A multichannel electrophysiological approach to noninvasively and precisely record human spinal cord activity.

The spinal cord is of fundamental importance for integrative processing in brain-body communication, yet routine noninvasive recordings in humans are hindered by vast methodological challenges. Here, we overcome these challenges by developing an easy-to-use electrophysiological approach based on high-density multichannel spinal recordings combined with multivariate spatial-filtering analyses. These advances enable a spatiotemporal characterization of spinal cord responses and demonstrate a sensitivity that permits assessing even single-trial responses. To furthermore enable the study of integrative processing along the neural processing hierarchy in somatosensation, we expand this approach by simultaneous peripheral, spinal, and cortical recordings and provide direct evidence that bottom-up integrative processing occurs already within the spinal cord and thus after the first synaptic relay in the central nervous system. Finally, we demonstrate the versatility of this approach by providing noninvasive recordings of nociceptive spinal cord responses during heat-pain stimulation. Beyond establishing a new window on human spinal cord function at millisecond timescale, this work provides the foundation to study brain-body communication in its entirety in health and disease.

Temporal-spectral signaling of sensory information and expectations in the cerebral processing of pain.

The perception of pain is shaped by somatosensory information about threat. However, pain is also influenced by an individual's expectations. Such expectations can result in clinically relevant modulations and abnormalities of pain. In the brain, sensory information, expectations (predictions), and discrepancies thereof (prediction errors) are signaled by an extended network of brain areas which generate evoked potentials and oscillatory responses at different latencies and frequencies. However, a comprehensive picture of how evoked and oscillatory brain responses signal sensory information, predictions, and prediction errors in the processing of pain is lacking so far. Here, we therefore applied brief painful stimuli to 48 healthy human participants and independently modulated sensory information (stimulus intensity) and expectations of pain intensity while measuring brain activity using electroencephalography (EEG). Pain ratings confirmed that pain intensity was shaped by both sensory information and expectations. In contrast, Bayesian analyses revealed that stimulus-induced EEG responses at different latencies (the N1, N2, and P2 components) and frequencies (alpha, beta, and gamma oscillations) were shaped by sensory information but not by expectations. Expectations, however, shaped alpha and beta oscillations before the painful stimuli. These findings indicate that commonly analyzed EEG responses to painful stimuli are more involved in signaling sensory information than in signaling expectations or mismatches of sensory information and expectations. Moreover, they indicate that the effects of expectations on pain are served by brain mechanisms which differ from those conveying effects of sensory information on pain.

Thermal stimulus task fMRI in the cervical spinal cord at 7 Tesla.

Although functional magnetic resonance imaging (fMRI) is widely applied in the brain, fMRI of the spinal cord is more technically demanding. Proximity to the vertebral column and lungs results in strong spatial inhomogeneity and temporal fluctuations in B0 . Increasing field strength enables higher spatial resolution and improved sensitivity to blood oxygenation level-dependent (BOLD) signal, but amplifies the effects of B0 inhomogeneity. In this work, we present the first task fMRI in the spinal cord at 7 T. Further, we compare the performance of single-shot and multi-shot 2D echo-planar imaging (EPI) protocols, which differ in sensitivity to spatial and temporal B0 inhomogeneity. The cervical spinal cords of 11 healthy volunteers were scanned at 7 T using single-shot 2D EPI at 0.75 mm in-plane resolution and multi-shot 2D EPI at 0.75 and 0.6 mm in-plane resolutions. All protocols used 3 mm slice thickness. For each protocol, the BOLD response to 13 10-s noxious thermal stimuli applied to the right thumb was acquired in a 10-min fMRI run. Image quality, temporal signal to noise ratio (SNR), and BOLD activation (percent signal change and z-stat) at both individual- and group-level were evaluated between the protocols. Temporal SNR was highest in single-shot and multi-shot 0.75 mm protocols. In group-level analyses, activation clusters appeared in all protocols in the ipsilateral dorsal quadrant at the expected C6 neurological level. In individual-level analyses, activation clusters at the expected level were detected in some, but not all subjects and protocols. Single-shot 0.75 mm generally produced the highest mean z-statistic, while multi-shot 0.60 mm produced the best-localized activation clusters and the least geometric distortion. Larger than expected within-subject segmental variation of BOLD activation along the cord was observed. Group-level sensory task fMRI of the cervical spinal cord is feasible at 7 T with single-shot or multi-shot EPI. The best choice of protocol will likely depend on the relative importance of sensitivity to activation versus spatial localization of activation for a given experiment. PRACTITIONER POINTS: First stimulus task fMRI results in the spinal cord at 7 T. Single-shot 0.75 mm 2D EPI produced the highest mean z-statistic. Multi-shot 0.60 mm 2D EPI provided the best-localized activation and least distortion.

