Mathias Wahl

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.

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

1H 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 1H MRSI and 1H‐decoupled 31P MRSI can specify to what extent phosphorylated components of total creatine and total choline contribute to this increase. Combined 1H and 31P 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 1H 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 31P MRS. The origin of this residual choline fraction remains to be investigated. Copyright

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.

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.

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. Hum Brain Mapp, 2011.

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.

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

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.

A Proposal for a Patient-Oriented Five-Dimensional Approach for Surveillance and Therapy in Multiple Sclerosis

The former and current multiple sclerosis (MS) classifications are essential for describing different phenotypes and disease dynamics. To establish personalized treatment regimes, further clinical and paraclinical parameters have to be considered such as imaging, cerebrospinal fluid (CSF) findings, past disease-modifying therapies (DMTs), and disease activity under these therapies. In clinical practice, this information is often difficult to overview. Especially, patients with a long course of disease offer an extensive medical history so that comprehending all of the necessary information can be very time consuming.

Multimodale Evaluation des somatosensorischen CC bei Gesunden und Patienten mit früher RRMS

Wir untersuchten bei 14 Probanden in einem Latenzbereich von 0–150 ms den Effekt von konditionierenden, nichtschmerzhaften, linksseitigen Stimuli des N. medianus auf die kortikale Verarbeitung nachfolgender rechtsseitiger N.-medianus-Teststimuli. Die IM-ISI betrugen 0, 5, 10, 15, 20, 40, 60 und 100 ms. Die SEF wurden mit einem 275-Kanal-MEG-Gerät aufgezeichnet. Ferner wurden intraund intermanuelle TLT der Finger sowie HOR durchgeführt. Als behaviorale Messgrößen transkallosaler somatosensorischer Prozessierung wurden CC-Indizes für TLT (Fehler im intermanuellen TaskFehler in den intramanuellen Tasks) und HOR [t[intermanuell]/(t[intramanuell RH]+t[intramanuell LH])] berechnet. Dieselben Methoden wurden bei 16 RRMS-Patienten (medianer EDSS±SD=1,0±1,2) mit normalem SEP des N. medianus und fehlenden klinischneurologischen Defiziten an beiden Armen angewendet. Ergebnisse

Kortikale Erregbarkeit und kortikokortikale Konnektivität

Die verfugbaren Protokolle zur Messung intrakortikaler und kortikospinaler Erregbarkeit des primaren motorischen Kortex mittels TMS werden im Detail in anderen Kapiteln besprochen (Kap. 5, 14–18, 34). In diesem Kapitel wird gezeigt wie diese Kennwerte kortikaler Erregbarkeit eingesetzt werden konnen, um verschiedene Funktionszustande des motorischen Kortex, z. B. vor, wahrend und nach einer Willkurbewegung, zu untersuchen.