Detailed mapping of the complex fiber structure and white matter pathways of the chimpanzee brain.

Long-standing questions about human brain evolution may only be resolved through comparisons with close living evolutionary relatives, such as chimpanzees. This applies in particular to structural white matter (WM) connectivity, which continuously expanded throughout evolution. However, due to legal restrictions on chimpanzee research, neuroscience research currently relies largely on data with limited detail or on comparisons with evolutionarily distant monkeys. Here, we present a detailed magnetic resonance imaging resource to study structural WM connectivity in the chimpanzee. This open-access resource contains (1) WM reconstructions of a postmortem chimpanzee brain, using the highest-quality diffusion magnetic resonance imaging data yet acquired from great apes; (2) an optimized and validated method for high-quality fiber orientation reconstructions; and (3) major fiber tract segmentations for cross-species morphological comparisons. This dataset enabled us to identify phylogenetically relevant details of the chimpanzee connectome, and we anticipate that it will substantially contribute to understanding human brain evolution.

Reproducibility of cerebral perfusion measurements using BOLD delay.

BOLD delay is an emerging, noninvasive method for assessing cerebral perfusion that does not require the use of intravenous contrast agents and is thus particularly suited for longitudinal monitoring. In this study, we assess the reproducibility of BOLD delay using data from 136 subjects with normal cerebral perfusion scanned on two separate occasions with scanners, sequence parameters, and intervals between scans varying between subjects. The effects of various factors on the reproducibility of BOLD delay, defined here as the differences in BOLD delay values between the scanning sessions, were investigated using a linear mixed model. Reproducibility was additionally assessed using the intraclass correlation coefficient of BOLD delay between sessions. Reproducibility was highest in the posterior cerebral artery territory. The mean BOLD delay test-retest difference after accounting for the aforementioned factors was 1.2 s (95% CI = 1.0 to 1.4 s). Overall, BOLD delay shows good reproducibility, but care should be taken when interpreting longitudinal BOLD delay changes that are either very small or are located in certain brain regions.

B 1 + $$ {B}_1

PURPOSE: Magnetization transfer saturation ( MTsat $$ \mathrm{MTsat} $$ ) is a useful marker to probe tissue macromolecular content and myelination in the brain. The increased B 1 + $$ {B}_1^{+} $$ -inhomogeneity at ≥ 7 $$ \ge 7 $$ T and significantly larger saturation pulse flip angles which are often used for postmortem studies exceed the limits where previous MTsat $$ \mathrm{MTsat} $$ B 1 + $$ {B}_1^{+} $$ correction methods are applicable. Here, we develop a calibration-based correction model and procedure, and validate and evaluate it in postmortem 7T data of whole chimpanzee brains. THEORY: The B 1 + $$ {B}_1^{+} $$ dependence of MTsat $$ \mathrm{MTsat} $$ was investigated by varying the off-resonance saturation pulse flip angle. For the range of saturation pulse flip angles applied in typical experiments on postmortem tissue, the dependence was close to linear. A linear model with a single calibration constant C $$ C $$ is proposed to correct bias in MTsat $$ \mathrm{MTsat} $$ by mapping it to the reference value of the saturation pulse flip angle. METHODS: C $$ C $$ was estimated voxel-wise in five postmortem chimpanzee brains. "Individual-based global parameters" were obtained by calculating the mean C $$ C $$ within individual specimen brains and "group-based global parameters" by calculating the means of the individual-based global parameters across the five brains. RESULTS: The linear calibration model described the data well, though C $$ C $$ was not entirely independent of the underlying tissue and B 1 + $$ {B}_1^{+} $$ . Individual-based correction parameters and a group-based global correction parameter ( C = 1 . 2 $$ C=1.2 $$ ) led to visible, quantifiable reductions of B 1 + $$ {B}_1^{+} $$ -biases in high-resolution MTsat $$ \mathrm{MTsat} $$ maps. CONCLUSION: The presented model and calibration approach effectively corrects for B 1 + $$ {B}_1^{+} $$ inhomogeneities in postmortem 7T data.

