Inferior Olive Research Articles

Panmedullary Edema with Inferior Olivary Hypertrophy in Bilateral Medial Medullary Infarction

Bilateral medial medullary infarction (MMI) is a rare type of stroke with poor outcomes. Inferior olivary nucleus hypertrophy results from a pathologic lesion in the Guillain-Mollaret triangle. The relationship between inferior olivary nucleus hypertrophy and the medullary lesion is obscure. To the best of our knowledge, only 1 autopsy case with unilateral medial medullary infarction that was associated with ipsilateral inferior olivary nucleus hypertrophy has been reported. We describe a rare case with acute infarction in the bilateral medial medulla oblongata accompanied by subacute bilateral inferior olivary nucleus hypertrophy and panmedullary edema. The hypertrophy appeared to have been caused by local ischemic damage to the termination of the central tegmental tract at the bilateral inferior olivary nucleus.

Accumulation of phosphorylated TDP‐43 in the CNS of a patient with Cockayne syndrome

Here, we report a case of Cockayne syndrome (CS) in a Japanese man who displayed a unique pathology of phosphorylated trans-activation response (TAR) DNA-binding protein 43 (pTDP-43) with abundant Rosenthal fibers. Many round pTDP-43-positive structures were detected throughout the CNS; however, most of them were located in two regions that also exhibited neuronal depletion: the cerebellar cortex and the inferior olivary nucleus. To a lesser extent, these aggregates were also present in the cerebellar white matter, around the subependymal regions in the brain stem, and in the spinal cord. Intraneuronal pTDP-43 inclusions were only observed in a small number of neurons in the inferior olivary nucleus. Double-label immunofluorescence revealed that many of the aggregates were localized to astrocytes. The observed distribution and the morphology of the pTDP-43-positive structures were unique and have not yet been reported. Therefore, a pTDP-43-related pathology may be implicated in CS as well as in other neurodegenerative diseases such as frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Whether the pathology of these diseases reflects a primary neurodegenerative process or a secondary reaction is not known.

An autopsy case of preclinical multiple system atrophy (MSA‐C)

Multiple system atrophy (MSA) is divided into two clinical subtypes: MSA with predominant parkinsonian features (MSA-P) and MSA with predominant cerebellar dysfunction (MSA-C). We report a 71-year-old Japanese man without clinical signs of MSA, in whom post mortem examination revealed only slight gliosis in the pontine base and widespread occurrence of glial cytoplasmic inclusions in the central nervous system, with the greatest abundance in the pontine base and cerebellar white matter. Neuronal cytoplasmic inclusions (NCIs) and neuronal nuclear inclusions (NNIs) were almost restricted to the pontine and inferior olivary nuclei. It was noteworthy that most NCIs were located in the perinuclear area, and the majority of NNIs were observed adjacent to the inner surface of the nuclear membrane. To our knowledge, only four autopsy cases of preclinical MSA have been reported previously, in which neuronal loss was almost entirely restricted to the substantia nigra and/or putamen. Therefore, the present autopsy case of preclinical MSA-C is considered to be the first of its kind to have been reported. The histopathological features observed in preclinical MSA may represent the early pattern of MSA pathology.

Contribution of olivofloccular circuitry developmental defects to atypical gaze in autism

Individuals with autism demonstrate atypical gaze, impairments in smooth pursuit, altered movement perception and deficits in facial perception. The olivofloccular neuronal circuit is a major contributor to eye movement control. This study of the cerebellum in 12 autistic and 10 control subjects revealed dysplastic changes in the flocculus of eight autistic (67%) and two control (20%) subjects. Defects of the oculomotor system, including avoidance of eye contact and poor or no eye contact, were reported in 88% of autistic subjects with postmortem-detected floccular dysplasia. Focal disorganization of the flocculus cytoarchitecture with deficit, altered morphology, and spatial disorientation of Purkinje cells (PCs); deficit and abnormalities of granule, basket, stellate and unipolar brush cells; and structural defects and abnormal orientation of Bergmann glia are indicators of profound disruption of flocculus circuitry in a dysplastic area. The average volume of PCs was 26% less in the dysplastic region than in the unaffected region of the flocculus (p<0.01) in autistic subjects. Moreover, the average volume of PCs in the entire cerebellum was 25% less in the autistic subjects than in the control subjects (p<0.001). Findings from this study and a parallel study of the inferior olive (IO) suggest that focal floccular dysplasia combined with IO neurons and PC developmental defects may contribute to oculomotor system dysfunction and atypical gaze in autistic subjects.

