Crystallization of high aspect ratio HKUST-1 thin films in nanoconfined channels for selective small molecule uptake.

We present the ability to create unique morphologies of a prototypical metal organic framework (MOF), HKUST-1, by carrying out its crystallization within a set of nano-confined fluidic channels. These channels are fabricated on cyclic olefin copolymer by the high-fidelity hot embossing imprinting method. The picoliter volume synthesis in the nanochannels is hypothesized to bias the balance between nucleation and growth rates to obtain high aspect ratio large-crystalline domains of HKUST-1, which are grown in defined morphologies due to the patterned nanochannels. Confined crystal growth is achieved in nanofluidic channels as shallow as 50 nm. HKUST-1 crystalline domains with aspect ratios greater than 2500, and lengths up to 144 µm are obtained using the nanochannels, exceeding values obtained using chemical modulation and other confinement methods. HKUST-1 crystals are characterized using optical microscopy and scanning electron microscopy with energy dispersive spectroscopy. Porosity of the MOF and selective molecular uptake is demonstrated through inclusion of anthracene and methylene blue within the HKUST-1 framework, and with exclusion of rhodamine B and riboflavin, characterized using a confocal fluorescence microscope. We attribute this selectivity to the analyte size and electrostatic characteristics. Nanoconfined crystallization of MOFs can thus yield control over crystalline morphology to create ideal MOF crystals for enabling selective molecular enrinchment and sensing.

Impact of Crystallographic Orientation Disorders on Electronic Heterogeneities in Metal Halide Perovskite Thin Films.

Metal halide perovskite thin films have achieved remarkable performance in optoelectronic devices but suffer from spatial heterogeneity in their electronic properties. To achieve higher device performance and reliability needed for widespread commercial deployment, spatial heterogeneity of optoelectronic properties in the perovskite thin film needs to be understood and controlled. Clear identification of the causes underlying this heterogeneity, most importantly the spatial heterogeneity in charge trapping behavior, has remained elusive. Here, a multimodal imaging approach consisting of photoluminescence, optical transmission, and atomic force microscopy is utilized to separate electronic heterogeneity from morphology variations in perovskite thin films. By comparing the degree of heterogeneity in highly oriented and randomly oriented polycrystalline perovskite thin film samples, we reveal that disorders in the crystallographic orientation of the grains play a dominant role in determining charge trapping and electronic heterogeneity. This work also demonstrates a polycrystalline thin film with uniform charge trapping behavior by minimizing crystallographic orientation disorder. These results suggest that single crystals may not be required for perovskite thin film based optoelectronic devices to reach their full potential.

The Relationship of Electrophysiologic Subthalamic Nucleus Length as a Predictor of Outcomes in Deep Brain Stimulation for Parkinson Disease.

BACKGROUND: Intraoperative measurement of subthalamic nucleus (STN) width through microelectrode recording (MER) is a common proxy for optimal electrode location during deep brain stimulation (DBS) surgery for Parkinson disease. We assessed whether the MER-determined STN width is a predictor of postoperative Unified Parkinson Disease Rating Scale (UPDRS) improvement. METHODS: Records were reviewed for patients who underwent single-sided STN DBS placement for Parkinson disease between 2005 and 2010 at the UAB Medical Center. Reviews of preoperative and 3-month postoperative UPDRS part III, intraoperative MER records, and postoperative MRI scans were conducted. RESULTS: The final cohort consisted of 73 patients (mean age 59 ± 9.7 years, length of disease 13 ± 9.7 years). STN widths were defined as depths associated with increased background activity and motor-driven, spiking action potentials on MER. The mean contralateral UPDRS improvement was 58% (± 24). The mean STN width was 5.1 mm (± 1.6, min = 0.0, max = 8.7). No significant relationship between STN width and UPDRS improvement was found, with and without AC-PC normalization (R2 < 0.05). CONCLUSION: This analysis raises questions about seeking the maximal electrophysiological width of STN as a proxy for optimal outcome in DBS for PD. We suggest this strategy for DBS placement in Parkinson disease be subject to more robust prospective investigation.

High-Throughput Microfluidic Labyrinth for the Label-free Isolation of Circulating Tumor Cells.

