Use of Functional Magnetic Resonance Imaging to Assess How Motor Phenotypes of Parkinson's Disease Respond to Deep Brain Stimulation.

BACKGROUND: Deep brain stimulation (DBS) is a well-accepted treatment of Parkinson's disease (PD). Motor phenotypes include tremor-dominant (TD), akinesia-rigidity (AR), and postural instability gait disorder (PIGD). The mechanism of action in how DBS modulates motor symptom relief remains unknown. OBJECTIVE: Blood oxygen level-dependent (BOLD) functional magnetic resonance imaging (fMRI) was used to determine whether the functional activity varies in response to DBS depending on PD phenotypes. MATERIALS AND METHODS: Subjects underwent an fMRI scan with DBS cycling ON and OFF. The effects of DBS cycling on BOLD activation in each phenotype were documented through voxel-wise analysis. For each region of interest, ANOVAs were performed using T-values and covariate analyses were conducted. Further, a correlation analysis was performed comparing stimulation settings to T-values. Lastly, T-values of subjects with motor improvement were compared to those who worsened. RESULTS: As a group, BOLD activation with DBS-ON resulted in activation in the motor thalamus (p < 0.01) and globus pallidus externa (p < 0.01). AR patients had more activation in the supplementary motor area (SMA) compared to PIGD (p < 0.01) and TD cohorts (p < 0.01). Further, the AR cohort had more activation in primary motor cortex (MI) compared to the TD cohort (p = 0.02). Implanted nuclei (p = 0.01) and phenotype (p = <0.01) affected activity in MI and phenotype alone affected SMA activity (p = <0.01). A positive correlation was seen between thalamic activation and pulse-width (p = 0.03) and between caudate and total electrical energy delivered (p = 0.04). CONCLUSIONS: These data suggest that DBS modulates network activity differently based on patient motor phenotype. Improved understanding of these differences may further our knowledge about the mechanisms of DBS action on PD motor symptoms and to optimize treatment.

King's Parkinson's Disease Pain Scale for Assessment of Pain Relief Following Deep Brain Stimulation for Parkinson's Disease.

OBJECTIVE: Pain is a prevalent and debilitating nonmotor symptom of Parkinson's disease (PD) that is often inadequately managed. Deep brain stimulation (DBS) has been shown to relieve pain in PD but an effective method of identifying which types of PD pain respond to DBS has not been established. We examine the effects of DBS on different types of PD pain using the King's Parkinson's disease pain scale (KPDPS), the only validated scale of PD pain. METHODS: We prospectively followed 18 PD patients undergoing subthalamic nucleus (STN) or Globus pallidus interna (GPi) DBS. Subjects completed the KPDPS, low back disability index (LBDI), and McGill pain questionnaire (MPQ), preoperatively and at six months postoperatively. Subjects underwent the unified Parkinson's disease rating scale-III (UPDRS-III) with preoperative scores ON medication and postoperative scores ON medication/DBS stimulation. RESULTS: Of the 18 patients, a total of 12 subjects had STN DBS and 6 had GPi DBS. As a group, subjects showed improvement in total KPDPS score at six-month postoperative follow-up (p = 0.004). Fluctuation and nocturnal pain were most significantly improved (p = 0.006, 0.01, respectively). Significant improvements were found in fluctuation-related pain domain following GPi DBS. CONCLUSIONS: In this pilot study, we are the first group to employ KPDPS to monitor pain relief following DBS in PD patients. We demonstrate that fluctuation-related pain and nocturnal pain significantly improve with DBS. Use of the KPDPS in the future will allow better understanding of how STN and GPi DBS treat PD pain over time.

A Comparison of Unilateral Deep Brain Stimulation (DBS), Simultaneous Bilateral DBS, and Staged Bilateral DBS Lead Accuracies.