Finding the best clearing approach - Towards 3D wide-scale multimodal imaging of aged human brain tissue.

The accessibility of new wide-scale multimodal imaging techniques led to numerous clearing techniques emerging over the last decade. However, clearing mesoscopic-sized blocks of aged human brain tissue remains an extremely challenging task. Homogenizing refractive indices and reducing light absorption and scattering are the foundation of tissue clearing. Due to its dense and highly myelinated nature, especially in white matter, the human brain poses particular challenges to clearing techniques. Here, we present a comparative study of seven tissue clearing approaches and their impact on aged human brain tissue blocks (> 5 mm). The goal was to identify the most practical and efficient method in regards to macroscopic transparency, brief clearing time, compatibility with immunohistochemical processing and wide-scale multimodal microscopic imaging. We successfully cleared 26 × 26 × 5 mm3-sized human brain samples with two hydrophilic and two hydrophobic clearing techniques. Optical properties as well as light and antibody penetration depths highly vary between these methods. In addition to finding the best clearing approach, we compared three microscopic imaging setups (the Zeiss Laser Scanning Microscope (LSM) 880 , the Miltenyi Biotec Ultramicroscope ll (UM ll) and the 3i Marianas LightSheet microscope) regarding optimal imaging of large-scale tissue samples. We demonstrate that combining the CLARITY technique (Clear Lipid-exchanged Acrylamide-hybridized Rigid Imaging compatible Tissue hYdrogel) with the Zeiss LSM 880 and combining the iDISCO technique (immunolabeling-enabled three-dimensional imaging of solvent-cleared organs) with the Miltenyi Biotec UM ll are the most practical and efficient approaches to sufficiently clear aged human brain tissue and generate 3D microscopic images. Our results point out challenges that arise from seven clearing and three imaging techniques applied to non-standardized tissue samples such as aged human brain tissue.

Apparent thinning of human visual cortex during childhood is associated with myelination.

Human cortex appears to thin during childhood development. However, the underlying microstructural mechanisms are unknown. Using functional magnetic resonance imaging (fMRI), quantitative MRI (qMRI), and diffusion MRI (dMRI) in children and adults, we tested what quantitative changes occur to gray and white matter in ventral temporal cortex (VTC) from childhood to adulthood, and how these changes relate to cortical thinning. T1 relaxation time from qMRI and mean diffusivity (MD) from dMRI provide independent and complementary measurements of microstructural properties of gray and white matter tissue. In face- and character-selective regions in lateral VTC, T1 and MD decreased from age 5 to adulthood in mid and deep cortex, as well as in their adjacent white matter. T1 reduction also occurred longitudinally in children's brain regions. T1 and MD decreases 1) were consistent with tissue growth related to myelination, which we verified with adult histological myelin stains, and 2) were correlated with apparent cortical thinning. In contrast, in place-selective cortex in medial VTC, we found no development of T1 or MD after age 5, and thickness was related to cortical morphology. These findings suggest that lateral VTC likely becomes more myelinated from childhood to adulthood, affecting the contrast of MR images and, in turn, the apparent gray-white boundary. These findings are important because they suggest that VTC does not thin during childhood but instead gets more myelinated. Our data have broad ramifications for understanding both typical and atypical brain development using advanced in vivo quantitative measurements and clinical conditions implicating myelin.

Measuring the iron content of dopaminergic neurons in substantia nigra with MRI relaxometry.

