamus. The vermis of the cerebellum also responded to monaural sound in subjects with unilateral tinnitus. In contrast, no cerebellar response was observed in control subjects. This suggests the involvement of the vermis of the cerebellum in unilateral tinnitus.
The present functional magnetic resonance imaging (fMRI) study presents data challenging the trad... more The present functional magnetic resonance imaging (fMRI) study presents data challenging the traditional view that sound is processed almost exclusively in the classical auditory pathway unless imbued with behavioral significance. In a first experiment, subjects were presented with broadband noise in on/off fashion as they performed an unrelated visual task. A conventional analysis assuming predictable sound-evoked responses demonstrated a typical activation pattern that was confined to classical auditory centers. In contrast, spatial independent component analysis (sICA) disclosed multiple networks of acoustically responsive brain centers. One network comprised classical auditory centers, but four others included nominally "nonauditory" areas: cingulo-insular cortex, mediotemporal limbic lobe, basal ganglia, and posterior orbitofrontal cortex, respectively. Functional connectivity analyses confirmed the sICA results by demonstrating coordinated activity between the involv...
Tinnitus is a phantom sound percept that can be severely disabling. Its pathophysiology is poorly... more Tinnitus is a phantom sound percept that can be severely disabling. Its pathophysiology is poorly understood, partly due to the inability to objectively measure neural correlates of tinnitus. Gaze-evoked tinnitus (GET) is a rare form of tinnitus that may arise after vestibular schwannoma removal. Subjects typically describe tinnitus in the deaf ear on the side of the surgery that can be modulated by peripheral eye gaze. This phenomenon offers a unique opportunity to study the relation between tinnitus and brain activity. We used functional magnetic resonance imaging in humans to show that in normal-hearing control subjects, peripheral gaze results in inhibition of the auditory cortex, but no detectable response in the medial geniculate body (MGB) and inferior colliculus (IC).
Although it is known that responses in the auditory cortex are evoked predominantly contralateral... more Although it is known that responses in the auditory cortex are evoked predominantly contralateral to the side of stimulation, the lateralization of responses at lower levels in the human central auditory system has hardly been studied. Furthermore, little is known on the functional interactions between the involved processing centers. In this study, functional MRI was performed using sound stimuli of varying left and right intensities. In normal hearing subjects, contralateral activation was consistently detected in the temporal lobe, thalamus and midbrain. Connectivity analyses showed that auditory information crosses to the contralateral side in the lower brainstem followed by ipsilateral signal conduction towards the auditory cortex, similar to the flow of auditory signals in other mammals. In unilaterally deaf subjects, activation was more symmetrical for the cortices but remained contralateral in the midbrain and thalamus. Input connection strengths were different only at cortical levels, and there was no evidence for plastic reorganization at subcortical levels. D
Evoked responses in functional magnetic resonance imaging (fMRI) are affected by the presence of ... more Evoked responses in functional magnetic resonance imaging (fMRI) are affected by the presence of acoustic scanner noise (ASN). Particularly, stimulus-related activation of the auditory system and deactivation of the default mode network have repeatedly been shown to diminish. In contrast, little is known about the influence of ASN on the spontaneous fluctuations in brain activity that are crucial for network-related neuroimaging methods like independent component analysis (ICA) or functional and effective connectivity analysis (ECA). The present study assessed the robustness of intrinsic connectivity networks in the human brain to the presence of ASN by comparing 'silent' (sparse) and 'noisy' (continuous) acquisition schemes, both during task performance and during rest. In agreement with existing literature, ASN strongly diminished conventional evoked response levels. In contrast, ICA and ECA robustly identified similar functional networks regardless of the scanning method. ASN affected the strength of only few independent components, and effective connectivity was hardly sensitive to ASN overall. However, unexpectedly, ICA revealed notable differences in the underlying neurodynamics. In particular, low-frequency network oscillations dominated in the commonly used continuous scanning environment, but signal spectra were significantly flatter during the less noisy sparse scanning runs. We tentatively attribute these differences to the ubiquitous influence of ASN on alertness and arousal.