BACKGROUND: Accuracy of lead placement within the brain can affect the outcome of deep brain stimulation (DBS) surgery. Whether performing unilateral lead implantation, simultaneous bilateral lead implantation, or staged bilateral lead implantation affects accuracy has not yet been assessed. We compare lead placement errors to evaluate whether one approach affords greater lead accuracy. METHODS: We retrospectively reviewed 205 leads placed in 125 DBS surgeries. The accuracy of lead placement, defined by differences in x, y, and z coordinates and error vector magnitudes, was compared between three surgery groups: unilateral leads, bilateral leads placed simultaneously, and bilateral leads placed in staged surgeries. We also compared accuracies between first and second leads within each bilateral cohort and between second leads of the bilateral cohorts. Finally, we examined the effect of target and age on accuracy. RESULTS: The accuracy of lead placement was comparable among unilateral, simultaneous bilateral, and staged bilateral leads. Timing of placement of the second lead in bilateral cases was not found to affect accuracy. The mean number of microelectrode trajectories was greater for first leads in simultaneous bilateral DBS (p = 0.032). No significant correlation between either age or target and accuracy was found. CONCLUSION: Although there may be other important reasons for performing DBS in a staged fashion, our study finds that neither laterality nor timing of second lead placement, patient age, or target site have significant impact on DBS lead accuracy, a finding that indicates with appropriate approach selection based on patient factors, accuracy does not have to be significantly compromised.

Exome sequencing reveals de novo WDR45 mutations causing a phenotypically distinct, X-linked dominant form of NBIA.

Neurodegeneration with brain iron accumulation (NBIA) is a group of genetic disorders characterized by abnormal iron deposition in the basal ganglia. We report that de novo mutations in WDR45, a gene located at Xp11.23 and encoding a beta-propeller scaffold protein with a putative role in autophagy, cause a distinctive NBIA phenotype. The clinical features include early-onset global developmental delay and further neurological deterioration (parkinsonism, dystonia, and dementia developing by early adulthood). Brain MRI revealed evidence of iron deposition in the substantia nigra and globus pallidus. Males and females are phenotypically similar, an observation that might be explained by somatic mosaicism in surviving males and germline or somatic mutations in females, as well as skewing of X chromosome inactivation. This clinically recognizable disorder is among the more common forms of NBIA, and we suggest that it be named accordingly as beta-propeller protein-associated neurodegeneration.

A disease-specific metabolic brain network associated with corticobasal degeneration.

Corticobasal degeneration is an uncommon parkinsonian variant condition that is diagnosed mainly on clinical examination. To facilitate the differential diagnosis of this disorder, we used metabolic brain imaging to characterize a specific network that can be used to discriminate corticobasal degeneration from other atypical parkinsonian syndromes. Ten non-demented patients (eight females/two males; age 73.9 ± 5.7 years) underwent metabolic brain imaging with (18)F-fluorodeoxyglucose positron emission tomography for atypical parkinsonism. These individuals were diagnosed clinically with probable corticobasal degeneration. This diagnosis was confirmed in the three subjects who additionally underwent post-mortem examination. Ten age-matched healthy subjects (five females/five males; age 71.7 ± 6.7 years) served as controls for the imaging studies. Spatial covariance analysis was applied to scan data from the combined group to identify a significant corticobasal degeneration-related metabolic pattern that discriminated (P < 0.001) the patients from the healthy control group. This pattern was characterized by bilateral, asymmetric metabolic reductions involving frontal and parietal cortex, thalamus, and caudate nucleus. These pattern-related changes were greater in magnitude in the cerebral hemisphere opposite the more clinically affected body side. The presence of this corticobasal degeneration-related metabolic topography was confirmed in two independent testing sets of patient and control scans, with elevated pattern expression (P < 0.001) in both disease groups relative to corresponding normal values. We next determined whether prospectively computed expression values for this pattern accurately discriminated corticobasal degeneration from multiple system atrophy and progressive supranuclear palsy (the two most common atypical parkinsonian syndromes) on a single case basis. Based upon this measure, corticobasal degeneration was successfully distinguished from multiple system atrophy (P < 0.001) but not progressive supranuclear palsy, presumably because of the overlap (∼ 24%) that existed between the corticobasal degeneration- and the progressive supranuclear palsy-related metabolic topographies. Nonetheless, excellent discrimination between these disease entities was achieved by computing hemispheric asymmetry scores for the corticobasal degeneration-related pattern on a prospective single scan basis. Indeed, a logistic algorithm based on the asymmetry scores combined with separately computed expression values for a previously validated progressive supranuclear palsy-related pattern provided excellent specificity (corticobasal degeneration: 92.7%; progressive supranuclear palsy: 94.1%) in classifying 58 testing subjects. In conclusion, corticobasal degeneration is associated with a reproducible disease-related metabolic covariance pattern that may help to distinguish this disorder from other atypical parkinsonian syndromes.

