Imaging white matter microstructure with gradient-echo phase imaging: Is ex vivo imaging with formalin-fixed tissue a good approximation of the in vivo brain?

PURPOSE: Ex vivo imaging is a commonly used approach to investigate the biophysical mechanism of orientation-dependent signal phase evolution in white matter. Yet, how phase measurements are influenced by the structural alteration in the tissue after formalin fixation is not fully understood. Here, we study the effects on magnetic susceptibility, microstructural compartmentalization, and chemical exchange measurement with a postmortem formalin-fixed whole-brain human tissue. METHODS: A formalin-fixed, postmortem human brain specimen was scanned with multiple orientations to the main magnetic field direction for robust bulk magnetic susceptibility measurement with conventional quantitative susceptibility imaging models. White matter samples were subsequently excised from the whole-brain specimen and scanned in multiple rotations on an MRI scanner to measure the anisotropic magnetic susceptibility and microstructure-related contributions in the signal phase and to validate the findings of the whole-brain data. RESULTS: The bulk isotropic magnetic susceptibility of ex vivo whole-brain imaging is comparable to in vivo imaging, with noticeable enhanced nonsusceptibility contributions. The excised specimen experiment reveals that anisotropic magnetic susceptibility and compartmentalization phase effect were considerably reduced in the formalin-fixed white matter specimens. CONCLUSIONS: Formalin-fixed postmortem white matter exhibits comparable isotropic magnetic susceptibility to previous in vivo imaging findings. However, the measured phase and magnitude data of the fixed white matter tissue shows a significantly weaker orientation dependency and compartmentalization effect. Alternatives to formalin fixation are needed to better reproduce the in vivo microstructural effects in postmortem samples.

Human brain pathology in myotonic dystrophy type 1: A systematic review.

Brain involvement in myotonic dystrophy type 1 (DM1) is characterized by heterogeneous cognitive, behavioral, and affective symptoms and imaging alterations indicative of widespread grey and white matter involvement. The aim of the present study was to systematically review the literature on brain pathology in DM1. We conducted a structured search in EMBASE (index period 1974-2017) and MEDLINE (index period 1887-2017) on December 11, 2017, using free text and index search terms related to myotonic dystrophy type 1 and brain structures or regions. Eligible studies were full-text studies reporting on microscopic brain pathology of DM1 patients without potentially interfering comorbidity. We discussed the findings based on the anatomical region and the nature of the anomaly. Neuropathological findings in DM1 can be classified as follows: (1) protein and nucleotide deposits; (2) changes in neurons and glial cells; and (3) white matter alterations. Most findings are unspecific to DM1 and may occur with physiological aging, albeit to a lesser degree. There are similarities and contrasts with Alzheimer's disease; both show the appearance of neurofibrillary tangles in the limbic system without plaque occurrence. Likewise, there is myelin loss and gliosis, and there are dilated perivascular spaces in the white matter resemblant of cerebral small vessel disease. However, we did not find evidence of lacunar infarction or microbleeding. The various neuropathological findings in DM1 are reflective of the heterogeneous clinical and neuroimaging features of the disease. The strength of conclusions from this study's findings is bounded by limited numbers of participants in studies, methodological constraints, and lack of assessed associations between histopathology and clinical or neuroimaging findings.

Mapping the trigeminal root entry zone and its pontine fibre distribution patterns.

INTRODUCTION: Recently, an additional trigeminothalamic tract - the dorsal trigeminothalamic tract - has been described in human brainstems by our group next to the known ventral trigeminothalamic tract. As various elements of the trigeminal system are known to be organised in a somatotopic fashion, the question arose whether the fibres within the trigeminal root show specific distributions patterns in their contribution to the ventral trigeminothalamic tract and dorsal trigeminothalamic tract specifically. METHODS: This study investigated the arrangement of the fibres in the trigeminal root by combining various imaging methods in the pons of 11 post-mortem specimens. The pons were investigated by polarised light imaging (PLI) (n = 4; to quantify fibre orientation; 100 µm interslice distance), histochemical staining methods (n = 3; to visualise the internal myeloarchitecture; 60 µm) and ultra-high field, post-mortem magnetic resonance imaging (MRI) (n = 4; for tractography; 500 µm interslice distance). RESULTS: This study shows that the fibres, from the point where the trigeminal root enters the brainstem, are distinctly arranged by their contribution to the ventral trigeminothalamic tract and dorsal trigeminothalamic tract. This finding is supported by both post-mortem, ultra-high dMRI and different light microscopy techniques. CONCLUSION: The data from this study suggest that the fibres in the superior half of the root contribute mainly to the ventral trigeminothalamic tract, whereas the fibres in the inferior half mainly contribute to the dorsal trigeminothalamic tract. Such a somatotopic organisation could possibly create new insights into the anatomical origin of trigeminal neuralgia and the clinical relevance of this somatotopic organisation should therefore be further explored.

