Altered frontostriatal coupling in pre-manifest HuntingtonÕs disease: effects of increasing cognitive load R. C. Wolf a , F. Sambataro b , N. Vasic a , C. Scho ¨ nfeldt-Lecuona a , D. Ecker c and B. Landwehrmeyer c a Department of Psychiatry and Psychotherapy III, University of Ulm, Germany; b Clinical Brain Disorders Branch, Genes Cognition and Psychosis Program, National Institute of Mental Health, National Institutes of Health, Bethesda, MD, USA; and c Department of Neurology, University of Ulm, Ulm, Germany Keywords: cognition, HuntingtonÕs disease, prefrontal cortex, pre-symptomatic, psychophysiological interactions Received 5 May 2008 Accepted 26 June 2008 Background and purpose: Functional neuroimaging studies have suggested a dys- function of prefrontal regions in clinically pre-symptomatic individuals with the HuntingtonÕs disease (HD) gene mutation (pre-HD) during cognitive processing. The objective of this study was to test the impact of cognitive demand on prefrontal connectivity in pre-HD individuals. Methods: Sixteen healthy controls and sixteen pre-HD subjects were studied using functional MRI and a verbal working memory task with increasing cognitive load. Load-dependent functional connectivity of the left dorsolateral prefrontal cortex (DLPFC) was investigated by means of psychophysi- ological interactions. Results: In pre-HD subjects, aberrant functional connectivity of the left DLPFC was found at high working memory load levels only. Compared with healthy controls, pre-HD individuals exhibited lower connectivity strength in the left putamen, the right anterior cingulate and the left medial prefrontal cortex. Pre-HD individuals close to the onset of motor symptoms additionally exhibited lower con- nectivity strength in the right putamen and the left superior frontal cortex. The con- nectivity strength in the left putamen was associated with several clinical measures including CAG repeat length, Unified Huntington’s Disease Rating Scale motor score and predicted years to manifest symptom onset. Conclusion: These findings suggest that early prefrontal connectivity abnormalities in pre-HD individuals are modulated by cognitive demand. Introduction HuntingtonÕs disease (HD) is an autosomal dominant inherited neurodegenerative disorder that is clinically characterized by progressive motor dysfunction, psy- chiatric disturbances and cognitive dysfunction. The disease is caused by an expansion of trinucleotide repeat encoding glutamine on chromosome 4, which results in a widespread degeneration of neurons, preferentially within regions of the striatum [1]. Nevertheless, subtle alterations of cortical morphology can be already de- tected during the pre-symptomatic stage [2,3], whilst overt cortical neurodegeneration becomes evident with progression of the disorder [4]. Cognitive dysfunction is intrinsic to HD, affecting attention, visuospatial abili- ties, memory and executive function [5–7]. The earliest cognitive manifestations of the illness have been shown in subjects who carry the HD mutation, but who remain pre-symptomatic for the motor disturbances (pre- manifest HD, pre-HD). Studies examining the pattern of cognitive deficits in pre-HD individuals have shown deficits in psychomotor speed [8], attention and execu- tive processing [9,10]. Interestingly, a dysfunction of episodic [11,12] and working memory (WM) [13] has also been reported. The functional neuroanatomy underlying cognitive dysfunction in pre-HD is not well known. Indirect evidence for an association between striatal abnormal- ities and cognitive performance in pre-HD individuals has been provided by neuropsychological and meta- bolic imaging studies. For instance, a decline in verbal episodic memory performance has been shown to be associated with volume decreases in the striatum with closer proximity to the onset of manifest motor symptoms [12]. Moreover, measures of striatal dopamine receptor binding predicted executive Correspondence: Robert Christian Wolf, MD, Department of Psychiatry and Psychotherapy III, University of Ulm, Leimgrubenweg 12–14, Ulm 89075, Germany (tel.: +49-731-50061571; fax: +49-731-50061502; e-mail: christian.wolf@uni-ulm.de). This work was carried out at Department of Psychiatry and Psychotherapy III in collaboration with the Department of Neurology, University of Ulm, Ulm, Germany. 1180 Ó 2008 The Author(s) Journal compilation Ó 2008 EFNS European Journal of Neurology 2008, 15: 1180–1190 doi:10.1111/j.1468-1331.2008.02253.x