An update on dual targeting strategy for cancer treatment.

The key issue in the treatment of solid tumors is the lack of efficient strategies for the targeted delivery and accumulation of therapeutic cargoes in the tumor microenvironment (TME). Targeting approaches are designed for more efficient delivery of therapeutic agents to cancer cells while minimizing drug toxicity to normal cells and off-targeting effects, while maximizing the eradication of cancer cells. The highly complicated interrelationship between the physicochemical properties of nanoparticles, and the physiological and pathological barriers that are required to cross, dictates the need for the success of targeting strategies. Dual targeting is an approach that uses both purely biological strategies and physicochemical responsive smart delivery strategies to increase the accumulation of nanoparticles within the TME and improve targeting efficiency towards cancer cells. In both approaches, either one single ligand is used for targeting a single receptor on different cells, or two different ligands for targeting two different receptors on the same or different cells. Smart delivery strategies are able to respond to triggers that are typical of specific disease sites, such as pH, certain specific enzymes, or redox conditions. These strategies are expected to lead to more precise targeting and better accumulation of nano-therapeutics. This review describes the classification and principles of dual targeting approaches and critically reviews the efficiency of dual targeting strategies, and the rationale behind the choice of ligands. We focus on new approaches for smart drug delivery in which synthetic and/or biological moieties are attached to nanoparticles by TME-specific responsive linkers and advanced camouflaged nanoparticles.

Neural activity in self-identified claustrophobic individuals under in-vivo stimuli: A human electroencephalography dataset.

The electrocortical activity in claustrophobic situations is a very limited field of study and has recently caught researchers' attention. This article represents a set of electroencephalographic (EEG) data obtained from twenty-two participants. The volunteers include 9 participants with self-identified claustrophobia and 13 healthy controls under in-vivo stimuli. The EEG data were recorded using Mitsar 31-channel EEG system. Before cortical signal recording, Individuals were asked to identify themselves as healthy controls or claustrophobic participants. The EEG data collection process consisted of three experimental conditions. In all conditions, the participants were asked to stay calm and keep their eyes open. The first experimental condition was at seated resting state in a relatively large and well-lit laboratory (8m × 15m) area. In the second experimental condition, the subjects entered a moderately-lit chamber and repeated the previous resting situation. The final condition of the EEG data acquisition was performed in the same chamber but with reduced dimensions. For each experimental condition, duration of data collection was approximately 300 s. This data can be used to understand the brain's response in claustrophobic situations through various statistical or data-driven methods.

Co-delivery of doxorubicin and conferone by novel pH-responsive ß-cyclodextrin grafted micelles triggers apoptosis of metastatic human breast cancer cells.

Adjuvant-aided combination chemotherapy is one of the most effective ways of cancer treatment by overcoming the multidrug resistance (MDR) and reducing the side-effects of anticancer drugs. In this study, Conferone (Conf) was used as an adjuvant in combination with Doxorubicin (Dox) for inducing apoptosis to MDA-MB-231 cells. Herein, the novel biodegradable amphiphilic ß-cyclodextrin grafted poly maleate-co-PLGA was synthesized by thiol-ene addition and ring-opening process. Micelles obtained from the novel copolymer showed exceptional properties such as small size of around 34.5 nm, CMC of 0.1 µg/mL, and cell internalization of around 100% at 30 min. These novel engineered micelles were used for combination delivery of doxorubicin-conferone with high encapsulation efficiency of near 100% for both drugs. Our results show that combination delivery of Dox and Conf to MDA-MB-231 cells had synergistic effects (CI < 1). According to cell cycle and Annexin-V apoptosis analysis, Dox-Conf loaded micelle significantly induce tumor cell apoptosis (more than 98% of cells population showed apoptosis at IC50 = 0.259 µg/mL). RT-PCR and western-blot tests show that Dox-Conf loaded ßCD-g-PMA-co-PLGA micelle induced apoptosis via intrinsic pathway. Therefore, the unique design of multi-functional pH-sensitive micelles open a new perspective for the development of nanomedicine for combination chemo-adjuvant therapy against malignant cancer.