Vagus nerve stimulation for primary headache disorders: An anatomical review to explain a clinical phenomenon.

BACKGROUND: Non-invasive stimulation of the vagus nerve has been proposed as a new neuromodulation therapy to treat primary headache disorders, as the vagus nerve is hypothesized to modulate the headache pain pathways in the brain. Vagus nerve stimulation can be performed by placing an electrode on the ear to stimulate the tragus nerve, which contains about 1% of the vagus fibers. Non-invasive vagus nerve stimulation (nVNS) conventionally refers to stimulation of the cervical branch of the vagus nerve, which is made up entirely of vagal nerve fibers. While used interchangeably, most of the research to date has been performed with nVNS or an implanted vagus nerve stimulation device. However, the exact mechanism of action of nVNS remains hypothetical and no clear overview of the effectiveness of nVNS in primary headache disorders is available. METHODS: In the present study, the clinical trials that investigated the effectiveness, tolerability and safety of nVNS in primary headache disorders were systematically reviewed. The second part of this study reviewed the central connections of the vagus nerve. Papers on the clinical use of nVNS and the anatomical investigations were included based on predefined criteria, evaluated, and results were reported in a narrative way. RESULTS: The first part of this review shows that nVNS in primary headache disorders is moderately effective, safe and well-tolerated. Regarding the anatomical review, it was reported that fibers from the vagus nerve intertwine with fibers from the trigeminal, facial, glossopharyngeal and hypoglossal nerves, mostly in the trigeminal spinal tract. Second, the four nuclei of the vagus nerve (nuclei of the solitary tract, nucleus ambiguus, spinal nucleus of the trigeminal nerve and dorsal motor nucleus (DMX)) show extensive interconnections. Third, the efferents from the vagal nuclei that receive sensory and visceral input (i.e. nuclei of the solitary tract and spinal nucleus of the trigeminal nerve) mainly course towards the main parts of the neural pain matrix directly or indirectly via other vagal nuclei. CONCLUSION: The moderate effectiveness of nVNS in treating primary headache disorders can possibly be linked to the connections between the trigeminal and vagal systems as described in animals.

Nigrosome-1 on Susceptibility Weighted Imaging to Differentiate Parkinson's Disease From Atypical Parkinsonism: An In Vivo and Ex Vivo Pilot Study.

BACKGROUND: Previous case-control studies have suggested that the absence of a swallow-tail appearance in the substantia nigra on high-resolution SWI, representing nigrosome-1, has high accuracy to identify Parkinson's disease (PD). The first goal of our study was to evaluate nigrosome-1 ex vivo using optimized high-resolution susceptibility sensitive MRI. Our second goal was to evaluate its diagnostic value in vivo using a clinical 3T SWI sequence to differentiate between PD and atypical parkinsonism (AP) in a cohort of patients with early-stage parkinsonism. MATERIAL/METHODS: Case-control pilot study to evaluate nigrosome-1 ex vivo (2 PD, 2 controls), using high-resolution susceptibility sensitive sequences at 11.7 T MRI. Next, evaluation of nigrosome-1 in vivo using a clinical 3 T SWI sequence in a prospective cohort of 60 patients with early-stage parkinsonism (39 PD, 21 AP). Moreover, 12 control subjects were scanned. The bilateral substantia nigra was evaluated by two neuroradiologists for the presence, absence or indecisive presence of nigrosome-1. The discriminative power was evaluated by Receiver-Operating Characteristic. RESULTS: We identified nigrosome-1 in ex vivo control subjects. Nigrosome-1 was not identified in the ex vivo PD cases. In our prospective clinical cohort study, the AUC for the swallow-tail sign to discriminate between PD and AP was 0.56 (0.41-0.71) for reader 1 and 0.68 (0.55-0.82) for reader 2. CONCLUSIONS: The diagnostic accuracy of the swallow-tail sign was marginal to discriminate between PD and AP using our clinical 3 T SWI sequence.