The aim of this fMRI study was to relate cortical fMRI responses to both physical and perceptual ... more The aim of this fMRI study was to relate cortical fMRI responses to both physical and perceptual sound level characteristics. Besides subjects with normal hearing, subjects with high-frequency sensorineural hearing loss were included, as distortion of loudness perception is a characteristic of such impairment. Cortical responses in both subject groups were analyzed as a function of the physical intensity and the perceived loudness of low and high-frequency stimuli. For the low-frequency stimuli, intensity levels ranged from 0 to 70 dB SL; for the highfrequency stimuli, intensity levels were set such that the corresponding loudness levels matched those of the low-frequency stimuli. Responses were found to increase significantly and predominantly linearly with intensity level and with loudness level. Response saturation at the highest levels was not apparent, but activation exhibited a steep rise between 0 and 10 dB for the low-frequency stimuli. The activation in the subjects with hearing loss increased significantly more strongly with stimulus intensity than that in the normally hearing subjects. This reflects loudness recruitment, characterized by a disproportionate increase in loudness with stimulus intensity. In contrast, the rate of activation increase as a function of loudness level did not differ between both subject groups. This demonstrates that fMRI activation at the level of the auditory cortex is more closely related to the percept of a stimulus (i.e., loudness) rather than to its physical characteristics (i.e., intensity).
Associative emotional learning, which is important for the social emotional functioning of indivi... more Associative emotional learning, which is important for the social emotional functioning of individuals and is often impaired in psychiatric illnesses, is in part mediated by dopamine and glutamate pathways in the brain. The protein DARPP-32 is involved in the regulation of dopaminergic and glutaminergic signaling. Consequently, it has been suggested that the haplotypic variants of the gene PPP1R1B that encodes DARPP-32 are associated with working memory and emotion processing. We hypothesized that PPP1R1B should have a significant influence on the network of brain regions involved in associative emotional learning that are rich in DARPP-32, namely the striatum, prefrontal cortex (comprising the medial frontal gyrus and inferior frontal gyrus (IFG)), amygdala and parahippocampal gyrus (PHG). Dynamic causal models were applied to functional MRI data to investigate how brain connectivity during an associative emotional learning task is affected by different single-nucleotide polymorphisms (SNPs) of PPP1R1B: rs879606, rs907094 and rs3764352. Compared to heterozygotes, homozygotes with GTA alleles displayed increased intrinsic connectivity between the IFG and PHG, as well as increased excitability of the PHG for negative emotional stimuli. We have also elucidated the directionality of these genetic influences. Our data suggest that homozygotes with GTA alleles involve stronger functional connections between brain areas in order to maintain activation of these regions. Homozygotes might engage a greater degree of motivational learning and integration of information to perform the emotional learning task correctly. We conclude that PPP1R1B is associated with the neural network involved in associative emotional learning.
Functional MRI was performed to investigate differences in the basic functional organization of t... more Functional MRI was performed to investigate differences in the basic functional organization of the primary and secondary auditory cortex regarding preferred stimulus lateralization and frequency. A modified sparse acquisition scheme was used to spatially map the characteristics of the auditory cortex at the level of individual voxels. In the regions of Heschl's gyrus and sulcus that correspond with the primary auditory cortex, activation was systematically strongest in response to contralateral stimulation. Contrarily, in the surrounding secondary active regions including the planum polare and the planum temporale, largescale preferences with respect to stimulus lateralization were absent. Regarding optimal stimulus frequency, low-to high-frequency spatial gradients were discernable along the Heschl's gyrus and sulcus in anterolateral to posteromedial direction, especially in the right hemisphere, consistent with the presence of a tonotopic organization in these primary areas. However, in the surrounding activated secondary areas frequency preferences were erratic. Lateralization preferences did not depend on stimulus frequency, and frequency preferences did not depend on stimulus lateralization. While the primary auditory cortex is topographically organized with respect to physical stimulus properties (i.e., lateralization and frequency), such organizational principles are no longer obvious in secondary and higher areas. This suggests a neural re-encoding of sound signals in the transition from primary to secondary areas, possibly in relation to auditory scene analysis and the processing of auditory objects.
