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In this representative cross-section of migraineurs, neck pain was more commonly associated with migraine than was nausea, a defining characteristic of the disorder. Awareness of neck pain as a common associated feature of migraine may improve diagnostic accuracy and have a beneficial impact on time to treatment.

Parkinson's disease (PD) presents clinically with varying degrees of resting tremor, rigidity, and bradykinesia. For decades, striatal-thalamo-cortical (STC) dysfunction has been implied in Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. Disclosure:The authors have reported no conflicts of interest. Specific Contributions of AuthorsMechelle M. Lewis: Data acquisition, analysis, and interpretation; obtaining funding for the study, administrative support for the study; primary drafting and critical revision of the manuscript. Guangwei Du: Data analysis and interpretation, drafting and critical revision of the manuscript, Suman Sen: Data acquisition, critical revision of the manuscript. Atsushi Kawaguchi: Statistical analysis of the data and data interpretation. Young Truong: Statistical analysis of the data, data interpretation, critical revision of the manuscript. Seonjoo Lee: Statistical analysis of the data and critical revision of the manuscript. Richard Mailman: Data interpretation and critical revision of the manuscript. Xuemei Huang: Conception and design of the study; data acquisition, analysis, and interpretation; drafting and critical revision of the manuscript; obtaining funding for the study; administration and supervision of the project. NIH Public Access Author ManuscriptNeuroscience. Author manuscript; available in PMC 2012 March 17. Zetusky et al., 1985), is less reliably responsive to dopaminergic modulation (Marjama-Lyons and Koller, 2000), and does not worsen at the same rate as bradykinesia and rigidity (Zetusky et al., 1985;Louis et al., 1999;Jankovic and Kapadia, 2001). Recent PD imaging studies suggest dopamine transporter levels and myocardial sympathetic degeneration correlate with hypokinesia/rigidity but not tremor (Spiegel et al., 2007). Finally, there is no correlation between rest tremor and striatal 18 Ffluorodopa uptake in PD patients (Vingerhoets et al., 1997).The pathological hallmark of PD is dopamine neuron loss in the substantia nigra pars compacta (SNc) of the basal ganglia (BG). For decades, a classic model emphasized the role of the BG in modulating cortical function through striatal-thalamo-cortical (STC) circuits (DeLong et al., 1984;Alexander et al., 1986;Albin et al., 1989), the dysfunction of which may lead to bradykinesia and rigidity. This model does not, however, explain PD resting tremor. Emerging evidence suggests the necessity of incorpating cerebello-thalamo-cortical (CTC) circuitry into discussions of motor function in both normal (Kelly et al., 2009) and dysfunctional (Deiber et al., 1993;Neychev et al., 2008;A...

The motor deficits in Parkinson's disease (PD) have been primarily associated with internally guided (IG), but not externally guided (EG), tasks. This study investigated the functional mechanisms underlying this phenomenon using genetically-matched twins. Functional magnetic resonance images were obtained from a monozygotic twin pair discordant for clinical PD. Single-photon emission computed tomography neuroimaging using [(123)I](-)-2-beta-carboxymethoxy-3-beta-(4-iodophenyl)tropane confirmed their disease-discordant status by demonstrating a severe loss of transporter binding in the PD-twin, whereas the non-PD-twin was normal. Six runs of functional magnetic resonance imaging (fMRI) data were acquired from each twin performing EG and IG right-hand finger sequential tasks. The percentage of voxels activated in each of several regions of interest (ROI) was calculated. Multiple analysis of variance was used to compare each twin's activity in ROIs constituting the striato-thalamo-cortical motor circuits [basal ganglia (BG)-cortical circuitry, but including the globus pallidus/putamen, thalamus, supplementary motor area, and primary motor cortex] and cerebello-thalamo-cortical circuits (cerebellar-cortical circuitry, including the cerebellum, thalamus, somatosensory cortex, and lateral premotor cortex). During the EG task, there were no significant differences between the twins in bilateral BG-cortical pathways, either basally or after levodopa, whereas the PD-twin had relatively increased activity in the cerebellar-cortical pathways basally that was normalized by levodopa. During the IG task, the PD-twin had less activation than the non-PD-twin in ROIs of the bilateral BG-cortical and cerebellar-cortical pathways. Levodopa normalized the hypoactivation in the contralateral BG-cortical pathway, but "over-corrected" the activation in the ipsilateral BG-cortical and bilateral cerebellar-cortical pathways. In this first fMRI study of twins discordant for PD, the data support the hypothesis that BG-cortical and cerebellar-cortical pathways are task-specifically influenced by PD. The levodopa-induced "over-activation" of BG-cortical and cerebellar-cortical pathways, and its relevance to both compensatory changes in PD and the long-term effects of levodopa in PD, merit further exploration.

