Longitudinal quantitative MRI assessment of cortical damage in multiple sclerosis: A pilot study.

PURPOSE: Quantitative MRI (qMRI) allows assessing cortical pathology in multiple sclerosis (MS) on a microstructural level, where cortical damage has been shown to prolong T1 -relaxation time and increase proton density (PD) compared to controls. However, the evolution of these changes in MS over time has not been investigated so far. In this pilot study we used an advanced method for the longitudinal assessment of cortical tissue change in MS patients with qMRI in comparison to cortical atrophy, as derived from conventional MRI. MATERIALS AND METHODS: Twelve patients with relapsing-remitting MS underwent 3T T1 /PD-mapping at two timepoints with a mean interval of 12 months. The respective cortical T1 /PD-values were extracted from the middle of the cortical layer and the cortical thickness was measured for surface-based identification of clusters with increasing/decreasing values. RESULTS: Statistical analysis showed clusters with increasing PD- and T1 -values over time (annualized rate for T1 /PD increase in these clusters: 3.4 ± 2.56% for T1 , P = 0.0007; 2.3 ± 2.59% for PD, P = 0.01). Changes are heterogeneous across the cortex and different patterns of longitudinal PD and T1 increase emerged. Analysis of the cortical thickness yielded only one small cluster indicating a decrease of cortical thickness. CONCLUSION: Changes of cortical tissue composition in MS seem to be reflected by a spatially inhomogeneous, multifocal increase of the PD values, indicating replacement of neural tissue by water, and of the T1 -relaxation time, a surrogate of demyelination, axonal loss, and gliosis. qMRI changes were more prominent than cortical atrophy, showing the potential of qMRI techniques to quantify microstructural alterations that remain undetected by conventional MRI. LEVEL OF EVIDENCE: 1 Technical Efficacy: Stage 1 J. Magn. Reson. Imaging 2017;46:1485-1490.

Spatiotemporal dynamics of bimanual integration in human somatosensory cortex and their relevance to bimanual object manipulation.

Little is known about the spatiotemporal dynamics of cortical responses that integrate slightly asynchronous somatosensory inputs from both hands. This study aimed to clarify the timing and magnitude of interhemispheric interactions during early integration of bimanual somatosensory information in different somatosensory regions and their relevance for bimanual object manipulation and exploration. Using multi-fiber probabilistic diffusion tractography and MEG source analysis of conditioning-test (C-T) median nerve somatosensory evoked fields in healthy human subjects, we sought to extract measures of structural and effective callosal connectivity between different somatosensory cortical regions and correlated them with bimanual tactile task performance. Neuromagnetic responses were found in major somatosensory regions, i.e., primary somatosensory cortex SI, secondary somatosensory cortex SII, posterior parietal cortex, and premotor cortex. Contralateral to the test stimulus, SII activity was maximally suppressed by 51% at C-T intervals of 40 and 60 ms. This interhemispheric inhibition of the contralateral SII source activity correlated directly and topographically specifically with the fractional anisotropy of callosal fibers interconnecting SII. Thus, the putative pathway that mediated inhibitory interhemispheric interactions in SII was a transcallosal route from ipsilateral to contralateral SII. Moreover, interhemispheric inhibition of SII source activity correlated directly with bimanual tactile task performance. These findings were exclusive to SII. Our data suggest that early interhemispheric somatosensory integration primarily occurs in SII, is mediated by callosal fibers that interconnect homologous SII areas, and has behavioral importance for bimanual object manipulation and exploration.

Motor callosal disconnection in early relapsing-remitting multiple sclerosis.

In relapsing-remitting multiple sclerosis (RRMS) the corpus callosum (CC) is often and early affected by macroscopic lesions when investigated by conventional MRI. We sought to determine to which extent microstructural and effective disconnection of the CC are already present in RRMS patients at the earliest stages of the disease prior to evidence of macroscopic CC lesion. We compared 16 very early RRMS patients (median expanded disability status scale (EDSS), 1.5; range, 0-2.0) to an age-matched group of healthy controls and focused analysis to the motor CC, i.e. that part of the CC relaying interhemispheric motor information. A combined functional magnetic resonance imaging/diffusion tensor imaging fiber-tracking procedure was applied to identify the callosal motor fibers (CMFs) connecting the hand areas of the primary motor cortices of the two hemispheres. Fractional anisotropy (FA) within the motor CC (FA-CC) assessed the CMF microstructural integrity. Bifocal paired transcranial magnetic stimulation (TMS) tested short-interval interhemispheric inhibition (S-IHI), an established measure of CMF effective connectivity. FA-CC and S-IHI were significantly reduced in early RRMS compared to healthy controls. Furthermore, a significant linear correlation between microstructure (FA-CC) and function (S-IHI) in the controls was broken down in the patients. These abnormalities were obtained in the absence of macroscopic CMF lesion in conventional MRI, and whilst motor hand/arm function in the nine-hole-peg test and corticospinal conduction time were normal. Findings suggest that reductions in FA and S-IHI may serve as surrogate markers of motor callosal disconnection at the earliest stages of RRMS prior to development of macroscopic lesion.

