Visualizing the trigeminovagal complex in the human medulla by combining ex-vivo ultra-high resolution structural MRI and polarized light imaging microscopy.

A trigeminovagal complex, as described in some animals, could help to explain the effect of vagus nerve stimulation as a treatment for headache disorders. However, the existence of a trigeminovagal complex in humans remains unclear. This study, therefore investigated the existence of the trigeminovagal complex in humans. One post-mortem human brainstem was scanned at 11.7T to obtain structural (T1-weighted) and diffusion magnetic resonance images ((d)MR images). Post-processing of dMRI data provided track density imaging (TDI) maps to investigate white matter at a smaller resolution than the imaging resolution. To evaluate the reconstructed tracts, the MR-scanned brainstem and three additional brainstems were sectioned for polarized light imaging (PLI) microscopy. T1-weighted images showed hyperintense vagus medullar striae, coursing towards the dorsomedial aspect of the medulla. dMRI-, TDI- and PLI-images showed these striae to intersect the trigeminal spinal tract (sp5) in the lateral medulla. In addition, PLI images showed that a minority of vagus fibers separated from the vagus trajectory and joined the trigeminal spinal nucleus (Sp5) and the sp5. The course of the vagus tract in the rostral medulla was demonstrated in this study. This study shows that the trigeminal- and vagus systems interconnect anatomically at the level of the rostral medulla where the vagus fibers intersect with the Sp5 and sp5. Physiological and clinical utility of this newly identified interconnection is a topic for further research.

White matter changes in the perforant path area in patients with amyotrophic lateral sclerosis.

OBJECTIVE: The aim of this study was to test the hypothesis that white matter degeneration of the perforant path - as part of the Papez circuit - is a key feature of amyotrophic lateral sclerosis (ALS), even in the absence of frontotemporal dementia (FTD) or deposition of pTDP-43 inclusions in hippocampal granule cells. METHODS: We used diffusion Magnetic Resonance Imaging (dMRI), polarized light imaging (PLI) and immunohistochemical analysis of post mortem hippocampus specimens from controls (n = 5) and ALS patients (n = 14) to study white matter degeneration in the perforant path. RESULTS: diffusion Magnetic Resonance Imaging demonstrated a decrease in fractional anisotropy (P = 0.01) and an increase in mean diffusivity (P = 0.01) in the perforant path in ALS compared to controls. PLI-myelin density was lower in ALS (P = 0.05) and correlated with fractional anisotropy (r = 0.52, P = 0.03). These results were confirmed by immunohistochemistry; both myelin (proteolipid protein, P = 0.03) and neurofilaments (SMI-312, P = 0.02) were lower in ALS. Two out of the fourteen ALS cases showed pTDP-43 pathology in the dentate gyrus, but with comparable myelination levels in the perforant path to other ALS cases. CONCLUSION: We conclude that degeneration of the perforant path occurs in ALS patients and that this may occur before, or independent of, pTDP-43 aggregation in the dentate gyrus of the hippocampus. Future research should focus on correlating the degree of cognitive decline to the amount of white matter atrophy in the perforant path.

Identification of the pedunculopontine nucleus and surrounding white matter tracts on 7T diffusion tensor imaging, combined with histological validation.

BACKGROUND: The pedunculopontine nucleus (PPN) has been studied as a possible target for deep brain stimulation (DBS) for Parkinson's disease (PD). However, identifying the PPN can be challenging as the PPN is poorly visualized on conventional or even high-resolution MR scans. From histological studies it is known that the PPN is surrounded by major white matter tracts, which could function as possible anatomical landmarks. METHODS: This study aimed to localize the PPN using 7T magnetic resonance (MR) imaging and diffusion tensor imaging (DTI) of its white matter borders in one post-mortem brain. Histological validation of the same specimen was performed. The PPN was segmented in both spaces, after which the two masks were compared using the Dice Similarity Index (DSI). The DSI compared the similarity of two samples on an inter-individual level and validated the MR findings. The error in distance between the center of the two 3D segmentations was measured by use of the Euclidean distance. RESULTS: The PPN can be found in between the superior cerebellar peduncle and the medial lemniscus on both the FA-maps of the DTI images and the histological sections. The histological transverse sections showed to be superior to recognize the PPN (DSI: 1.0). The DTI images have a DSI of 0.82. The overlap-masks of both spaces showed a DSI of 0.32, whereas the concatenation-masks of both spaces showed a remarkable overlap, a DSI of 0.94. Euclidean distance of the overlap- and concatenation-mask in the two spaces showed to be 1.29 mm and 1.59 mm, respectively. CONCLUSION: This study supports previous findings that the PPN can be identified using FA-maps of DTI images. For possible clinical application in DBS localization, in vivo validation of the findings of our study is needed.

A probabilistic atlas of the cerebellar white matter.