Reliability of resting-state functional connectivity in the human spinal cord: Assessing the impact of distinct noise sources.

The investigation of spontaneous fluctuations of the blood-oxygen-level-dependent (BOLD) signal has recently been extended from the brain to the spinal cord, where it has stimulated interest from a clinical perspective. A number of resting-state functional magnetic resonance imaging (fMRI) studies have demonstrated robust functional connectivity between the time series of BOLD fluctuations in bilateral dorsal horns and between those in bilateral ventral horns, in line with the functional neuroanatomy of the spinal cord. A necessary step prior to extension to clinical studies is assessing the reliability of such resting-state signals, which we aimed to do here in a group of 45 healthy young adults at the clinically prevalent field strength of 3T. When investigating connectivity in the entire cervical spinal cord, we observed fair to good reliability for dorsal-dorsal and ventral-ventral connectivity, whereas reliability was poor for within- and between-hemicord dorsal-ventral connectivity. Considering how prone spinal cord fMRI is to noise, we extensively investigated the impact of distinct noise sources and made two crucial observations: removal of physiological noise led to a reduction in functional connectivity strength and reliability - due to the removal of stable and participant-specific noise patterns - whereas removal of thermal noise considerably increased the detectability of functional connectivity without a clear influence on reliability. Finally, we also assessed connectivity within spinal cord segments and observed that while the pattern of connectivity was similar to that of whole cervical cord, reliability at the level of single segments was consistently poor. Taken together, our results demonstrate the presence of reliable resting-state functional connectivity in the human spinal cord even after thoroughly accounting for physiological and thermal noise, but at the same time urge caution if focal changes in connectivity (e.g. due to segmental lesions) are to be studied, especially in a longitudinal manner.

Automated slice-specific z-shimming for functional magnetic resonance imaging of the human spinal cord.

Functional magnetic resonance imaging (fMRI) of the human spinal cord faces many challenges, such as signal loss due to local magnetic field inhomogeneities. This issue can be addressed with slice-specific z-shimming, which compensates for the dephasing effect of the inhomogeneities using a slice-specific gradient pulse. Here, we aim to address outstanding issues regarding this technique by evaluating its effects on several aspects that are directly relevant for spinal fMRI and by developing two automated procedures in order to improve upon the time-consuming and subjective nature of manual selection of z-shims: one procedure finds the z-shim that maximizes signal intensity in each slice of an EPI reference-scan and the other finds the through-slice field inhomogeneity for each EPI-slice in field map data and calculates the required compensation gradient moment. We demonstrate that the beneficial effects of z-shimming are apparent across different echo times, hold true for both the dorsal and ventral horn, and are also apparent in the temporal signal-to-noise ratio (tSNR) of EPI time-series data. Both of our automated approaches were faster than the manual approach, lead to significant improvements in gray matter tSNR compared to no z-shimming and resulted in beneficial effects that were stable across time. While the field-map-based approach performed slightly worse than the manual approach, the EPI-based approach performed as well as the manual one and was furthermore validated on an external corticospinal data-set (N > 100). Together, automated z-shimming may improve the data quality of future spinal fMRI studies and lead to increased reproducibility in longitudinal studies.