Combined (1)H and (31)P spectroscopy provides new insights into the pathobiochemistry of brain damage in multiple sclerosis.

(1)H MRSI has evolved as an important tool to study the onset and progression of brain damage in multiple sclerosis. Abnormal increases in total creatine, total choline and myoinositol have been noted in multiple sclerosis. However, the pathobiochemical mechanisms related to these changes are still largely unclear. The combination of (1)H MRSI and (1)H-decoupled (31)P MRSI can specify to what extent phosphorylated components of total creatine and total choline contribute to this increase. Combined (1)H and (31)P MRSI data were obtained at 3 T in 22 patients with multiple sclerosis and in 23 healthy controls, and aligned with structural MRI to allow for correction for partial volume effects caused by cerebrospinal fluid and lesion load. A significant increase in total creatine was found in multiple sclerosis, and this was attributed to equal changes in the phosphorylated and unphosphorylated components. The concentrations of the putative glial markers total creatine and myoinositol in lesion-free (1)H MRSI voxels correlated with the global lesion load. We conclude that changes in total creatine are not related to altered energy metabolism, but rather indicate gliosis. Together with the increase in myoinositol, total creatine can be considered as a biomarker for disease severity. A significant total choline increase was mainly a result of choline components not visible by (31)P MRS. The origin of this residual choline fraction remains to be investigated.

Ocrelizumab Treatment in Patients with Primary Progressive Multiple Sclerosis: Short-term Safety Results from a Compassionate Use Programme in Germany.

OBJECTIVES: In January 2018, the European Union (EU) approved ocrelizumab in relapsing multiple sclerosis (RMS) and as the first disease-modifying therapy (DMT) for patients with primary progressive multiple sclerosis (PPMS) with efficacy proven in a phase 3 randomised controlled trial. Eleven months prior to the European regulatory approval, a compassionate use programme (CUP) made ocrelizumab available to 489 patients with PPMS in Germany, thereby for the first time providing a therapeutic option to patients with PPMS who could not participate in ocrelizumab studies. Here, we report real-world patient characteristics and short-term safety data of patients with PPMS treated with ocrelizumab in this CUP. PATIENTS AND METHODS: This CUP was initiated in February 2017 - shortly before US Food and Drug administration approval in March 2017 - and ended in January 2018, following ocrelizumab approval in the EU. Adult patients (age ≥18 years) with PPMS who had a positive benefit/risk ratio according to the treating physician were eligible for inclusion at German treatment centres. The main exclusion criteria were current/recent treatment with other immune therapies and unresolved/chronic/active infections. Patients received methylprednisolone and an antihistamine before treatment with intravenous ocrelizumab in 6-month cycles. The first ocrelizumab dose was a 300 mg infusion followed by a second 300 mg infusion 2 weeks later; subsequent doses were delivered as a single 600 mg infusion. Adverse events were reported immediately. RESULTS: Of 580 requests received from 104 centres, 525 patients met the eligibility criteria. Thirty-five patients did not participate due to withdrawal by the treating physician, and one due to death prior to treatment. A total of 489 patients received at least one 600 mg dose of ocrelizumab (administered as two 300 mg infusions) and 51 received a second dose. Due to termination of the CUP upon marketing authorisation, the maximum follow-up period was 12 months. Median patient age was 52 years (range: 24-73), and 49% were female. Previous immunomodulatory or immunosuppressive therapies had been received by 41% of patients, with the most commonly used being glucocorticoids, mitoxantrone, interferon-ß and glatiramer acetate. Patients with a previous malignancy, serious disease or infection (42 patients, 9%) had recovered from this prior to the CUP. Nine serious adverse events and 70 non-serious adverse events were reported in 40 patients. Adverse event categories were generally consistent with the known safety profile of ocrelizumab; one patient had carry-over progressive multifocal leukoencephalopathy (PML) due to previous natalizumab treatment. CONCLUSION: This CUP provides first real-world observations of ocrelizumab for the treatment of PPMS in a large patient cohort in Germany, supporting that ocrelizumab is generally well-tolerated in clinical practice. Physicians should be vigilant for early symptoms of PML, as to date, 9 PML cases that were all confounded have been reported in patients treated with ocrelizumab worldwide, with 8 carry-over cases from a prior DMT.

Human motor corpus callosum: topography, somatotopy, and link between microstructure and function.