Imaging of the cerebellar cortex, deep cerebellar nuclei and their connectivity are gaining attraction, due to the important role the cerebellum plays in cognition and motor control. Atlases of the cerebellar cortex and nuclei are used to locate regions of interest in clinical and neuroscience studies. However, the white matter that connects these relay stations is of at least similar functional importance. Damage to these cerebellar white matter tracts may lead to serious language, cognitive and emotional disturbances, although the pathophysiological mechanism behind it is still debated. Differences in white matter integrity between patients and controls might shed light on structure-function correlations. A probabilistic parcellation atlas of the cerebellar white matter would help these studies by facilitating automatic segmentation of the cerebellar peduncles, the localization of lesions and the comparison of white matter integrity between patients and controls. In this work a digital three-dimensional probabilistic atlas of the cerebellar white matter is presented, based on high quality 3T, 1.25mm resolution diffusion MRI data from 90 subjects participating in the Human Connectome Project. The white matter tracts were estimated using probabilistic tractography. Results over 90 subjects were symmetrical and trajectories of superior, middle and inferior cerebellar peduncles resembled the anatomy as known from anatomical studies. This atlas will contribute to a better understanding of cerebellar white matter architecture. It may eventually aid in defining structure-function correlations in patients with cerebellar disorders.

Dentatorubrothalamic tract localization with postmortem MR diffusion tractography compared to histological 3D reconstruction.

Diffusion-weighted imaging (DWI) tractography is a technique with great potential to characterize the in vivo anatomical position and integrity of white matter tracts. Tractography, however, remains an estimation of white matter tracts, and false-positive and false-negative rates are not available. The goal of the present study was to compare postmortem tractography of the dentatorubrothalamic tract (DRTT) by its 3D histological reconstruction, to estimate the reliability of the tractography algorithm in this specific tract. Recent studies have shown that the cerebellum is involved in cognitive, language and emotional functions besides its role in motor control. However, the exact working mechanism of the cerebellum is still to be elucidated. As the DRTT is the main output tract it is of special interest for the neuroscience and clinical community. A postmortem human brain specimen was scanned on a 7T MRI scanner using a diffusion-weighted steady-state free precession sequence. Tractography was performed with PROBTRACKX. The specimen was subsequently serially sectioned and stained for myelin using a modified Heidenhain-Woelke staining. Image registration permitted the 3D reconstruction of the histological sections and comparison with MRI. The spatial concordance between the two modalities was evaluated using ROC analysis and a similarity index (SI). ROC curves showed a high sensitivity and specificity in general. Highest measures were observed in the superior cerebellar peduncle with an SI of 0.72. Less overlap was found in the decussation of the DRTT at the level of the mesencephalon. The study demonstrates high spatial accuracy of postmortem probabilistic tractography of the DRTT when compared to a 3D histological reconstruction. This gives hopeful prospect for studying structure-function correlations in patients with cerebellar disorders using tractography of the DRTT.

An investigation into the functional and structural connectivity of the Default Mode Network.

Connectivity analyses based on both resting-state (rs-)fMRI and diffusion weighted imaging studies suggest that the human brain contains regions that act as hubs for the entire brain, and that elements of the Default Mode Network (DMN) play a pivotal role in this network. In the present study, the detailed functional and structural connectivity of the DMN was investigated. Resting state fMRI (35 minute duration) and Diffusion Weighted Imaging (DWI) data (256 directions) were acquired from forty-seven healthy subjects at 3 T. Tractography was performed on the DWI data. The resting state data were analysed using a combination of Independent Component Analysis, partial correlation analysis and graph theory. This forms a data driven approach for examining the connectivity of the DMN. ICA defined regions of interest were used as a basis for a partial correlation analysis. The resulting partial correlation coefficients were used to compute graph theoretical measures. This was performed on a single subject basis, and combined to compute group results depicting the spatial distribution of betweenness centrality within the DMN. Hubs with high betweenness centrality were frequently found in association areas of the brain. This approach makes it possible to distinguish the hubs in the DMN as belonging to different anatomical association systems. The start and end points of the fibre tracts coincide with hubs found using the resting state analysis.

Recent advancements in diffusion MRI for investigating cortical development after preterm birth-potential and pitfalls.

Preterm infants are born during a critical period of brain maturation, in which even subtle events can result in substantial behavioral, motor and cognitive deficits, as well as psychiatric diseases. Recent evidence shows that the main source for these devastating disabilities is not necessarily white matter (WM) damage but could also be disruptions of cortical microstructure. Animal studies showed how moderate hypoxic-ischemic conditions did not result in significant neuronal loss in the developing brain, but did cause significantly impaired dendritic growth and synapse formation alongside a disturbed development of neuronal connectivity as measured using diffusion magnetic resonance imaging (dMRI). When using more advanced acquisition settings such as high-angular resolution diffusion imaging (HARDI), more advanced reconstruction methods can be applied to investigate the cortical microstructure with higher levels of detail. Recent advances in dMRI acquisition and analysis have great potential to contribute to a better understanding of neuronal connectivity impairment in preterm birth. We will review the current understanding of abnormal preterm cortical development, novel approaches in dMRI, and the pitfalls in scanning vulnerable preterm infants.