Determining the Neural Substrate for Encoding a Memory of Human Pain and the Influence of Anxiety.

To convert a painful stimulus into a briefly maintainable construct when the painful stimulus is no longer accessible is essential to guide human behavior and avoid dangerous situations. Because of the aversive nature of pain, this encoding process might be influenced by emotional aspects and could thus vary across individuals, but we have yet to understand both the basic underlying neural mechanisms as well as potential interindividual differences. Using fMRI in combination with a delayed-discrimination task in healthy volunteers of both sexes, we discovered that brain regions involved in this working memory encoding process were dissociable according to whether the to-be-remembered stimulus was painful or not, with the medial thalamus and the rostral anterior cingulate cortex encoding painful and the primary somatosensory cortex encoding nonpainful stimuli. Encoding of painful stimuli furthermore significantly enhanced functional connectivity between the thalamus and medial prefrontal cortex (mPFC). With regards to emotional aspects influencing encoding processes, we observed that more anxious participants showed significant performance advantages when encoding painful stimuli. Importantly, only during the encoding of pain, the interindividual differences in anxiety were associated with the strength of coupling between medial thalamus and mPFC, which was furthermore related to activity in the amygdala. These results indicate not only that there is a distinct signature for the encoding of a painful experience in humans, but also that this encoding process involves a strong affective component.SIGNIFICANCE STATEMENT To convert the sensation of pain into a briefly maintainable construct is essential to guide human behavior and avoid dangerous situations. Although this working memory encoding process is implicitly contained in the majority of studies, the underlying neural mechanisms remain unclear. Using fMRI in a delayed-discrimination task, we found that the encoding of pain engaged the activation of the medial thalamus and the functional connectivity between the thalamus and medial prefrontal cortex. These fMRI data were directly and indirectly related to participants' self-reported trait and state anxiety. Our findings indicate that the mechanisms responsible for the encoding of noxious stimuli differ from those for the encoding of innocuous stimuli, and that these mechanisms are shaped by an individual's anxiety levels.

Denoising spinal cord fMRI data: Approaches to acquisition and analysis.

Functional magnetic resonance imaging (fMRI) of the human spinal cord is a difficult endeavour due to the cord's small cross-sectional diameter, signal drop-out as well as image distortion due to magnetic field inhomogeneity, and the confounding influence of physiological noise from cardiac and respiratory sources. Nevertheless, there is great interest in spinal fMRI due to the spinal cord's role as the principal sensorimotor interface between the brain and the body and its involvement in a variety of sensory and motor pathologies. In this review, we give an overview of the various methods that have been used to address the technical challenges in spinal fMRI, with a focus on reducing the impact of physiological noise. We start out by describing acquisition methods that have been tailored to the special needs of spinal fMRI and aim to increase the signal-to-noise ratio and reduce distortion in obtained images. Following this, we concentrate on image processing and analysis approaches that address the detrimental effects of noise. While these include variations of standard pre-processing methods such as motion correction and spatial filtering, the main focus lies on denoising techniques that can be applied to task-based as well as resting-state data sets. We review both model-based approaches that rely on externally acquired respiratory and cardiac signals as well as data-driven approaches that estimate and correct for noise using the data themselves. We conclude with an outlook on techniques that have been successfully applied for noise reduction in brain imaging and whose use might be beneficial for fMRI of the human spinal cord.

Investigating resting-state functional connectivity in the cervical spinal cord at 3T.

