The Symbol Digit Modalities Test is an easy test used to assess cognitive impairment in a wide range of neurological diseases, like multiple sclerosis. We adapted the oral version of this cognitive task making it suitable for functional Magnetic Resonance Imaging studies. Symbol Digit Modalities Test performance was associated with increased brain activity in frontal and parietal areas involved in selective attention and working memory functions. These may provide the basis for future studies assessing potential abnormal cortical activations in multiple sclerosis patients and other clinical populations.