Caudate nucleus: influence of dopaminergic input on sequence learning and brain activation in Parkinsonism
Introduction
Cognitive deficits in non-demented Parkinson's disease (PD) patients have been reported to affect various domains such as executive strategies, visuomotor processing and working memory Cooper et al., 1991, Ghilardi et al., 2003, Pillon et al., 1989, Taylor et al., 1990. Neuropsychological assessment (Brown and Marsden, 1990) and imaging studies Cools et al., 2002, Mattay et al., 2002, Nakamura et al., 2001, Owen et al., 1998 have generally attributed cognitive decline in PD to frontal lobe dysfunction, although specific cognitive deficits have also been associated with temporo-parietal dysfunction Mentis et al., 2002, Mohr et al., 1992. Proposed mechanisms of frontal impairment in PD include direct effects of reduced dopaminergic input to frontal cortex Mattay et al., 2002, Ouchi et al., 1999, Scatton et al., 1982, as well as indirect effects of striatal dopamine loss on the function of downstream nodes of the cortico-striato-pallido-thalamocortical (CSPTC) loops and related pathways Carbon et al., 2003, Middleton and Strick, 2002, Wichmann and DeLong, 1996. Non-dopaminergic mechanisms have also been implicated, with involvement of cholinergic Agid et al., 1984, Rinne et al., 1991 and noradrenergic systems Marié et al., 1995, Stern et al., 1984. The heterogeneity of observations may result from the effects of disease stage and task variation in the assessment of cognitive dysfunction in PD Cools et al., 2001, Kulisevsky, 2000. As one example of cognitive tasks that are impaired in PD (Brown and Marsden, 1990), sequence learning involves caudate nucleus function Aldridge and Berridge, 1998, Brown et al., 2003, Kermadi and Joseph, 1995, Nakamura et al., 2001, Saint-Cyr, 2003 and was therefore chosen to serve as a cognitive paradigm in this study.
In the current study, we propose a novel approach to separate possible co-existent mechanisms related to sequence learning in PD. We designed this study to focus on the relationship between striatal dopaminergic innervation and the activity of higher order CSPTC circuitry during sequence learning. The caudate nucleus plays a key role in the processing of sequential information Aldridge and Berridge, 1998, Brown et al., 2003, Kermadi and Joseph, 1995, Nakamura et al., 2001, Saint-Cyr, 2003. However, contrary to the performance of sequenced movements during which dopamine release has been reported (Goerendt et al., 2003), it is unknown whether dopaminergic neurotransmission is the key factor in the cognitive processing of sequential spatial information, or whether aspects of striatal functioning apart from dopaminergic innervation determine brain activation and performance during sequence learning. Substantial evidence from studies in primates and human subjects supports a crucial role of dopaminergic transmission in normal cognition Desimone, 1995, Ghilardi et al., 2003, Goldman-Rakic, 1998, Kimberg et al., 2001, Mehta et al., 1999, Mehta et al., 2001, Mozley et al., 2001, Müller et al., 1998, Verhoeff et al., 2001. Moreover, sequential processing Brooks, 2001, Brown and Marsden, 1990, Shipley et al., 2002, Westwater et al., 1998, particularly the initial acquisition of information Cooper and Sagar, 1993, Taylor et al., 1990, is impaired in PD. In summary, this body of knowledge from different studies suggests that there may be an interaction of the dopaminergic modulation exerted by nigro-striatal projections on the caudate nucleus, leading to downstream changes in cortical functions as well as changes in cognitive functions, such as sequence learning performance. Thus, we hypothesized that (1) the acquisition of sequential information is related to the integrity of dopaminergic input to the caudate nucleus; and (2) the integrity of dopaminergic input to the caudate nucleus correlates significantly with brain activation responses during sequence learning. To examine this hypothesis, we used a novel dual tracer PET imaging approach to assess dopaminergic integrity and regional cerebral blood flow (rCBF) in PD patients and healthy controls. We used the imaging data to test our hypotheses by correlating striatal dopamine transporter (DAT) binding measures with learning performance indices and with concurrent regional activation responses.
Section snippets
Materials and methods
Twelve PD patients and six healthy controls underwent PET imaging with both [18F]fluoropropyl-βCIT (FPCIT) and 15O labeled water (H215O) to determine the relationship of striatal DAT binding and motor sequence learning and associated brain activation responses.
Learning performance
ACQ performance measured during H215O PET did not differ significantly in the PD and normal volunteer groups (P > 0.5). The mean ACQ index was 3.5 ± 0.6 (mean ± SE) for PD patients and 3.3 ± 1.2 for controls. ACQ indices were not different for the left and right hemiparkinsonian cohorts (left hemiparkinsonian 3.4 ± 0.9; right hemiparkinsonian 3.8 ± 0.8; P > 0.5).
Striatal DAT binding
Striatal DAT binding was compared across groups. We found that mean (left–right averaged) putamen SOR was reduced by 42.6% in PD
Discussion
This combined behavioral and multitracer PET study is the first to demonstrate the specific relationship between dopaminergic input to the caudate nucleus and sequence learning performance in early stage PD patients. We identified corresponding relationships between caudate dopaminergic function and learning-related brain activation responses in these patients and in age-matched controls. In normal subjects, caudate DAT binding predicted activation during learning in major cortical and
Conclusions
Our findings indicate that dopaminergic input to the caudate nucleus is associated with the activity of brain circuits linked to cognitive functioning in health and early PD. In normal subjects, caudate dopaminergic integrity is correlated with thalamic, midbrain, and prefrontal activation responses during sequence learning. These relationships are partially lost in early stage PD, with the dorsal and ventral lateral prefrontal cortex remaining linked to caudate dopaminergic input. The
Acknowledgements
This work was supported by NIH RO1 NS 35069 and NIH P50 NS 38370. Dr. Carbon was supported by the Veola T. Kerr Fellowship of the Parkinson Disease Foundation. Dr. Eidelberg was supported by NIH K24 NS 02101 and Dr. Ghilardi was supported by NIH KO8 NS 01961. The authors thank Dr. Lucy L. Brown for her valuable contributions in functional anatomical discussions. We additionally extend thanks to Mr. Sherwin Su and Ms. Loreta Palazzo for editorial assistance. We acknowledge the valuable technical
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