Electroencephalographic Activity in Patients with Claustrophobia: A Pilot Study.

BACKGROUND: Exposure to small confined spaces evokes physiological responses such as increased heart rate in claustrophobic patients. However, little is known about electrocortical activity while these people are functionally exposed to such phobic situations. The aim of this study was to examine possible changes in electrocortical activity in this population. METHOD: Two highly affected patients with claustrophobia and two healthy controls participated in this in vivo study during which electroencephalographic (EEG) activity was continuously recorded. Relative power spectral density (rPSD) was compared between two situations of being relaxed in a well-lit open area, and sitting in a relaxed chair in a small (90 cm × 180 cm × 155 cm) chamber with a dim light. This comparison of rPSDs in five frequency bands of EEG was intended to investigate possible patterns of change in electrical activity during fear-related situation. This possible change was also compared between claustrophobic patients and healthy controls in all cortical areas. RESULTS: Statistical models showed that there is a significant interaction between groups of participants and experimental situations in all frequency bands (P < 0.01). In other words, claustrophobic patients showed significantly different changes in electrical activity while going from rest to the test situation. Clear differences were observed in alpha and theta bands. In the theta band, while healthy controls showed an increase in rPSD, claustrophobic patients showed an opposite decrease in the power of electrical activity when entering the confined chamber. In alpha band, both groups showed an increase in rPSD, though this increase was significantly higher for claustrophobic patients. CONCLUSION: The effect of in vivo exposure to confined environments on EEG activity is different in claustrophobic patients than in healthy controls. Most of this contrast is observed in central and parietal areas of the cortex, and in the alpha and theta bands.

Novel Methotrexate-Ciprofloxacin Loaded Alginate-Clay Based Nanocomposite as Anticancer and Antibacterial Co-Drug Delivery System.

Purpose: In last decades, by increasing multi-drug resistant microbial pathogens an urgent demand was felt in the development of novel antimicrobial agents. Methods: Promising nanocomposites composed of clay/alginate/imidazolium-based ionic liquid, have been developed via intercalation of calcium alginate and ionic liquid by ion exchange method. These tailored nanocomposites were used as nanocarriers to simultaneously deliver methotrexate (MTX), and ciprofloxacin (CIP), as anticancer and antibacterial agents, respectively to MCF-7 breast cancer cells. Nanocomposites were fully characterized by scanning electron microscopy studies (SEM), X-ray diffraction (XRD), Fourier transforms infrared (FTIR) spectroscopy, and thermogravimetric analysis (TGA) methods. The in vitro antimicrobial potential of the mentioned nanocomposites in free and dual-drug loaded form was investigated on Pseudomonas aeruginosa and Escherichia coli bacteria. The antitumor activity of nano-formulations was evaluated by both MTT assay and cell cycle arrest. Results: The dual drug-loaded nanocomposites with exceptionally high loading efficiency (MTX: 99 ±0.4% and CIP: 98 ±1.2%) and mean particle size of 70 nm were obtained with obvious pH-responsive MTX and CIP release (both drugs release rate was increased at pH 5.8 compared to 7.4). The antibacterial activity of CIP-loaded nanocomposites was significantly higher in comparison with free CIP (P <0.001). The antitumor activity results revealed that MTX cytotoxicity on MCF-7 cells was significantly higher in nano-formulations compared to free MTX (P <0.001). Both MTX-loaded nanocomposites caused S-phase arrest in MCF-7 cells compared to non-treated cells (P ˂ 0.001). Conclusion: Newly developed smart nanocomposites are potentially effective pH-sustainable delivery systems for enhanced tumor therapy.

Objective assessment of spasticity by pendulum test: a systematic review on methods of implementation and outcome measures.

