Publications

{Background Ketamine is receiving increasing attention as a rapid-onset antidepressant in patients suffering from major depressive disorder (MDD) with treatment resistance or severe suicidal ideation. Ketamine modulates several neurotransmitter systems, including norepinephrine via the norepinephrine transporter (NET), both peripherally and centrally. The locus coeruleus (LC), which has high NET concentration, has been attributed to brain networks involved in depression. Thus we investigated the effects of single-dose of racemic ketamine on the LC using resting state functional MRI. Methods Fifty-nine healthy participants (mean age 25.57 $\pm$ 4.72) were examined in a double-blind, randomized, placebo-controlled study with 7 Tesla MRI. We investigated the resting state functional connectivity (rs-fc) of the LC before and one hour after subanesthetic ketamine injection (0.5 mg/kg), as well as associations between its rs-fc and a common polymorphism in the NET gene (rs28386840). Results A significant interaction of drug and time was revealed, and post hoc testing showed decreased rs-fc between LC and the thalamus after ketamine administration compared with baseline levels, including the mediodorsal, ventral anterior, ventral lateral, ventral posterolateral and centromedian nuclei. The rs-fc reduction was more pronounced in NET rs28386840 [AA] homozygous subjects than in [T] carriers. Conclusions We demonstrated acute rs-fc changes after ketamine administration in the central node of the norepinephrine pathway. These findings may contribute to understanding the antidepressant effect of ketamine at the system level, supporting modes of action on networks subserving aberrant arousal regulation in depression.}

{One of the principal goals in functional magnetic resonance imaging (fMRI) is the detection of local activation in the human brain. However, lack of statistical power and inflated false positive rates have recently been identified as major problems in this regard. Here, we propose a non-parametric and threshold-free framework called LISA to address this demand. It uses a non-linear filter for incorporating spatial context without sacrificing spatial precision. Multiple comparison correction is achieved by controlling the false discovery rate in the filtered maps. Compared to widely used other methods, it shows a boost in statistical power and allows to find small activation areas that have previously evaded detection. The spatial sensitivity of LISA makes it especially suitable for the analysis of high-resolution fMRI data acquired at ultrahigh field ($\geq$7 Tesla).}

{Long-TE gradient recalled-echo (GRE) scans are prone to phase artifacts due to B0 inhomogeneity. We propose a learning-based approach that does not rely on navigator readouts and allows to infer phase error offsets directly from corrupted data. Our method does not need to be pre-trained on a database of medical images that match a contrast/acquisition protocol of the input image. A sufficient input is a raw multi-coil spectrum of the image that needs to be corrected. We train a convolutional neural network to predict phase offsets for each k-space line of a 2D image. We synthesize training examples online by reconvolving the corrupted spectrum with point spread functions (PSFs) of the coil sensitivity profiles and superimposing artificial phase errors, which we attempt to predict. We evaluate our approach on \textquotedblleftin vivo\textquotedblright data acquired with GRE sequence, and demonstrate an improvement in image quality after phase error correction.}

{Neurodevelopmental disorders, such as ASD and ADHD, affect males about three to four times more often than females. 16p11.2 hemideletion is a copy number variation that is highly associated with neurodevelopmental disorders. Previous work from our lab has shown that a mouse model of 16p11.2 hemideletion (del/+) exhibits male-specific behavioral phenotypes. We, therefore, aimed to investigate with magnetic resonance imaging (MRI), whether del/+ animals also exhibited a sex-specific neuroanatomical endophenotype. Using the Allen Mouse Brain Atlas, we analyzed the expression patterns of the 27 genes within the 16p11.2 region to identify which gene expression patterns spatially overlapped with brain structural changes. MRI was performed ex vivo and the resulting images were analyzed using Voxel-based morphometry for T1-weighted sequences and tract-based spatial statistics for diffusion-weighted images. In a subsequent step, all available in situ hybridization (ISH) maps of the genes involved in the 16p11.2 hemideletion were aligned to Waxholm space and clusters obtained by sex-specific group comparisons were analyzed to determine which gene(s) showed the highest expression in these regions. We found pronounced sex-specific changes in male animals with increased fractional anisotropy in medial fiber tracts, especially in those proximate to the striatum. Moreover, we were able to identify gene expression patterns spatially overlapping with male-specific structural changes that were associated with neurite outgrowth and the MAPK pathway. Of note, previous molecular studies have found convergent changes that point to a sex-specific dysregulation of MAPK signaling. This convergent evidence supports the idea that ISH maps can be used to meaningfully analyze imaging data sets.}

{The invention relates to a liquid supply device for animals, especially for rodents, wherein a bottom of a liquid supply channel connecting a container and a tray is inclined by at least 1\mbox{$^\circ$} and by at most 5\mbox{$^\circ$} with respect to a reference plane.}

{Several well-established methods exist for recording and measuring the underlying signals of the brain; methods such as electrophysiology and fMRI, when taken together, have the capacity to disclose both local and global neuronal activity. Thus, we aimed to employ both techniques to construct a functional model of the insular cortex (IC), a recipient of afferents relaying information from the body\textquoterights viscera. For our work, we performed a series of fMRI experiments in the anesthetized macaque (n \textequals 11), where we measured the responses to interoceptive stimulation (e.g. lower gastrointestinal tract, cutaneous temperature, auricular vagus nerve branch, gustation); and exploited the gross functional anatomical localizations (area: 4mm2) of these functions to establish a foundation for subsequent electrophysiological sampling (area: 1mm2, n \textequals 4) across the IC. Using these methods, our results reveal a topographic organization of interoceptive processing and highlight its functional similarity to that of the human insular cortex. As localized by fMRI and electrophysiology, two anatomically discrete areas along the mid-anterior dorsal IC were responsive to oral and gustatory sensations. However, our fMRI results disclosed lower gastrointestinal activity to be predominantly correlated with the ventral anterior IC. Such results already depict a select arrangement of multi-modal inputs within the macaque insula. As the IC is the primary cortical recipient of interoceptive inputs, the manner in which this information is organized may disclose how these inputs are relayed to form a conscious percept of the body\textquoterights physiological state, contribute to emotional embodiment, and provide top-down influence on bodily function.}

