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.

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 good 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.

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.

The neural computation of human prosocial choices in complex motivational states.

Motives motivate human behavior. Most behaviors are driven by more than one motive, yet it is unclear how different motives interact and how such motive combinations affect the neural computation of the behaviors they drive. To answer this question, we induced two prosocial motives simultaneously (multi-motive condition) and separately (single motive conditions). After the different motive inductions, participants performed the same choice task in which they allocated points in favor of the other person (prosocial choice) or in favor of themselves (egoistic choice). We used fMRI to assess prosocial choice-related brain responses and drift diffusion modeling to specify how motive combinations affect individual components of the choice process. Our results showed that the combination of the two motives in the multi-motive condition increased participants' choice biases prior to the behavior itself. On the neural level, these changes in initial prosocial bias were associated with neural responses in the bilateral dorsal striatum. In contrast, the efficiency of the prosocial decision process was comparable between the multi-motive and the single-motive conditions. These findings provide insights into the computation of prosocial choices in complex motivational states, the motivational setting that drives most human behaviors.

Differences in Neuronal Representation of Mental Rotation in Patients With Complex Regional Pain Syndrome and Healthy Controls.

Spatial integration of parts of the body is impaired in patients with complex regional pain syndrome (CRPS). Because the training of mental rotation (MR) has been shown to be among the effective therapy strategies for CRPS, impairment of MR is also important for the pathophysiological understanding of CRPS. The aim of this study was to evaluate whether differences in the neural representation of MR occur between patients with CRPS and healthy controls (HC). Therefore, we included 15 patients with chronic CRPS and 15 age- and gender-matched HC. We assessed behavioral (accuracy and reaction time for MR of both hands), clinical (Disabilities of Arm, Shoulder and Hand questionnaire) and magnetic resonance imaging (T1-weighted, function magnetic resonance imaging during MR) data. Reaction times in the patient group were delayed compared with HC without a lateralization effect for the affected hand side. Although both groups showed an activation pattern typical for MR, only HC showed a highly significant contrast for the rotated versus unrotated hands in the right intraparietal sulcus. Patients with CRPS showed a reduction of functional magnetic resonance imaging activation in areas including the subthalamic nucleus, nucleus accumbens, and putamen. Regression analysis for the CRPS group emphasized the importance of putamen and nucleus accumbens activation for MR performance. This study highlights the reduced access of patients with CRPS for mental resources modulating arousal, emotional response, and subcortical sensorimotor integration. PERSPECTIVE: This study localized the underlying neural responses for impaired mental rotation in patients with complex regional pain syndrome as a decrease in basal ganglia (putamen) and nucleus accumbens activation.

Motor imagery training: Kinesthetic imagery strategy and inferior parietal fMRI activation.

Motor imagery (MI) is the mental simulation of action frequently used by professionals in different fields. However, with respect to performance, well-controlled functional imaging studies on MI training are sparse. We investigated changes in fMRI representation going along with performance changes of a finger sequence (error and velocity) after MI training in 48 healthy young volunteers. Before training, we tested the vividness of kinesthetic and visual imagery. During tests, participants were instructed to move or to imagine moving the fingers of the right hand in a specific order. During MI training, participants repeatedly imagined the sequence for 15 min. Imaging analysis was performed using a full-factorial design to assess brain changes due to imagery training. We also used regression analyses to identify those who profited from training (performance outcome and gain) with initial imagery scores (vividness) and fMRI activation magnitude during MI at pre-test (MIpre ). After training, error rate decreased and velocity increased. We combined both parameters into a common performance index. FMRI activation in the left inferior parietal lobe (IPL) was associated with MI and increased over time. In addition, fMRI activation in the right IPL during MIpre was associated with high initial kinesthetic vividness. High kinesthetic imagery vividness predicted a high performance after training. In contrast, occipital activation, associated with visual imagery strategies, showed a negative predictive value for performance. Our data echo the importance of high kinesthetic vividness for MI training outcome and consider IPL as a key area during MI and through MI training.

Increased ventral premotor cortex recruitment after arm training in an fMRI study with subacute stroke patients.