Diffusion tensor characteristics of gyrencephaly using high resolution diffusion MRI in vivo at 7T.

Gyrification of the human cerebral cortex allows for the surface expansion that accommodates many more cortical neurons in comparison to other mammals. For neuroimaging, however, it forms a feature that complicates analysis. For example, it has long been established that cortical layers do not occupy the same depth in gyri and sulci. Recently, in vivo diffusion imaging has provided insights into the fibre architecture of the cortex, usually showing radial tensor orientations. This makes it relevant to investigate whether cortical diffusion tensor metrics depend on the gyral pattern. High-resolution (1mm isotropic) diffusion weighted MRI of the medial wall of the hemispheres was performed at 7 T. Diffusion data were resampled to surfaces in the cortex and underlying white matter, where the cortical surfaces obeyed the equivolume principle for cortical laminae over the cortical curvature. Diffusion tensor metrics were averaged over bins of curvature to obtain maps of characteristic patterns in the gyrus. Diffusivity, anisotropy and radiality varied with curvature. Radiality was maximal in intermediate layers of the cortex next to the crown of the gyrus, not in white matter or on the crown. In the fundus, the deep cortical layers had tangential tensor orientations. In the white matter, tensor orientation changed from radial on the crown to tangential under the banks and fundus. White matter anisotropy gradually increased from the crown to the fundus. The characteristic pattern in the gyrus demonstrated here is in accordance with ex vivo diffusion MR microscopy and histological studies. The results indicate the necessity of taking into account the gyral pattern when cortical diffusion data is analysed. Additionally, the data suggest a confound for tractography approaches when reaching the gyrus, resulting in a possible bias towards the gyral crown. The implications for mechanisms that could drive cortical folding are discussed.

Classification and localization of early-stage Alzheimer's disease in magnetic resonance images using a patch-based classifier ensemble.

INTRODUCTION: Classification methods have been proposed to detect Alzheimer's disease (AD) using magnetic resonance images. Most rely on features such as the shape/volume of brain structures that need to be defined a priori. In this work, we propose a method that does not require either the segmentation of specific brain regions or the nonlinear alignment to a template. Besides classification, we also analyze which brain regions are discriminative between a group of normal controls and a group of AD patients. METHODS: We perform 3D texture analysis using Local Binary Patterns computed at local image patches in the whole brain, combined in a classifier ensemble.We evaluate our method in a publicly available database including very mild-to-mild AD subjects and healthy elderly controls. RESULTS: For the subject cohort including only mild AD subjects, the best results are obtained using a combination of large (30×30×30 and 40×40×40 voxels) patches. A spatial analysis on the best performing patches shows that these are located in the medial-temporal lobe and in the periventricular regions. When very mild AD subjects are included in the dataset, the small (10×10×10 voxels) patches perform best, with the most discriminative ones being located near the left hippocampus. CONCLUSION: We show that our method is able not only to perform accurate classification, but also to localize dis-criminative brain regions, which are in accordance with the medical literature. This is achieved without the need to segment-specific brain structures and without performing nonlinear registration to a template, indicating that the method may be suitable for a clinical implementation that can help to diagnose AD at an earlier stage.

Tractography demonstrates dentate-rubro-thalamic tract disruption in an adult with cerebellar mutism.

A 55-year-old female is presented with transient cerebellar mutism caused by a well-circumscribed left pontine infarction due to postoperative basilar perforator occlusion. Although conventional T2 imaging shows a well-demarcated lesion confined to the pontine region, diffusion tensor imaging shows an asymmetry in fractional anisotropy in the superior cerebellar peduncle. This supports the general hypothesis that cerebellar mutism is caused by functional disruption of the dentate-rubro-thalamic tract. Correlating postoperative anatomic changes to a heterogenic clinical syndrome remains challenging, however.

Structure Tensor Informed Fiber Tractography (STIFT) by combining gradient echo MRI and diffusion weighted imaging.