{The Locus Coeruleus (LC) noradrenergic (NE) neuromodulatory system is critically involved in regulation of neural excitability via its diffuse ascending projections. Tonic NE release in the forebrain is essential for maintenance of vigilant states and increases the signal-to-noise ratio of cortical sensory responses. The impact of phasic NE release on cortical activity and sensory processing is less explored. We have previously reported that LC microstimulation caused a transient desynchronization of the population activity in the medial prefrontal cortex (mPFC), similar to noxious somatosensory stimuli. The LC receives nociceptive information from the medulla and therefore may mediate sensory signaling to its forebrain targets. Here, we performed extracellular recordings in LC and mPFC while presenting noxious stimuli in urethane-anesthetized rats. A brief train of foot shocks produced a robust phasic response in the LC and a transient change in the mPFC power spectrum with the strongest modulation in gamma (30-90 Hz) range. The LC phasic response preceded prefrontal gamma power increase and cortical modulation was proportional to the LC excitation. We also quantitatively characterized distinct cortical states and showed that sensory responses in both LC and mPFC depend on the ongoing cortical state. Finally, cessation of the LC firing by bilateral local iontophoretic injection of clonidine, $\alpha$2-adrenoreceotor agonist, completely eliminated sensory responses in the mPFC without shifting cortex to less excitable state. Together, our results suggest that the LC phasic response induces gamma power increase in the prefrontal cortex and is essential for mediating sensory information along ascending noxious pathway.}

{Measuring longitudinal relaxation times is a requirement for absolute quantification. In this work, to more accurately measure the concentrations of metabolites in vivo at 9.4T, the relaxation of 5 metabolites was measured using an inversion recovery MC-STEAM technique.}

{Looming sounds can be an ideal warning notification for emergency braking. This agrees with studies that have consistently demonstrated preferential brain processing for looming stimuli. This study investigates and demonstrates that looming sounds can similarly benefit emergency braking in managing a vehicle with adaptive cruise control (ACC). Specifically, looming auditory notifications induced the faster emergency braking times relative to a static auditory notification. Next, we compare the event-related potential (ERP) evoked by a looming notification, relative to its static equivalent. Looming notifications evoke a smaller fronto-central N2 amplitude than their static equivalents. Thus, we infer that looming sounds are consistent with the visual experience of an approaching collision and, hence, induced a corresponding performance benefit. Subjective ratings indicate no significant differences in the perceived workload across the notification conditions. Overall, this work suggests that auditory warnings should have congruent physical properties with the visual events that they warn for.}

{Braking responses are faster when drivers hear looming sounds that increase in intensity, relative to sounds with constant intensity (Gray, 2011). This finding agrees with research that has shown preferential neural processing for looming stimuli (e.g., Tyll et al., 2013). It remains unknown if the looming benefit reported by Gray (2011) was due to the perceived saliency of looming sounds, or as a result of their ability to re-direct attention away from vehicle control to braking. The current study was conducted in a driving simulation for a vehicle with automated lateral and longitudinal control. Participants were only required to perform emergency braking if the lead vehicle suddenly braked. We found fastest braking times when these instances were accompanied by a looming sound (M\textequals825 ms), relative to a constant sound (M\textequals844 ms), or no sound (M\textequals1098 ms; F(1.29, 23.3)\textequals200, p\textless.05, ?2\textequals0.9). There was no significant difference in false brakings induced by looming and constant sounds (t(18)\textequals.57, p\textequals.58). Thus, we find that looming sounds facilitate braking without increasing a bias for braking. This work demonstrates that looming sounds can hasten braking directly, even in the absence of task-switching. We discuss the implications of this work to auditory warning design.}

{A snapCEST sequence was optimized for imaging of protein CEST effects at 3T with low saturation power. Full Z-spectrum sampling allows Lorentzian fitting of amide, NOE, semisolid MT, and water pools. Validation against data acquired at 9.4T demonstrates effective labeling of selective amide and NOE CEST effects at 3T. Data acquired in a brain tumor patients demonstrates clinical feasibility.}

{MRI of post mortem samples in formalin is an essential tool for validation purposes and comparison with clinical histology, since fixation preserve several microstructural tissue features. We found that the dielectric properties of the fixative influences image quality attained in whole brain post mortem samples at 9.4T. The standard fixative prevented high quality MRI across the entire sample. By using a high conductivity fixative with less field focussing, a more homogeneous excitation was achieved without any drop outs and T1 mapping could be performed using rapid inversion recovery techniques.}

{Spinal cord injury (SCI) is a very heterogeneous disease that makes it difficult to identify a single biomarker during rehabilitation therapy in order to predict the future patient status. In this study, we applied Magnetic Resonance Spectroscopy to examine specific metabolic markers in the pons 10 weeks after injury and correlated them with changes of the clinical status obtained twice during early rehabilitation.}