Progressive ataxia and palatal tremor: T1-weighted with magnetization transfer pulse hyperintensity in the inferior olivary nucleus

Progressive ataxia and palatal tremor (PAPT) is a rare distinct clinical entity characterized by symptomatic palatal tremor associated with progressive ataxia1,2. Few cases have been described in literature, and MRI findings show, in most cases, cerebellar atrophy and bilateral olivary hypertrophy with signal change1. We report a case where MRI study at 3T demonstrated marked bilateral olivary complex hyperintensity at T1, with magnetization transfer contrast pulse (MTC) sequence, which was subtle at conventional T2 and FLAIR sequences at 1,5 and [...]

Distribution of methionine-enkephalin in the minipig brainstem

We have studied the distribution of immunoreactive cell bodies and axons are containing methionine-enkephalin in the minipig brainstem. Immunoreactive axons were widely distributed, whereas the distribution of perikarya was less widespread. A high or moderate density of axons containing methionine-enkephalin were found from rostral to caudal levels in the substantia nigra, nucleus interpeduncularis, nucleus reticularis tegmenti pontis, nucleus dorsalis raphae, nucleus centralis raphae, nuclei dorsalis and ventralis tegmenti of Gudden, locus ceruleus, nucleus sensorius principalis nervi trigemini, nucleus cuneatus externalis, nucleus tractus solitarius, nuclei vestibularis inferior and medialis, nucleus ambiguus, nucleus olivaris inferior and in the nucleus tractus spinalis nervi trigemini. Immunoreactive perikarya were observed in the nuclei centralis and dorsalis raphae, nucleus motorius nervi trigemini, nucleus centralis superior, nucleus nervi facialis, nuclei parabrachialis medialis and lateralis, nucleus ventralis raphae, nucleus reticularis lateralis and in the formatio reticularis. We have also described the presence of perikarya containing methionine-enkephalin in the nuclei nervi abducens, ruber, nervi oculomotorius and nervi trochlearis. These results suggest that in the minipig the pentapeptide may be involved in many physiological functions (for example, proprioceptive and nociceptive information; motor, respiratory and cardiovascular mechanisms).

Postnatal Loss of P/Q-Type Channels Confined to Rhombic-Lip-Derived Neurons Alters Synaptic Transmission at the Parallel Fiber to Purkinje Cell Synapse and Replicates GenomicCacna1aMutation Phenotype of Ataxia and Seizures in Mice

Ataxia, episodic dyskinesia, and thalamocortical seizures are associated with an inherited loss of P/Q-type voltage-gated Ca(2+) channel function. P/Q-type channels are widely expressed throughout the neuraxis, obscuring identification of the critical networks underlying these complex neurological disorders. We showed recently that the conditional postnatal loss of P/Q-type channels in cerebellar Purkinje cells (PCs) in mice (purky) leads to these aberrant phenotypes, suggesting that intrinsic alteration in PC output is a sufficient pathogenic factor for disease initiation. The question arises whether P/Q-type channel deletion confined to a single upstream cerebellar synapse might induce the pathophysiological abnormality of genomically inherited P/Q-type channel disorders. PCs integrate two excitatory inputs, climbing fibers from inferior olive and parallel fibers (PFs) from granule cells (GCs) that receive mossy fiber (MF) input derived from precerebellar nuclei. In this study, we introduce a new mouse model with a selective knock-out of P/Q-type channels in rhombic-lip-derived neurons including the PF and MF pathways (quirky). We found that in quirky mice, PF-PC synaptic transmission is reduced during low-frequency stimulation. Using focal light stimulation of GCs that express optogenetic light-sensitive channels, channelrhodopsin-2, we found that modulation of PC firing via GC input is reduced in quirky mice. Phenotypic analysis revealed that quirky mice display ataxia, dyskinesia, and absence epilepsy. These results suggest that developmental alteration of patterned input confined to only one of the main afferent cerebellar excitatory synaptic pathways has a significant role in generating the neurological phenotype associated with the global genomic loss of P/Q-type channel function.