Structural connectivity research in the human brain in vivo relies heavily on fiber tractography in diffusion-weighted MRI (DWI). The accurate mapping of white matter pathways would gain from images with a higher resolution than the typical ~2mm isotropic DWI voxel size. Recently, high field gradient echo MRI (GE) has attracted considerable attention for its detailed anatomical contrast even within the white and gray matter. Susceptibility differences between various fiber bundles give a contrast that might provide a useful representation of white matter architecture complementary to that offered by DWI. In this paper, Structure Tensor Informed Fiber Tractography (STIFT) is proposed as a method to combine DWI and GE. A data-adaptive structure tensor is calculated from the GE image to describe the morphology of fiber bundles. The structure tensor is incorporated in a tractography algorithm to modify the DWI-based tracking direction according to the contrast in the GE image. This GE structure tensor was shown to be informative for tractography. From closely spaced seedpoints (0.5mm) on both sides of the border of 1) the optic radiation and inferior longitudinal fasciculus 2) the cingulum and corpus callosum, STIFT fiber bundles were clearly separated in white matter and terminated in the anatomically correct areas. Reconstruction of the optic radiation with STIFT showed a larger anterior extent of Meyer's loop compared to a standard tractography alternative. STIFT in multifiber voxels yielded a reduction in crossing-over of streamlines from the cingulum to the adjacent corpus callosum, while tracking through the fiber crossings of the centrum semiovale was unaffected. The STIFT method improves the anatomical accuracy of tractography of various fiber tracts, such as the optic radiation and cingulum. Furthermore, it has been demonstrated that STIFT can differentiate between kissing and crossing fiber configurations. Future investigations are required to establish the applicability in more white matter pathways.

White matter changes in the trigeminal spinal tract in chronic migraineurs: an ex vivo study combining ultra-high-field diffusion tensor imaging and polarized light imaging microscopy.

ABSTRACT: Chronic migraine (CM) is a disabling neurologic disorder that affects approximately 2% of the general population. Neuroimaging studies show functional involvement of trigeminal structures, such as the trigeminal spinal nucleus (Sp5) in migraine. However, structural changes in the Sp5 and the afferent trigeminal spinal tract (sp5) have never been found. The aim of this study was to test the hypothesis that white matter changes in the sp5 are a key feature of brain alterations in patients with CM. We used diffusion magnetic resonance imaging and polarized light imaging of postmortem brainstem specimens from healthy controls (n = 5) and patients with CM (n = 5) to study white matter alterations in the sp5. Within the sp5, diffusion magnetic resonance imaging metrics included fractional anisotropy, mean diffusivity, axial diffusivity, and radial diffusivity values. Polarized light imaging was used to assess myelin density by a measure of the retardance values in the sp5. This study provides histological evidence that structural alterations occur in the sp5 in patients with CM as compared with healthy controls. Myelin density, as assessed by retardance values, showed to be higher, and a corresponding increase in fractional anisotropy values was observed. In addition, accompanying decreases in mean diffusivity, axial diffusivity, and radial diffusivity values were observed. This study shows that the sp5 undergoes neuroplastic changes, a feature which substantiates evidence for the hyperactivity of the Sp5 in patients with migraine. More insights are needed to observe whether these changes only occur in patients with CM.

Mixed-methods exploration of students' motivation in using augmented reality in neuroanatomy education with prosected specimens.

The use of augmented reality (AR) in teaching and studying neuroanatomy has been well researched. Previous research showed that AR-based learning of neuroanatomy has both alleviated cognitive load and was attractive to young learners. However, how the attractiveness of AR effects student motivation has not been discovered. Therefore, the motivational effects of AR were investigated in this research by the use of quantitative and qualitative methods. Motivation elicited by the GreyMapp-AR, an AR application, was investigated in medical and biomedical sciences students (n = 222; mean age: 19.7 ± 1.4 years) using the instructional measure of motivation survey (IMMS). Additional components (i.e., attention, relevance, confidence, and satisfaction) were also evaluated with motivation as measured by IMMS. Additionally, 19 students underwent audio-recorded individual interviews which were transcribed for qualitative analysis. Males regarded the relevance of AR significantly higher than females (P < 0.024). Appreciation of the GreyMapp-AR program was found to be significantly higher in students studying biomedical sciences as compared to students studying medicine (P < 0.011). Other components and scores did not show significant differences between student groups. Students expressed that AR was beneficial in increasing their motivation to study subcortical structures, and that AR could be helpful and motivating for preparing an anatomy examination. This study suggests that students are motivated to study neuroanatomy by the use of AR, although the components that make up their individual motivation can differ significantly between groups of students.

A systematic review of the proposed mechanisms underpinning pain relief by primary motor cortex stimulation in animals.

