Cerebral blood flow responses to dorsal and ventral STN DBS correlate with gait and balance responses in Parkinson's disease.

OBJECTIVES: The effects of subthalamic nucleus (STN) deep brain stimulation (DBS) on gait and balance vary and the underlying mechanisms remain unclear. DBS location may alter motor benefit due to anatomical heterogeneity in STN. The purposes of this study were to (1) compare the effects of DBS of dorsal (D-STN) versus ventral (V-STN) regions on gait, balance and regional cerebral blood flow (rCBF) and (2) examine the relationships between changes in rCBF and changes in gait and balance induced by D-STN or V-STN DBS. METHODS: We used a validated atlas registration to locate and stimulate through electrode contacts in D-STN and V-STN regions of 37 people with Parkinson's disease. In a within-subjects, double-blind and counterbalanced design controlled for DBS settings, we measured PET rCBF responses in a priori regions of interest and quantified gait and balance during DBS Off, unilateral D-STN DBS and unilateral V-STN DBS. RESULTS: DBS of either site increased stride length without producing significant group-level changes in gait velocity, cadence or balance. Both sites increased rCBF in subcortical regions and produced variable changes in cortical and cerebellar regions. DBS-induced changes in gait velocity are related to premotor cortex rCBF changes during V-STN DBS (r=-0.40, p=0.03) and to rCBF changes in the cerebellum anterior lobe during D-STN DBS (r=-0.43, p=0.02). CONCLUSIONS: DBS-induced changes in gait corresponded to rCBF responses in selected cortical and cerebellar regions. These relationships differed during D-STN versus V-STN DBS, suggesting DBS acts through distinct neuronal pathways dependent on DBS location.

Dopamine pathway loss in nucleus accumbens and ventral tegmental area predicts apathetic behavior in MPTP-lesioned monkeys.

Apathy, primarily defined as a lack of motivation, commonly occurs in people with Parkinson disease (PD). Although dysfunction of basal ganglia pathways may contribute to apathy, the role of dopamine remains largely unknown. We investigated the role of dopaminergic pathways in the manifestation of apathetic behaviors by measuring the effects of the selective dopaminergic neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) on monkeys' willingness to attempt goal directed behaviors, distinct from their ability to perform tasks. Fifteen macaques received variable doses of MPTP, had PET scans with [(11)C]-dihydrotetrabenazine (DTBZ), [(11)C]-2ß-3ß-4-fluorophenyltropane (CFT), and [(18)F]-fluorodopa (FD) and performed tasks to assess apathetic behaviors and motor impairment. At 8 weeks post-MPTP, primates were euthanized and stereological cell counts and dopamine measurements were done. Apathy scores were compared to motor scores, in vitro and in vivo dopaminergic measures. Apathy scores increased following MPTP and correlated with DTBZ (r(S) = -0.85), CFT (r(S) = -0.87), and FD (r(S) = -0.85) specific uptake in nucleus accumbens (NAcc,) and dopaminergic cell counts in ventral tegmental area (VTA, r(S) = -0.80). Dopaminergic cell loss in VTA provided significant predictive power for apathy scores after controlling for the influence of cell loss in SN. Additionally, forward step-wise regression analyses indicated that neuropathological changes in the VTA-NAcc pathway predict apathetic behavior better than motor impairment or neuropathological changes in the nigrostriatal network. Our findings suggest that dopaminergic dysfunction within the VTA-NAcc pathway plays a role in the manifestation of apathetic behaviors in MPTP-lesioned primates. Similar changes in people with PD may contribute to apathy.

Effects of deep brain stimulation of dorsal versus ventral subthalamic nucleus regions on gait and balance in Parkinson's disease.