{Introduction: Task-based fMRI data collected from Human Connectome Project were analyzed using the general linear model. The acquired Z values were plotted as a histogram. Theoretically, the null distribution of Z values should resemble a standard Gaussian distribution. However, we found that the histogram of Z values is often not centered around zero [mean shifted]. In fact, 12 percent of over 3000 Z maps showed a systematic shift bigger than 0.2 standard deviation.This is problematic because statistical inference based on mean shifted Z values can lead to incorrect results. Conclusions: Head motion parameters showed small but significant correlation with the mode of the Z value distribution. Furthermore, shift of the Z value distribution was not dependent on subject based on comparison between motor tfMRI and language tfMRI. Lastly, voxels within white matter region also showed systematically shifted Z values which implies that neuronal alone is not causing the shift. Further investigation is required to pinpoint the cause of the Z score distribution shift. Methods: Material Task-evoked fMRI and motion parameters were acquired from Human Connectome Project WU-Minn HCP 1200 Subjects Data (HCP S1200)[4]. Motor tfMRI and language tfMRI were used in this study. In motor tfMRI (N\textequals1049), the design consisted of five motor tasks including left finger tapping, right finger tapping, left toe squeezing, right toe squeezing and tongue moving blocks. In language tfMRI (N\textequals1048), the design included story block where subjects were presented auditory stories and math block where subjects were presented math task aurally. Acquired images were preprocessed by minimal HCP preprocessing pipeline[2]. Head motion data included estimated rotation in three coordinates, estimated translation in three coordinates and derivative of each parameter for each acquired slices. Method Acquired HCP fMRI images were further processed with high-pass filter discarding temporal frequency below 1/100Hz[3]. Then analysis was performed using general linear model (GLM)[1]. With results from GLM analysis, statistical inference was performed. With motor tfMRI, two Z maps were produced for each subjects contrasting left finger tapping blocks to right finger tapping blocks and contrasting left toe squeezing blocks to right toe squeezing blocks. With language tfMRI, story block and math block was contrasted to create another Z map for each subjects. Shift of the Z score distributions were represented as three values; mean, median and mode. Mode of the distribution was estimated; (mode) \textequals 3\textasteriskcentered(median) - 2\textasteriskcentered(mean) Head motion was represented as four variables; maximum head rotation, maximum head translation, summed root mean square (RMS) of head rotation and summed root mean square (RMS) of head translation Results: Among 3146 Z maps, about 12 were shifted more than 0.2 standard deviation. An example of shifted Z value distribution is shown in figure 1. Analysis 1: Correlation between mode of the Z value distribution and head motion variables were very small (Table 1). Biggest correlation was shown between language tfMRI Z map and maximum head translation (Pearson\textquotesingles r \textequals 0.217, p\textless 0.01). Analysis 2: Z map shift in finger tapping contrast and toe tapping contrast were highly correlated (Pearson\textquotesingles r \textequals 0.696, p \textless 0.01). However, Z map shift in language tfMRI was not correlated with neither that of finger tapping contrast (Pearson\textquotesingles r \textequals -0.012, p \textequals 0.70) nor toe squeezing contrast (Pearson\textquotesingles r \textequals -0.073, p \textequals 0.02). Analysis 3: Z score distribution for voxels within the white matter was shifted as well. Range of the Z distribution shift within white matter was similar to range of the Z distribution shift within the whole brain.}

{Pseudo-continuous-arterial-spin-labeling (PCASL) has been successfully applied in the liver and kidney providing high signal-to-noise-ratio. The goal of this work is to assess the potential of PCASL technique to measure the pulmonary perfusion at 1.5 T. Effective labeling of pulmonary blood flow was achieved by ECG triggering and an orientation of the labeling plane perpendicular to the pulmonary trunk. Fast True-FISP imaging with short TE of 0.9 ms was used to obtain high signal from lung parenchyma. The PCASL-True-FISP technique provides high quality perfusion images of the lung and allows quantitative measurements of pulmonary perfusion both in multiple breath-holds and under free breathing condition.}

{In this work, we measured eddy currents for a very high order B0 shim system. The eddy currents were measured using two methods: a low-resolution B0 mapping sequence and a NMR field camera. The high temporal resolution of the field camera allowed the eddy currents to be corrected using a digital pre-emphasis setup.}

{Purpose Metabolite cycling (MC) is an MRS technique for the simultaneous acquisition of water and metabolite spectra that avoids chemical exchange saturation transfer effects and for which water may serve as a reference signal or contain additional information in functional or diffusion studies. Here, MC was developed for human investigations at ultrahigh field. Methods MC-STEAM and MC-semi-LASER are introduced at 9.4T with an optimized inversion pulse and elaborate coil setup. Experimental and simulation results are given for the implementation of adiabatic inversion pulses for MC. The two techniques are compared, and the effect of frequency and phase correction based on the MC water spectra is evaluated. Finally, absolute quantification of metabolites is performed. Results The proposed coil configuration results in a maximum math formula of 48 $\mu$$\Tau$ in a voxel within the occipital lobe. Frequency and phase correction of single acquisitions improve signal-to-noise ratio (SNR) and linewidth, leading to high-resolution spectra. The improvement of SNR of N-acetylaspartate (SNRNAA) for frequency aligned data, acquired with MC-STEAM and MC-semi-LASER, are 37 and 30, respectively (P \textless 0.05). Moreover, a doubling of the SNRNAA for MC-semi-LASER in comparison with MC-STEAM is observed (P \textless 0.05). Concentration levels for 18 metabolites from the human occipital lobe are reported, as acquired with both MC-STEAM and MC-semi-LASER. Conclusion This work introduces a novel methodology for single-voxel MRS on a 9.4T whole-body scanner and highlights the advantages of semi-LASER compared to STEAM in terms of excitation profile. In comparison with MC-STEAM, MC-semi-LASER yields spectra with higher SNR.}

{The anterior insular cortex (AIC) is often regarded as a key \textquotedblleftnode\textquotedblright of the salience network that mediates the central representation and goal-directed control of homeostatic bodily states by coordinating brain networks. Given the possible role of the AIC in brain network dynamics, we combined electrophysiology and electrical microstimulation in the left and right AIC with functional magnetic resonance imaging (fMRI) to examine blood-oxygen-level-dependent (BOLD) signal changes in cortical and subcortical areas in 4 anesthetized macaque monkeys in a 7T scanner. 10-channel laminar electrodes were introduced in the \textquoteleftvon Economo neuron area\textquoteright of the AIC to record ongoing spontaneous neuronal activity during two-shot echo-planar imaging with a temporal resolution of 2 seconds. Focusing on the local field potential gamma band (56-79 Hz) unilateral events were detected and used to trigger the BOLD signal, a method called \textquoteleftneural-event-triggered fMRI\textquoteright (NET-fMRI) (Logothetis et al. Nature 2012 491:547-53). The results showed markedly different patterns of whole-brain activation and deactivation for the left and right AIC. Subsequently, the laminar electrodes were replaced with single channel iridium electrodes to alternately deliver electrical microstimulation pulses (200$\mu$s biphasic charge-balanced pulses with a 100 Hz frequency) to the left and right AIC. Although the stimulations activated the same brain areas (e.g. amygdala, thalamus) the whole-brain activity following left stimulation tended to be stronger and more prevalent. These results, combined with our tract-tracing data begin to unravel the functional organization underlying the role of the AIC in functional brain networks and brainstem autonomic control regulation.}