The corpus callosum (CC) is the principal white matter fiber bundle connecting neocortical areas of the two hemispheres. Although an object of extensive research, important details about the anatomical and functional organization of the human CC are still largely unknown. Here we focused on the callosal motor fibers (CMFs) that connect the primary motor cortices (M1) of the two hemispheres. Topography and somatotopy of CMFs were explored by using a combined functional magnetic resonance imaging/diffusion tensor imaging fiber-tracking procedure. CMF microstructure was assessed by fractional anisotropy (FA), and CMF functional connectivity between the hand areas of M1 was measured by interhemispheric inhibition using paired-pulse transcranial magnetic stimulation. CMFs mapped onto the posterior body and isthmus of the CC, with hand CMFs running significantly more anteriorly and ventrally than foot CMFs. FA of the hand CMFs but not FA of the foot CMFs correlated linearly with interhemispheric inhibition between the M1 hand areas. Findings demonstrate that CMFs connecting defined body representations of M1 map onto a circumscribed region in the CC in a somatotopically organized manner. The significant and topographically specific positive correlation between FA and interhemispheric inhibition strongly suggests that microstructure can be directly linked to functional connectivity. This provides a novel way of exploring human brain function that may allow prediction of functional connectivity from variability of microstructure in healthy individuals, and potentially, abnormality of functional connectivity in neurological or psychiatric patients.

The human motor corpus callosum.

The corpus callosum (CC) is the largest white matter fiber bundle to connect the two hemispheres of the brain. It is thought to be essential for interhemispheric transfer of information. The motor CC is that part of the CC which connects the primary motor cortices. Relatively little is known, in particular in humans, about where these fibers are located in the CC, what their function is, and how the structure of the motor CC relates to its function. This review surveys current knowledge about the human motor CC, with a focus on recent studies which assessed the motor CC by multimodal advanced neurophysiological and neuroimaging techniques.

Callosal anatomical and effective connectivity between primary motor cortices predicts visually cued bimanual temporal coordination performance.

Default in-phase coupling of hand movements needs to be suppressed when temporal coordination is required for out-of-phase bimanual movements. There is lack of knowledge on how the brain overrides these default in-phase movements to enable a required interval of activity between hands. We used a visually cued bimanual temporal coordination (vc-BTC) paradigm with a constant rhythmical time base of 1 s, to test the accuracy of in-phase and out-of-phase (0.1, 0.2,…,0.9) finger tapping. We hypothesized that (1) stronger anatomical and effective interhemispheric connectivity between the hand areas of the primary motor cortex (M1HAND) predict higher temporal offsets between hands in the out-of-phase conditions of the vc-BTC; (2) patients with relapsing-remitting multiple sclerosis (RRMS) and clinically isolated syndrome (CIS) have reduced interhemispheric connectivity and altered between-hand coupling. Anatomical connectivity was determined by fractional anisotropy of callosal hand motor fibers (FA-hCMF). Effective connectivity was probed by short interval interhemispheric inhibition (S-IHI) using paired-coil transcranial magnetic stimulation (TMS). In healthy subjects, higher FA-hCMF and S-IHI correlated with higher temporal offsets between hands in the out-of-phase conditions of the tapping test. FA-hCMF was reduced in patients with RRMS but not in CIS, while S-IHI was reduced in both patient groups. These abnormalities were associated with smaller temporal offsets between hands leading to less deviation from the required phasing in the out-of-phase tapping conditions. Findings provide multiple levels of evidence that callosal anatomical and effective connectivity between the hand areas of the motor cortices play important roles in visually cued bimanual temporal coordination performance.

Development of biomarkers for multiple sclerosis as a neurodegenerative disorder.

Multiple sclerosis (MS) is the most common neurological disorder leading to permanent disability in young adults in the developed world. While traditionally conceived as an autoimmune inflammatory disease it is becoming increasingly evident that axonal and neuronal degeneration occur, at least partly independent of inflammation, and already at the earliest stages of the disease. In addition, it is the progressive neurodegeneration which determines the amount of accumulating clinical disability. Therefore, MS should be considered as a neurodegenerative disorder. Development of disease-modifying drugs to treat MS is currently highly dynamic. Already, several drugs have shown short-term efficacy to delay progression of clinical disability, but the ultimate aim is to halt disease progression. In this context, the development of sensitive, reliable and valid biomarkers to measure neurodegeneration is an indispensible need to facilitate successful informative clinical trials. While no such biomarker is currently fully established, several promising candidate biomarkers obtained with multimodal techniques, including cerebrospinal fluid and serum analysis, neuroimaging and neurophysiology, are presently developed and evaluated. This paper compiles an up-to-date critical review of the available knowledge of candidate biomarkers of neurodegenerative processes in MS.