BACKGROUND: Instrumented pendulum test is an objective and repeatable biomechanical method of assessment for spasticity. However, multitude of sensor technologies and plenty of suggested outcome measures, confuse those interested in implementing this method in practice. Lack of a standard agreement on the definition of experimental setup and outcome measures adds to this ambiguity and causes the results of one study not to be directly attainable by a group that uses a different setup. In this systematic review of studies, we aim to reduce the confusion by providing pros and cons of the available choices, and also by standardizing the definitions. METHODS: A literature search was conducted for the period of 1950 to the end of 2019 on PubMed, Science Direct, Google Scholar and IEEE explore; with keywords of "pendulum test" and "Spasticity". RESULTS: Twenty-eight studies with instrumented pendulum test for assessment of spasticity met the inclusion criteria. All the suggested methods of implementation were compared and advantages and disadvantages were provided for each sensor technology. An exhaustive list categorized outcome measures in three groups of angle-based, angular velocity-based, and angular acceleration-based measures with all different names and definitions. CONCLUSIONS: With the aim of providing standardized methodology with replicable and comparable results, sources of dissimilarity and ambiguity among research strategies were found and explained with the help of graphical representation of pendulum movement stages and corresponding parameters on the angular waveforms. We hope using the provided tables simplify the choices when implementing pendulum test for spasticity evaluation, improve the consistency when reporting the results, and disambiguate inconsistency in the literature.

Synthesis and characterization of novel P(HEMA-LA-MADQUAT) micelles for co-delivery of methotrexate and Chrysin in combination cancer chemotherapy.

A Novel poly [2-hydroxyethyl methacrylate-Lactide-dimethylaminoethyl methacrylate quaternary ammonium alkyl halide] [P(HEMA-LA-MADQUAT)] copolymer was synthesized through combination of ring opening polymerization (ROP) and 'free' radical initiated polymerization methods. This newly developed copolymer was fully characterized by FT-IR, 1HNMR and 13CNMR spectroscopy. Micellization of the copolymer was performed by dialysis membrane method and obtained micelles were characterized by FESEM, dynamic light scattering (DLS), zeta potential (ξ), and critical micelle concentration (CMC) measurements. This copolymer was developed with the aim of co-delivering two different anticancer drugs: methotrexate (MTX) and chrysin. In vitro cytotoxicity effect of MTX@Chrysin-loaded P(HEMA-LA-MADQUAT) was also studied through assessing the survival rate of breast cancer cell line (MCF-7) and DAPI staining assays. Cationic micelle (and surface charge of + 7.6) with spherical morphology and an average diameter of 55 nm and CMC of 0.023 gL-1 was successfully obtained. Micelles showed the drug loaded capacity around 87.6 and 86.5% for MTX and Chrysin, respectively. The cytotoxicity assay of a drug-free nanocarrier on MCF-7 cell lines indicated that this developed micelles were suitable nanocarriers for anticancer drugs. Furthermore, the MTX@Chrysin-loaded micelle had more efficient anticancer performance than free dual anticancer drugs (MTX @ chrysin), confirmed by MTT assay and DAPI stainingmethods. Therefore, we envision that this recently developed novel micelle can enhance the efficacy of chemotherapeutic agents, MTX and Chrysin, combination chemotherapy and has the potential to be used as an anticancer drug delivery system for in vivo studies. Therefore, this recently developed novel micelle can enhance the efficacy of chemotherapeutic agents, MTX and Chrysin, combination chemotherapy and has the potential to be used as an anticancer drug delivery system for in vivo studies.

Carbon quantum dots: recent progresses on synthesis, surface modification and applications.

Generally, carbon nanoparticles with a size of 10 nm (or less) are called carbon quantum dots (CQDs, C-dots or CD), which have created huge excitement due to their advantages in chemical inertness, high water solubility, excellent biocompatibility, resistance to photobleaching and various optical superiority. In this article, we describe the recent advancements in the area of CQDs; concentrating on their synthesis techniques, size control, surface modification approaches, optical properties, luminescent mechanism, and their applications in bioimaging, biosensing, drug delivery and catalysis.

Patterns and predictors of freezing of gait improvement following rasagiline therapy: A pilot study.

