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tently overestimate the correlation between physical disablity and cognitive impairment in MS patients.56

While some studies report that cognitive function is independent of fatigue,63,180 others raise the possibility that they might be caused by a disruption of the same neural circuits (see Fischer 2000 for discussion). Depression is generally not strongly related to overall cognitive function. One study of 20 MS patients found that cognitive deficits (attention, visuomotor search, and verbal fluency) were independent of depressive symptoms.96 Of these, only frontal function impairment was correlated with depression. However, only 4 percent had significant depression scores, and all of these had secondary progressive MS.53 A cross-sectional study of 24 patients found significant association of cognitive impairment (using tests of abstract verbal and nonverbal memory) with depression, but not with the degree of neurological impairment, specific neurological symptoms, disability, or handicap.68

Neuropathological Correlates

The traditional view that MS is characterized by discrete lesions does not explain the memory and cognitive changes, which would require a more widespread, bilateral change, especially since the complaints often arise early. Recent evidence from the studies of Ian McDonald in Great Britain and Bruce Trapp in the United States indicates that the effects of demyelination and the destruction of axons occur very early in MS and are widespread. Moreover, the process undoubtedly has been going on for a long time before a person experiences the first symptom.

MRI has recently allowed speculation of localization of specific mental changes.139 Although MRI studies of MS patients have reported correlations between cognitive impairment and total lesion burden (the percentage of the brain that shows lesions on MRI scans), neuroimaging techniques have not reached the point where neuropathological changes can be linked to specific aspects of cognitive impairment (reviewed in 2000 by Rovaris and Filippi147). Research on cognitive changes in MS is still in its early stages, and most studies have been relatively small and have not followed changes in individuals. In addition, the application of techniques that allow detection of more specific neuropathological changes, particularly axonal pathology, might provide more useful insights into the causes of cognitive impairment.

Pathological Laughing and Crying

Pathological laughing and crying is a distinctive type of cognitive change that occurs in a variety of neurological disorders including stroke, amyotropic lateral sclerosis (ALS), Alzheimer's disease, cerebral tumors, and MS. The syndrome is defined as a sudden loss of emotional control—for example, laughing, crying, or both in response to nonspecific, often inconsequential stimuli for no



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