BackgroundDepression and anxiety frequently accompany the motor manifestations of isolated adult-onset focal dystonias. Whether the body region affected when this type of dystonia first presents is associated with the severity of these neuropsychiatric symptoms is unknown.ObjectivesThe aim of this study was to determine whether depression, anxiety and social anxiety vary by dystonia onset site and evaluate whether pain and dystonia severity account for any differences.MethodsPatients with isolated focal dystonia evaluated within 5 years from symptom onset, enrolled in the Natural History Project of the Dystonia Coalition, were included in the analysis. Individual onset sites were grouped into five body regions: cervical, laryngeal, limb, lower cranial and upper cranial. Neuropsychiatric symptoms were rated using the Beck Depression Inventory, Hospital Anxiety and Depression Scale and Liebowitz Social Anxiety Scale. Pain was estimated using the 36-Item Short Form Survey.ResultsFour hundred and seventy-eight subjects met our inclusion criteria. High levels of depression, anxiety and social anxiety occurred in all groups; however, the severity of anxiety and social anxiety symptoms varied by onset site group. The most pronounced differences were higher anxiety in cervical and laryngeal, lower anxiety in upper cranial and higher social anxiety in laryngeal. Increases in pain were associated with worse neuropsychiatric symptom scores within all groups. Higher anxiety and social anxiety in laryngeal and lower anxiety in upper cranial persisted after correcting for pain and dystonia severity.ConclusionAnxiety and social anxiety severity vary by onset site of focal dystonia, and this variation is not explained by differences in pain and dystonia severity.
Background PD is associated with disrupted connectivity to a large number of distributed brain regions. How the disease alters the functional topological organization of the brain, however, remains poorly understood. Furthermore, how levodopa modulates network topology in PD is largely unknown. Objectives We used resting state functional MRI (rsfMRI) and graph theory to determine how small-world architecture is altered in PD and affected by levodopa administration. Methods Twenty-one PD patients and 20 controls underwent functional MRI scanning. PD patients were scanned off medication and one hour after 200mg levodopa. Imaging data were analyzed using 226 nodes comprising 10 intrinsic brain networks. Correlation matrices were generated for each subject and converted into cost thresholded, binarized adjacency matrices. Cost-integrated whole brain global and local efficiencies were compared across groups and tested for relationships with disease duration and severity. Results Data from two patients and four controls were excluded due to excess motion. Patients off medication showed no significant changes in global efficiency and overall local efficiency, but in a subnetwork analysis did show increased local efficiency in Executive (p=0.006), and Salience (p=0.018) networks. Levodopa significantly decreased local (p=0.039) efficiency in patients except within the Subcortical network where it significantly increased local efficiency (p=0.007). Conclusions Levodopa modulates global and local efficiency measures of small-world topology in PD suggesting that degeneration of nigrostriatal neurons in PD may be associated with a large-scale network reorganization, and that levodopa tends to normalize the disrupted network topology in PD.
Diffusion tensor imaging (DTI) of the substantia nigra has shown promise in detecting and quantifying neurodegeneration in Parkinson disease (PD). It remains unknown, however, whether differences in microstructural changes within the basal ganglia underlie PD motor subtypes. We investigated microstructural changes within the basal ganglia of mild to moderately affected PD patients using DTI and sought to determine if microstructural changes differ between the tremor dominant (TD) and postural instability/gait difficulty (PIGD) subtypes. Fractional anisotropy, mean diffusivity, radial, and axial diffusivity were obtained from bilateral caudate, putamen, globus pallidus, and substantia nigra of 21 PD patients (12 TD and 9 PIGD) and 20 age-matched healthy controls. T-tests and ANOVA methods were used to compare PD patients, subtypes, and controls, and Spearman correlations tested for relationships between DTI and clinical measures. We found our cohort of PD patients had reduced fractional anisotropy within the substantia nigra and increased mean and radial diffusivity within the substantia nigra and globus pallidus compared to controls, and that changes within those structures were largely driven by the PIGD subtype. Across all PD patients fractional anisotropy within the substantia nigra correlated with disease stage, while in PIGD patients increased diffusivity within the globus pallidus correlated with disease stage and motor severity. We conclude that PIGD patients have more severely affected microstructural changes within the substantia nigra compared to TD, and that microstructural changes within the globus pallidus may be particularly relevant for the manifestation of the PIGD subtype.
Parkinson's disease (PD) is a circuit-level disorder with clinically-determined motor subtypes. Despite evidence suggesting each subtype may have different pathophysiology, few neuroimaging studies have examined levodopa-induced differences in neural activation between tremor dominant (TD) and postural instability/gait difficulty (PIGD) subtype patients during a motor task. The goal of this functional MRI (fMRI) study was to examine task-induced activation and connectivity in the cortico-striatal-thalamo-cortical motor circuit in healthy controls, TD patients, and PIGD patients before and after levodopa administration. Fourteen TD and 12 PIGD cognitively-intact patients and 21 age- and sex-matched healthy controls completed a right-hand, paced tapping fMRI paradigm. Collectively, PD patients off medication (OFF) showed hypoactivation of the motor cortex relative to healthy controls, even when controlling for performance. After levodopa intake, the PIGD patients had significantly increased activation in the left putamen compared with TD patients and healthy controls. Psychophysiological interaction analysis revealed that levodopa increased effective connectivity between the posterior putamen and other areas of the motor circuit during tapping in TD patients, but not in PIGD patients. This novel, levodopa-induced difference in the neural responses between PD motor subtypes may have significant implications for elucidating the mechanisms underlying the distinct phenotypic manifestations and enabling the classification of motor subtypes objectively using fMRI.
GABAA receptor availability changes within sensorimotor regions have been reported in some isolated forms of dystonia. Whether similar abnormalities underlie symptoms in cervical dystonia is not known. In the present study, a total of 15 cervical dystonia patients and 15 age- and sex-matched controls underwent 11C-flumazenil PET/CT scanning. The density of available GABAA receptors was estimated using a Simplified Reference Tissue Model 2. Group differences were evaluated using a two-sample T-test, and correlations with dystonia severity, as measured by the Toronto Western Spasmodic Torticollis Rating Scale, and disease duration were evaluated using a regression analysis. Voxel-based analyses revealed increased GABAA availability within the right precentral gyrus in brain motor regions previously associated with head turning and the left parahippocampal gyrus. GABAA availability within the bilateral cerebellum was negatively correlated with dystonia severity, and GABAA availability within the right thalamus and a variety of cerebellar and cortical regions were negatively correlated with disease duration. While GABAA availability changes within primary motor areas could represent a partial compensatory response to loss of inhibition within sensorimotor network, GABAergic signaling impairment within the cerebellum may be a key contributor to dystonia severity.
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