Functional MRI was used to investigate the characteristics of the human cerebral response to dyna... more Functional MRI was used to investigate the characteristics of the human cerebral response to dynamic ripples. Dynamic ripples are sound stimuli containing regular spectrotemporal modulations, which are of major importance in speech processing; however, in contrast to speech, dynamic ripples can be characterized fully by a limited number of parameters. Extensive activation consisting of multiple separate regions was found bilaterally in the auditory cortex, particularly along the Heschl's gyri. This agrees with the presence of a structural cortical subdivision into functional fields. The level and the extent of activation were measured and correlated highly (R 2 ϭ 0.97). Both measures depended strongly on the spectral density, temporal frequency, and amplitude of the modulations and matched the perceptual discernibility of the spectrotemporal modulations. The largest responses occurred for parameter values near the optimal human sensitivity. The drift direction of the modulations did not influence the activation. No quantitative differences were found between the two hemispheres. Average brain activation levels proved to be separable with regard to the spectral density and temporal frequency of the modulations. Topographic mappings of the modulation density and frequency onto the cortical surface were shown, approximately in posterolateral-to-anteromedial and lateral-to-medial directions, respectively. Posterolateral regions were most sensitive to spectrotemporal features at a scale similar to phonemes. Anteromedial regions, however, were also relatively sensitive to smaller scale acoustic features. This spatially dependent sensitivity suggests a functional topographic and hierarchical organization of the auditory cortex.
Due to a typesetting error, the index under "min" in Eq. is incorrect. The index should read i ≥ ... more Due to a typesetting error, the index under "min" in Eq. is incorrect. The index should read i ≥ j instead of i ≤ j. For the reader's convenience, the entire correct Eq. (5) appears here.
In the context of neuroimaging experiments, it is essential to account for the multiple compariso... more In the context of neuroimaging experiments, it is essential to account for the multiple comparisons problem when thresholding statistical mappings. Various methods are in use to deal with this issue, but they differ in their signal detection power for small-and large-scale effects. In this paper, we comprehensively describe a new method that is based on control of the false discovery rate (FDR). Our method increases sensitivity by exploiting the spatially clustered nature of neuroimaging effects. This is achieved by using a sliding window technique, in which FDR-control is first applied at a regional level. Thus, a new statistical map that is related to the regionally achieved FDR is derived from the available voxelwise P-values. On the basis of receiver operating characteristic (ROC) curves, thresholding based on this map is demonstrated to have better discriminatory power than conventional thresholding based on P-values. Secondly, it is shown that the resulting maps can be thresholded at a level that results in control of the global FDR. By means of statistical arguments and numerical simulations under widely varying conditions, our method is validated, characterized, and compared to some other common voxel-based methods (uncorrected thresholding, Bonferroni correction, and conventional FDR-control). It is found that our method shows considerably higher sensitivity as compared to conventional FDR-control, while still controlling the achieved FDR at the same level or better. Finally, our method is applied to two diverse neuroimaging experiments to assess its practical merits, resulting in substantial improvements as compared to the other methods.
In this study, the application of factor analytic (FA) rotation methods in the context of neuroim... more In this study, the application of factor analytic (FA) rotation methods in the context of neuroimaging data analysis was explored. Three FA algorithms (ProMax, QuartiMax, and VariMax) were employed to carry out blind source separation in a functional magnetic resonance imaging (fMRI) experiment that involved a basic audiovisual stimulus paradigm. The outcomes were compared with those from three common independent component analysis (ICA) methods (FastICA, InfoMax, and Jade). When applied in the spatial domain (sFA), all three FA methods performed satisfactorily and comparably to the ICA methods. The QuartiMax and VariMax methods resulted in highly similar outcomes, while the ProMax results more closely resembled those from the FastICA and InfoMax ICA analyses. All methods were able to identify multiple distinct contributing factors of neural origin, including e.g. the central auditory system, the mediotemporal limbic lobe, the basal ganglia, and the motor system. In addition, various contributions from artifacts could be observed, but these constituted different factors that were well separated from those with neural effects. When applied in the temporal domain (tFA), the factor analytic methods performed drastically worse, in the sense that the spatial activation maps revealed activation much more diffusely throughout the brain and the corresponding time courses were less pronouncedly related to the employed stimulus paradigm. Temporal ICA performed better than tFA, with the possible exception of the Jade method, but still did worse than any of the spatial FA or ICA methods. In conclusion, the present findings suggest that sFA forms a viable and useful alternative to ICA in the context of fMRI data analyses, and indicate that sFA methods complement the range of blind source separation methods that are currently in use in fMRI already.