Whole-brain functional imaging at cellular resolution using light-sheet microscopy

Brain function relies on communication between large populations of neurons across multiple brain areas, a full understanding of which would require knowledge of the time-varying activity of all neurons in the central nervous system. Here we use light-sheet microscopy to record activity, reported through the genetically encoded calcium indicator GCaMP5G, from the entire volume of the brain of the larval zebrafish in vivo at 0.8 Hz, capturing more than 80% of all neurons at single-cell resolution. Demonstrating how this technique can be used to reveal functionally defined circuits across the brain, we identify two populations of neurons with correlated activity patterns. One circuit consists of hindbrain neurons functionally coupled to spinal cord neuropil. The other consists of an anatomically symmetric population in the anterior hindbrain, with activity in the left and right halves oscillating in antiphase, on a timescale of 20 s, and coupled to equally slow oscillations in the inferior olive.

Symptomatic palatal tremor of cortical origin due to stroke

Palatal tremor (PT) is usually considered a movement disorder that presents with recurring rhythmic contractions of the soft palate. The inferior olive shows a characteristic pseudohypertrophy secondary to brainstem lesions in the triangle of Mollaret and Guillain that interrupt dentato-olivary and tegmental pathways. We report a 35-year-old man with a history of uncontrolled hypertension who presented to the emergency department with PT after a left middle cerebral artery ischemic stroke. The diagnostic work-up consisted of brain MRI, which revealed restricted diffusion over the left frontoparietal lobes without involvement of the brainstem. During hospitalization, the patient reported two brief episodes of soft palate and base-of-the-tongue high-frequency, low-amplitude and rhythmic tremor that resolved after intravenous administration of lorazepam. A 2-hour video electroencephalogram showed no abnormalities. After initiation of levetiracetam therapy, no further spells were reported by the patient. At the 2-month follow-up, the patient had had no episodes of stereotypical PT or upper limb tremors since discharge. This report provides further evidence of the central role of the cortex in the generation of PT. The cortical origin of symptomatic palatal tremor (SPT) should be considered in patients presenting after an acute ischemic insult, particularly if there is no evidence of a brainstem lesion. Potential causes of SPT of cortical origin include focal epilepsy and diaschisis.

The inferior olivary nucleus: A postmortem study of essential tremor cases versus controls

The pathogenesis of essential tremor is poorly understood. Historically, it has been hypothesized that the inferior olivary nucleus plays an important role in the generation of tremor in essential tremor, yet a detailed, controlled, anatomic-pathological study of that brain region has yet to be conducted. A detailed postmortem study was undertaken of the microscopic changes in the inferior olivary nucleus of 14 essential tremor cases versus 15 age-matched controls at the Essential Tremor Centralized Brain Repository. A series of metrics was used to quantify microscopic neuronal and glial changes in the inferior olivary nucleus and its input and output tracts. Olivary linear neuronal density also was assessed. Cases and controls did not differ from one another with respect to any of the assessed metrics (P values ranged from 0.23 to 1.0). Olivary linear neuronal density also was similar in cases and controls (P = 0.62). Paddle-shaped neurons, a morphologic shape change in olivary neurons, which, to our knowledge, have not been previously recognized, occurred to an equal degree in essential tremor cases and controls (P = 0.89) and were correlated with several markers of neuronal loss and gliosis. A systematic postmortem study of the microscopic changes in the inferior olivary nucleus did not detect any differences between cases and controls. These data, along with positron emission tomography data, which have failed to identify any metabolic abnormality of the olive, indicate that, if the olive is involved in essential tremor, then there is no clearly identifiable structural or metabolic correlate.

Progressive ataxia and palatal tremor associated with dense pontine calcification: A unique case

Progressive ataxia and palatal tremor associated with dense pontine calcification: A unique case

Nucleo-olivary inhibition balances the interaction between the reactive and adaptive layers in motor control

In the acquisition of adaptive motor reflexes to aversive stimuli, the cerebellar output fulfills a double purpose: it controls a motor response and it relays a sensory prediction. However, the question of how these two apparently incompatible goals might be achieved by the same cerebellar area remains open. Here we propose a solution where the inhibition of the Inferior Olive (IO) by the cerebellar Deep Nuclei (DN) translates the motor command signal into a sensory prediction allowing a single cerebellar area to simultaneously tackle both aspects of the problem: execution and prediction. We demonstrate that having a graded error signal, the gain of the Nucleo-Olivary Inhibition (NOI) balances the generation of the response between the cerebellar and the reflexive controllers or, in other words, between the adaptive and the reactive layers of behavior. Moreover, we show that the resulting system is fully autonomous and can either acquire or erase adaptive responses according to their utility.