OBJECTIVES: Freezing of gait (FoG) is a challenging clinical symptom in Parkinson's disease with variable improvements in FoG with rasagiline. In this prospective, uncontrolled, pre-/post- treatment pilot study, we explore the clinical variables that contribute to this variability and those that predict improvement. PATIENTS AND METHODS: Frequency and duration of FoG, along with other standardized scales, were evaluated in 18 optimally medicated PD participants with intractable FoG, prior to and after completion of a 90-day course of 1mg daily rasagiline. Gait tasks were video-recorded and analyzed by two independent reviewers. After evaluating the simple main effect, hierarchical cluster analysis was used to identify subgroups for treatment responsiveness. Bidirectional elimination stepwise regression analysis was conducted to identify which clinical variables predicted reduction in frequency of FoG events post-treatment. RESULTS: There were no overall pre-/post- treatment improvements, a result driven by a heterogeneous response to treatment. Three subgroups were identified: improved (n=6) with a 136% and 162% reduction in FoG count and duration; worsened (n=5) with 154% and 141% increase in FoG count and duration; and no change (n=3). The final predictive model had good explanatory power (adjusted-R2=0.9898, p<0.01), explaining 99% of the variance between the improved and worsened groups. In this model, lower UPDRS gait scores, higher LEDD dose, lower anxiety scores, lower FOG-Q scores, and higher UPDRS scores for lower extremity rigidity and rise from chair, predicted FoG-related rasagiline benefit. CONCLUSION: Using both objective and subjective measures for FoG, the current pilot study identified a set of clinical variables that may elucidate the heterogeneous FoG-responsiveness following rasagiline treatment and aid in predicting improvement.

Predicting Improvement in Writer's Cramp Symptoms following Botulinum Neurotoxin Injection Therapy.

INTRODUCTION: Writer's cramp is a specific focal hand dystonia causing abnormal posturing and tremor in the upper limb. The most popular medical intervention, botulinum neurotoxin type A (BoNT-A) therapy, is variably effective for 50-70% of patients. BoNT-A non-responders undergo ineffective treatment and may experience significant side effects. Various assessments have been used to determine response prediction to BoNT-A, but not in the same population of patients. METHODS: A comprehensive assessment was employed to measure various symptom aspects. Clinical scales, full upper-limb kinematic measures, self-report, and task performance measures were assessed for nine writer's cramp patients at baseline. Patients received two BoNT-A injections then were classified as responders or non-responders based on a quantified self-report measure. Baseline scores were compared between groups, across all measures, to determine which scores predicted a positive BoNT-A response. RESULTS: Five of nine patients were responders. No kinematic measures were predictably different between groups. Analyses revealed three features that predicted a favorable response and separated the two groups: higher than average cramp severity and cramp frequency, and below average cramp latency. DISCUSSION: Non-kinematic measures appear to be superior in making such predictions. Specifically, measures of cramp severity, frequency, and latency during performance of a specific set of writing and drawing tasks were predictive factors. Since kinematic was not used to determine the injection pattern and the injections were visually guided, it may still be possible to use individual patient kinematics for better outcomes.

Haptic Feedback Manipulation During Botulinum Toxin Injection Therapy for Focal Hand Dystonia Patients: A Possible New Assistive Strategy.

Abnormality of sensorimotor integration in the basal ganglia and cortex has been reported in the literature for patients with task-specific focal hand dystonia (FHD). In this study, we investigate the effect of manipulation of kinesthetic input in people living with writer's cramp disorder (a major form of FHD). For this purpose, severity of dystonia is studied for 11 participants while the symptoms of seven participants have been tracked during five sessions of assessment and Botulinum toxin injection (BoNT-A) therapy (one of the current suggested therapies for dystonia). BoNT-A therapy is delivered in the first and the third session. The goal is to analyze the effect of haptic manipulation as a potential assistive technique during BoNT-A therapy. The trial includes writing, hovering, and spiral/sinusoidal drawing subtasks. In each session, the subtasks are repeated twice when (a) a participant uses a normal pen, and (b) when the participant uses a robotics-assisted system (supporting the pen) which provides a compliant virtual writing surface and manipulates the kinesthetic sensory input. The results show (p-value using one-sample t-tests) that reducing the writing surface rigidity significantly decreases the severity of dystonia and results in better control of grip pressure (an indicator of dystonic cramping). It is also shown that (p-value based on paired-samples t-test) using the proposed haptic manipulation strategy, it is possible to augment the effectiveness of BoNT-A therapy. The outcome of this study is then used in the design of an actuated pen as a writing-assistance tool that can provide compliant haptic interaction during writing for FHD patients.