We present "Labyrinth," a label-free microfluidic device to isolate circulating tumor cells (CTCs) using the combination of long loops and sharp corners to focus both CTCs and white blood cells (WBCs) at a high throughput of 2.5 mL/min. The high yield (>90%) and purity (600 WBCs/mL) of Labyrinth enabled us to profile gene expression in CTCs. As proof of principle, we used previously established cancer stem cell gene signatures to profile single cells isolated from the blood of breast cancer patients. We observed heterogeneous subpopulations of CTCs expressing genes for stem cells, epithelial cells, mesenchymal cells, and cells transitioning between epithelial and mesenchymal. Labyrinth offers a cell-surface marker-independent single-cell isolation platform to study heterogeneous CTC subpopulations.

The effect of unilateral subthalamic nucleus deep brain stimulation on depression in Parkinson's disease.

BACKGROUND: Depression is common in Parkinson's disease (PD) and adversely affects quality of life. Both unilateral and bilateral subthalamic (STN) deep brain stimulation (DBS) effectively treat the motor symptoms of PD, but questions remain regarding the impact of unilateral STN DBS on non-motor symptoms, such as depression. METHODS: We report changes in depression, as measured by the Hamilton Depression Rating Scale (HAMD-17), in 50 consecutive PD patients who underwent unilateral STN DBS. Participants were also evaluated with UPDRS part III, Parkinson's Disease Questionnaire-39, and Pittsburgh Sleep Quality Index. The primary outcome was change in HAMD-17 at 6 months versus pre-operative baseline, using repeated measures analysis of variance (ANOVA). Secondary outcomes included the change in HAMD-17 at 3, 12, 18, and 24 months post-operatively and correlations amongst outcome variables using Pearson correlation coefficients. As a control, we also evaluated changes in HAMD-17 in 25 advanced PD patients who did not undergo DBS. RESULTS: Participants with unilateral STN DBS experienced significant improvement in depression 6 months post-operatively (4.94 ± 4.02) compared to preoperative baseline (7.90 ± 4.44) (mean ± SD) (p = <0.0001). HAMD-17 scores did not correlate with UPDRS part III at any time-point. Interestingly, the HAMD-17 was significantly correlated with sleep quality and quality of life at baseline, 3 months, and 6 months post-operatively. Participants without DBS experienced no significant change in HAMD-17 over the same interval. CONCLUSION: Unilateral STN DBS improves depression 6 months post-operatively in patients with PD. Improvement in depression is maintained over time and correlates with improvement in sleep quality and quality of life.

Pregnancy in a Series of Dystonia Patients Treated with Deep Brain Stimulation: Outcomes and Management Recommendations.

BACKGROUND: Medically refractory dystonia affects children and young adults, and deep brain stimulation (DBS) can allow some patients to regain functional independence. Women with dystonia treated with DBS may wish to conceive a child, but there is limited published information on pregnancy and DBS. OBJECTIVE: To describe a series of dystonia patients treated with DBS who later became pregnant and provide guidelines for women treated with DBS considering conception. METHODS: We reviewed all dystonia DBS cases implanted at the University of California, San Francisco, and University of Alabama at Birmingham from 1998 to 2015 and identified patients who became pregnant. Patient records were reviewed and structured interviews were conducted. RESULTS: Six dystonia patients were identified [1 currently pregnant and 7 live births (including 1 twin pair)]. Patients (n = 5) with pre- and postoperative BFMDRS (Burke-Fahn-Marsden Dystonia Rating Scale) scores improved by 65.9% after DBS. All pregnancies and deliveries were uncomplicated (the delivery mode was not influenced by the presence of DBS), except for 1 child, who was born premature at 35 weeks' gestation. Stimulation remained on (n = 3) or off (n = 4) during deliveries. DBS neurostimulators did not hinder breastfeeding. CONCLUSIONS: In this small sample, pregnancy, delivery, and breastfeeding were safe in dystonia patients treated with DBS. The presence of DBS should not be a contraindication to pregnancy.

Spatial topographies of unilateral subthalamic nucleus deep brain stimulation efficacy for ipsilateral, contralateral, midline, and total Parkinson disease motor symptoms.