In Parkinson's disease, the depletion of iron-rich dopaminergic neurons in nigrosome 1 of the substantia nigra precedes motor symptoms by two decades. Methods capable of monitoring this neuronal depletion, at an early disease stage, are needed for early diagnosis and treatment monitoring. Magnetic resonance imaging (MRI) is particularly suitable for this task due to its sensitivity to tissue microstructure and in particular, to iron. However, the exact mechanisms of MRI contrast in the substantia nigra are not well understood, hindering the development of powerful biomarkers. In the present report, we illuminate the contrast mechanisms in gradient and spin echo MR images in human nigrosome 1 by combining quantitative 3D iron histology and biophysical modeling with quantitative MRI on post mortem human brain tissue. We show that the dominant contribution to the effective transverse relaxation rate (R2*) in nigrosome 1 originates from iron accumulated in the neuromelanin of dopaminergic neurons. This contribution is appropriately described by a static dephasing approximation of the MRI signal. We demonstrate that the R2* contribution from dopaminergic neurons reflects the product of cell density and cellular iron concentration. These results demonstrate that the in vivo monitoring of neuronal density and iron in nigrosome 1 may be feasible with MRI and provide directions for the development of biomarkers for an early detection of dopaminergic neuron depletion in Parkinson's disease.

A novel approach for assessing hypoperfusion in stroke using spatial independent component analysis of resting-state fMRI.

Individualized treatment of acute stroke depends on the timely detection of ischemia and potentially salvageable tissue in the brain. Using functional MRI (fMRI), it is possible to characterize cerebral blood flow from blood-oxygen-level-dependent (BOLD) signals without the administration of exogenous contrast agents. In this study, we applied spatial independent component analysis to resting-state fMRI data of 37 stroke patients scanned within 24 hr of symptom onset, 17 of whom received follow-up scans the next day. Our analysis revealed "Hypoperfusion spatially-Independent Components" (HICs) whose spatial patterns of BOLD signal resembled regions of delayed perfusion depicted by dynamic susceptibility contrast MRI. These HICs were detected even in the presence of excessive patient motion, and disappeared following successful tissue reperfusion. The unique spatial and temporal features of HICs allowed them to be distinguished with high accuracy from other components in a user-independent manner (area under the curve = 0.93, balanced accuracy = 0.90, sensitivity = 1.00, and specificity = 0.85). Our study therefore presents a new, noninvasive method for assessing blood flow in acute stroke that minimizes interpretative subjectivity and is robust to severe patient motion.

Mapping Short Association Fibers in the Early Cortical Visual Processing Stream Using In Vivo Diffusion Tractography.

Short association fibers (U-fibers) connect proximal cortical areas and constitute the majority of white matter connections in the human brain. U-fibers play an important role in brain development, function, and pathology but are underrepresented in current descriptions of the human brain connectome, primarily due to methodological challenges in diffusion magnetic resonance imaging (dMRI) of these fibers. High spatial resolution and dedicated fiber and tractography models are required to reliably map the U-fibers. Moreover, limited quantitative knowledge of their geometry and distribution makes validation of U-fiber tractography challenging. Submillimeter resolution diffusion MRI-facilitated by a cutting-edge MRI scanner with 300 mT/m maximum gradient amplitude-was used to map U-fiber connectivity between primary and secondary visual cortical areas (V1 and V2, respectively) in vivo. V1 and V2 retinotopic maps were obtained using functional MRI at 7T. The mapped V1-V2 connectivity was retinotopically organized, demonstrating higher connectivity for retinotopically corresponding areas in V1 and V2 as expected. The results were highly reproducible, as demonstrated by repeated measurements in the same participants and by an independent replication group study. This study demonstrates a robust U-fiber connectivity mapping in vivo and is an important step toward construction of a more complete human brain connectome.

Does higher sampling rate (multiband + SENSE) improve group statistics - An example from social neuroscience block design at 3T.