The study of spontaneous fluctuations in the blood-oxygen-level-dependent (BOLD) signal has recently been extended from the brain to the spinal cord. Two ultra-high field functional magnetic resonance imaging (fMRI) studies in humans have provided evidence for reproducible resting-state connectivity between the dorsal horns as well as between the ventral horns, and a study in non-human primates has shown that these resting-state signals are impacted by spinal cord injury. As these studies were carried out at ultra-high field strengths using region-of-interest (ROI) based analyses, we investigated whether such resting-state signals could also be observed at the clinically more prevalent field strength of 3T. In a reanalysis of a sample of 20 healthy human participants who underwent a resting-state fMRI acquisition of the cervical spinal cord, we were able to observe significant dorsal horn connectivity as well as ventral horn connectivity, but no consistent effects for connectivity between dorsal and ventral horns, thus replicating the human 7T results. These effects were not only observable when averaging along the acquired length of the spinal cord, but also when we examined each of the acquired spinal segments separately, which showed similar patterns of connectivity. Finally, we investigated the robustness of these resting-state signals against variations in the analysis pipeline by varying the type of ROI creation, temporal filtering, nuisance regression and connectivity metric. We observed that - apart from the effects of band-pass filtering - ventral horn connectivity showed excellent robustness, whereas dorsal horn connectivity showed moderate robustness. Together, our results provide evidence that spinal cord resting-state connectivity is a robust and spatially consistent phenomenon that could be a valuable tool for investigating the effects of pathology, disease progression, and treatment response in neurological conditions with a spinal component, such as spinal cord injury.

Intrinsically organized resting state networks in the human spinal cord.

Spontaneous fluctuations in functional magnetic resonance imaging (fMRI) signals of the brain have repeatedly been observed when no task or external stimulation is present. These fluctuations likely reflect baseline neuronal activity of the brain and correspond to functionally relevant resting-state networks (RSN). It is not known however, whether intrinsically organized and spatially circumscribed RSNs also exist in the spinal cord, the brain's principal sensorimotor interface with the body. Here, we use recent advances in spinal fMRI methodology and independent component analysis to answer this question in healthy human volunteers. We identified spatially distinct RSNs in the human spinal cord that were clearly separated into dorsal and ventral components, mirroring the functional neuroanatomy of the spinal cord and likely reflecting sensory and motor processing. Interestingly, dorsal (sensory) RSNs were separated into right and left components, presumably related to ongoing hemibody processing of somatosensory information, whereas ventral (motor) RSNs were bilateral, possibly related to commissural interneuronal networks involved in central pattern generation. Importantly, all of these RSNs showed a restricted spatial extent along the spinal cord and likely conform to the spinal cord's functionally relevant segmental organization. Although the spatial and temporal properties of the dorsal and ventral RSNs were found to be significantly different, these networks showed significant interactions with each other at the segmental level. Together, our data demonstrate that intrinsically highly organized resting-state fluctuations exist in the human spinal cord and are thus a hallmark of the entire central nervous system.

Dopaminergic receptor blockade changes a functional connectivity network centred on the amygdala.

Resting-state connectivity has become an increasingly important measure in characterizing the functional integrity of brain circuits in neuro-psychiatric conditions. One approach that has recently gained prominence in this regard-and which we use in this study-is to investigate how resting-state connectivity depends on the integrity of certain neuromodulator systems. Here, we use a pharmacological challenge in combination with functional magnetic resonance imaging to investigate the impact of dopaminergic receptor blockade on whole brain functional connectivity in twenty healthy human subjects. Administration of the D2-receptor antagonist haloperidol led to a profound change in functional integration in network nodes linked to the amygdala. Compared to placebo and baseline measurements, network-based statistics and pairwise connectivity analyses revealed reduced connectivity and decreased link strength between the amygdala and the bilateral posterior cingulate cortex and other cortical areas. This was complemented by less extensive but very circumscribed enhanced connectivity between the amygdala and the right putamen during D2-receptor blockade. It will be interesting to investigate whether these pharmacologically induced shifts in resting-state connectivity will similarly be evident in clinical conditions that involve a dysfunction of the dopaminergic system. Our findings might also aid in interpreting alterations in more complex states, such as those seen psychiatric conditions and their treatment. Hum Brain Mapp 37:4148-4157, 2016. © 2016 Wiley Periodicals, Inc.