BACKGROUND: Subthalamic nucleus (STN) deep brain stimulation is a successful intervention for medically refractory Parkinson disease, although its efficacy depends on optimal electrode placement. Even though the predominant effect is observed contralaterally, modest improvements in ipsilateral and midline symptoms are also observed. OBJECTIVE: To elucidate the role of contact location of unilateral deep brain stimulation on contralateral, ipsilateral, and axial subscores of Parkinson disease motor symptoms. METHODS: Eighty-six patients receiving first deep brain stimulation STN electrode placements were identified, yielding 73 patients with 3-month follow-up. Total preoperative and postoperative Unified Parkinson Disease Rating Scale Part III scores were obtained and divided into contralateral, ipsilateral, and midline subscores. Contact location was determined on immediate postoperative magnetic resonance imaging. A 3-dimensional ordinary "kriging" algorithm generated spatial interpolations for total, ipsilateral, contralateral, and midline symptom categories. Interpolative reconstructions were performed in the axial planes (z = -0.5, -1.0, -1.5, -3.5, -4.5, -6.0) and a sagittal plane (x = 12.0). Interpolation error and significance were quantified by use of a cross-validation technique and quantile-quantile analysis. RESULTS: There was an overall reduction in Unified Parkinson Disease Rating Scale Part III symptoms: total = 37.0 ± 24.11% (P < .05), ipsilateral = 15.9 ± 51.8%, contralateral = 56.2 ± 26.8% (P < .05), and midline = 26.5 ± 34.7%. Kriging interpolation was performed and cross-validated with quantile-quantile analysis with high correlation (R2 > 0.92) and demonstrated regions of efficacy for each symptom category. Contralateral symptoms demonstrated broad regions of efficacy across the peri-STN area. The ipsilateral and midline regions of efficacy were constrained and located along the dorsal STN and caudal zona incerta. CONCLUSION: We provide evidence for a unique functional topographic window in which contralateral, ipsilateral, and midline structures may achieve the best efficacy. Although there are overlapping regions, laterality demonstrates distinct topographies. Surgical optimization should target the intersection of optimal regions for these symptom categories.

The relationship between clinical phenotype and early staged bilateral deep brain stimulation in Parkinson disease.

OBJECT: While many centers place bilateral deep brain stimulation (DBS) systems simultaneously, unilateral subthalamic nucleus (STN) DBS followed by a staged contralateral procedure has emerged as a treatment option for many patients. However, little is known about whether the preoperative phenotype predicts when staged placement of a DBS electrode in the opposite STN will be required. The authors aimed to determine whether preoperative clinical phenotype predicts early staged placement of a second STN DBS electrode in patients who undergo unilateral STN DBS for Parkinson disease (PD). METHODS: Eighty-two consecutive patients with advanced PD underwent unilateral STN DBS contralateral to the most affected hemibody and had at least 2 years of follow-up. Multivariate logistic regression analysis determined preoperative characteristics that predicted staged placement of a second electrode in the opposite STN. Preoperative measurements included aspects of the Unified Parkinson's Disease Rating Scale (UPDRS), motor asymmetry index, and body weight. RESULTS: At 2-year follow-up, 28 (34%) of the 82 patients had undergone staged placement of a contralateral electrode while the remainder chose to continue with unilateral stimulation. Statistically significant improvements in UPDRS total and Part 3 scores were retained at the end of the 2-year follow-up period in both subsets of patients. Multivariate logistic regression analysis showed that the most important predictors for early staged placement of a second subthalamic stimulator were low asymmetry index (OR 13.4, 95% CI 2.8-64.9), high tremor subscore (OR 7.2, CI 1.5-35.0), and low body weight (OR 5.5, 95% CI 1.4-22.3). CONCLUSIONS: This single-center study provides evidence that elements of the preoperative PD phenotype predict whether patients will require early staged bilateral STN DBS. These data may aid in the management of patients with advanced PD who undergo STN DBS.

Unilateral subthalamic nucleus deep brain stimulation improves sleep quality in Parkinson's disease.