Multiband (MB) or Simultaneous multi-slice (SMS) acquisition schemes allow the acquisition of MRI signals from more than one spatial coordinate at a time. Commercial availability has brought this technique within the reach of many neuroscientists and psychologists. Most early evaluation of the performance of MB acquisition employed resting state fMRI or the most basic tasks. In this study, we tested whether the advantages of using MB acquisition schemes generalize to group analyses using a cognitive task more representative of typical cognitive neuroscience applications. Twenty-three subjects were scanned on a Philips 3 â€‹T scanner using five sequences, up to eight-fold acceleration with MB-factors 1 to 4, SENSE factors up to 2 and corresponding TRs of 2.45s down to 0.63s, while they viewed (i) movie blocks showing complex actions with hand object interactions and (ii) control movie blocks without hand object interaction. Data were processed using a widely used analysis pipeline implemented in SPM12 including the unified segmentation and canonical HRF modelling. Using random effects group-level, voxel-wise analysis we found that all sequences were able to detect the basic action observation network known to be recruited by our task. The highest t-values were found for sequences with MB4 acceleration. For the MB1 sequence, a 50% bigger voxel volume was needed to reach comparable t-statistics. The group-level t-values for resting state networks (RSNs) were also highest for MB4 sequences. Here the MB1 sequence with larger voxel size did not perform comparable to the MB4 sequence. Altogether, we can thus recommend the use of MB4 (and SENSE 1.5 or 2) on a Philips scanner when aiming to perform group-level analyses using cognitive block design fMRI tasks and voxel sizes in the range of cortical thickness (e.g. 2.7 â€‹mm isotropic). While results will not be dramatically changed by the use of multiband, our results suggest that MB will bring a moderate but significant benefit.

Locus coeruleus imaging as a biomarker for noradrenergic dysfunction in neurodegenerative diseases.

Pathological alterations to the locus coeruleus, the major source of noradrenaline in the brain, are histologically evident in early stages of neurodegenerative diseases. Novel MRI approaches now provide an opportunity to quantify structural features of the locus coeruleus in vivo during disease progression. In combination with neuropathological biomarkers, in vivo locus coeruleus imaging could help to understand the contribution of locus coeruleus neurodegeneration to clinical and pathological manifestations in Alzheimer's disease, atypical neurodegenerative dementias and Parkinson's disease. Moreover, as the functional sensitivity of the noradrenergic system is likely to change with disease progression, in vivo measures of locus coeruleus integrity could provide new pathophysiological insights into cognitive and behavioural symptoms. Locus coeruleus imaging also holds the promise to stratify patients into clinical trials according to noradrenergic dysfunction. In this article, we present a consensus on how non-invasive in vivo assessment of locus coeruleus integrity can be used for clinical research in neurodegenerative diseases. We outline the next steps for in vivo, post-mortem and clinical studies that can lay the groundwork to evaluate the potential of locus coeruleus imaging as a biomarker for neurodegenerative diseases.

Biophysically motivated efficient estimation of the spatially isotropic R2* component from a single gradient-recalled echo measurement.

PURPOSE: To propose and validate an efficient method, based on a biophysically motivated signal model, for removing the orientation-dependent part of R2* using a single gradient-recalled echo (GRE) measurement. METHODS: The proposed method utilized a temporal second-order approximation of the hollow-cylinder-fiber model, in which the parameter describing the linear signal decay corresponded to the orientation-independent part of R2* . The estimated parameters were compared to the classical, mono-exponential decay model for R2* in a sample of an ex vivo human optic chiasm (OC). The OC was measured at 16 distinct orientations relative to the external magnetic field using GRE at 7T. To show that the proposed signal model can remove the orientation dependence of R2* , it was compared to the established phenomenological method for separating R2* into orientation-dependent and -independent parts. RESULTS: Using the phenomenological method on the classical signal model, the well-known separation of R2* into orientation-dependent and -independent parts was verified. For the proposed model, no significant orientation dependence in the linear signal decay parameter was observed. CONCLUSIONS: Since the proposed second-order model features orientation-dependent and -independent components at distinct temporal orders, it can be used to remove the orientation dependence of R2* using only a single GRE measurement.

Microstructural imaging of human neocortex in vivo.

