Neuroimaging Advances in Amyotrophic Lateral Sclerosis
Further differences in cortical pattern activation in fMRI have been observed in ALS patients during processing of socio-emotional and sensory stimuli.40,41
sensory stimuli supported earlier findings of EEG studies42 supported by findings of structural changes measured by DTI.41
Future Perspectives
Differences in functional processing of and were Future
studies will highlight other changes in non-motor pathways in ALS with no obvious clinical equivalent. Neuroimaging can provide keys to the understanding of the overall pathological changes in the course of ALS.
Current Status
Neuroimaging is a clinical tool with a great deal of potential, although its clinical application of functional neuroimaging with respect to ALS remains speculative. To summarise, non-invasive structural and functional brain imaging substantially adds to our understanding of the pathophysiology of ALS. Structural neuroimaging is currently able to support the clinical diagnosis of ALS in routine clinical practice. However, work is in progress to improve the feasibility and quality and therefore the predictive value of this technique for ALS diagnosis and prognosis. There is increasing evidence that functional changes beyond the primary motor network exist in ALS, i.e. in frontal areas. The functional involvement of visual, auditory and somatosensory cortical areas seems to be associated with ALS, although anatomical and clinical evidence of dysfunction of sensory processing is limited. Whether these functional changes will be of diagnostic relevance in the future or whether they are instead an epiphenomenon evident in certain patients, in which case occurrence may depend on selection bias in studies, is unknown. Further research, for example using functional imaging, is necessary.
The clinical implications of structural neuroimaging are undoubted, but in the case of functional studies the implications remain controversial. The lack of sufficient standardisation hampers the comparability of studies. General guidelines for neuroimaging studies in the clinical setting would be helpful. Functional studies may define the heterogeneity of cognitive/extramotor changes in ALS and related conditions. However, the diagnostic relevance of imaging results may be limited by individual anatomical and functional differences, and this in turn may limit the use of functional imaging as a diagnostic marker. A further limitation to the clinical application of fMRI is the cost of the procedure to the patient and to the overall health service budget. A thorough cost–benefit analysis is a prerequisite for any clinical application.
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The pharmaceutical industry and clinical researchers are still looking for an objective biomarker of disease progression or functional improvement to determine the efficacy of disease-modifying agents.23 Structural and spectroscopic non-invasive imaging techniques have been discussed as promising candidates.43,44
In the future, functional
imaging technigues such as fMRI might add to this field as potential in vivo progress markers.45
In the future, it can be expected that more
studies will combine structural and functional neuroimaging in the same patient cohort. The two techniques complement one another. Degradation of, for example, ascending and descending pathways of white-matter fibres (measured by DTI) may cause disruption of cerebral function (measured by fMRI). Cortical volume loss (measured by VBM) may cause changes in cortical network functioning (again measured by fMRI). Combined non-invasive neuroimaging techniques may be useful tools to assess prognosis and study rehabilitation strategies for ALS patients. However, the combination of structural and functional imaging techniques requires careful interpretation of findings. Co-existence of changes on a structural and functional level does not automatically imply causality. Lack of evidence for functional or structural disruption does not imply that findings on the other level are not trustworthy and should be regarded as false-positives. Acquisition and analysis methods strongly influence results and outcomes. Overall, neuroimaging may in the future extend its use as a tool in clinical diagnosis and as a biomarker of disease progression and efficacy of therapeutic treatment. The matter of preservation of cognitive functions in the course of ALS is a key issue in the discussion of life-sustaining treatments in ALS patients. An improved understanding of structural and functional changes in ALS is a prerequisite for providing adequate treatment to ALS patients at any stage of the disease, and neuroimaging may help us to achieve this objective. n
Dorothée Lulé is a Senior Research Scientist in the Department of Neurology at the University of Ulm. Prior to this she was a Post-doctoral Research Associate with the Coma Research Group of Liège (Belgium) and with the Department of Psychology from the University of Würzburg. Her main academic interests are in the design and interpretation of fMRI trials in neurological and psychiatric disorders (especially ALS). Among others, she investigates how alterations on cortical level
may affect cognitive function, affective state and quality of life. Dr Lulé obtained her first PhD at the Medical Psychology from the University of Tübingen and her second PhD from the International Graduate School of Molecular Medicine.
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