Experimental treatments for treating neuropathic pain include transcranial magnetic stimulation (TMS) and invasive electric motor cortex stimulation (iMCS) of the primary motor cortex (M1). Mechanisms of action of both methods, however, remain largely elusive. Within this paper, we focus on animal-based experiments in order to investigate the biological mechanisms that are involved in alleviating pain by use of TMS and/or iMCS. Therefore, this paper systematically reviewed the animal-based evidence on these mechanisms. Multiple online databases were systematically searched and retrieved articles were assessed using predefined inclusion and exclusion criteria. Twenty-three suitable articles were included; six on TMS and seventeen on iMCS. In general, iMCS and TMS were found to impact the primary motor cortex structure and function in animals. Furthermore, structural and functional changes within the thalamus, striatum, periaqueductal grey, rostral ventromedial medulla and dorsal horn were reported to occur. Although widespread, all areas in which structural and functional changes occurred after TMS and iMCS have been found to be interconnected anatomically. This could provide a rationale for future investigations of treating neuropathic pain by use of neuromodulation.

Neuroanatomy Learning: Augmented Reality vs. Cross-Sections.

Neuroanatomy education is a challenging field which could benefit from modern innovations, such as augmented reality (AR) applications. This study investigates the differences on test scores, cognitive load, and motivation after neuroanatomy learning using AR applications or using cross-sections of the brain. Prior to two practical assignments, a pretest (extended matching questions, double-choice questions and a test on cross-sectional anatomy) and a mental rotation test (MRT) were completed. Sex and MRT scores were used to stratify students over the two groups. The two practical assignments were designed to study (1) general brain anatomy and (2) subcortical structures. Subsequently, participants completed a posttest similar to the pretest and a motivational questionnaire. Finally, a focus group interview was conducted to appraise participants' perceptions. Medical and biomedical students (n = 31); 19 males (61.3%) and 12 females (38.7%), mean age 19.2 ± 1.7 years participated in this experiment. Students who worked with cross-sections (n = 16) showed significantly more improvement on test scores than students who worked with GreyMapp-AR (P = 0.035) (n = 15). Further analysis showed that this difference was primarily caused by significant improvement on the cross-sectional questions. Students in the cross-section group, moreover, experienced a significantly higher germane (P = 0.009) and extraneous cognitive load (P = 0.016) than students in the GreyMapp-AR group. No significant differences were found in motivational scores. To conclude, this study suggests that AR applications can play a role in future anatomy education as an add-on educational tool, especially in learning three-dimensional relations of anatomical structures.

The spatial correspondence and genetic influence of interhemispheric connectivity with white matter microstructure.

Microscopic features (that is, microstructure) of axons affect neural circuit activity through characteristics such as conduction speed. To what extent axonal microstructure in white matter relates to functional connectivity (synchrony) between brain regions is largely unknown. Using MRI data in 11,354 subjects, we constructed multivariate models that predict functional connectivity of pairs of brain regions from the microstructural signature of white matter pathways that connect them. Microstructure-derived models provided predictions of functional connectivity that explained 3.5% of cross-subject variance on average (ranging from 1-13%, or r = 0.1-0.36) and reached statistical significance in 90% of the brain regions considered. The microstructure-function relationships were associated with genetic variants, co-located with genes DAAM1 and LPAR1, that have previously been linked to neural development. Our results demonstrate that variation in white matter microstructure predicts a fraction of functional connectivity across individuals, and that this relationship is underpinned by genetic variability in certain brain areas.

Ex vivo visualization of the trigeminal pathways in the human brainstem using 11.7T diffusion MRI combined with microscopy polarized light imaging.

Classic anatomical atlases depict a contralateral hemispheral representation of each side of the face. Recently, however, a bilateral projection of each hemiface was hypothesized, based on animal studies that showed the coexistence of an additional trigeminothalamic tract sprouting from the trigeminal principal sensory nucleus that ascends ipsilaterally. This study aims to provide an anatomical substrate for the hypothesized bilateral projection. Three post-mortem human brainstems were scanned for anatomical and diffusion magnetic resonance imaging at 11.7T. The trigeminal tracts were delineated in each brainstem using track density imaging (TDI) and tractography. To evaluate the reconstructed tracts, the same brainstems were sectioned for polarized light imaging (PLI). Anatomical 11.7T MRI shows a dispersion of the trigeminal tract (tt) into a ventral and dorsal portion. This bifurcation was also seen on the TDI maps, tractography results and PLI images of all three specimens. Referring to a similar anatomic feature in primate brains, the dorsal and ventral tracts were named the dorsal and ventral trigeminothalamic tract (dtt and vtt), respectively. This study shows that both the dtt and vtt are present in humans, indicating that each hemiface has a bilateral projection, although the functional relevance of these tracts cannot be determined by the present anatomical study. If both tracts convey noxious stimuli, this could open up new insights into and treatments for orofacial pain in patients.