Graph theoretical analysis of magnetoencephalographic functional connectivity in Alzheimer's disease.

In this study we examined changes in the large-scale structure of resting-state brain networks in patients with Alzheimer's disease compared with non-demented controls, using concepts from graph theory. Magneto-encephalograms (MEG) were recorded in 18 Alzheimer's disease patients and 18 non-demented control subjects in a no-task, eyes-closed condition. For the main frequency bands, synchronization between all pairs of MEG channels was assessed using a phase lag index (PLI, a synchronization measure insensitive to volume conduction). PLI-weighted connectivity networks were calculated, and characterized by a mean clustering coefficient and path length. Alzheimer's disease patients showed a decrease of mean PLI in the lower alpha and beta band. In the lower alpha band, the clustering coefficient and path length were both decreased in Alzheimer's disease patients. Network changes in the lower alpha band were better explained by a 'Targeted Attack' model than by a 'Random Failure' model. Thus, Alzheimer's disease patients display a loss of resting-state functional connectivity in lower alpha and beta bands even when a measure insensitive to volume conduction effects is used. Moreover, the large-scale structure of lower alpha band functional networks in Alzheimer's disease is more random. The modelling results suggest that highly connected neural network 'hubs' may be especially at risk in Alzheimer's disease.

Magnetoencephalographic evaluation of resting-state functional connectivity in Alzheimer's disease.

Statistical interdependencies between magnetoencephalographic signals recorded over different brain regions may reflect the functional connectivity of the resting-state networks. We investigated topographic characteristics of disturbed resting-state networks in Alzheimer's disease patients in different frequency bands. Whole-head 151-channel MEG was recorded in 18 Alzheimer patients (mean age 72.1 years, SD 5.6; 11 males) and 18 healthy controls (mean age 69.1 years, SD 6.8; 7 males) during a no-task eyes-closed resting state. Pair-wise interdependencies of MEG signals were computed in six frequency bands (delta, theta, alpha1, alpha2, beta and gamma) with the synchronization likelihood (a nonlinear measure) and coherence and grouped into long distance (intra- and interhemispheric) and short distance interactions. In the alpha1 and beta band, Alzheimer patients showed a loss of long distance intrahemispheric interactions, with a focus on left fronto-temporal/parietal connections. Functional connectivity was increased in Alzheimer patients locally in the theta band (centro-parietal regions) and the beta and gamma band (occipito-parietal regions). In the Alzheimer group, positive correlations were found between alpha1, alpha2 and beta band synchronization likelihood and MMSE score. Resting-state functional connectivity in Alzheimer's disease is characterized by specific changes of long and short distance interactions in the theta, alpha1, beta and gamma bands. These changes may reflect loss of anatomical connections and/or reduced central cholinergic activity and could underlie part of the cognitive impairment.

EEG synchronization likelihood in mild cognitive impairment and Alzheimer's disease during a working memory task.

OBJECTIVE: Synchronization likelihood analysis of resting state EEG has shown that cognitive dysfunction in Alzheimer's disease (AD) and its precursor mild cognitive impairment (MCI) are associated with a loss of functional connectivity in high (upper alpha and beta) frequency bands. Working memory tasks are known to change functional connectivity, but it is unknown whether this increases the differences between AD, MCI and healthy controls. Our objective was to investigate the behavior of synchronization likelihood of multichannel EEG in AD, MCI and cognitively healthy controls, both at rest and during a working memory task. METHODS: EEGs (200 Hz sample frequency, 21 channels, average reference) were recorded at rest as well as during a visual working memory task in 14 patients with AD according to the NINCDS-ADRDA criteria (mean age 76.4; SD 13.6), 11 patients with MCI according to the criteria of Petersen (mean age 78.4; SD 6.4) and 14 with subjective memory complaints but no demonstrable memory disturbance (mean age 61.6; SD 26.6). The synchronization likelihood was computed over 19 channels, comparing each channel with all the other channels for the 0.5-4, 4-8, 8-10, 10-12, 12-30, 30-50 Hz frequency bands. RESULTS: The synchronization likelihood was significantly decreased in the upper alpha (10-12) and beta (12-30) bands in AD compared to persons with subjective memory complaints. The working memory task scores strongly correlated with Mini-Mental State Examination scores. During the working memory task the synchronization likelihood was significantly higher in MCI compared to the control subjects in the lower alpha band (8-10 Hz). CONCLUSIONS: Decrease of beta band synchronization occurs in mild AD, both in a resting condition and during a working memory task. SIGNIFICANCE: Decrease of beta band synchronization in mild AD is a robust finding. The present study confirms our findings in a different cohort of patients, using alternative frequency bands. The diagnostic value of the synchronization likelihood in AD and MCI needs to be further established.