The Reciprocal Cerebellar Circuitry in Human Hereditary Ataxia

Clinicoanatomic correlation in the spinocerebellar ataxias (SCA) and Friedreich's ataxia (FRDA) is difficult as these diseases differentially affect multiple sites in the central and peripheral nervous systems. A new way to study cerebellar ataxia is the systematic analysis of the "reciprocal cerebellar circuitry" that consists of tightly organized reciprocal connections between Purkinje cells, dentate nuclei (DN), and inferior olivary nuclei (ION). This circuitry is similar to but not identical with the "cerebellar module" in experimental animals. Neurohumoral transmitters operating in the circuitry are both inhibitory (γ-aminobutyric acid in corticonuclear and dentato-olivary fibers) and excitatory (glutamate in olivocerebellar or climbing fibers). Glutamatergic climbing fibers also issue collaterals to the DN. The present study applied five immunohistochemical markers in six types of SCA (1, 2, 3, 6, 7, 17), genetically undefined SCA, FRDA, and FRDA carriers to identify interruptions within the circuitry: calbindin-D28k, neuron-specific enolase, glutamic acid decarboxylase, and vesicular glutamate transporters 1 and 2. Lesions of the cerebellar cortex, DN, and ION were scored according to a guide as 0 (normal), 1 (mild), 2 (moderate), and 3 (severe). Results of each of the five immunohistochemical stains were examined separately for each of the three regions. Combining scores of each anatomical region and each stain yielded a total score as an indicator of pathological severity. Total scores ranged from 16 to 38 in SCA-1 (nine cases); 22 to 39 in SCA-2 (six cases); 9 to 15 in SCA-3 (four cases); and 13 and 25 in SCA-6 (two cases). In single cases of SCA-7 and SCA-17, scores were 16 and 31, respectively. In two genetically undefined SCA, scores were 36 and 37, respectively. In nine cases of FRDA, total scores ranged from 11 to 19. The low scores in SCA-3 and FRDA reflect selective atrophy of the DN. The FRDA carriers did not differ from normal controls. These observations offer a semiquantitative assessment of the critical role of the DN in the ataxic phenotype of SCA and FRDA while other parts of the circuitry appear less important.

No association between polymorphisms in the glutamate transporter SLC1A2 and Parkinson's disease

Essential tremor (ET) and Parkinson disease (PD) are clearly distinct disorders. However, there is considerable clinical and pathophysiological overlap.1 ET patients are at an approximately fourfold risk to develop PD compared to population controls. Both, ET and PD, have a genetic component. For PD numerous monogenic forms are known and genome-wide-association-studies (GWAS) in sporadic patients have uncovered a number of disease associated genetic variants. For ET only two GWAS studies have been performed up to date.2, 3 In one of them we discovered an association between variants in the major glutamate reuptake transporter of the brain (EAAT2 encoded by the SLC1A gene) and ET.3 The strongest association was found for the intronic single nucleotide polymorphism (SNP) rs3794087. To investigate whether SNPs in or around the SLC1A2 gene are also associated with PD we undertook a two-part study. The study was approved by the local ethics committees and written informed consent was obtained from all participants. Firstly, we investigated the association between our ET lead SNP rs3794087 and PD in three previously described large German PD case/control samples (1798 PD patients, 1482 controls, a detailed description of the samples can be found in reference 4). Genotyping was performed using a TaqMan® assay. Association was assessed using PLINK.5 We calculated Hardy-Weinberg equilibrium (HWE, p-exclusion 95% and the SNP was in HWE. No significant p-values were obtained for rs3794087, neither in the complete sample (p=0.775), nor in the subsamples from Kiel (p=0.623), Lubeck (p=0.998) or Tubingen (p=0.766)(Table 1). Secondly, we analysed all 45 SNPs in the region of the SLC1A gene typed in the first stage sample of a large GWAS performed for PD (1713 PD patients, 3978 controls, a detailed description of the samples can be found in reference 6). All SNPs were in HWE. Two SNPs (rs12294045, p=0.034; rs3847618, p=0.035) yielded nominally significant p-values. Both p-values do not withstand Bonferroni correction for multiple testing (Bonferroni corrected alpha-level p<0.001). The ET associated lead SNP rs3794087 was excluded from the GWAS analysis because the samples are partially overlapping with the Tubingen samples from the first analysis. A list of all SNPs with allele frequencies and p-values can be found in supporting table 2. In summary, we conclude that we didn’t find any evidence for association between SNPs in the SLC1A2 gene and PD neither in our three German samples nor in the GWAS-sample which contains American and German samples. A previous GWAS identified association between SNPs in the LINGO1 gene and ET.2 Also in this case most groups, including our own, could not find association of these variants with PD.7 SLC1A2 encodes the predominant glutamate reuptake transporter EAAT2 in the brain which removes glutamate from the synaptic cleft. Interestingly EAAT2 is strongly expressed in the inferior olive, a structure implicated in rhythm generation in ET but not in the substantia nigra which is subject to neurodegeneration in PD. Therefore we hypothesize that SLC1A2 is an ET specific gene, not involved in the pathogenesis of PD. Table 1 Association results between SNP rs3794087 and PD