Reliability of task-based fMRI in the dorsal horn of the human spinal cord.

The application of functional magnetic resonance imaging (fMRI) to the human spinal cord is still a relatively small field of research and faces many challenges. Here we aimed to probe the limitations of task-based spinal fMRI at 3T by investigating the reliability of spinal cord blood oxygen level dependent (BOLD) responses to repeated nociceptive stimulation across two consecutive days in 40 healthy volunteers. We assessed the test-retest reliability of subjective ratings, autonomic responses, and spinal cord BOLD responses to short heat pain stimuli (1s duration) using the intraclass correlation coefficient (ICC). At the group level, we observed robust autonomic responses as well as spatially specific spinal cord BOLD responses at the expected location, but no spatial overlap in BOLD response patterns across days. While autonomic indicators of pain processing showed good-to-excellent reliability, both ß-estimates and z-scores of task-related BOLD responses showed poor reliability across days in the target region (gray matter of the ipsilateral dorsal horn). When taking into account the sensitivity of gradient-echo echo planar imaging (GE-EPI) to draining vein signals by including the venous plexus in the analysis, we observed BOLD responses with fair reliability across days. Taken together, these results demonstrate that heat pain stimuli as short as one second are able to evoke a robust and spatially specific BOLD response, which is however strongly variable within participants across time, resulting in low reliability in the dorsal horn gray matter. Further improvements in data acquisition and analysis techniques are thus necessary before event-related spinal cord fMRI as used here can be reliably employed in longitudinal designs or clinical settings.

Body size interacts with the structure of the central nervous system: A multi-center in vivo neuroimaging study.

Clinical research emphasizes the implementation of rigorous and reproducible study designs that rely on between-group matching or controlling for sources of biological variation such as subject's sex and age. However, corrections for body size (i.e. height and weight) are mostly lacking in clinical neuroimaging designs. This study investigates the importance of body size parameters in their relationship with spinal cord (SC) and brain magnetic resonance imaging (MRI) metrics. Data were derived from a cosmopolitan population of 267 healthy human adults (age 30.1±6.6 years old, 125 females). We show that body height correlated strongly or moderately with brain gray matter (GM) volume, cortical GM volume, total cerebellar volume, brainstem volume, and cross-sectional area (CSA) of cervical SC white matter (CSA-WM; 0.44≤r≤0.62). In comparison, age correlated weakly with cortical GM volume, precentral GM volume, and cortical thickness (-0.21≥r≥-0.27). Body weight correlated weakly with magnetization transfer ratio in the SC WM, dorsal columns, and lateral corticospinal tracts (-0.20≥r≥-0.23). Body weight further correlated weakly with the mean diffusivity derived from diffusion tensor imaging (DTI) in SC WM (r=-0.20) and dorsal columns (-0.21), but only in males. CSA-WM correlated strongly or moderately with brain volumes (0.39≤r≤0.64), and weakly with precentral gyrus thickness and DTI-based fractional anisotropy in SC dorsal columns and SC lateral corticospinal tracts (-0.22≥r≥-0.25). Linear mixture of sex and age explained 26±10% of data variance in brain volumetry and SC CSA. The amount of explained variance increased at 33±11% when body height was added into the mixture model. Age itself explained only 2±2% of such variance. In conclusion, body size is a significant biological variable. Along with sex and age, body size should therefore be included as a mandatory variable in the design of clinical neuroimaging studies examining SC and brain structure.

Neurobiological mechanisms underlying the blocking effect in aversive learning.