Both the basal ganglia and cerebellum are known to influence cortical motor and motor-associated areas via the thalamus. Whereas striato-thalamo-cortical (STC) motor circuit dysfunction has been implicated clearly in Parkinson's disease (PD), the role of the cerebello-thalamo-cortical (CTC) motor circuit has not been well defined. Functional magnetic resonance imaging (fMRI) is a convenient tool for studying the role of the CTC in vivo in PD patients, but large inter-individual differences in fMRI activation patterns require very large numbers of subjects in order to interpret data from cross-sectional, case control studies. To understand the role of the CTC during PD progression, we obtained longitudinal fMRI two years apart from five PD (57 ± 8 yr) and five Controls (57 ± 9 yr) performing either externally-(EG) or internally-guided (IG) sequential finger movements. All PD subjects had unilateral motor symptoms at baseline, but developed bilateral symptoms at follow-up. Within-group analyses were performed by comparing fMRI activation patterns between baseline and follow-up scans. Between-group comparisons were made by contrasting fMRI activation patterns generated by the more-affected and less-affected hands of PD subjects with the dominant and non-dominant hands of Controls, respectively. Compared to baseline, Controls showed changes in CTC circuits, but PD subjects had increased recruitment of both cortical motor-associated and cerebellar areas. Compared to Controls, PD subjects demonstrated augmented recruitment of CTC circuits over time that was statistically significant when the IG task was performed by the hand that transitioned from non-symptomatic to symptomatic. This longitudinal fMRI study demonstrates increased recruitment of the CTC motor circuit concomitant with PD progression, suggesting a role of the CTC circuit in accommodation to, or pathophysiology of, PD. KeywordsParkinson's disease; Longitudinal; FMRI; Cerebellum; Neurocircuits; Motor Control Corresponding Author: Xuemei Huang, MD, PhD, Department of Neurology, Penn State University -Milton S. Hershey Medical Center, H037, 500 University Drive, Hershey, PA 17033-0850, Office phone: 717-531-1803; Fax: 717-531-0465, Xuemei@psu.edu. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. NIH Public Access Author ManuscriptNeuroscience. Author manuscript; available in PMC 2011 March 17. Parkinson's disease (PD) is a progressive, neurodegenerative disorder characterized by asymmetrical onset of motor symptoms such as bradykinesia, rigidity, and tremor. The principal pathology in PD is the loss of dopamine...

We address the empirical bandwidth choice problem in cases where the range of dependence may be virtually arbitrarily long. Assuming that the observed data derive from an unknown function of a Gaussian process, it is argued that, unlike more traditional contexts of statistical inference, in density estimation there is no clear role for the classical distinction between short-and long-range dependence. Indeed, the ''boundaries'' that separate different modes of behaviour for optimal bandwidths and mean squared errors are determined more by kernel order than by traditional notions of strength of dependence, for example, by whether or not the sum of the covariances converges. We provide surprising evidence that, even for some strongly dependent data sequences, the asymptotically optimal bandwidth for independent data is a good choice. A plug-in empirical bandwidth selector based on this observation is suggested. We determine the properties of this choice for a wide range of different strengths of dependence. Properties of cross-validation are also addressed.