Deep brain stimulation significantly decreases disability from low back pain in patients with advanced Parkinson's disease.

BACKGROUND: Up to 60% of Parkinson's disease (PD) patients suffer from low back pain (LBP) during the course of their disease. How LBP affects daily functional status and how to manage this aspect of PD has not been adequately explored. METHODS: We examined 16 patients undergoing bilateral subthalamic nucleus deep brain stimulation (STN DBS) who met the inclusion criteria for moderate disability from LBP, as classified by the Oswestry Low Back Pain Disability Index (OLBPD). RESULTS: Thirteen of 16 patients had attempted additional treatments for LBP, including medical management, massage, chiropractic, epidural steroid injections and/or surgery, with minimal relief. Following DBS, there was a significant improvement in the OLBPD at both the 6-month and 1-year time points (p < 0.02, p < 0.005, respectively). A mean improvement of 31.7% on the OLBPD score was noted. The Visual Analogue Scale (VAS) similarly decreased significantly at 1 year (p = 0.015). There was no correlation between the OLBPD score and other measures, including the Unified Parkinson's Disease Rating Scale (UPDRS), age and other nonmotor symptoms. CONCLUSION: Given the prevalent yet undertreated disability associated with LBP in PD, these results are novel in that they show that STN DBS has a significant positive effect on disability associated with LBP.

The Influence of Bilateral Subthalamic Nucleus Deep Brain Stimulation on Impulsivity and Prepulse Inhibition in Parkinson's Disease Patients.

BACKGROUND: At least 14% of Parkinson disease (PD) patients develop impulse control disorders (ICDs). The pathophysiology behind these behaviors and the impact of deep brain stimulation in a real-life setting remain unclear. OBJECTIVES: We prospectively examined the impact of bilateral subthalamic nucleus deep brain stimulation (STN-DBS) on ICDs in PD patients, as well as the relationship between impaired sensorimotor gaiting and impulsivity. METHODS: Patients undergoing bilateral STN-DBS were assessed for ICDs preoperatively and 1-year postoperatively using a validated questionnaire (QUIP-RS). A subset of patients completed the Balloon Analogue Risk Task (BART) and auditory prepulse inhibition (PPI) testing. RESULTS: Analysis revealed 12 patients had an improvement in score assessing ICDs ('good responders'; p = 0.006) while 4 had a worse or stable score ('poor responders'; p > 0.05). Good responders further exemplified a significant decrease in hypersexual behavior (p = 0.005) and binge eating (p = 0.01). Impaired PPI responses also significantly correlated with impulsivity in BART (r = -0.72, p = 0.044). DISCUSSION: Following bilateral STN-DBS, 75% of our cohort had a reduction in ICDs, thus suggesting deep brain stimulation effectively manages ICDs in PD. The role of impaired PPI in predisposition to ICDs in PD warrants further investigation.

ß-Propeller protein-associated neurodegeneration: a new X-linked dominant disorder with brain iron accumulation.