Functional Ability Improved in Essential Tremor by IncobotulinumtoxinA Injections Using Kinematically Determined Biomechanical Patterns - A New Future.

OBJECTIVE: Effective treatment for functional disability caused by essential tremor is a significant unmet need faced by many clinicians today. Current literature regarding focal therapy by botulinum toxin type A (BoNT-A) injections uses fixed dosing regimens, which cannot be individualized, provides only limited functional benefit and unacceptable muscle weakness commonly occurs. This 38-week open label study, the longest to-date, demonstrates how kinematic technology addressed all these issues by guiding muscle selection. METHOD: Participants (n = 24) were assessed at weeks 0, 6, 16, 22, 32, and 38 and injected with incobotulinumtoxinA at weeks 0, 16, and 32. Clinical assessments including UPDRS tremor items, Fahn-Tolosa-Marin (FTM) tremor rating scale assessing tremor severity, writing and functional ability, quality of life questionnaire (QUEST) and objective kinematic assessments were completed at every visit. Participants performed two postural and two weight-bearing scripted tasks with motion sensors placed over the wrist, elbow and shoulder joints. These sensors captured angular tremor amplitude (RMS units) and acceleration joint motion that was segmented into directional components: flexion-extension (F/E), pronation-supination and radial-ulnar at the wrist, F/E at the elbow, and F/E and adduction-abduction at the shoulder. Injection parameters were determined using kinematics, followed by the clinician's determination of which muscles would contribute to the specific upper limb tremor biomechanics and dosing per participant. RESULTS: Multi-joint biomechanical recordings allowed individualized muscle selection and showed significant improvement in whole-arm function, FTM parts A-C scores, at week 6 which continued throughout the study. By week 38, the total FTM score statistically significantly reduced from 16.2±4.6 at week 0 to 9.5±6.3 (p<0.0005). UPDRS item 21 score rating action tremor was significantly reduced from 2.6±0.5 at week 0 to 1.6±1.1 (p = 0.01) at week 32. Quality of life (QUEST) significantly improved from 40.3±15.8 at week 0 to 31.1±15.3 (p = 0.035) at week 32 and to 27.8±15.3 (p = 0.028) at week 38. Kinematics provided an objective, secondary outcome measure, which showed a significant decrease in tremor amplitude in the wrist and shoulder joints (p<0.05). Eight participants (40%) self-reported mild weakness in injected muscles but had no interference in arm function. CONCLUSION: Kinematic tremor assessments provide the injector unique insight to objectively individualize and personalize injection parameters demonstrating BoNT-A effectively alleviates functional disability caused by essential tremor. Kinematic technology is a promising method for standardizing assessments and for focal upper limb tremor treatment. TRIAL REGISTRATION: ClinicalTrials.gov NCT02427646.

Kinematic and kinetic assessment of upper limb movements in patients with writer's cramp.

BACKGROUND: The assessment and treatment of writer's cramp is complicated due to the variations in the forces and angles of involved joints. Additionally, in some cases compensatory movements for cramp relief further complicates assessment. Currently these variables are subjectively measured with clinical scales and visual assessments. This subjectivity makes it difficult to successfully administer interventions such as Botulinum toxin injection or orthotics resulting in poor efficacy and significant side effects. METHOD: A multi-sensor system was used to record finger and wrist forces along with deviation angles at the wrist, elbow and shoulder while 9 patients with writer's cramp performed a series of standardized tasks on surfaces inclined at different angles. Clinical, kinetic, and kinematic information regarding cramping was collected. RESULTS: First, four tasks appeared to best predict cramp occurrence. Second, unique biomechanical profiles emerged for patients regarding force, angles and cramp severity. Third, cluster analyses using these features showed a clear separation of patients into two severity classes. Finally, a relationship between severity and kinetic-kinematic information suggested that primary cramping versus compensatory movements could be potentially inferred. CONCLUSIONS: The results demonstrate that using a set of standardized tasks and objective measures, individual profiles for arm movements and applied forces associated with writer's cramp can be generated. The clinician can then accurately target the biomechanics specifically, whether it is with injection or other rehabilitative measures, fulfilling an important unmet need in the treatment of writer's cramp.