{Purpose To describe the process of calibrating a B0 shim system using high-degree (or high order) spherical harmonic models of the measured shim fields, to provide a method that considers amplitude dependency of these models, and to show the advantage of very high-degree B0 shimming for whole-brain and single-slice applications at 9.4 Tesla (T). Methods An insert shim with up to fourth and partial fifth/sixth degree (order) spherical harmonics was used with a Siemens 9.4T scanner. Each shim field was measured and modeled as input for the shimming algorithm. Optimal shim currents can therefore be calculated in a single iteration. A range of shim currents was used in the modeling to account for possible amplitude nonlinearities. The modeled shim fields were used to compare different degrees of whole-brain B0 shimming on healthy subjects. Results The ideal shim fields did not correctly shim the subject brains. However, using the modeled shim fields improved the B0 homogeneity from 55.1 (second degree) to 44.68 Hz (partial fifth/sixth degree) on the whole brains of 9 healthy volunteers, with a total applied current of 0.77 and 6.8 A, respectively. Conclusions The necessity of calibrating the shim system was shown. Better B0 homogeneity drastically reduces signal dropout and distortions for echo-planar imaging, and significantly improves the linewidths of MR spectroscopy imaging.}

{The temporal difference (TD) learning framework is a major paradigm for understanding value-based decision making and related neural activities (e.g., dopamine activity). The representation of time in neural processes modeled by a TD framework, however, is poorly understood. To address this issue, we propose a TD formulation that separates the time of the operator (neural valuation processes), which we refer to as internal time, from the time of the observer (experiment), which we refer to as conventional time. We provide the formulation and theoretical characteristics of this TD model based on internal time, called internal-time TD, and explore the possible consequences of the use of this model in neural value-based decision making. Due to the separation of the two times, internal-time TD computations, such as TD error, are expressed differently, depending on both the time frame and time unit. We examine this operator-observer problem in relation to the time representation used in previous TD models. An internal time TD value function exhibits the co-appearance of exponential and hyperbolic discounting at different delays in intertemporal choice tasks. We further examine the effects of internal time noise on TD error, the dynamic construction of internal time, and the modulation of internal time with the internal time hypothesis of serotonin function. We also relate the internal TD formulation to research on interval timing and subjective time.}

{In binocular rivalry, our perception alternates spontaneously between mutually exclusive or mixed interpretations, although the physical stimulus remains constant. This enables us to study visual consciousness, as it allows a dissociation of sensory processing and conscious perception. Previous BOLD fMRI imaging studies in humans have implicated the role of the fronto-parietal network in mediating perceptual alternations. However, the extent of and the nature of these modulations has been argued to reflect consequences of conscious perception, like introspection, monitoring and decision making. To resolve this issue we used a no-report binocular rivalry paradigm of vertically moving gratings, based on an Optokinetic Nystagmus (OKN) read-out of the content of consciousness. We show that slow cortical states in the delta-theta (1-9 Hz), and beta (20-40 Hz) regimes coupled via their up and down states, in the prefrontal cortex, are predictive of an upcoming change only when the percept switches spontaneously, but not physically. Physical transitions in the animal\textquoterights percept manifest themselves strongly post-switch in the same oscillatory range. Moreover, we also show a clear dissociation between the change in the polarity of the OKN and this slow-state activity preceding a spontaneous transition. Furthermore, we found robust modulation in visually selective spiking activity recorded from the prefrontal cortex contingent on the animal\textquoterights perception. The magnitude of these modulations was comparable to the activity elicited in response to presentation of monocular visual input. Taken together, these results strongly suggest that oscillatory activity in the prefrontal cortex plays a central role in refreshing the content of visual consciousness and spiking activity is modulated in accordance with conscious perception in a no report binocular rivalry paradigm.}

{Current neuroscientific models of bodily self-consciousness (BSC) argue that inaccurate integration of sensory signals leads to altered states of BSC. Indeed, using virtual reality technology, observers viewing a fake or virtual body while being exposed to tactile stimulation of the real body, can experience illusory ownership over\textendashand mislocalization towards\textemdashthe virtual body (Full-Body Illusion, FBI). Among the sensory inputs contributing to BSC, the vestibular system is believed to play a central role due to its importance in estimating self-motion and orientation. This theory is supported by clinical evidence that vestibular loss patients are more prone to altered BSC states, and by recent experimental evidence that visuo-vestibular conflicts can disrupt BSC in healthy individuals. Nevertheless, the contribution of vestibular information and self-motion perception to BSC remains largely unexplored. Here, we investigate the relationship between alterations of BSC and self-motion sensitivity in healthy individuals. Fifteen participants were exposed to visuo-vibrotactile conflicts designed to induce an FBI, and subsequently to visual rotations that evoked illusory self-motion (vection). We found that synchronous visuo-vibrotactile stimulation successfully induced the FBI, and further observed a relationship between the strength of the FBI and the time necessary for complete vection to arise. Specifically, higher self-reported FBI scores across synchronous and asynchronous conditions were associated to shorter vection latencies. Our findings are in agreement with clinical observations that vestibular loss patients have higher FBI susceptibility and lower vection latencies, and argue for increased visual over vestibular dependency during altered states of BSC.}