BACKGROUND: Sleep disturbances are common in Parkinson's disease (PD). Bilateral subthalamic nucleus (STN) deep brain stimulation (DBS) is superior to best medical therapy in the treatment of motor symptoms in advanced PD, and observational studies suggest that bilateral STN DBS improves sleep in these patients as well. Unilateral STN DBS also improves motor function in PD, but its effects on sleep have not been extensively investigated. METHODS: We report the effects of unilateral STN DBS on subjective sleep quality as measured by the Pittsburgh Sleep Quality Index (PSQI) in 53 consecutive PD patients. These subjects completed the PSQI prior to surgery and at 3 and 6 months post-operatively. The primary outcome measure was the change in the global PSQI at 6 months post-operatively versus the pre-operative baseline, measured with repeated measures analysis of variance (ANOVA). RESULTS: Patients with PD who underwent unilateral STN DBS had a significant improvement in PSQI at 6 months post-operatively (baseline 9.30 ± 0.56 (mean ± SEM), 6 months: 7.93 ± 0.56, p = 0.013). Supplemental analyses showed that subjects selected for STN DBS placed on the right had worse baseline subjective sleep quality and more improvement in PSQI at 6 months compared to patients who received left STN DBS. CONCLUSION: This prospective case series study provides evidence that unilateral STN DBS improves subjective sleep quality in patients with PD at up to 6 months post-operatively as measured by the PSQI.

Activation of subthalamic neurons by contralateral subthalamic deep brain stimulation in Parkinson disease.

Multiple studies have shown bilateral improvement in motor symptoms in Parkinson disease (PD) following unilateral deep brain stimulation (DBS) of the subthalamic nucleus (STN) and internal segment of the globus pallidus, yet the mechanism(s) underlying this phenomenon are poorly understood. We hypothesized that STN neuronal activity is altered by contralateral STN DBS. This hypothesis was tested intraoperatively in humans with advanced PD using microelectrode recordings of the STN during contralateral STN DBS. We demonstrate alterations in the discharge pattern of STN neurons in response to contralateral STN DBS including short latency, temporally precise, stimulation frequency-independent responses consistent with antidromic activation. Furthermore, the total discharge frequency during contralateral high frequency stimulation (160 Hz) was greater than during low frequency stimulation (30 Hz) and the resting state. These findings demonstrate complex responses to DBS and imply that output activation throughout the basal ganglia-thalamic-cortical network rather than local inhibition is a therapeutic mechanism of DBS.

Construction of relational topographies from the quantitative measurements of functional deep brain stimulation using a 'roving window' interpolation algorithm.

The delivery of stimulus by a deep brain stimulation (DBS) contact electrode at a particular location may lead to a quantifiable physiologic effect, both intraoperatively and postoperatively. Consequently, measured data values can be attributed to discrete scattered points in neuroanatomic space, allowing for interpolative techniques to generate a topographic map of spatial patterns. Ultimately, by relating the topographies of various intraoperative measurements to the postoperative counterparts and neuroanatomic atlases, outcome-guided adjustments to electrode position can be pursued intraoperatively. In this study, 52 Parkinson's disease patients were tested with a postoperative trial of stimulation and thresholds were recorded for motor adverse effects. A 'roving window' interpolation algorithm was adapted to generate a topographic map of voltage threshold along selected axial, coronal and sagittal planes. By developing these relational topographies for a variety of intraoperative and postoperative effects, a multivariable approach towards DBS optimization emerges.

Relief of acquired stuttering associated with Parkinson's disease by unilateral left subthalamic brain stimulation.

PURPOSE: In this article, the authors report a case of acquired stuttering associated with Parkinson's disease (PD) that was responsive to unilateral subthalamic nucleus deep-brain stimulation (STN DBS) in the language-dominant hemisphere. METHOD: A single-subject, masked, multiple baseline design was used to evaluate the effects of unilateral left STN DBS on stuttering associated with PD. The patient underwent 3 formal speech assessments of spontaneous speech and the reading of passages with DBS off and on. Speech samples were videotaped and placed in random order, and 2 independent speech-language pathologists calculated the percentage of stuttered syllables and classified individual stuttering events. RESULTS: Stuttering improved significantly in the DBS-on condition. In total, 10% of syllables were affected by stuttering events with DBS off, and less than 1% of syllables were affected by stuttering events with DBS on (n = 2,281 syllables, p < .00001, in a chi(2) test). The effect of unilateral STN DBS on stuttering was relatively independent of whether the patient was on or off dopaminergic medications. CONCLUSION: This article emphasizes the important role of the subthalamic region in the motor control of speech and language.