Current theories of classical conditioning assume that learning depends on the predictive relationship between events, not just on their temporal contiguity. Here we employ the classic experiment substantiating this reasoning-the blocking paradigm-in combination with functional magnetic resonance imaging (fMRI) to investigate whether human amygdala responses in aversive learning conform to these assumptions. In accordance with blocking, we demonstrate that significantly stronger behavioral and amygdala responses are evoked by conditioned stimuli that are predictive of the unconditioned stimulus than by conditioned stimuli that have received the same pairing with the unconditioned stimulus, yet have no predictive value. When studying the development of this effect, we not only observed that it was related to the strength of previous conditioned responses, but also that predictive compared with nonpredictive conditioned stimuli received more overt attention, as measured by fMRI-concurrent eye tracking, and that this went along with enhanced amygdala responses. We furthermore observed that prefrontal regions play a role in the development of the blocking effect: ventromedial prefrontal cortex (subgenual anterior cingulate) only exhibited responses when conditioned stimuli had to be established as nonpredictive for an outcome, whereas dorsolateral prefrontal cortex also showed responses when conditioned stimuli had to be established as predictive. Most importantly, dorsolateral prefrontal cortex connectivity to amygdala flexibly switched between positive and negative coupling, depending on the requirements posed by predictive relationships. Together, our findings highlight the role of predictive value in explaining amygdala responses and identify mechanisms that shape these responses in human fear conditioning.

Cortical and subcortical responses to high and low effective placebo treatments.

The effectiveness of placebo treatments depends on the recipient's expectations, which are at least in part shaped by previous experiences. Thus, positive past experience together with an accordant verbal instruction should enhance outcome expectations and subsequently lead to higher placebo efficacy. This should be reflected in subjective valuation reports and in activation of placebo-related brain structures. We tested this hypothesis in a functional magnetic resonance imaging study, where subjects experienced different levels of pain relief and conforming information about price levels for two placebo treatments during a manipulation phase, thereby establishing a weak and a strong placebo. As expected, both placebos led to a significant pain relief and the strong placebo induced better analgesic efficacy. Individual placebo value estimates reflected treatment efficacy, i.e. subjects were willing to pay more money for the strong placebo even though pain stimulation was completed at this time. On the neural level, placebo effects were associated with activation of the rostral anterior cingulate cortex, the anterior insula, and the ventral striatum and deactivations in the thalamus and secondary somatosensory cortex. However, only placebo-related responses in rostral anterior cingulate cortex were consistent across both the anticipation of painful stimuli and their actual administration. Most importantly, rostral anterior cingulate cortex responses were higher for the strong placebo, thus mirroring the behavioral effects. These results directly link placebo analgesia to anticipatory activity in the ventral striatum, a region involved in reward processing, and highlight the role of the rostral anterior cingulate cortex, as its activity consistently scaled with increasing analgesic efficacy.

Thermal Stimulus Task fMRI in the Cervical Spinal Cord at 7 Tesla.

PURPOSE: Although functional MRI is widely applied in the brain, fMRI of the spinal cord is more technically demanding. Proximity to the vertebral column and lungs results in strong spatial inhomogeneity and temporal fluctuations in B0. Increasing field strength enables higher spatial resolution and improved sensitivity to BOLD signal, but amplifies the effects of B0 inhomogeneity. In this work, we present the first stimulus task fMRI in the spinal cord at 7 T. Further, we compare the performance of single-shot and multi-shot 2D EPI protocols, as they differ in sensitivity to spatial and temporal B0 inhomogeneity. METHODS: The cervical spinal cords of 11 healthy volunteers were scanned at 7 T using single-shot 2D EPI at 0.75 mm in-plane resolution and multi-shot 2D EPI at 0.75 and 0.6 mm in-plane resolutions. For each protocol, the BOLD response to thirteen 10-second noxious thermal stimuli applied to the right thumb was acquired in a 10-minute fMRI run. Image quality, temporal SNR, and BOLD activation (percent signal change and z-stat) at both individual- and group-level were evaluated between the protocols. RESULTS: Temporal SNR was highest in single-shot and multi-shot 0.75 mm protocols. In group-level analyses, activation clusters appeared in all protocols in the ipsilateral dorsal quadrant at the expected C6 neurological level. In individual-level analyses, activation clusters at the expected level were detected in some, but not all subjects and protocols. Single-shot 0.75 mm generally produced the highest mean z-statistic, while multi-shot 0.60 mm produced the best-localized activation clusters and the least geometric distortion. Larger than expected within-subject segmental variation of BOLD activation along the cord was observed. CONCLUSION: Group-level sensory task fMRI of the cervical spinal cord is feasible at 7 T with single-shot or multi-shot EPI. The best choice of protocol will likely depend on the relative importance of sensitivity to activation versus spatial localization of activation for a given experiment.