Solution to the inverse problem of estimating gap-junctional and inhibitory conductance in inferior olive neurons from spike trains by network model simulation

The inferior olive (IO) possesses synaptic glomeruli, which contain dendritic spines from neighboring neurons and presynaptic terminals, many of which are inhibitory and GABAergic. Gap junctions between the spines electrically couple neighboring neurons whereas the GABAergic synaptic terminals are thought to act to decrease the effectiveness of this coupling. Thus, the glomeruli are thought to be important for determining the oscillatory and synchronized activity displayed by IO neurons. Indeed, the tendency to display such activity patterns is enhanced or reduced by the local administration of the GABA-A receptor blocker picrotoxin (PIX) or the gap junction blocker carbenoxolone (CBX), respectively. We studied the functional roles of the glomeruli by solving the inverse problem of estimating the inhibitory (gi) and gap-junctional conductance (gc) using an IO network model. This model was built upon a prior IO network model, in which the individual neurons consisted of soma and dendritic compartments, by adding a glomerular compartment comprising electrically coupled spines that received inhibitory synapses. The model was used in the forward mode to simulate spike data under PIX and CBX conditions for comparison with experimental data consisting of multi-electrode recordings of complex spikes from arrays of Purkinje cells (complex spikes are generated in a one-to-one manner by IO spikes and thus can substitute for directly measuring IO spike activity). The spatiotemporal firing dynamics of the experimental and simulation spike data were evaluated as feature vectors, including firing rates, local variation, auto-correlogram, cross-correlogram, and minimal distance, and were contracted onto two-dimensional principal component analysis (PCA) space. gc and gi were determined as the solution to the inverse problem such that the simulation and experimental spike data were closely matched in the PCA space. The goodness of the match was confirmed by an analysis of variance (ANOVA) of the PCA scores between the experimental and simulation spike data. In the PIX condition, gi was found to decrease to approximately half its control value. CBX caused an approximately 30% decrease in gc from control levels. These results support the hypothesis that the glomeruli are control points for determining the spatiotemporal characteristics of olivocerebellar activity and thus may shape its ability to convey signals to the cerebellum that may be used for motor learning or motor control purposes.

Feasibility of creating a high-resolution 3D diffusion tensor imaging based atlas of the human brainstem: A case study at 11.7T

A three-dimensional stereotaxic atlas of the human brainstem based on high resolution ex vivo diffusion tensor imaging (DTI) is introduced. The atlas consists of high resolution (125-255 μm isotropic) three-dimensional DT images of the formalin-fixed brainstem acquired at 11.7 T. The DTI data revealed microscopic neuroanatomical details, allowing three-dimensional visualization and reconstruction of fiber pathways including the decussation of the pyramidal tract fibers, and interdigitating fascicles of the corticospinal and transverse pontine fibers. Additionally, strong gray-white matter contrasts in the apparent diffusion coefficient (ADC) maps enabled precise delineation of gray matter nuclei in the brainstem, including the cranial nerve and the inferior olivary nuclei. Comparison with myelin-stained histology shows that at the level of resolution achieved in this study, the structural details resolved with DTI contrasts in the brainstem were comparable to anatomical delineation obtained with histological sectioning. Major neural structures delineated from DTI contrasts in the brainstem are segmented and three-dimensionally reconstructed. Further, the ex vivo DTI data are nonlinearly mapped to a widely-used in vivo human brain atlas, to construct a high-resolution atlas of the brainstem in the Montreal Neurological Institute (MNI) stereotaxic coordinate space. The results demonstrate the feasibility of developing a 3D DTI based atlas for detailed characterization of brainstem neuroanatomy with high resolution and contrasts, which will be a useful resource for research and clinical applications.