{Real-time monitoring of biological processes under physiological and pathological conditions is still a great challenge for magnetic resonance imaging (MRI), despite its extensive clinical applications. Calcium(II) is an ideal target for functional MRI purposes, as it is involved in immense number of signaling events in the brain as a secondary messenger. For instance, its extracellular concentration substantially fluctuates during the ischemic stroke [1, 2]. Thus, possibility to track calcium(II) signaling noninvasively would deepen the understanding of numerous physiological processes and allow direct monitoring of neuronal activity. With that objective, two MR contrast agents bearing same calcium chelating part were employed. They were designed in such a manner that one agent (compound 1) triggers MRI signal changes at variable calcium(II) concentrations, while the other (compound 2) remains calcium-insensitive and does not alter MRI signal at different calcium(II) concentrations. In vitro experiments demonstrated that compound 1 exhibits \textgreater90 \textpercent increase in longitudinal relaxivity (r1) upon saturation with calcium(II), while r1 of compound 2 remained constant at same conditions, making them ideal candidates for studying the calcium(II) fluctuations as a calcium-responsive and a control MRI agent, respectively. To monitor calcium(II) changes in vivo, a model of ischemic stroke and the remote middle cerebral artery occlusion (MCAo) approach was used. For these experiments, contrast agents were intracranially injected in Wistar rats (300-340 g), using osmotic pumps for continuous agent delivery (1 $\mu$L/h). Thereafter, silicone coated threat (occluder) was introduced through support tubing, and connected with intra-arterial tubing placed inside the common carotid artery. Preparation was completed when occluder was advanced until 2 mm after bifurcation with pterygopalatine artery. First set of MRI acquisitions (7T Bruker BioSpec 70/30 USR) was divided in three parts: pre-ischemia, ischemia, and reperfusion periods, and consisted of acquiring T1-weighted imaging protocol every two minutes. Ischemia was caused and held for 50-60 min by advancing the occluder for 6-8 mm until resistance was felt; later the reperfusion was performed, with reverse occluder actions. Following T1-weighted imaging part, diffusion-weighted and T2-weighted (after more than 4 hours from the onset of ischemia) imaging protocols were acquired to confirm occurrence of stroke. MRI data analysis of acquired T1-weighted signals was based on Kmeans clustering, and obtained results were compared for various numbers of clusters (2-6). The reported MRI signals were normalized to the first acquired signal (at t\textequals0 min). The in vivo experiments confirmed in vitro responses of employed MR contrast agents. Specifically, T1-weighted images and corresponding masks with 2 clusters show that clusters 1 (cluster with the larger mean value) clearly correspond to center of injections (Figure 1a). Furthermore, the T1-weighted MRI signal of compound 1 varied noticeably because of MCAo stimulation. The MRI signal declined upon MCAo induction, which can be explained through drop of [Ca2+] and accordingly r1 reduction of compound 1. Consequently, r1 recovered upon reperfusion and restoration of [Ca2+], hence also the initial MRI signal trend. On the other hand, the MRI signal of compound 2 changed solely due to continuous injection of the contrast agent, and did not show any alterations to MCAo induction or tissue reperfusion (Figure 1b). In conclusion, calcium-responsive MRI probes were employed here to demonstrate calcium(II) monitoring in vivo upon the ischemic stroke induction. Considering that neuronal activity is always accompanied with calcium(II) flux, this method yet allows visualization and mapping of neural activity using calcium(II) as its direct indicator. To this end, the introduction of this methodology may circumvent the use of conventional fMRI based on BOLD signal and enable assessment of neuronal activity in direct fashion.}

{Full-field visual rotation around the vertical axis induces a sense of self-motion (vection), optokinetic nystagmus (OKN), and, eventually, also motion sickness (MS). If the lights are then suddenly switched off, optokinetic afternystagmus (OKAN) occurs. This is due to the discharge of the velocity storage mechanism (VSM), a central integrative network that has been suggested to be involved in motion sickness. We previously showed that visually induced motion sickness (VIMS) following optokinetic stimulation is dependent on vection intensity. To shed light on this relationship, the current study investigated whether vection intensity is related to VSM activity, and thus, to the OKAN. In repetitive trials (eight per condition), 15 stationary participants were exposed to 120 s of visual yaw rotation (60\mbox{$^\circ$}/s), followed by 90 s in darkness. The visual stimulus either induced strong vection (i.e., scene rotating normally) or weak vection (central and peripheral part moving in opposite directions). Eye movements and subjective vection intensity were continuously measured. Results showed that OKAN occurred less frequently and with lower initial magnitude in the weak-vection condition compared to the strong-vection condition. OKAN decay time constants were not significantly different. The results suggest that the stimuli that produced strong vection also enhanced the charging of the VSM. As VSM activity presumably is a factor in motion sickness, the enhanced VSM activity in our strong-vection condition hints at an involvement of the VSM in VIMS, and could explain why visual stimuli producing a strong sense of vection also elicit high levels of VIMS.}

{Teleoperation of Unmanned Aerial Vehicles (UAVs) is a valuable tool in scenarios where the operator needs to be protected from hazardous environments or where on-board operation is impossible. Technical limitations, e.g., sensor performance, noise and latencies introduced in the transmission, and ineffective display of the information to the operator can lead to reduced performance and in the worst case a loss of the remote vehicle. The spatial decoupling between the operator and the vehicle is one of the main challenges in teleoperation. This dissertation provides an analysis of providing two types of additional feedback, i.e., vehicle-state and task-related motion feedback, by physically moving the operator using the CyberMotion Simulator. The additional information included in the motion feedback can be used by the operator to improve performance and control behavior of remote UAVs.}

{In this work, a novel acceleration method (MultiNet PyGrappa) is introduced which enables high in-plane acceleration factors for non-lipid suppressed 1H MRSI data. By using a variable density undersampling scheme and reconstructing the missing data points with multiple neural networks, this method enables a more robust reconstruction of highly undersampled data. High resolution metabolite maps acquired at 9.4T in the human brain using the proposed method are presented.}

{Magnetic resonance spectroscopic imaging (MRSI) is a powerful tool for mapping metabolite levels across the brain, however, it generally suffers from long scan times. This severely hinders its application in clinical settings. Additionally, the presence of nuisance signals (e.g. the subcutaneous lipid signals close to the skull region in brain metabolite mapping) makes it challenging to apply conventional acceleration techniques to shorten the scan times. The goal of this work is, therefore, to increase the overall applicability of high resolution metabolite mapping using 1H MRSI by introducing a novel GRAPPA acceleration acquisition/reconstruction technique. An improved reconstruction method (MultiNet) is introduced that uses machine learning, specifically neural networks, to reconstruct accelerated data. The method is further modified to use more neural networks with nonlinear hidden layers and is then combined with a variable density undersampling scheme (MultiNet PyGRAPPA) to enable higher in-plane acceleration factors of R \textequals 5.6 and R \textequals 7 for a non-lipid suppressed ultra-short TR and TE 1H FID MRSI sequence. The proposed method is evaluated for high resolution metabolite mapping of the human brain at 9.4T. The results show that the proposed method is superior to conventional GRAPPA: there is no significant residual lipid aliasing artifact in the images when the proposed MultiNet method is used. Furthermore, the MultiNet PyGRAPPA acquisition/reconstruction method with R \textequals 5.6 results in reproducible high resolution metabolite maps (with an in-plane matrix size of 64 $\times$ 64) that can be acquired in 2.8 min on 9.4T. In conclusion, using multiple neural networks to predict the missing points in GRAPPA reconstruction results in a more reliable data recovery while keeping the noise levels under control. Combining this high fidelity reconstruction with variable density undersampling (MultiNet PyGRAPPA) enables higher in-plane acceleration factors even for non-lipid suppressed 1H FID MRSI, without introducing any structured aliasing artifact in the image.}