Neurodegenerative disorders with high iron in the basal ganglia encompass an expanding collection of single gene disorders collectively known as neurodegeneration with brain iron accumulation. These disorders can largely be distinguished from one another by their associated clinical and neuroimaging features. The aim of this study was to define the phenotype that is associated with mutations in WDR45, a new causative gene for neurodegeneration with brain iron accumulation located on the X chromosome. The study subjects consisted of WDR45 mutation-positive individuals identified after screening a large international cohort of patients with idiopathic neurodegeneration with brain iron accumulation. Their records were reviewed, including longitudinal clinical, laboratory and imaging data. Twenty-three mutation-positive subjects were identified (20 females). The natural history of their disease was remarkably uniform: global developmental delay in childhood and further regression in early adulthood with progressive dystonia, parkinsonism and dementia. Common early comorbidities included seizures, spasticity and disordered sleep. The symptoms of parkinsonism improved with l-DOPA; however, nearly all patients experienced early motor fluctuations that quickly progressed to disabling dyskinesias, warranting discontinuation of l-DOPA. Brain magnetic resonance imaging showed iron in the substantia nigra and globus pallidus, with a 'halo' of T1 hyperintense signal in the substantia nigra. All patients harboured de novo mutations in WDR45, encoding a beta-propeller protein postulated to play a role in autophagy. Beta-propeller protein-associated neurodegeneration, the only X-linked disorder of neurodegeneration with brain iron accumulation, is associated with de novo mutations in WDR45 and is recognizable by a unique combination of clinical, natural history and neuroimaging features.

Lateral medullary stroke in patient with granulomatous polyangiitis.

Granulomatous polyangiitis (GPA), also known as Wegener granulomatosis, is a systemic antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis that infrequently affects the central nervous system. We report a 41-year-old man with lateral medullary infarction who developed rapidly progressive renal failure. He was diagnosed with GPA based on positive serum c-ANCA and antiproteinase 3 antibodies and demonstration of pauci-immune crescentic glomerulonephritis on kidney biopsy. He was treated with Coumadin, pulse steroids, cyclophosphamide, and plasmapheresis. He had resolution of his neurologic deficits and improvement in renal function. This case report highlights the importance to consider GPA vasculitis in the differential diagnosis of stroke in patients with development of acute kidney injury.

Time to initiation of symptomatic treatment in untreated Parkinson disease in the Parkinson progression marker initiative cohort: A 10-year follow up.

BACKGROUND: Initiation of symptomatic therapy in Parkinson disease is a disease progression milestone, and its prediction is important. Previous studies were limited in duration and number of variables included in their predictive models. OBJECTIVES: To identify predictors of time to initiation of symptomatic therapy in patients with PD not on treatment, using a large pool of candidate variables from the Parkinson's Progression Markers Initiative dataset, analyzed at ten years. METHODS: Kaplan Meier survival curve was used to estimate time to initiation of symptomatic treatment. Potential predictors included 33 baseline clinical, imaging, biofluid, and genetic biomarkers. Univariate Cox regression was used for variable selection, significant predictors subsequently entering a multivariate Cox proportional hazard model, which was further reduced using the Akaike Information Criterion into a final reduced model. RESULTS: Of 425 participants with Parkinson's Disease, 406 initiated symptomatic therapy at last follow up. The outcome was censored for 4.5% of the sample. The risk of initiating symptomatic therapy was 65% (95%CI 60-70%) within the first year from enrollment. Predictors included dopamine transporter SPECT, the Movement Disorders Society Unified Parkinson Disease Rating Scale, and anxiety (State Trait Anxiety Inventory). CONCLUSIONS: Baseline dopamine transporter SPECT specific binding ratio was found to be the most impactful predictor for time to initiation of symptomatic therapy in this 10-year follow up analysis of the Progressive Parkinson Markers Initiative cohort, when treatment status was known for 95.5% of the sample.

Effect of Directional Deep Brain Stimulation on Sensory Thresholds in Parkinson's Disease.