Post-mortem 11.7 Tesla Magnetic Resonance Imaging vs. Polarized Light Imaging Microscopy to Measure the Angle and Orientation of Dorsal Root Afferents in the Human Cervical Dorsal Root Entry Zone.

Background: Destruction of the afferents by dorsal root entry zone (DREZ) surgery may be an effective treatment of intractable neuropathic pain, though it remains a high-risk surgical intervention. Potential complications due to the lesioning of structures within the cervical spinal cord other than the DREZ can be minimized by accurate knowledge of the optimal insertion angle [i.e., the angle between the DREZ and the posterior median sulcus (PMS)]. The employed insertion angle was based on measurements between the DREZ and the PMS on post-mortem transverse slices. However, new, more sophisticated imaging techniques are currently available and are thought to yield higher spatial resolution and more accurate images. Obejctive: This article measures the angle between the DREZ and the PMS on 11.7T post-mortem magnetic resonance images and compares these findings with polarized light imaging (PLI) microscopy images of the same specimens in order to quantify fiber orientation within the DREZ. Methods: To visualize the anatomy of the cervical DREZ, magnetic resonance imaging (MRI), diffusion-weighted MRI (dMRI), probabilistic tractography, and PLI were performed on three post-mortem human cervical spinal cords at level C5-C6. The MR data was used to measure the angle between the DREZ and the PMS. MR images were complemented by probabilistic tractography results. Then, the orientation of fibers within the DREZ was quantified by use of PLI microscopy. Results: Median angle between the DREZ and the PMS, as measured on MR-images, was found to be 40.1° (ranging from 34.2° to 49.1°) and 39.8° (ranging from 31.1° to 47.8°) in the left and right hemicord, respectively. Median fiber orientation within the DREZ, as quantified by PLI, was 28.5° (ranging from 12.0° to 44.3°) and 27.7° (ranging from 8.5° to 38.1°) in the left and right hemicord, respectively. Conclusion: Our study, which provides an improved understanding of the anatomy of the DREZ, the angle between the DREZ and the PMS and the median fiber orientation within the DREZ, could contribute to safer DREZ-lesioning surgery to treat chronic neuropathic pain in the future.

Systematic Review and Neural Network Analysis to Define Predictive Variables in Implantable Motor Cortex Stimulation to Treat Chronic Intractable Pain.

Implantable motor cortex stimulation (iMCS) has been performed for >25 years to treat various intractable pain syndromes. Its effectiveness is highly variable and, although various studies revealed predictive variables, none of these were found repeatedly. This study uses neural network analysis (NNA) to identify predictive factors of iMCS treatment for intractable pain. A systematic review provided a database of patient data on an individual level of patients who underwent iMCS to treat refractory pain between 1991 and 2017. Responders were defined as patients with a pain relief of >40% as measured by a numerical rating scale (NRS) score. NNA was carried out to predict the outcome of iMCS and to identify predictive factors that impacted the outcome of iMCS. The outcome prediction value of the NNA was expressed as the mean accuracy, sensitivity, and specificity. The NNA furthermore provided the mean weight of predictive variables, which shows the impact of the predictive variable on the prediction. The mean weight was converted into the mean relative influence (M), a value that varies between 0 and 100%. A total of 358 patients were included (202 males [56.4%]; mean age, 54.2 ±13.3 years), 201 of whom were responders to iMCS. NNA had a mean accuracy of 66.3% and a sensitivity and specificity of 69.8% and 69.4%, respectively. NNA further identified 6 predictive variables that had a relatively high M: 1) the sex of the patient (M = 19.7%); 2) the origin of the lesion (M = 15.1%); 3) the preoperative numerical rating scale score (M = 9.2%); 4) preoperative use of repetitive transcranial magnetic stimulation (M = 7.3%); 5) preoperative intake of opioids (M = 7.1%); and 6) the follow-up period (M = 13.1%). The results from the present study show that these 6 predictive variables influence the outcome of iMCS and that, based on these variables, a fair prediction model can be built to predict outcome after iMCS surgery. PERSPECTIVE: The presented NNA analyzed the functioning of computational models and modeled nonlinear statistical data. Based on this NNA, 6 predictive variables were identified that are suggested to be of importance in the improvement of future iMCS to treat chronic pain.