Oculopalatal tremor

Oculopalatal tremor (OPT) is an acquired disorder resulting from the interruption of a specific brainstem circuitry, the dentato-rubro-olivary pathway or Guillain-Mollaret triangle. The recent literature on OPT and olivary hypertrophy was reviewed with specific interest regarding causes, diagnostic procedures, physiopathology and therapies. OPT is associated with inferior olivary hypertrophy, and recent findings have provided a better understanding of its intimate mechanisms. A dual-mechanism model, combining an oscillator (inferior olive) and a modulator/amplifier (cerebellum), best explains the development of OPT. Electrotonic coupling and specific Ca channels contribute to oscillations of inferior olivary nucleus neurons in OPT. Improvement of visual symptoms can be achieved with oral gabapentin or memantine. Both the neuronal circuitry and the physiopathology of OPT are now better understood. This opens up an era of specific therapy for this rare cause of disabling oscillopsia.

Topography of Inferior Olivary Neurons that Encode Canal and Otolith Inputs

Vestibular information arising from rotational head movement and that from translational head movement are detected respectively by the semicircular canal and otolith organ in the inner ear. Spatiotemporal cues are in turn processed by the vestibulo-olivo-cerebellar pathway for sensorimotor coordination, but the role of the inferior olive (IO) in this pathway remains unclear. To address whether rotational and translational movements are differentially represented in the IO, we studied the distribution pattern of IO neurons recruited into the circuitry following selective activation of receptor hair cells of the horizontal semicircular canal or the utricle in adult rats. Neurons in the beta nucleus of IO (IOβ) and dorso-medial cell column of IO were responsive to horizontal translation, but not rotation. Notably, otolith-related neurons were observable largely in the rostral IOβ. In contrast, the subnucleus A of IO (IOA), subnucleus C of IO (IOC), and dorsal cap of Kooy (IOK) were responsive to horizontal rotation, but not translation. In the IOA, these canal-related neurons were clustered in the medial portion of the subnucleus. In the IOC, canal-related neurons were skewed towards the rostral half. In the IOK, canal-related neurons were found throughout the subnucleus. These indicate that the distributions of canal- and otolith-related neurons encoding horizontal motions are clearly segregated in the IO. These discrete IO subnuclei therefore provide a topographic map for temporal and adaptive operations of sensorimotor coordination and spatial reference.

Teaching Video Neuro Images : Micronystagmus of oculopalatal tremor

Three months after brainstem hemorrhage, MRI revealed a hyperintense lesion of the left inferior olivary nucleus of a 45-year-old man (figure). The patient was completely asymptomatic, but exhibited oculopalatal tremor (OPT), rhythmic palatal oscillations, and small-amplitude vertical pendular nystagmus of the right eye, best visualized on fundus examination (see video).

Diffusion Tensor Imaging in a Child with Hypertrophic Olivary Degeneration

Hypertrophic olivary degeneration (HOD) is caused by disruptive lesions affecting components of the Guillain-Mollaret triangle (GMT). We present conventional magnetic resonance and diffusion tensor imaging (DTI) findings in a 6-year-old girl with HOD after surgery for a midbrain pilocytic astrocytoma. To our knowledge, this is the first dedicated DTI analysis of GMT in a child with HOD in the literature. In our patient, we found higher fractional anisotropy (FA) and axial diffusivity values of the inferior olivary nucleus (ION) and lower FA, but higher radial diffusivity (RD) values of all other GMT components compared to age-matched controls. Increased FA values of the ION may be explained by increased packing of white matter fibers. However, associated hyperintense T2 signal is contradictory and the association between increased FA values and hyperintense T2 signal remains unclear. Low FA and high RD values of the other GMT components likely reflect demyelination with axonal degeneration and correlate well with histopathological findings.