{The relatively low spatial resolution (ca. 250 mm3) of 1H-MRS hinders its application towards probing heterogeneous diseased tissue, e.g. tumor tissue. Therefore, we present mmqCEST, a metabolic imaging technique based on the saturation transfer from RF-tagged metabolites to the bulk water [1]. mmqCEST decodes a frequency-dependent metabolite-weighted contrast in the Z-spectra into (multicolor) quantitative metabolic maps with a high spatial resolution (ca. 3.4 mm3).}

{Purpose The goal of this study is to develop and evaluate a multiline balanced steady-state free-precession (bSSFP) sequence for passband functional MRI at ultrahigh field. Methods Passband bSSFP functional MRI experiments using a visual task were performed on a 9.4 T system with echo trains ranging from one up to seven echoes. We analyze the acquisition efficiency, temporal and thermal signal-to-noise ratio, as well as the observed blood oxygen\textendashlevel-dependent (BOLD) signal changes. Results With increasing repetition time and echo train length, the BOLD-related signal change as well as the thermal and temporal noise were improved. Activation patterns and signal changes were stable and reproducible across subjects. Conclusions We propose a multiline bSSFP for functional BOLD imaging that approaches the speed of echo-planar imaging and that shows an increased BOLD sensitivity compared with single-line bSSFP.}

{We examined the dynamic functional connectivity of the von Economo neuron (VEN) area of the anterior insula cortex (AIC) using two-shot echo-planar functional magnetic resonance imaging with direct electrical stimulation (DES-fMRI), seed-based connectivity analysis (SBCA), and local field potential recordings (NET-fMRI) in the anesthetized macaque monkey. The electrical stimulation (n\textequals3) of the left or right VEN area activated several distinct subcortical limbic nuclei (e.g. amygdala, midline thalamic nucleus [MTN]) and high-order cortical areas (e.g. superior temporal sulcus, extrastriate visual areas). Both the left and the right stimulation produced a rather lateralized activation pattern, with the activation elicited from one side roughly mirroring the activation obtained from the other side. Nevertheless, stimulation of the left VEN area elicited a consistently more intense and broader bilateral activation. The correlation patterns obtained with a SBCA of the same data set, using the left and right VEN area as seeds, confirmed the activation patterns elicited by the electrical stimulation. Conversely, SBCA using spontaneous data sets, collected in the same animals without electrical stimulation, revealed not only a correlation between both VEN areas but also a broader bilateral correlation pattern that remained identical regardless of the seeded side. Whereas many limbic and cortical activations produced by the electrical stimulations were matched by a correlation with the spontaneous activity of the VEN areas, the MTN was neither correlated nor anticorrelated with the spontaneous activity. Finally, in the NET-fMRI with the same spontaneous functional scans, the occurrence of oscillatory events (e.g. alpha, theta, gamma) in the left or right VEN area triggered varying patterns of activity that differed from the electrical stimulation patterns while being nonetheless markedly asymmetric. Events from the left or right VEN area often correlated with respectively massive activation or deactivation patterns. The present study reveals that small individual regions of the brain can simultaneously display a broad diversity of functional connectivity patterns. The asymmetric activity patterns associated with the left and right VEN areas corroborate prior evidence for a left-right functional asymmetry in the AIC (Craig, 2005, Trends Cogn Sci). The spatially restricted or broad activation of limbic and high-order regions from the right and left VEN areas, respectively, might underlie the asymmetric role of the AIC in monitoring internal bodily states during cognitive processes, including subjective perceptual awareness.}

{Due to high sensitivity to B1+-inhomogeneities, Chemical Exchange Saturation Transfer MRI requires a correction or mitigation of the B1+-inhomogeneity at ultra-high magnetic field strengths (B0 $\geq$ 7 Tesla). A novel approach for mitigation of B1+-inhomogeneity effects that affects the saturation process is presented. The method employs two interleaved excitation modes during the saturation pulse train. Simulations show a decrease of the relative difference of the MTRRex metric caused by B1+ inhomogeneity. This \textquotedblleftMultiple Interleaved Mode Saturation\textquotedblright scheme leads to improved homogeneity in both, phantom and in vivo measurements at 7 Tesla.}

{We analyzed the areal distribution of von Economo (VEN) and fork (FN) neurons in the human anterior insular cortex (AIC). The AIC, including the frontoinsula (FI), from eight freshly-fixed human brains (3 pairs of left and right insulae, and 5 single left or right insulae) were cut in the coronal plane at a 50-micron thickness. The sections were stained with cresyl violet to reveal all neuronal cell bodies and the proximal portion of their dendrites (Nissl stain), with silver nitrate to reveal myelinated fibers (Gallyas stain), or with an anti-parvalbumin antibody to reveal local interneurons. All stained sections were digitized with a 0.5-micron in plane resolution and 1-micron vertical stack using a scanning microscope. The distribution of the VEN and FN was charted using high-magnification examination of the Nissl slides. The AIC was parcellated using low-magnification examination of all three sets of slides with pre-established multi-architectonic criteria (Evrard et al., J Comp Neurol 2014 522:64-97). The VEN and FN were co-mingled within a rather vast region (or \textquoteleftVEN domain\textquoteright) inside the ventral agranular region of AIC, with no apparent extension in the dorsal AIC or the dysgranular and granular insula. The VEN domain was delimited by a rather abrupt reduction of the numbers of both neurons. A comparison of the localization of the VEN domain with the architectonic parcellation of the AIC revealed (1) that its overall outer limit optimally overlapped with sharp architectonic boundaries, and (2) that it was further subdivided into at least three distinct architectonic areas (or \textquoteleftVEN areas\textquoteright), rather than being homogeneous. While these three areas consistently occurred, their exact topology differed between the left and right hemispheres. Our prior examination of the macaque AIC revealed a complete overlap of the delimitation of a VEN/FN cluster with architectonic boundaries; however, this cluster formed one unique architectonic area, rather than being divided into several areas (Horn FM and Evrard HC, in preparation). The highly consistent overlap of the VEN distribution and architectonic boundaries (or \textquotedblleftelemental localization\textquotedblright) in humans and monkeys indicates the existence of a robust selective pressure on the development of the AIC throughout evolution. The multiplication of the number of VEN areas likely correlates with the disproportionately faster growth of the AIC, including in particular FI, in humans compared to other primate species (Bauernfeind et al., J Hum Evol 2013 64:263-79). This multiplication might underlie the possible evolutionary emergence of the subjective awareness of feelings in the human AIC (Craig, Nat Rev Neurosci 2009 10:59-70).}