In functional MRI experiments on the central auditory system, activation caused by acoustic scann... more In functional MRI experiments on the central auditory system, activation caused by acoustic scanner noise is a dominating factor that partially masks the hemodynamic response signals to sound stimuli of interest. In this study, the nonlinear interaction between auditory responses to single scans and those to tone stimuli was investigated. By using irregular acquisition repetition times and quasi-random stimulus timings, the brain responses to pure tone stimuli were analyzed, as well as their interaction with scanner noise. The tone frequencies were chosen to match either the fundamental frequency of the scanner noise (730 Hz) or a region with little spectral power (4.70 kHz). The hemodynamic responses could be characterized by amplitudes of 1.3% and a time-to-peak of 4.0 -4.5 sec in the absence of scanner noise. Interaction effects due to a single previous scan typically decreased the response magnitudes to 0.9%. The functional shape of the interaction was analyzed and could be described by a highly separable, dominantly symmetric interaction function that fairly agreed with a low-order Volterra expansion of a simple nonlinear model. Interactions were stronger and more complex in shape when the spectral content of the tone stimulus and the scanner noise were more similar. Magn Reson Med 53:49 -60, 2005.
Although orderly representations of sound frequency in the brain play a guiding role in the inves... more Although orderly representations of sound frequency in the brain play a guiding role in the investigation of auditory processing, a rigorous statistical evaluation of cortical tonotopic maps has so far hardly been attempted. In this report, the group-level significance of local tonotopic gradients was assessed using mass-multivariate statistics. The existence of multiple fields on the superior surface of the temporal lobe in both hemispheres was shown. These fields were distinguishable on the basis of tonotopic gradient direction and may likely be identified with the human homologues of the core areas AI and R in primates. Moreover, an objective comparison was made between the usage of volumetric and surface-based registration methods. Although the surface-based method resulted in a better registration across subjects of the grey matter segment as a whole, the alignment of functional subdivisions within the cortical sheet did not appear to improve over volumetric methods. This suggests that the variable relationship between the structural and the functional characteristics of auditory cortex is a limiting factor that cannot be overcome by morphology-based registration techniques alone. Finally, to illustrate how the proposed approach may be used in clinical practice, the method was used to test for focal differences regarding the tonotopic arrangements in healthy controls and tinnitus patients. No significant differences were observed, suggesting that tinnitus does not necessarily require tonotopic reorganisation to occur. Hum Brain Mapp 00:000-000, Published online in Wiley Online Library (wileyonlinelibrary. com). V C 2013 Wiley Periodicals, Inc. r Langers r r 2 r r Langers r r 14 r r Langers r r 16 r r 2D and 3D Assessment of Tonotopic Organisation r r 17 r
This report presents and validates a method for the group-level statistical assessment of indepen... more This report presents and validates a method for the group-level statistical assessment of independent component analysis (ICA) outcomes. The method is based on a matching of individual component maps to corresponding aggregate maps that are obtained from concatenated data. Group-level statistics are derived that include an explicit correction for selection bias. Outcomes were validated by means of calculations with artificial null data. Although statistical inferences were found to be incorrect if bias was neglected, the use of the proposed bias correction sufficed to obtain valid results. This was further confirmed by extensive calculations with artificial data that contained known effects of interest. While uncorrected statistical assessments systematically violated the imposed confidence level thresholds, the corrected method was never observed to exceed the allowed false positive rate. Yet, bias correction was found to result in a reduced sensitivity and a moderate decrease in discriminatory power. The method was also applied to analyze actual fMRI data. Various effects of interest that were detectable in the aggregate data were similarly revealed by the retrospective matching method. In particular, stimulus-related responses were extensive. Nevertheless, differences were observed regarding their spatial distribution. The presented findings indicate that the proposed method is suitable for neuroimaging analyses. Finally, a number of generalizations are discussed. It is concluded that the proposed method provides a framework that may supplement many of the currently available group ICA methods with validated unbiased group inferences. Hum Brain Mapp 31:727-742,
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Papers by Dave Langers