The neocortex of the human brain is the seat of higher brain function. Modern imaging techniques, chief among them magnetic resonance imaging (MRI), allow non-invasive imaging of this important structure. Knowledge of the microstructure of the neocortex has classically come from post-mortem histological studies of human tissue, and extrapolations from invasive animal studies. From these studies, we know that the scale of important neocortical structure spans six orders of magnitude, ranging from the size of axonal diameters (microns), to the size of cortical areas responsible for integrating sensory information (centimetres). MRI presents an opportunity to move beyond classical methods, because MRI is non-invasive and MRI contrast is sensitive to neocortical microstructure over all these length scales. MRI thus allows inferences to be made about neocortical microstructure in vivo, i.e. MRI-based in vivo histology. We review recent literature that has applied and developed MRI-based in vivo histology to probe the microstructure of the human neocortex, focusing specifically on myelin, iron, and neuronal fibre mapping. We find that applications such as cortical parcellation (using [Formula: see text] maps as proxies for myelin content) and investigation of cortical iron deposition with age (using [Formula: see text] maps) are already contributing to the frontiers of knowledge in neuroscience. Neuronal fibre mapping in the cortex remains challenging in vivo, but recent improvements in diffusion MRI hold promise for exciting applications in the near future. The literature also suggests that utilising multiple complementary quantitative MRI maps could increase the specificity of inferences about neocortical microstructure relative to contemporary techniques, but that further investment in modelling is required to appropriately combine the maps. In vivo histology of human neocortical microstructure is undergoing rapid development. Future developments will improve its specificity, sensitivity, and clinical applicability, granting an ever greater ability to investigate neuroscientific and clinical questions about the human neocortex.

Overlapping frontoparietal networks for tactile and visual parametric working memory representations.

Previous working memory (WM) research based on non-human primate electrophysiology and human EEG has shown that frontal brain regions maintain frequencies of flutter stimulation across different sensory modalities by means of a supramodal parametric WM code. These findings imply that frontal regions encode the memorized frequencies in a sensory-unspecific, quantitative format. Here, we explored which brain regions maintain information about frequencies provided by different sensory modalities at the level of activity pattern across fMRI voxel populations. Moreover, we sought evidence for a supramodal multivariate WM representation. Participants maintained the same set of frequencies of tactile vibration and visual flicker for a 6 s WM delay in a frequency discrimination task. A support vector regression model for multivariate pattern analysis was applied. We observed that sensory cortices were only selective for memoranda of their corresponding modalities, while frontoparietal regions exhibited distinguishable activity patterns to memorized frequencies regardless of sensory modality. A common multivariate code was not evident in our data. Collectively, we show that mnemonic representations for stimulus frequencies are maintained throughout the cortical hierarchy, in line with the suggested transformation of information across different representational formats. Although evidence for a supramodal multivariate code is absent, our findings underpin the generalized role of the frontoparietal cortex for maintaining quantitative information across sensory modalities.

Effects of propofol anesthesia on the processing of noxious stimuli in the spinal cord and the brain.

Drug-induced unconsciousness is an essential component of general anesthesia, commonly attributed to attenuation of higher-order processing of external stimuli and a resulting loss of information integration capabilities of the brain. In this study, we investigated how the hypnotic drug propofol at doses comparable to those in clinical practice influences the processing of somatosensory stimuli in the spinal cord and in primary and higher-order cortices. Using nociceptive reflexes, somatosensory evoked potentials and functional magnet resonance imaging (fMRI), we found that propofol abolishes the processing of innocuous and moderate noxious stimuli at low to medium concentration levels, but that intense noxious stimuli evoked spinal and cerebral responses even during deep propofol anesthesia that caused profound electroencephalogram (EEG) burst suppression. While nociceptive reflexes and somatosensory potentials were affected only in a minor way by further increasing doses of propofol after the loss of consciousness, fMRI showed that increasing propofol concentration abolished processing of intense noxious stimuli in the insula and secondary somatosensory cortex and vastly increased processing in the frontal cortex. As the fMRI functional connectivity showed congruent changes with increasing doses of propofol - namely the temporal brain areas decreasing their connectivity with the bilateral pre-/postcentral gyri and the supplementary motor area, while connectivity of the latter with frontal areas is increased - we conclude that the changes in processing of noxious stimuli during propofol anesthesia might be related to changes in functional connectivity.