Effective Management of Upper Limb Parkinsonian Tremor by IncobotulinumtoxinA Injections Using Sensor-based Biomechanical Patterns.

BACKGROUND: Focal treatment of Parkinson's disease tremor by botulinum toxin type A incobotulinumtoxinA (BoNT-A) injections has been inadequately investigated and at best provides modest relief with significant muscle weakness. Complexity of multi-joint tremulous movements results in non-individualized dosing regimens. This 38-week open-label study used kinematic technology to guide muscle selection and improve efficacy of incobotulinumtoxinA (BoNT-A) injections for Parkinson's disease tremor. METHODS: Participants (n=28) attended study visits at weeks 0, 6, 16, 22, 32, and 38, and were injected with BoNT-A at weeks 0, 16, and 32. During each visit, clinical tremor scales, the Unified Parkinson's Disease Rating Scale (UPDRS) and the Fahn-Tolosa-Marin (FTM), and kinematic assessments were conducted. Participants performed rest and postural scripted tasks with motion sensors placed over the wrist, elbow, and shoulder joints where tremor was quantified by angular root mean square (RMS) amplitude in multiple degrees of freedom at each joint. Injection parameters were determined using the clinician's interpretation of which muscles would contribute to the upper limb tremor biomechanics analyzed kinematically. RESULTS: Kinematic measures of tremor amplitude allowed detailed segmentation of tremor into directional components at each arm joint permitting a statistically significant decrease in mean UPDRS item 20 (rest tremor) at week 16 (p=0.006) and at week 32 (p=0.014), and in FTM tremor severity scores at week 6 (p=0.024). Ten participants perceived mild muscle weakness following the third treatment, which did not interfere with performing activities of daily living. DISCUSSION: Kinematics is a simple method for standardizing assessments and treatment of upper limb Parkinson's disease tremor, thereby personalizing tremor therapy and optimizing the effect of BoNT-A injections for Parkinson's disease tremor.

Auto detection and segmentation of physical activities during a Timed-Up-and-Go (TUG) task in healthy older adults using multiple inertial sensors.

BACKGROUND: Recently, much attention has been given to the use of inertial sensors for remote monitoring of individuals with limited mobility. However, the focus has been mostly on the detection of symptoms, not specific activities. The objective of the present study was to develop an automated recognition and segmentation algorithm based on inertial sensor data to identify common gross motor patterns during activity of daily living. METHOD: A modified Time-Up-And-Go (TUG) task was used since it is comprised of four common daily living activities; Standing, Walking, Turning, and Sitting, all performed in a continuous fashion resulting in six different segments during the task. Sixteen healthy older adults performed two trials of a 5 and 10 meter TUG task. They were outfitted with 17 inertial motion sensors covering each body segment. Data from the 10 meter TUG were used to identify pertinent sensors on the trunk, head, hip, knee, and thigh that provided suitable data for detecting and segmenting activities associated with the TUG. Raw data from sensors were detrended to remove sensor drift, normalized, and band pass filtered with optimal frequencies to reveal kinematic peaks that corresponded to different activities. Segmentation was accomplished by identifying the time stamps of the first minimum or maximum to the right and the left of these peaks. Segmentation time stamps were compared to results from two examiners visually segmenting the activities of the TUG. RESULTS: We were able to detect these activities in a TUG with 100% sensitivity and specificity (n = 192) during the 10 meter TUG. The rate of success was subsequently confirmed in the 5 meter TUG (n = 192) without altering the parameters of the algorithm. When applying the segmentation algorithms to the 10 meter TUG, we were able to parse 100% of the transition points (n = 224) between different segments that were as reliable and less variable than visual segmentation performed by two independent examiners. CONCLUSIONS: The present study lays the foundation for the development of a comprehensive algorithm to detect and segment naturalistic activities using inertial sensors, in hope of evaluating automatically motor performance within the detected tasks.