Trigeminal nociceptive transmission in migraineurs predicts migraine attacks.

Several lines of evidence suggest a major role of the trigeminovascular system in the pathogenesis of migraine. Using functional magnetic resonance imaging (fMRI), we compared brain responses during trigeminal pain processing in migraine patients with those of healthy control subjects. The main finding is that the activity of the spinal trigeminal nuclei in response to nociceptive stimulation showed a cycling behavior over the migraine interval. Although interictal (i.e., outside of attack) migraine patients revealed lower activations in the spinal trigeminal nuclei compared with controls, preictal (i.e., shortly before attack) patients showed activity similar to controls, which demonstrates that the trigeminal activation level increases over the pain-free migraine interval. Remarkably, the distance to the next headache attack was predictable by the height of the signal intensities in the spinal nuclei. Migraine patients scanned during the acute spontaneous migraine attack showed significantly lower signal intensities in the trigeminal nuclei compared with controls, demonstrating activity levels similar to interictal patients. Additionally we found-for the first time using fMRI-that migraineurs showed a significant increase in activation of dorsal parts of the pons, previously coined "migraine generator." Unlike the dorsal pons activation usually linked to migraine attacks, the gradient-like activity following nociceptive stimulation in the spinal trigeminal neurons likely reflects a raise in susceptibility of the brain to generate the next attack, as these areas increase their activity long before headache starts. This oscillating behavior may be a key player in the generation of migraine headache, whereas attack-specific pons activations are most likely a secondary event.

Single, slice-specific z-shim gradient pulses improve T2*-weighted imaging of the spinal cord.

T2*-weighted imaging of the spinal cord suffers from signal dropouts that hamper blood-oxygenation-level-dependent functional magnetic resonance imaging (fMRI). They are due to field inhomogeneities caused by the different magnetic susceptibilities of the vertebrae and the intervertebral disks that vary periodically along the cord and, thus, cannot be compensated appropriately with conventional (constant) shimming. In this study, a single, slice-specific gradient pulse ("z-shim") is applied in echo-planar imaging of axial sections in order to compensate for the corresponding through-slice signal dephasing without affecting the acquisition time, i.e. the temporal resolution. Based on a reference acquisition sampling a range of compensation moments, the value yielding the maximum signal amplitude within the spinal cord is determined for each slice. Severe N/2 ghosting for larger compensation moments is avoided by applying the gradient pulse after the corresponding reference echoes. Furthermore, first-order flow compensation in the slice direction of both the slice-selection and the z-shim gradient pulse considerably reduces signal fluctuations in the cerebro-spinal fluid surrounding the spinal cord, i.e. would minimize ringing artifacts in fMRI. Phantom and in vivo experiments show the necessity to use slice-specific compensation moments in the presence of local susceptibility differences. Measurements performed in a group of 24 healthy volunteers at 3T demonstrate that this approach improves T2*-weighted imaging of axial sections of the cervical spinal cord by (i) increasing the signal intensity (overall by about 20%) and (ii) reducing signal intensity variations along the cord (by about 80%). Thus, it may help to improve the feasibility and reliability of fMRI of the spinal cord.

Intentional social distance regulation alters affective responses towards victims of violence: an FMRI study.