OBJECTIVE: Deep brain stimulation (DBS) of the subthalamic nucleus (STN) improves motor function, including gait and stability, in people with Parkinson's disease (PD) but differences in DBS contact locations within the STN may contribute to variability in the degree of improvement. Based on anatomical connectivity, dorsal STN may be preferentially involved in motor function and ventral STN in cognitive function. METHODS: To determine whether dorsal DBS affects gait and balance more than ventral DBS, a double blind evaluation of 23 PD patients with bilateral STN DBS was conducted. Each participant underwent gait analysis and balance testing off Parkinson's medication under three DBS conditions (unilateral DBS in the dorsal STN region, unilateral DBS in the ventral STN region and both stimulators off) on 1 day. RESULTS: Improvements were seen in Unified Parkinson's Disease Rating Scale (UPDRS)-III scores and velocity in walking trials as fast as possible (Fast gait) and preferred pace (Pref gait), as well as stride length for Fast and Pref gait, with dorsal and ventral stimulation compared with the off condition (post hoc tests, p<0.05). However, there were no differences with dorsal compared to ventral stimulation. Balance, assessed using the multi-item mini-Balance Evaluation Systems Test (mini-BESTest), was similar across conditions. CONCLUSIONS: Absence of differences in gait and balance between the dorsal and ventral conditions suggests motor connections involved in gait and balance may be more diffusely distributed in STN than previously thought, as opposed to neural connections involved in cognitive processes, such as response inhibition, which are more affected by ventral stimulation.

Novel THAP1 sequence variants in primary dystonia.

BACKGROUND: THAP1 encodes a transcription factor (THAP1) that harbors an atypical zinc finger domain and regulates cell proliferation. An exon 2 insertion/deletion frameshift mutation in THAP1 is responsible for DYT6 dystonia in Amish-Mennonites. Subsequent screening efforts in familial, mainly early-onset, primary dystonia identified additional THAP1 sequence variants in non-Amish subjects. OBJECTIVE: To examine a large cohort of subjects with mainly adult-onset primary dystonia for sequence variants in THAP1. METHODS: With high-resolution melting, all 3 THAP1 exons were screened for sequence variants in 1,114 subjects with mainly adult-onset primary dystonia, 96 with unclassified dystonia, and 600 controls (400 neurologically normal and 200 with Parkinson disease). In addition, all 3 THAP1 exons were sequenced in 200 subjects with dystonia and 200 neurologically normal controls. RESULTS: Nine unique melting curves were found in 19 subjects from 16 families with primary dystonia and 1 control. Age at dystonia onset ranged from 8 to 69 years (mean 48 years). Sequencing identified 6 novel missense mutations in conserved regions of THAP1 (G9C [cervical, masticatory, arm], D17G [cervical], F132S [laryngeal], I149T [cervical and generalized], A166T [laryngeal], and Q187K [cervical]). One subject with blepharospasm and another with laryngeal dystonia harbored a c.-42C>T variant. A c.57C>T silent variant was found in 1 subject with segmental craniocervical dystonia. An intron 1 variant (c.71+9C>A) was present in 7 subjects with dystonia (7/1,210) but only 1 control (1/600). CONCLUSIONS: A heterogeneous collection of THAP1 sequence variants is associated with varied anatomical distributions and onset ages of both familial and sporadic primary dystonia.

Subthalamic nucleus stimulation-induced regional blood flow responses correlate with improvement of motor signs in Parkinson disease.

