fMRI evidence of brain reorganization during attention and memory tasks in multiple sclerosis
Introduction
Dysfunction of higher cognitive abilities is a frequent finding in patients with multiple sclerosis (MS) Beatty et al., 1990, Heaton et al., 1985, Peyser et al., 1980. The estimated prevalence ranges from 30% to 70% Heaton et al., 1985, Rao et al., 1991. Neuropsychological impairment in MS typically consists of deficits in memory, attention and speed of information processing.
Whereas detailed information is available on the neuropsychological profile of MS-related cognitive dysfunction, less is known about its pathophysiology. Although previous studies have shown that the extent and severity of the macroscopic and microscopic brain changes seen on conventional and non-conventional magnetic resonance imaging (MRI) are related to neuropsychologic measures of cognitive performance in MS Comi et al., 1995, Huber et al., 1992, Rovaris et al., 2002, Swirsky-Sacchetti et al., 1992, van Buchem et al., 1998, MRI findings leave cognitive dysfunction in MS largely unexplained.
Useful information on MS-related cognitive decline has come from functional imaging studies including positron emission tomography (PET) and single photon emission computed tomography (SPECT) showing a relation between reduced cerebral blood flow and metabolism in specific brain areas and cognitive dysfunction Blinkenberg et al., 2000, Brooks et al., 1984, Paulesu et al., 1996, Pozzilli et al., 1991. These studies, however, have assessed cerebral blood flow or metabolism at rest, when neural activity does not necessarily correspond to task-related neural activity. Cognitive behavior is tested in a separate session using clinical tests that have poor neuroanatomic specificity, and then compared with indices of brain function over large brain regions, resulting in modest imaging–behavior relations.
Changes in brain activity related to specific cognitive tasks can also be studied with blood oxygenation level dependent (BOLD) functional MRI (fMRI), a technique with relatively high spatial and temporal resolution. An fMRI study on patients with recently diagnosed MS has described altered cortical activation during a sustained attention task (Staffen et al., 2002). The investigators interpreted this activation pattern, accompanied by intact neuropsychological performance, as a compensatory mechanism, expression of neuronal plasticity during the early stages of the disease. Altered brain activation patterns have also been found in patients with MS and reduced attentional performance (Penner et al., 2001). This study nevertheless gave no information on the relationship between brain functional changes and the extent of macroscopic brain lesions (disease burden) in MS. Others failed to find a correlation between brain functional changes during the counting Stroop test in patients with MS and the whole brain matter lesion load or the regional lesion load. In contrast, they found a relation between activation changes in the prefrontal cortices and brain atrophy (Parry et al., 2003). Several fMRI data on motor function have showed a strong correlation between the extent of changes in fMRI activation and the MRI lesion burden, suggesting that functional changes in cortical and subcortical motor-related areas can limit impairment secondary to brain damage in MS Pantano et al., 2002a, Pantano et al., 2002b, Reddy et al., 2002, Rocca et al., 2002.
In this study, using fMRI, we investigated multiple cognitive functions including sustained attention, information processing speed, working memory and memory retrieval in patients with relapsing-remitting MS (RRMS) with no or mild overall cognitive impairment. We compared activation patterns during the Paced Auditory Serial Addition Test (PASAT) and a recall task, in patients and matched healthy subjects. We also determined whether fMRI activation changes in patients depended on the extent of macroscopic brain tissue damage as measured on conventional MRI.
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Subjects
Twenty-two right-handed patients with RRMS (Lublin and Reingold, 1996) (14 women and 8 men aged between 22 and 50 years, median age 30.5; median disease duration 9 years, range 1–16) participated in the study. Inclusion criteria were the following: no or mild overall cognitive impairment defined as a Mini Mental Status Examination (MMSE) (Folstein et al., 1975) score higher than 26; no concomitant therapy with antidepressant, psychoactive or corticosteroid drugs; no history of alcohol or drug
Neuropsychological and conventional MRI data
In our population of 22 patients, neither the SDMT nor the WLG scores differed significantly from the corresponding scores in controls. But patients had significantly lower scores at the SRT, SPART, and PASAT (Table 1).
When we used the cut-off scores obtained from healthy subjects, of the 22 patients, 14 (63.6%) had an impairment of the SRT; 11 (50%) of the SPART; 10 (45.4%) of the PASAT 2 s; 9 (40.9%) of the SDMT; and 5 (22.7%) of the WLG. Of the 22 patients, 4 therefore had no cognitive
Discussion
Consistent with previous studies, despite their mild clinical disability, most of the patients with MS we studied (18 of 22) had cognitive impairment Amato et al., 1995, van den Burg et al., 1987. Only four patients showed no cognitive dysfunction. In contrast with others, we found no significant correlation between neuropsychological measures and disease burden as measured by T2LL Rao et al., 1989b, Sperling et al., 2001, Swirsky-Sacchetti et al., 1992. One explanation for this finding is our
Acknowledgements
We thank Professors Cesare Fieschi and Gian Luigi Lenzi for their continuous support, and Valter Nucciarelli for his technical assistance.
This work was supported by MURST “Progetto Giovani Ricercatori” and Ministero della Salute (RF01.167), Italy.
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