Introduction Patients with dorsolateral prefrontal cortex (DLPFC) lesions commonly experience deficits on CR tasks that involve maintaining or shifting hypotheses in working memory in response to feedback. 1–4 Similar executive function deficits have been detected in patients with subcortical lesions involving the basal ganglia, 5,6 thalamus 7,8 and cerebellum. 9–11 These lesion studies suggest that common, yet apparently disparate, neural systems may mediate CR task performance. Non-human primate studies have demonstrated the existence of multiple parallel frontal-subcortical circuits. 12 One such circuit involving the DLPFC, basal ganglia (caudate nucleus) and thalamus (ante- rior and mediodorsal nuclei) has been implicated in such complex behaviors as working memory and rule-based learning. 13 More recently, anatomical interconnections have been demonstrated between the DLPFC and the lateral cerebellum via the ventral segment of the dentate nucleus and the mediodorsal nucleus of the thalamus. 14 The present study was designed to examine the possible participation of these frontal-subcortical circuits in intact humans while performing a CR task. Whole-brain fMRI was used to detect regional changes in blood oxygenation associated with increased neural activity. 15,16 In clinical settings, CR is typically assessed with the Wisconsin Card Sorting Task (WCST). The WCST can not be easily adapted to fMRI scanning, since problem solving does not occur in response to a finite number of time-locked stimulus presentations. Additionally, the ratio of positive to negative feedback is not fixed across subjects and the solutions are defined a priori in a fixed order, thereby creating problems for repeat testing. To circumvent these limitations, we used an alternative task 17 with demonstrated sensitivity to CR deficits in patients with prefrontal 2 and basal ganglia 5,18 lesions. Subjects and Methods Eleven normal volunteers (four males and seven females; ages 19–45 years, mean 29 years; mean education 16.5 years) participated in the study. All subjects were strongly right-handed (mean laterality quotient 87.8 on the Edinburgh Handedness Inventory 19 ). Potential subjects were excluded if they Brain Imaging 1 1 1 1 1 p © Rapid Science Publishers Vol 8 No 8 27 May 1997 1987 LESIONS involving the dorsolateral prefrontal lobes may produce deficits on conceptual reasoning (CR) tasks in humans. Such deficits can also occur with subcortical lesions involving the basal ganglia, thalamus, or cere- bellum, suggesting a common, yet widespread, neural network supporting this executive function. Here we report the results of a whole brain functional magnetic resonance imaging (fMRI) experiment in healthy volun- teers while performing a CR task. Compared to a senso- rimotor control condition, the CR task resulted in discrete subcortical activation sites primarily involving the right basal ganglia, right thalamus and left lateral cerebellum. Cortical activation was present in multiple systems, including the dorsolateral prefrontal and infe- rior frontal/insular areas; posterior parietal, superior extrastriate, and premotor areas; inferior extrastriate and middle temporal regions; and midline pre-supple- mentary motor and anterior cingulate regions. Our find- ings provide strong evidence that CR is mediated by interacting neural systems involving the cerebral cortex, basal ganglia, thalamus, and cerebellum. Key words: Basal ganglia; Cerebellum; Conceptual reasoning; Functional magnetic resonance imaging (fMRI); Parietal cortex; Prefrontal cortex; Thalamus Functional MRI evidence for subcortical participation in conceptual reasoning skills Stephen M. Rao, 1,2,3,4,CA Julie A. Bobholz, 1 Thomas A. Hammeke, 1,3 Allyson C. Rosen, 1 Scott J. Woodley, 1 Joseph M. Cunningham, 1 Robert W. Cox, 4 Elliot A. Stein, 3,4 and Jeffrey R. Binder 1,2,4 Departments of 1 Neurology, 2 Cellular Biology and Anatomy, and 3 Psychiatry and Behavioral Medicine, and 4 Biophysics Research Institute, Medical College of Wisconsin, 9200 West Wisconsin Avenue, Milwaukee, WI 53226, USA CA,1 Corresponding Author and Address NeuroReport 8, 1987–1993 (1997)