{In contrast to spatial memory acquired in enclosed spaces (i.e., rooms), memory for navigable spaces (e.g., buildings) is less well understood. We had subjects learn eight target objects spread across a virtual environment, consisting of two apparent regions. Separation of regions was triggered by visual and semantic similarity (wall colour, object categories), walking distance and turning angle complexity (longest and most complex path at transition point), and spatio-temporal contingency (regions learned subsequently). A subsequent pointing task revealed increased pointing latency with increasing corridor distance to the target, and a facilitative effect of being bodily aligned with the local corridor. Moreover, pointing to targets located within one\textquoterights current region was faster compared to pointing to targets in the other region, and alignment with region specific orientations enhanced pointing latency. In sum, our results indicate the formation of local and regional memory units that manifest in the form of spatial reference frames. Our local and regional effects give way to the interpretation that, when confronted with a complex navigable space, multiple levels of spatial integration are stored, potentially in a hierarchical fashion. Importantly, our results cannot be explained by concepts of exclusive local corridor units or exclusive global, all-embracing memory units.}

{Ultralow-field (ULF) nuclear magnetic resonance spectroscopy (MRS) and magnetic resonance imaging (MRI) are promising spectroscopy and imaging methods allowing for, e.g., the simultaneous detection of multiple nuclei or imaging in the vicinity of metals. To overcome the inherently low signal-to-noise ratio that usually hampers a wider application, we present an alternative approach to prepolarized ULF MRS employing hyperpolarization techniques like signal amplification by reversible exchange (SABRE) or Overhauser dynamic nuclear polarization (ODNP). Both techniques allow continuous hyperpolarization of 1H as well as other MR-active nuclei. For the implementation, a superconducting quantum interference device (SQUID)-based ULF MRS/MRI detection scheme was constructed. Due to the very low intrinsic noise level, SQUIDs are superior to conventional Faraday detection coils at ULFs. Additionally, the broadband characteristics of SQUIDs enable them to simultaneously detect the MR signal of different nuclei such as 13C, 19F, or 1H. Since SQUIDs detect the MR signal directly, they are an ideal tool for a quantitative investigation of hyperpolarization techniques such as SABRE or ODNP.}

{Holistic processing is the tendency to perceive an object as an indecomposable whole rather than by its parts. Psychological research has shown that faces are processed holistically. However, recent studies have shown that non-expertise objects with salient Gestalt information are also processed holistically, questioning whether this phenomena is unique to faces. Neuroimaging studies have linked holistic processing of faces to brain activity in face-responsive regions of the occipital-temporal cortex. However, these studies specifically localized face-responsive brain regions, but not object, scene or perceptual grouping related brain regions. In this study, we aimed to explore the neural correlates of holistic face processing in a larger range of brain regions, in order to investigate how specific the activation is to face regions. We used fMRI to record the brain activity of subjects performing a composite face task. Participants viewed pairs of faces and determined whether the top halves of the faces were the same or different. Additionally, we localized specific regions of interest defined by their responses to faces, objects, scenes and perceptual grouping, allowing us to investigate how activity in these regions changed during the composite face task. Surprisingly, we found that activity in the occipital face area, fusiform face area and anterior temporal face area did not show a clear pattern of activity relating to the behavioural composite effect. However, activity in the parahippocampal place area, superior parietal lobule and early visual cortex all showed a pattern of activity consistent with the behavioural composite effect. These results suggest that holistic processing occurs in brain regions involved in spatial processing, perceptual grouping and early vision, rather than being limited to face-responsive brain regions. We hypothesize that holistic perception may be driven by these factors rather than identity discrimination, in line with the behavioural finding of the composite effect in non-expertise objects.}

{Highly synchronized oscillations, or ripples (\textasciitilde200Hz), are generated in the hippocampus (HPC) during awake immobility or non-REM (NREM) sleep and has long been suggested to mediate the hippocampal-cortical communication underlying memory consolidation. The medial prefrontal cortex (mPFC) receives direct input from the HPC and many mnemonic processes depend on these two brain regions. The HPC-mPFC pathway is considered critical for consolidation of declarative memory and is currently one of the most studied memory-related pathways. A memory-supporting network is, however, not limited by the HPC and the mPFC. The thalamic mediodorsal (MD) nucleus is likely a part of an extended memory network. The MD is reciprocally connected with the mPFC and has long been implicated in different mnemonic functions. Our fMRI-based mapping of the whole brain activity associated with ripples occurrence suggested that silencing of a subset of subcortical regions, including thalamus, may reduce interference for hippocampal-cortical communication (Logothetis et al., 2012). We characterized neural activity in the MD around times of the hippocampal ripples in spontaneously behaving rats. Generally, the MD population activity was strongly suppressed around ripples. A substantial reduction of the MD firing occurred 0.4 - 2.4 sec (mean: 1.1 $\pm$ 0.1 sec) before the ripple peak and lasted for 2.1 $\pm$ 0.2 sec. Moreover, the degree of MD activity suppression correlated with the ripple amplitude. The ripple-associated decrease of the MD firing rate was the strongest and the most consistent during awake immobility. In contrast, during NREM sleep bidirectional modulation of the MD activity was observed: the MD firing was actually enhanced around ripples that were temporally coupled with sleep spindles, while it was decreased around spindle-uncoupled ripples. Our results suggest possible competitive interaction between the hippocampal-cortical and thalamo-cortical networks supporting \textquoteleftoff-line\textquoteright and \textquotelefton-line\textquoteright information processing, respectively.}