Developing 3D microscopy with CLARITY on human brain tissue: Towards a tool for informing and validating MRI-based histology.

Recent breakthroughs in magnetic resonance imaging (MRI) enabled quantitative relaxometry and diffusion-weighted imaging with sub-millimeter resolution. Combined with biophysical models of MR contrast the emerging methods promise in vivo mapping of cyto- and myelo-architectonics, i.e., in vivo histology using MRI (hMRI) in humans. The hMRI methods require histological reference data for model building and validation. This is currently provided by MRI on post mortem human brain tissue in combination with classical histology on sections. However, this well established approach is limited to qualitative 2D information, while a systematic validation of hMRI requires quantitative 3D information on macroscopic voxels. We present a promising histological method based on optical 3D imaging combined with a tissue clearing method, Clear Lipid-exchanged Acrylamide-hybridized Rigid Imaging compatible Tissue hYdrogel (CLARITY), adapted for hMRI validation. Adapting CLARITY to the needs of hMRI is challenging due to poor antibody penetration into large sample volumes and high opacity of aged post mortem human brain tissue. In a pilot experiment we achieved transparency of up to 8 mm-thick and immunohistochemical staining of up to 5 mm-thick post mortem brain tissue by a combination of active and passive clearing, prolonged clearing and staining times. We combined 3D optical imaging of the cleared samples with tailored image processing methods. We demonstrated the feasibility for quantification of neuron density, fiber orientation distribution and cell type classification within a volume with size similar to a typical MRI voxel. The presented combination of MRI, 3D optical microscopy and image processing is a promising tool for validation of MRI-based microstructure estimates.

Neuronal correlates of continuous manual tracking under varying visual movement feedback in a virtual reality environment.

To accurately guide one's actions online, the brain predicts sensory action feedback ahead of time based on internal models, which can be updated by sensory prediction errors. The underlying operations can be experimentally investigated in sensorimotor adaptation tasks, in which moving under perturbed sensory action feedback requires internal model updates. Here we altered healthy participants' visual hand movement feedback in a virtual reality setup, while assessing brain activity with functional magnetic resonance imaging (fMRI). Participants tracked a continually moving virtual target object with a photorealistic, three-dimensional (3D) virtual hand controlled online via a data glove. During the continuous tracking task, the virtual hand's movements (i.e., visual movement feedback) were repeatedly periodically delayed, which participants had to compensate for to maintain accurate tracking. This realistic task design allowed us to simultaneously investigate processes likely operating at several levels of the brain's motor control hierarchy. FMRI revealed that the length of visual feedback delay was parametrically reflected by activity in the inferior parietal cortex and posterior temporal cortex. Unpredicted changes in visuomotor mapping (at transitions from synchronous to delayed visual feedback periods or vice versa) activated biological motion-sensitive regions in the lateral occipitotemporal cortex (LOTC). Activity in the posterior parietal cortex (PPC), focused on the contralateral anterior intraparietal sulcus (aIPS), correlated with tracking error, whereby this correlation was stronger in participants with higher tracking performance. Our results are in line with recent proposals of a wide-spread cortical motor control hierarchy, where temporoparietal regions seem to evaluate visuomotor congruence and thus possibly ground a self-attribution of movements, the LOTC likely processes early visual prediction errors, and the aIPS computes action goal errors and possibly corresponding motor corrections.

Changes in Effective Connectivity Between Dorsal and Ventral Prefrontal Regions Moderate Emotion Regulation.