To investigate therapy associated changes in the cerebral representation of movement after stroke, we used functional magnetic resonance imaging (fMRI) during an active and a passive motor task for the affected and unaffected hand before and after a three week comprehensive hand motor training. Twelve patients in the subacute phase from 2 to 9 weeks after mild to moderate motor stroke were recruited. During fMRI, the active task comprised fist clenching, which was precisely controlled for motor performance by visual feedback of force and frequency. The passive task consisted of wrist flexion-extension of 1Hz frequency by means of a pneumatic driven splint. Arm Ability Training (AAT) was conducted one hour per day over 3 weeks in addition to inward rehabilitative therapy. Performance gain was tested using movements trained with AAT, but also with conventional hand motor tests (Nine-Hole-Peg Test, Box-and-Block Test). Rehabilitation therapy and AAT resulted in considerable improvement of performance in trained tasks and other hand motor functions (e.g., Nine-Hole-Peg Test). FMRI activation in the ventral premotor cortex (vPMC) of the lesioned hemisphere increased over time for the active task only for the affected hand. No such change was present for the passive wrist extension task or the active task with the unaffected hand. In addition, only for the post measurement of the active task performed with the affected hand, bilateral vPMC shows a more pronounced activation than in healthy controls. This finding contradicts the simple "near to normal is good recovery" opinion.

Connectivity-Based Predictions of Hand Motor Outcome for Patients at the Subacute Stage After Stroke.

BACKGROUND: Connectivity-based predictions of hand motor outcome have been proposed to be useful in stroke patients. We intended to assess the prognostic value of different imaging methods on short-term (3 months) and long-term (6 months) motor outcome after stroke. METHODS: We measured resting state functional connectivity (rsFC), diffusion weighted imaging (DWI) and grip strength in 19 stroke patients within the first days (5-9 days) after stroke. Outcome measurements for short-term (3 months) and long-term (6 months) motor function was assessed by the Motricity Index (MI) of the upper limb and the box and block test (BB). Patients were predominantly mildly affected since signed consent was necessary at inclusion. We performed a multiple stepwise regression analysis to compare the predictive value of rsFC, DWI and clinical measurements. RESULTS: Patients showed relevant improvement in both motor outcome tests. As expected grip strength at inclusion was a predictor for short- and long-term motor outcome as assessed by MI. Diffusion-based tract volume (DTV) of the tracts between ipsilesional primary motor cortex and contralesional anterior cerebellar hemisphere showed a strong trend (p = 0.05) for a predictive power for long-term motor outcome as measured by MI. DTV of the interhemispheric tracts between both primary motor cortices was predictive for both short- and long-term motor outcome in BB. rsFC was not associated with motor outcome. CONCLUSIONS: Grip strength is a good predictor of hand motor outcome concerning strength-related measurements (MI) for mildly affected subacute patients. Therefore additional connectivity measurements seem to be redundant in this group. Using more complex movement recruiting bilateral motor areas as an outcome parameter, DTV and in particular interhemispheric pathways might enhance predictive value of hand motor outcome.

The Role of Left Hemispheric Structures for Emotional Processing as a Monitor of Bodily Reaction and Felt Chill - a Case-Control Functional Imaging Study.

Background: The particular function of the left anterior human insula on emotional arousal has been illustrated with several case studies. Only after left hemispheric insula lesions, patients lose their pleasure in habits such as listening to joyful music. In functional magnetic resonance imaging studies (fMRI) activation in the left anterior insula has been associated with both processing of emotional valence and arousal. Tight interactions with different areas of the prefrontal cortex are involved in bodily response monitoring and cognitive appraisal of a given stimulus. Therefore, a large left hemispheric lesion including the left insula should impair the bodily response of chill experience (objective chill response) but leave the cognitive aspects of chill processing (subjective chill response) unaffected. Methods: We investigated a patient (MC) with a complete left hemispheric media cerebral artery stroke, testing fMRI representation of pleasant (music) and unpleasant (harsh sounds) chill response. Results: Although chill response to both pleasant and unpleasant rated sounds was confirmed verbally at passages also rated as chilling by healthy participants, skin conductance response was almost absent in MC. For a healthy control (HC) objective and subjective chill response was positively associated. Bilateral prefrontal fMRI-response to chill stimuli was sustained in MC whereas insula activation restricted to the right hemisphere. Diffusion imaging together with lesion maps revealed that left lateral tracts were completely damaged but medial prefrontal structures were intact. Conclusion: With this case study we demonstrate how bodily response and cognitive appraisal are differentially participating in the internal monitor of chill response.