Long-term effect of motor cortex stimulation in patients suffering from chronic neuropathic pain: An observational study.

BACKGROUND: Motor cortex stimulation (MCS) was introduced as a last-resort treatment for chronic neuropathic pain. Over the years, MCS has been used for the treatment of various pain syndromes but long-term follow-up is unknown. METHODS: This paper reports the results of MCS from 2005 until 2012 with a 3-year follow-up. Patients who suffered from chronic neuropathic pain treated with MCS were studied. The analgesic effect was determined as successful by decrease in pain-intensity on the visual analog scale (VAS) of at least 40%. The modifications in drug regimens were monitored with use of the medication quantification scale (MQS). Stimulation parameters and complications were also noted. Interference of pain with quality of life (QoL), the Quality of Life Index (QLI), was determined with use of a specific subset of questions from the MPQ-DLV score. RESULTS: Eighteen patients were included. Mean pre-operative VAS changed from 89.4 ± 11.2 to 53.1 ± 25.0 after three years of follow-up (P < 0.0001). A successful outcome was achieved in seven responders (38.9%). All patients in the responder group suffered from pain caused by a central lesion. With regard to all the patients with central pain lesions (n = 10) and peripheral lesions (n = 8), a significant difference in response to MCS was noticed (P = 0.002). MQS scores and QLI-scores diminished during the follow-up period (P = 0.210 and P = 0.007, respectively). CONCLUSION: MCS seems a promising therapeutic option for patients with refractory pain syndromes of central origin.

New Insights in Trigeminal Anatomy: A Double Orofacial Tract for Nociceptive Input.

Orofacial pain in patients relies on the anatomical pathways that conduct nociceptive information, originating from the periphery towards the trigeminal sensory nucleus complex (TSNC) and finally, to the thalami and the somatosensorical cortical regions. The anatomy and function of the so-called trigeminothalamic tracts have been investigated before. In these animal-based studies from the previous century, the intracerebral pathways were mapped using different retro- and anterograde tracing methods. We review the literature on the trigeminothalamic tracts focusing on these animal tracer studies. Subsequently, we related the observations of these studies to clinical findings using fMRI trials. The intracerebral trigeminal pathways can be subdivided into three pathways: a ventral (contralateral) and dorsal (mainly ipsilateral) trigeminothalamic tract and the intranuclear pathway. Based on the reviewed evidence we hypothesize the co-existence of an ipsilateral nociceptive conduction tract to the cerebral cortex and we translate evidence from animal-based research to the human anatomy. Our hypothesis differs from the classical idea that orofacial pain arises only from nociceptive information via the contralateral, ventral trigeminothalamic pathway. Better understanding of the histology, anatomy and connectivity of the trigeminal fibers could contribute to the discovery of a more effective pain treatment in patients suffering from various orofacial pain syndromes.

Generalized synchronization of MEG recordings in Alzheimer's Disease: evidence for involvement of the gamma band.

The purpose of this study was to investigate interdependencies in whole-head magnetoencephalography (MEG) of Alzheimer patients and healthy control subjects. Magnetoencephalograms were recorded in 20 Alzheimer patients (11 men; mean age, 69.0 years [standard deviation, 8.2 years]); Mini-Mental State Examination score, 21.3 points; range, 15 to 27 points) and 20 healthy control subjects (9 men; mean age, 66.4 years [standard deviation, 9.0 years]) during a no-task eyes-closed condition with a 151 channel whole-head MEG system. Synchronization likelihood (a new measure for linear as well as nonlinear interdependencies between signals) and coherence were computed for each channel in different frequency bands (2 to 6, 6 to 10, 10 to 14, 14 to 18, 18 to 22, 22 to 40 Hz). Synchronization was lower in Alzheimer patients in the upper alpha band (10 to 14 Hz), the upper beta band (18 to 22 Hz), and the gamma band (22 to 40 Hz). In contrast, coherence did not show significant group differences at the p<0.05 level. The synchronization likelihood showed a spatial pattern (high synchronization central, parietal and right frontal; low synchronization, occipital and temporal). This study confirms a widespread loss of functional interactions in the alpha and beta bands, and provides the first evidence for loss of gamma band synchronization in Alzheimer's disease. Synchronization likelihood may be more sensitive to detect such changes than the commonly used coherence analysis.