Deep brain stimulation of the subthalamic nucleus (STN DBS) improves motor symptoms in idiopathic Parkinson's disease, yet the mechanism of action remains unclear. Previous studies indicate that STN DBS increases regional cerebral blood flow (rCBF) in immediate downstream targets but does not reveal which brain regions may have functional changes associated with improved motor manifestations. We studied 48 patients with STN DBS who withheld medication overnight and underwent PET scans to measure rCBF responses to bilateral STN DBS. PET scans were performed with bilateral DBS OFF and ON in a counterbalanced order followed by clinical ratings of motor manifestations using Unified Parkinson Disease Rating Scale 3 (UPDRS 3). We investigated whether improvement in UPDRS 3 scores in rigidity, bradykinesia, postural stability and gait correlate with rCBF responses in a priori determined regions. These regions were selected based on a previous study showing significant STN DBS-induced rCBF change in the thalamus, midbrain and supplementary motor area (SMA). We also chose the pedunculopontine nucleus region (PPN) due to mounting evidence of its involvement in locomotion. In the current study, bilateral STN DBS improved rigidity (62%), bradykinesia (44%), gait (49%) and postural stability (56%) (paired t-tests: P < 0.001). As expected, bilateral STN DBS also increased rCBF in the bilateral thalami, right midbrain, and decreased rCBF in the right premotor cortex (P < 0.05, corrected). There were significant correlations between improvement of rigidity and decreased rCBF in the SMA (r(s) = -0.4, P < 0.02) and between improvement in bradykinesia and increased rCBF in the thalamus (r(s) = 0.31, P < 0.05). In addition, improved postural reflexes correlated with decreased rCBF in the PPN (r(s) = -0.38, P < 0.03). These modest correlations between selective motor manifestations and rCBF in specific regions suggest possible regional selectivity for improvement of different motor signs of Parkinson's disease.

Neural correlates of STN DBS-induced cognitive variability in Parkinson disease.

BACKGROUND: Although deep brain stimulation of the subthalamic nucleus (STN DBS) in Parkinson disease (PD) improves motor function, it has variable effects on working memory (WM) and response inhibition (RI) performance. The purpose of this study was to determine the neural correlates of STN DBS-induced variability in cognitive performance. METHODS: We measured bilateral STN DBS-induced blood flow changes (PET and [(15)O]-water on one day) in the supplementary motor area (SMA), dorsolateral prefrontal cortex (DLPFC), anterior cingulate cortex (ACC), and right inferior frontal cortex (rIFC) as well as in exploratory ROIs defined by published meta-analyses. STN DBS-induced WM and RI changes (Spatial Delayed Response and Go-No-Go on the next day) were measured in 24 PD participants. On both days, participants withheld PD medications overnight and conditions (OFF vs. ON) were administered in a counterbalanced, double-blind manner. RESULTS: As predicted, STN DBS-induced DLPFC blood flow change correlated with change in WM, but not RI performance. Furthermore, ACC blood flow change correlated with change in RI but not WM performance. For both relationships, increased blood flow related to decreased cognitive performance in response to STN DBS. Of the exploratory regions, only blood flow changes in DLPFC and ACC were correlated with performance. CONCLUSIONS: These results demonstrate that variability in the effects of STN DBS on cognitive performance relates to STN DBS-induced cortical blood flow changes in DLPFC and ACC. This relationship highlights the need to further understand the factors that mediate the variability in neural and cognitive response to STN DBS.

Unilateral vs. bilateral STN DBS effects on working memory and motor function in Parkinson disease.

Bilateral subthalamic nucleus deep brain stimulation (STN DBS) can reduce working memory while improving motor function in Parkinson disease (PD), but findings are variable. One possible explanation for this variability is that the effects of bilateral STN DBS on working memory function depend in part on functional or disease asymmetry. The goal of this study was to determine the relative contributions of unilateral DBS to the effects seen with bilateral DBS. Motor (Unified Parkinson Disease Rating Scale Part III, UPDRS) and working memory function (Spatial Delayed Response, SDR) were measured in 49 PD patients with bilateral STN DBS while stimulators were Both-off, Left-on, Right-on and Both-on in a randomized, double-blind manner. Patients were off PD medications overnight. Effects of unilateral DBS were compared to effects of bilateral STN DBS. Mean UPDRS and SDR responses to Left-on vs. Right-on conditions did not differ (p>.20). However, improvement in contralateral UPDRS was greater and SDR performance was more impaired by unilateral DBS in the more affected side of the brain than in the less affected side of the brain (p=.008). The effect of unilateral DBS on the more affected side on contralateral UPDRS and SDR responses was equivalent to that of bilateral DBS. These results suggest that motor and working memory function respond to unilateral STN DBS differentially depending on the asymmetry of motor symptoms.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced acute transient dystonia in monkeys associated with low striatal dopamine.