OBJECTIVE: Previous studies showed that deep brain stimulation (DBS) relieves pain symptoms in Parkinson disease (PD) patients when programmed for motor-symptom relief. One factor involved in pain processing is sensory perception of stimuli. With the advent of directional leads, we explore whether directional DBS affects quantitative sensory testing (QST) metrics acutely. METHODS: PD patients with subthalamic (STN) DBS and directional leads were tested in 5 settings (DBS-OFF, DBS-ON with omnidirectional stimulation, and DBS-ON) for each of three directional segments of contact used for clinical programming. The Unified Parkinson's Disease Rating Scale (UPDRS-III) assessed patient's motor skills at time of study visit at clinical contact and at contact which produced optimal sensory threshold (defined by the greatest tolerance to mechanical stimuli). Correlation analyses were performed between stimulation parameters [amplitude, frequency, pulse width (PW), total electrical energy delivered (TEED)] and outcome metrics. RESULTS: Sensory thresholds were obtained in nine patients. Directional stimulation did not significantly alter patient perceptions of sensory stimulus [cold pain (p = 0.69), warm pain (p = 0.99), Von frey fibers (p = 0.09), pin-prick (p = 0.88), vibration (p = 0.40), pressure (p = 0.98)]. With correlation analysis, increasing PW at the posterior contact increased pin prick and vibration sensitivity (p < 0.001). Additionally, an increase in TEED caused a decrease in sensitivity to warm detection when using the anterior (p = 0.04), lateral (p = 0.02), and medial contacts (p = 0.03), and also caused a decrease in sensitivity to cold detection when using the medial contact (p = 0.03). UPDRS-III remained stable during testing. CONCLUSION: Motor benefit can be acutely maintained at directional contacts, whereas directional stimulation can modulate thermal and mechanical sensitivity. Further investigation will determine whether these changes are maintained chronically or can be improved with optimized programming.

Sex-specific effects of subthalamic nucleus stimulation on pain in Parkinson's disease.

OBJECTIVE: Deep brain stimulation (DBS) of the subthalamic nucleus (STN) is known to reduce motor symptoms of Parkinson's disease (PD). The effects of DBS on various nonmotor symptoms often differ from patient to patient. The factors that determine whether or not a patient will respond to treatment have not been elucidated. Here, the authors evaluated sex differences in pain relief after DBS for PD. METHODS: The authors prospectively evaluated 20 patients preoperatively and postoperatively after bilateral STN DBS with the validated numeric rating scale (NRS), Revised Oswestry Disability Index for low-back pain (RODI), and King's Parkinson's Disease Pain Scale (KPDPS) and assessed the impact of sex as a biological variable. RESULTS: The cohort consisted of 6 female and 14 male patients with a mean duration of 11.8 ± 2.0 months since DBS surgery. Females were significantly older (p = 0.02). Covariate analysis, however, showed no effect of age, stimulation settings, or other confounding variables. KPDPS total scores statistically significantly improved only among males (p < 0.001). Males improved more than females in musculoskeletal and chronic subsets of the KPDPS (p = 0.03 and p = 0.01, respectively). RODI scores significantly improved in males but not in females (p = 0.03 and p = 0.30, respectively). Regarding the NRS score, the improvements seen in both sexes in NRS were not significant. CONCLUSIONS: Although it is well recognized that pain complaints in PD are different between men and women, this study is unique in that it examines the sex-specific DBS effects on this symptom. Considering sex as a biological variable may have important implications for DBS pain outcome studies moving forward.

Functional MRI Signature of Chronic Pain Relief From Deep Brain Stimulation in Parkinson Disease Patients.

