Journal of the International Neuropsychological Society (2009), 15, 383–393. Copyright © 2009 INS. Published by Cambridge University Press. Printed in the USA. doi:10.1017/S1355617709090535 383 INTRODUCTION Information processing speed impairments are among the most significant cognitive deficits observed in persons with multiple sclerosis (MS) (e.g., DeLuca et al., 2004; Denney et al., 2004; Nocentini et al., 2006). Processing speed has typically been defined as the execution time needed to carry out a cognitive task or the amount of work conducted in a certain period of time. Processing speed deficits have been reported to underlie other cognitive impairments in MS, such as working memory (DeLuca et al., 2004; Demaree et al., 1999; Lengenfelder et al., 2006) and episodic memory (Arnett, 2004; DeLuca et al., 1994; Gaudino et al., 2001), and may be related to quality of life (Barker-Collo, 2006). Despite the significant impact of processing speed in MS, the functional neural networks involved in processing speed deficits in MS have yet to be investigated. The purpose of the current study was to examine the cerebral mechanisms associated with processing speed deficits in MS using functional magnetic resonance imaging (fMRI). Processing speed impairments in MS have been assessed by several neuropsychological tests including the Paced Au- ditory Serial Addition Task (PASAT) (e.g., Archibald & Fisk, 2000; Litvan et al., 1988) and the Sternberg task (Arnett, 2004; Litvan et al., 1988). It is unclear whether poor perfor- mance on these tasks is actually a result of deficient process- ing speed, working memory, or both (Lengenfelder et al., 2006). In the current study, it was a goal to examine the neu- ral correlates associated with rapid decision making by using a modified version of the Symbol Digit Modalities Task (mSDMT) (Smith, 1982). The SDMT is a task of complex scanning and visual tracking (Shum et al., 1990), as well as processing speed with minimal working memory involve- ment, which has been consistently shown to be highly sensi- tive to processing speed impairments in MS (e.g., Henry & Beatty, 2006; Nocentini et al., 2006; Sepulcre et al., 2006). Examination of processing speed deficits in multiple sclerosis using functional magnetic resonance imaging HELEN M. GENOVA, 1, 2, 3 FRANK G. HILLARY, 4 GLENN WYLIE, 3 BART RYPMA, 5, 6 and JOHN DELUCA 1,2,3 1 Graduate School of Biomedical Sciences, University of Medicine and Dentistry of New Jersey, Newark, New Jersey 2 Department of Physical Medicine and Rehabilitation, University of Medicine and Dentistry of New Jersey, Newark, New Jersey 3 Kessler Foundation Research Center, West Orange, New Jersey 4 Department of Psychology, Pennsylvania State University, University Park, Pennsylvania 5 School of Behavioral and Brain Sciences, University of Texas—Dallas, Dallas, Texas 6 Department of Psychiatry University of Texas Southwestern Medical Center, Dallas, Texas (Received January 23, 2008; Final Revision January 11, 2009; Accepted January 12, 2009) Abstract Although it is known that processing speed deficits are one of the primary cognitive impairments in multiple sclerosis (MS), the underlying neural mechanisms responsible for impaired processing speed remain undetermined. Using BOLD functional magnetic resonance imaging, the current study compared the brain activity of 16 individuals with MS to 17 healthy controls (HCs) during performance of a processing speed task, a modified version of the Symbol Digit Modalities Task. Although there were no differences in performance accuracy, the MS group was significantly slower than HCs. Although both groups showed similar activation involving the precentral gyrus and occipital cortex, the MS showed significantly less cerebral activity than HCs in bilateral frontal and parietal regions, similar to what has been reported in aging samples during speeded tasks. In the HC group, processing speed was mediated by frontal and parietal regions, as well as the cerebellum and thalamus. In the MS group, processing speed was mediated by insula, thalamus and anterior cingulate. It therefore appears that neural networks involved in processing speed differ between MS and HCs, and our findings are similar to what has been reported in aging, where damage to both white and gray matter is linked to processing speed impairments ( JINS, 2009, 15, 383–393). Keywords: Multiple sclerosis, Processing speed, fMRI, Symbol Digit Modalities Task, Brain mapping, Cognition Correspondence and reprint requests to: Helen M. Genova, Neuropsy- chology and Neuroscience Laboratory, Kessler Foundation Research Center, 300 Executive Drive, Suite 010, West Orange, New Jersey 07052. E-mail: hgenova@kmrrec.org