Unilateral intracarotid infusion of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) in baboons produces transient contralateral dystonia lasting 2-3 weeks followed by chronic hemiparkinsonism. We now extend this model to Macaca nemestrina and Macaca fascicularis. MPTP was infused unilaterally into the internal carotid artery of two M. nemestrina and 11 M. fascicularis. Effects were assessed with blinded clinical ratings of dystonia and Parkinsonism; [18F]-6-fluoro-DOPA (FDOPA) positron emission tomography; and postmortem measurements of striatal dopamine content. In two M. nemestrina, MPTP 0.4 mg/kg intracarotid produced acute dystonia within 24 h then chronic Parkinsonism starting 3 weeks later. In three M. fascicularis, MPTP 0.4 mg/kg produced acute dystonia within 3-8 h but two others died from large hemispheric infarcts within 1 day. A much lower dose, MPTP 0.1 mg/kg produced no clinical manifestations (n=1), whereas MPTP 0.25 mg/kg produced consistent transient dystonia and ipsiversive turning within 1-3 days followed by chronic Parkinsonism at 3 weeks (n=5). One week after MPTP, striatal FDOPA uptake decreased an average of 69% in M. nemestrina (0.4 mg/kg); and decreased an average of 70+/-21% in M. fascicularis (0.25 mg/kg). Striatal dopamine was reduced an average 66% in the first day (n=2) during acute dystonia, 98% at 3 days (n=1) and 99%+/-2.3% at 2-4 months (n=5). M. nemestrina had a clinical response similar to baboons whereas M. fascicularis seemed more sensitive to MPTP. These findings extend the model of MPTP-induced transient dystonia followed by chronic hemiparkinsonism to M. nemestrina and M. fascicularis and demonstrate that the early dystonic phase is accompanied by striatal dopamine deficiency.

Prevalence of parkinsonism and relationship to exposure in a large sample of Alabama welders.

OBJECTIVE: To estimate the prevalence of parkinsonism in welders in Alabama and to compare this prevalence with that in a general population sample. METHODS: The authors screened 1,423 welders from Alabama who were referred for medical-legal evaluation for Parkinson disease (PD). Standardized videotaped assessments using the Unified Parkinson's Disease Rating Scale motor subsection 3 (UPDRS3) were obtained. Patients provided information regarding exposure to welding fumes and job titles. Job titles were matched with Department of Labor Standard Occupational Codes (SOCs). Diagnoses were assigned based on quantitative criteria for the diagnosis of PD using two thresholds for diagnosis. With use of the number of active welders in this screening with parkinsonism as the numerator and the age-adjusted number of welders in each SOC as the denominator, the prevalence of parkinsonism in Alabama welders was estimated using conservative assumptions and compared with general population data from Copiah County, MS. RESULTS: With use of conservative and liberal case definitions of parkinsonism, the estimated prevalence of parkinsonism among active male welders age 40 to 69 statewide was 977 to 1,336 cases/100,000 population. The prevalence of parkinsonism was higher among welders vs age-standardized data for the general population (prevalence ratio = 10.19, 95% CI 4.43 to 23.43). CONCLUSION: The estimated prevalence of parkinsonism was higher within a sample of male Alabama welders vs the general population of male residents of Copiah County, MS.

Case report and review of literature: leptomeningeal relapse in epithelial ovarian cancer.

The diagnosis of leptomeningeal relapse in a patient with epithelial ovarian cancer was confirmed by the presence of malignant ovarian cells in the cerebrospinal fluid. There was no clinical evidence of tumor spread elsewhere. Therapy, including intrathecal methotrexate and whole-brain irradiation led to transient clinical improvement. International literature review revealed only 13 other cases of leptomeningeal carcinomatosis in epithelial ovarian cancer; all died within 15 months following the diagnosis of leptomeningeal spread.