A neural complexity measure applied to MEG data in Alzheimer's disease.

OBJECTIVE: A measure of neural complexity (C(N)) (Proc. Natl Acad. Sci. USA 91 (1994) 5033) was applied to magnetoencephalography (MEG) data to test the hypothesis that C(N) decreases when information processing in the brain is impaired, as is the case in patients with Alzheimer's Disease (AD). METHODS: One hundred and fifty-one channel MEGs were recorded in 20 AD patients and 20 healthy age-matched controls in a resting condition with eyes open (EO) and eyes closed (EC). Artifact-free epochs of 117 channels were selected for analysis. C(N) and D(2) were computed in different frequency bands, and correlated with the MMSE. RESULTS: The Group x Frequency band interaction was significant for both C(N) and D(2). C(N) was higher in AD, as compared with controls, in the 2-4 and 4-8Hz bands, and D(2) was higher in AD patients in the 14-20 and 20-30Hz bands. The C(N) was higher in the EC condition compared to the EO condition, whereas the D(2) was higher in the EO condition. CONCLUSIONS: The hypothesis of Tononi et al. (Proc. Natl Acad. Sci. USA 91 (1994) 5033) that the neural complexity decreases in AD patients has to be rejected. However, both neural complexity and the correlation dimension did show differences between controls and AD patients which depended on frequency band.

Hypoxia in fetal lambs: a study with (1)H-MNR spectroscopy of cerebrospinal fluid.

In fetal lambs, severe hypoxia (SH) will lead to brain damage. Mild hypoxia (MH) is thought to be relatively safe for the fetal brain because compensating mechanisms are activated. We questioned whether MH, leading to mild acidosis, induces changes in cerebral metabolism. Metabolites in cerebrospinal fluid (CSF) samples, as analyzed by proton magnetic resonance spectroscopy, were studied in two groups of seven anesthetized near-term fetal lambs. In group I, SH leading to acidosis with an arterial pH <7.1 was achieved. In group II, MH with an intended pH of 7.23--7.27 was reached [start of MH (SMH)], and maintained during 2 h [end of MH (EMH)]. During SH, choline levels in CSF, a possible indicator of cell membrane damage, were increased. Both during SH and at EMH, CSF levels of lactic acid, alanine, phenylalanine, tyrosine, lysine, branched chain amino acids, and hypoxanthine were increased compared with control values and with SMH, respectively. At EMH, the hypoxanthine CSF-to-blood ratio was increased as compared with SMH. These results indicate that prolonged MH leads to energy degradation in the fetal lamb brain and may not be as safe as assumed.

Auditory evoked potentials from auditory cortex, medial geniculate nucleus, and inferior colliculus during sleep-wake states and spike-wave discharges in the WAG/Rij rat.

OBJECTIVE: Click auditory evoked potentials (AEP) were simultaneously recorded from the auditory cortex (ACx), the medial geniculate nucleus (MGN), and the inferior colliculus (IC) in the freely moving WAG/Rij rat, to investigate state-dependent changes of the AEP in different anatomical locations along the auditory pathway. METHODS: AEPs obtained during active (AW) and passive wakefulness (PW), slow wave sleep (SWS), rapid-eye-movement sleep (REM) and generalized spike-wave discharges (SWD; a specific trait of the WAG/Rij rat, a genetic model for absence epilepsy), were compared. RESULTS: The early components in ACx, MGN and IC were stable throughout the sleep-wake cycle and SWD, apart from a slight increase in the IC during SWD. At all three locations a prominent enlargement of a later component (i.e., N32 in IC, N33 in MGN, and N44 in ACx) was found during SWS and SWD. CONCLUSIONS: The early AEP components are not modulated by the normal sleep-wake states, and are not impaired during SWD. A strong state-dependent modulation of a later AEP component occurs at all three anatomical locations investigated. This suggests that apart from the thalamic burst firing mode, additional mechanisms must exist for the enlargement of the AEP during EEG-synchronized states at the prethalamic and cortical level.

Proton magnetic resonance spectroscopy of fetal lamb brain during hypoxia.

Proton magnetic resonance spectroscopy of fetal lamb brain was performed simultaneously with repeated measurements of fetal arterial oxygen saturation during decrease of oxygen supply. Magnetic resonance spectra displayed the same metabolite peaks as detected in the human fetal brain. Cerebral lactate signals could be detected during fetal hypoxia.