Reappraisal, the cognitive reevaluation of a potentially emotionally arousing event, has been proposed to be based upon top-down appraisal systems within the prefrontal cortex (PFC). It still remains unclear, however, how different prefrontal regions interact to control and regulate emotional responses. We used fMRI and dynamic causal modeling (DCM) to characterize the functional interrelationships among dorsal and ventral PFC regions involved in reappraisal. Specifically, we examined the effective connectivity between the inferior frontal gyrus (IFG), dorsolateral PFC (DLPFC), and other reappraisal-related regions (supplementary motor area, supramarginal gyrus) during the up- and downregulation of emotions in response to highly arousing extreme sports film clips. We found DLPFC to be the central node of the prefrontal emotion regulation network, strongly interconnected with the IFG. The DCM analysis further revealed excitatory changes of connection strength from the DLPFC to the IFG and strong inhibitory changes of connection strength between the IFG and DLPFC during reappraisal. These bidirectional changes in connectivity strength indicate a feedback mechanism by which the IFG may select one out of several possible goal-appropriate reappraisals held active in working memory (represented in the DLPFC) and inhibits the DLPFC once the selection process is completed.

The quest for the best: The impact of different EPI sequences on the sensitivity of random effect fMRI group analyses.

We compared the sensitivity of standard single-shot 2D echo planar imaging (EPI) to three advanced EPI sequences, i.e., 2D multi-echo EPI, 3D high resolution EPI and 3D dual-echo fast EPI in fixed effect and random effects group level fMRI analyses at 3T. The study focused on how well the variance reduction in fixed effect analyses achieved by advanced EPI sequences translates into increased sensitivity in the random effects group level analysis. The sensitivity was estimated in a functional MRI experiment of an emotional learning and a reward based learning tasks in a group of 24 volunteers. Each experiment was acquired with the four different sequences. The task-related response amplitude, contrast level and respective t-value were proxies for the functional sensitivity across the brain. All three advanced EPI methods increased the sensitivity in the fixed effects analyses, but standard single-shot 2D EPI provided a comparable performance in random effects group analysis when whole brain coverage and moderate resolution are required. In this experiment inter-subject variability determined the sensitivity of the random effects analysis for most brain regions, making the impact of EPI pulse sequence improvements less relevant or even negligible for random effects analyses. An exception concerns the optimization of EPI reducing susceptibility-related signal loss that translates into an enhanced sensitivity e.g. in the orbitofrontal cortex for multi-echo EPI. Thus, future optimization strategies may best aim at reducing inter-subject variability for higher sensitivity in standard fMRI group studies at moderate spatial resolution.

Causal Influence of Articulatory Motor Cortex on Comprehending Single Spoken Words: TMS Evidence.

Classic wisdom had been that motor and premotor cortex contribute to motor execution but not to higher cognition and language comprehension. In contrast, mounting evidence from neuroimaging, patient research, and transcranial magnetic stimulation (TMS) suggest sensorimotor interaction and, specifically, that the articulatory motor cortex is important for classifying meaningless speech sounds into phonemic categories. However, whether these findings speak to the comprehension issue is unclear, because language comprehension does not require explicit phonemic classification and previous results may therefore relate to factors alien to semantic understanding. We here used the standard psycholinguistic test of spoken word comprehension, the word-to-picture-matching task, and concordant TMS to articulatory motor cortex. TMS pulses were applied to primary motor cortex controlling either the lips or the tongue as subjects heard critical word stimuli starting with bilabial lip-related or alveolar tongue-related stop consonants (e.g., "pool" or "tool"). A significant cross-over interaction showed that articulatory motor cortex stimulation delayed comprehension responses for phonologically incongruent words relative to congruous ones (i.e., lip area TMS delayed "tool" relative to "pool" responses). As local TMS to articulatory motor areas differentially delays the comprehension of phonologically incongruous spoken words, we conclude that motor systems can take a causal role in semantic comprehension and, hence, higher cognition.