We used functional magnetic resonance imaging (fMRI) to investigate brain processes underlying control of emotional responses towards a person in distress by cognitive social distance modulation. fMRI and peripheral physiological responses (startle response and electrodermal activity) were recorded from 24 women while they watched victim-offender scenes and modulated their social distance to the victim by cognitive reappraisal. We found that emotional responses, including startle eyeblink and amygdala responses, can effectively be modulated by social distance modulation. Furthermore, our data provide evidence that activity in the dorsomedial prefrontal cortex (dmPFC) and the anterior paracingulate cortex (aPCC), two brain regions that have previously been associated with brain processes related to distant and close others, is differentially modulated by intentional social distance modulation: activity in the dmPFC increased with increasing disengagement from the victim and activity in the aPCC increased with increasing engagement with the victim. We suggest that these two regions play opposing roles in cognitive modulation of social distance and affective responses towards persons in distress that enable the adaptive and flexible social behavior observed in humans.

Cortico-Brainstem Mechanisms of Biased Perceptual Decision-Making in the Context of Pain.

Prior expectations can bias how we perceive pain. Using a drift diffusion model, we recently showed that this influence is primarily based on changes in perceptual decision-making (indexed as shift in starting point). Only during unexpected application of high-intensity noxious stimuli, altered information processing (indexed as increase in drift rate) explained the expectancy effect on pain processing. Here, we employed functional magnetic resonance imaging to investigate the neural basis of both these processes in healthy volunteers. On each trial, visual cues induced the expectation of high- or low-intensity noxious stimulation or signaled equal probability for both intensities. Participants categorized a subsequently applied electrical stimulus as either low- or high-intensity pain. A shift in starting point towards high pain correlated negatively with right dorsolateral prefrontal cortex activity during cue presentation underscoring its proposed role of "keeping pain out of mind". This anticipatory right dorsolateral prefrontal cortex signal increase was positively correlated with periaqueductal gray (PAG) activity when the expected high-intensity stimulation was applied. A drift rate increase during unexpected high-intensity pain was reflected in amygdala engagement and increased functional connectivity between amygdala and PAG. Our findings suggest involvement of the PAG in both decision-making bias and altered information processing to implement expectancy effects on pain. PERSPECTIVE: Modulation of pain through expectations has been linked to changes in perceptual decision-making and altered processing of afferent information. Our results suggest involvement of the dorsolateral prefrontal cortex, amygdala, and periaqueductal gray in these processes.

Corticocortical connections mediate primary visual cortex responses to auditory stimulation in the blind.

Blind individuals have to rely on nonvisual information to a greater extent than sighted to efficiently interact with the environment, and consequently exhibit superior skills in their spared modalities. These performance advantages are often paralleled by responses in the occipital cortex, which have been suggested to be essential for nonvisual processing in the blind. However, it is currently unclear through which pathways (i.e., thalamocortical or corticocortical connections) nonvisual information reaches the occipital cortex of the blind. Here, we used functional magnetic resonance imaging to study blind and matched sighted humans with an auditory discrimination paradigm and used dynamic causal modeling to investigate the effective connectivity underlying auditory activations in the primary visual cortex of blind volunteers. Model comparison revealed that a model connecting the medial geniculate nucleus (MGN), primary auditory cortex (A1), and primary visual cortex (V1) in a bidirectional manner outperformed all other models in both groups. Regarding inference on model parameters, we observed that basic auditory mechanisms (i.e., sensory input to MGN and connections from MGN to A1) did not differ significantly between the two groups. In contrast, we found clear evidence for stronger corticocortical connections from A1 to V1 in the blind, whereas results with regard to thalamocortical enhancement (from MGN to V1 and, in a control analysis, from the lateral geniculate nucleus to V1) were not consistent. These results suggest that plastic changes especially in corticocortical connectivity allow auditory information to evoke responses in the primary visual cortex of blind individuals.