Load- and practice-dependent increases in cerebro-cerebellar activation in verbal working memory: an fMRI study Matthew P. Kirschen, a,b S.H. Annabel Chen, a Pamela Schraedley-Desmond, a and John E. Desmond a,b, * a Department of Radiology, Stanford University School of Medicine, Stanford, CA 94305, USA b Neurosciences Program, Stanford University School of Medicine, Stanford, CA 94305, USA Received 24 April 2004; revised 23 August 2004; accepted 25 August 2004 Available online 13 November 2004 Load-dependent and practice-related changes in neocortical and cerebellar structures involved in verbal working memory (VWM) were investigated using functional MRI (fMRI) and a two alternative forced choice Sternberg paradigm. Using working memory loads ranging from 2 to 6 letters, regions exhibiting linear and quadratic trends in load-dependent activations were identified. Behaviorally, reaction time measurements revealed significant linear increases with increasing memory load, and significant decreases with increased task practice. Brain activations indicated a preponderance of linear load-dependent responses in both superior (lobule VI/Crus I) and inferior (lobule VIIB/ VIIIA) cerebellar hemispheres, as well as in areas of neocortex including left precentral (BA 6), inferior frontal (BA 47), para- hippocampal (BA 35), inferior parietal (BA 40), cingulate (BA 32), and right inferior and middle frontal (BA 46/47) regions. Fewer voxels exhibited quadratic without linear trends with the most prominent of these activations located in left inferior parietal (BA 40), precuneus, and parahippocampal regions. Analysis of load  session interactions revealed that right inferior cerebellar and left inferior parietal activations increased with practice, as did the correlations between activation in each region with reaction time, suggesting that changes in this cerebro-cerebellar network underlie practice-related increases in efficiency of VWM performance. These results replicate and extend our previous findings of fMRI activation in the cerebellum during VWM, and demonstrate predominately linear increases in cerebro-cerebellar activation with increasing memory load as well as changes in network function with increased task proficiency. D 2004 Elsevier Inc. All rights reserved. Keywords: fMRI; Cerebellum; Verbal working memory; Neuroimaging; Task practice; Cerebro-cerebellar networks; Memory load Introduction The cerebellum is an intricate structure that has traditionally been thought of as primarily responsible for motor control functions (e.g., muscle coordination) and balance. Although cognitive deficits have been associated with cerebellar damage since the early 1800s (Schmahmann, 1997), the role of the cerebellum in cognitive circuitry has not been thoroughly studied until the past decade. Recent clinical studies have demonstrated various cognitive deficits with a variety of cerebellar pathologies including neurodegenerative syndromes (Botez-Marquard and Botez, 1997), cerebellar tumors (Fiez et al., 1992; Silveri et al., 1994), genetic diseases (Burk et al., 2003; Wang et al., 1992), substance abuse (Desmond et al., 2003), and traumatic brain injury (McCrea et al., 2002). Schmahmann and Sherman (1997; 1998) proposed a cerebellar cognitive affective syndrome based on patients with disease confined to the cerebellum that included deficits of executive functioning, spatial memory, cognition, language, and personality changes. Although the interpretation of these clinical studies might be clouded by extra-cerebellar involve- ment (Daum et al., 1993), neuroimaging and neurophysiological studies have also shown cerebellar activation during cognitive tasks (Desmond and Fiez, 1998), substantiating the claim that cerebellar function extends beyond sensory–motor function into the cognitive domain. The present functional magnetic resonance imaging (fMRI) study is designed to study the contribution of the cerebellum to a specific cognitive process, verbal working memory (VWM), with increasing memory load and task practice. VWM is the temporary storage and manipulation of units of information in memory, allowing the brain to perform higher cognitive functions such as language comprehension and reasoning. Behaviorally, the relation- ship between VWM load and reaction time (RT) has been shown to be linear (Sternberg, 1966). Desmond et al. (1997) proposed a model of the cerebro- cerebellar circuitry underlying VWM in which both the superior and inferior cerebellar hemispheres provide supportive processing to enhance efficiency of neocortical functions through a feed- 1053-8119/$ - see front matter D 2004 Elsevier Inc. All rights reserved. doi:10.1016/j.neuroimage.2004.08.036 * Corresponding author. Department of Radiology, Stanford University School of Medicine, Lucas MRS Imaging Center, 1201 Welch Road, MC: 5488, Stanford, CA 94305-5488. Fax: +1 650 723 5795. E-mail address: jdesmond@stanford.edu (J.E. Desmond). Available online on ScienceDirect (www.sciencedirect.com). www.elsevier.com/locate/ynimg NeuroImage 24 (2005) 462 – 472