BACKGROUND: Chronic pain occurs in 83% of Parkinson disease (PD) patients and deep brain stimulation (DBS) has shown to result in pain relief in a subset of patients, though the mechanism is unclear. OBJECTIVE: To compare functional magnetic resonance imaging (MRI) data in PD patients with chronic pain without DBS, those whose pain was relieved (PR) with DBS and those whose pain was not relieved (PNR) with DBS. METHODS: Functional MRI (fMRI) with blood oxygen level-dependent activation data was obtained in 15 patients in control, PR, and PNR patients. fMRI was obtained in the presence and absence of a mechanical stimuli with DBS ON and DBS OFF. Voxel-wise analysis using pain OFF data was used to determine which regions were altered during pain ON periods. RESULTS: At the time of MRI, pain was scored a 5.4 ± 1.2 out of 10 in the control, 4.25 ± 1.18 in PNR, and 0.8 ± 0.67 in PR cohorts. Group analysis of control and PNR groups showed primary somatosensory (SI) deactivation, whereas PR patients showed thalamic deactivation and SI activation. DBS resulted in more decreased activity in PR than PNR (P < .05) and more activity in anterior cingulate cortex (ACC) in PNR patients (P < .05). CONCLUSION: Patients in the control and PNR groups showed SI deactivation at baseline in contrast to the PR patients who showed SI activation. With DBS ON, the PR cohort had less activity in SI, whereas the PNR had more anterior cingulate cortex activity. We provide pilot data that patients whose pain responds to DBS may have a different fMRI signature than those who do not, and PR and PNR cohorts produced different brain responses when DBS is employed.

Effect of low-frequency deep brain stimulation on sensory thresholds in Parkinson's disease.

OBJECTIVE Chronic pain is a major distressing symptom of Parkinson's disease (PD) that is often undertreated. Subthalamic nucleus (STN) deep brain stimulation (DBS) delivers high-frequency stimulation (HFS) to patients with PD and has been effective in pain relief in a subset of these patients. However, up to 74% of patients develop new pain concerns while receiving STN DBS. Here the authors explore whether altering the frequency of STN DBS changes pain perception as measured through quantitative sensory testing (QST). METHODS Using QST, the authors measured thermal and mechanical detection and pain thresholds in 19 patients undergoing DBS via HFS, low-frequency stimulation (LFS), and off conditions in a randomized order. Testing was performed in the region of the body with the most pain and in the lower back in patients without chronic pain. RESULTS In the patients with chronic pain, LFS significantly reduced heat detection thresholds as compared with thresholds following HFS (p = 0.029) and in the off state (p = 0.010). Moreover, LFS resulted in increased detection thresholds for mechanical pressure (p = 0.020) and vibration (p = 0.040) compared with these thresholds following HFS. Neither LFS nor HFS led to changes in other mechanical thresholds. In patients without chronic pain, LFS significantly increased mechanical pain thresholds in response to the 40-g pinprick compared with thresholds following HFS (p = 0.032). CONCLUSIONS Recent literature has suggested that STN LFS can be useful in treating nonmotor symptoms of PD. Here the authors demonstrated that LFS modulates thermal and mechanical detection to a greater extent than HFS. Low-frequency stimulation is an innovative means of modulating chronic pain in PD patients receiving STN DBS. The authors suggest that STN LFS may be a future option to consider when treating Parkinson's patients in whom pain remains the predominant complaint.

Photoperiodic response of the hypothalamo-pituitary-gonad axis in male and female canaries, Serinus canaria.

Although the gonadal photoperiodic response and its influence upon the song control system in canaries have been extensively studied, photoperiodic regulation of the GnRH system has not been investigated. To examine the relationship between photoperiod and the reproductive neuroendocrine system in male and female canaries, three groups of canaries were exposed to chronic short days (8L:16D; Phsens), acute long days (18L:6D; Phstim) and chronic long days (also 18L:6D; Phrefr) to induce the reproductive states of photosensitivity, photostimulation, and photorefractoriness, respectively. Brain sections were processed for GnRH immunocytochemistry. The canaries in this study did not demonstrate consistent or uniform responses to different photoperiodic treatments. In males, gonad size varied with photoperiod; Phstim males had larger gonads than either the Phsens or Phrefr males. In contrast, there was no difference between groups in female gonad size as a result of photoperiodic treatment. Brain GnRH cell number, cell size, and fiber density were similar in all groups. The results suggest that canaries are not as obligatory photoperiodic as previously thought (or at least not all varieties of domestic canaries are). This could be a result of many years of domestication, the natural history of the species, phylogenetic constraint, or a combination of these factors.