The influence of viewpoint and object detail in blind people when matching pictures to complex objects.

We examined haptic viewpoint effects in blindfolded-sighted (BS) and visually impaired subjects: early blind (EB), late blind (LB), and very low vision (VLV). Participants felt complex objects and matched tangible pictures to them. In experiment 1, the EB and BS subjects had similar overall performance. Experiment 2 showed that the presence of a detail on the target object lowered performance in the BS subjects, and that matching accuracy was lower overall for top views for the blind subjects. In experiments 3-5, EB, LB, VLV, and BS subjects made judgments about perspective pictures of a model house with more salient object details. In experiment 3, performance was higher for side views than for corner views. Elevated side views were identified more readily than elevated corner views in experiment 4. Performance for top views was higher than for elevated side views in experiment 5, given the relative simplicity of the top-view depictions and salient details. The EB and BS participants had somewhat lower matching accuracy scores than the other groups. We suggest that visual experience is helpful, but not essential for picture perception. Viewpoint effects may vary with experience and object complexity, but the relevant experience need not be specifically visual in nature.

Bilateral effects of unilateral subthalamic deep brain stimulation on Parkinson's disease at 1 year.

OBJECTIVE: To quantify the benefit of unilateral subthalamic nucleus (STN) deep brain stimulation (DBS) on contralateral, ipsilateral, and axial symptoms of advanced Parkinson's disease. METHODS: Thirty-seven patients received unilateral STN DBS and were rated on the Unified Parkinson's Disease Rating Scale (UPDRS) and timed tests of motor function in the "practically defined off" state at baseline and at 3, 6, and 12 months postoperatively. RESULTS: UPDRS motor scores improved significantly at 3, 6, and 12 months relative to the preoperative baseline (P < 0.001, 37.1% at 1 year). There was improvement in the contralateral UPDRS subscores (P < 0.001, 54.6% at 1 year), and although contralateral benefit was larger on all outcome measures, ipsilateral benefit was present at 3 and 6 months on the UPDRS subscore (P = 0.013 and 23.5%, P = 0.005 and 27.7%, respectively). A trend toward ipsilateral benefit was present on the UPDRS subscore at 12 months; however, the effect was not statistically significant. Two timed tests of motor function in the upper extremities showed significant ipsilateral benefit in bradykinesia at 12 months (P < 0.001 and P = 0.014, respectively). Significant benefit was also observed in the UPDRS part 2 "off" medications and the UPDRS part 4 after unilateral STN DBS at 12 months (both P < 0.001). CONCLUSION: Considering the bilateral effects and tolerability of unilateral STN DBS, unilateral stimulation followed by a contralateral procedure later, if necessary, is a reasonable option for patients with advanced Parkinson's disease, especially with prominent asymmetry.

Weight changes associated with unilateral STN DBS and advanced PD.

Weight gain following bilateral subthalamic nucleus deep brain stimulation (STN DBS) in Parkinson disease (PD) has been characterized previously, but little is known about changes in weight following unilateral STN DBS. Weight gain of approximately 10 kg at one year after bilateral STN DBS for PD has been noted in previous studies, and PD in the absence of DBS has been associated with weight loss. A case-control comparison evaluated the change in weight following unilateral STN DBS in PD. In 39 patients who underwent unilateral STN DBS for PD, we measured the weight change over 1 year versus both preoperative weight change and the weight change in 40 age- and disease severity-matched PD controls without DBS. Regression analyses incorporating age, gender, baseline weight in case or control were conducted to assess weight changes. At 12 months following surgery, the mean weight of unilateral STN DBS patients increased by 4.3+/-7.2 kg versus the preoperative baseline weight (p<0.001) and this increase was 4.8 kg compared with the controls (p=0.015). Over a 1 year time interval, weight gain occurred in 41% of the preoperative unilateral STN DBS patients and 45% of the PD controls, while 85% of the unilateral STN DBS patients had gained weight at 12 months after surgery (p<0.0001, respectively, chi square test). We conclude that unilateral STN DBS in PD is associated with weight gain, which offsets weight loss associated with advanced PD.