{Forming a persistentmemory trace requires hippocampal-cortical interaction. Population bursts in the hippocampal network occurring during awake immobility or NREMsleep propagate throughout the entire hippocampal formation and generate transient dynamic interactions locally, but also between the hippocampus (HPC) and cortex. This synchronized population activity is revealed in the local field potentials as brief, high-frequency (about 200 Hz) oscillations, or ripples, which are thought to mediate the hippocampal-cortical communication underlying memory consolidation [1]. The medial prefrontal cortex (mPFC) receives direct input from the HPC andmanymnemonic processes depend on these two brain regions [2]. The HPC-mPFC pathway is considered critical for consolidation of declarative memory and is currently one of the most studied memory-related pathways. A memory-supporting network is, however, not limited by the HPC and the mPFC. The thalamic mediodorsal (MD) nucleus is likely a part of an extended memory network. The MD is reciprocally connected with the mPFC and has long been implicated in different mnemonic functions [3]. Our fMRI-based mapping of the whole brain activity associated with ripples occurrence suggested that silencing of a subset of subcortical regions, including thalamus, may reduce interference for hippocampal-cortical communication [4]. We characterized neural activity in the MD around times of the hippocampal ripples in spontaneously behaving rats. Generally, the MD population activity was strongly suppressed around ripples. A substantial reduction of MD firing occurred 0.4\textendash2.4 sec (mean: 1.1$\pm$0.1 sec) before the ripple peak and lasted for 2.1$\pm$0.2 sec. Moreover, the degree of MD activity suppression correlated with the ripple amplitude. The ripple-associated decrease of the MD firing rate was the strongest and the most consistent during awake immobility. In contrast, during NREM sleep bidirectional modulation of the MD activity was observed: the MD firing was actually enhanced around ripples that were temporally coupled with sleep spindles, while it was decreased around spindle-uncoupled ripples. Our results suggest possible competitive interaction between the hippocampal-cortical and thalamo-cortical networks supporting \textquoteleftoff-line\textquoteright and \textquotelefton-line\textquoteright information processing, respectively.}

{Major depressive disorder (MDD) is characterized by a biased emotion perception. In the auditory domain, MDD patients have been shown to exhibit attenuated processing of positive emotions expressed by speech melody (prosody). So far, no neuroimaging studies examining the neural basis of altered processing of emotional prosody in MDD are available. In this study, we addressed this issue by examining the emotion bias in MDD during evaluation of happy, neutral, and angry prosodic stimuli on a five-point Likert scale during functional magnetic resonance imaging (fMRI). As expected, MDD patients rated happy prosody less intense than healthy controls (HC). At neural level, stronger activation in the middle superior temporal gyrus (STG) and the amygdala was found in all participants when processing emotional as compared to neutral prosody. MDD patients exhibited an increased activation of the amygdala during processing prosody irrespective of valence while no significant differences between groups were found for the STG, indicating that altered processing of prosodic emotions in MDD occurs rather within the amygdala than in auditory areas. Concurring with the valence-specific behavioral effect of attenuated evaluation of positive prosodic stimuli, activation within the left amygdala of MDD patients correlated with ratings of happy, but not neutral or angry prosody. Our study provides first insights in the neural basis of reduced experience of positive information and an abnormally increased amygdala activity during prosody processing.}

{Rhythmic drumming has long been used to alter consciousness and induce states of trance. Rhythm-induced trance is common in shamanism, humanity\textquoterights most ancient healing tradition. Despite similar techniques across cultures and powerful phenomenology, little is known about the mechanisms underlying trance. We examined the neural correlates of rhythm-induced trance in experienced shamanic practitioners. In the first study, we used fMRI to examine the neural patterns associated with trance. Shamanic practitioners (n\textequals15) underwent 8 minute brain scans while they listened to rhythmic drumming and entered a trance state (or remained in non-trance in a control condition). In trance, brain networks displayed notable reconfigurations, including increased connectivity in regions associated with internal thought (the default mode\textquoterights posterior cingulate cortex) and cognitive control (dorsal anterior cingulate cortex and insula), as well as decreased connectivity within the brainstem and auditory pathway. This network configuration suggests perceptual decoupling and that the repetitive drumming was gated out to maintain an internally oriented stream of consciousness. In a follow-up EEG study, we used a similar design to examine auditory gating and network activity while shamanic practitioners (n\textequals18) experienced rhythm-induced trance and a control state. In response to clicks embedded in the drumming, the N100 and P200 ERP components were decreased during Trance. This indicates decreased sensory encoding and elaborative processing during trance. Together this work suggests that repetitive drumming promotes an internally directed state via perceptual decoupling, and explicates why trance is a common way to promote insight across cultures.}

{Previous behavioral and neurophysiological research has shown better memory for horizontal than for vertical locations. In these studies, participants navigated toward these locations. In the present study we investigated whether the orientation of the spatial plane per se was responsible for this difference. We thus had participants learn locations visually from a single perspective and retrieve them from multiple viewpoints. In three experiments, participants studied colored tags on a horizontally or vertically oriented board within a virtual room and recalled these locations with different layout orientations (Exp. 1) or from different room-based perspectives (Exps. 2 and 3). All experiments revealed evidence for equal recall performance in horizontal and vertical memory. In addition, the patterns for recall from different test orientations were rather similar. Consequently, our results suggest that memory is qualitatively similar for both vertical and horizontal two-dimensional locations, given that these locations are learned from a single viewpoint. Thus, prior differences in spatial memory may have originated from the structure of the space or the fact that participants navigated through it. Additionally, the strong performance advantages for perspective shifts (Exps. 2 and 3) relative to layout rotations (Exp. 1) suggest that configurational judgments are not only based on memory of the relations between target objects, but also encompass the relations between target objects and the surrounding room-for example, in the form of a memorized view.}