Dynamic decomposition of motion in essential and parkinsonian tremor.

BACKGROUND: Treatment options for essential (ET) and Parkinson disease (PD) tremor are suboptimal, with significant side effects. Botulinum toxin type A (BoNT A) is successfully used in management of various focal movement disorders but is not widely used for tremor. METHOD: This study examines complexity of wrist tremor in terms of involvement of its three anatomical degrees of freedom (DOF) in two common situations of rest and posture. The study examines tremor in 11 ET and 17 PD participants by kinematic decomposition of motion in 3-DOF. RESULTS: Tremor decomposition showed the motion involved more than one DOF (<70% contribution in one DOF) in most ET (rest: 100%, posture: 64%) and PD (rest: 77%, posture: 77%) patients. Task variation resulted in change in both amplitude and composition in ET, but not in PD. Amplitude significantly increased from rest to posture in ET. Directional bias was observed at the wrist for ET (pronation), and PD (extension, ulnar deviation, pronation). Average agreement between clinical visual and kinematic selection of muscles was 55% across all subjects. CONCLUSION: This study shows the complexity of tremor and the difficulty in visual judgment of tremor, which may be key to the success of targeted focal treatments such as BoNT A.

Subgroup analysis of PD tremor with loading: action tremor as a combination of classical rest and physiological tremor.

BACKGROUND: In Parkinson disease, tremor is a challenging symptom to manage, partly due to inadequate characterization. The current (classic) model of tremor is characterized by a resting tremor with a single strong peak in 3.5-6.5Hz range. The presence of action tremor, including postural, isometric, and kinetic tremors, has been disputed in the literature but not comprehensively evaluated. Analysis of hand tremor in action compared to rest, and possible subgrouping of tremor trends, may improve characterization. METHODS: Twenty Parkinson patients and 14 controls were recruited. Tremor amplitude was measured across 9 sequentially loaded tasks, in off and on medication states. Tremor energy was separated into 2 frequency bands (B1, 3.5-6.5Hz; B2=physiological tremor, 7.5-16.5Hz) across all activity levels. Automatic classification was used for subgroup analysis. FINDINGS: Automatic classification yielded 3 predominant tremor trends (G1, G2, and G3). These were significantly different from each other and from controls. G1 demonstrated closest resemblance to classical Parkinsonian tremor, with highest tremor energy at rest and with overall dominance in B1 for lower loads. G2-G3 did not show tremor energy dominance in either band. Medication reduced tremor energy only for G1 in both B1 and B2. INTERPRETATION: Subgrouping the loading effect on tremor is a novel and viable method of rationalizing (non-classic) action tremor in Parkinson disease. Rest and action tremors appear not to be limited to 3.5-6.5Hz and may have considerable share of physiological tremor. Finding the contribution of each frequency band to total tremor energy and their trends with load may optimize therapy options.

The dopaminergic system in upper limb motor blocks (ULMB) investigated during bimanual coordination in Parkinson's disease (PD).

Upper limb motor blocks (ULMB) (inability to initiate or sudden discontinue in voluntary movements) have been identified in both unimanual and bimanual tasks in individuals with Parkinson's disease (PD). In particular, ULMB have been observed during rhythmic bimanual coordination when switching between phase patterns which is required (e.g. between in-phase and anti-phase). While sensory-perceptual mechanisms have recently been suggested to be involved in lower limb freezing, there has been no consensus on the mechanism that evokes ULMB or whether motor blocks respond to dopamine replacement like other motor symptoms of PD. The current study investigated the occurrence of ULMB in PD participants without ('off') and with ('on') dopamine replacement using bimanual wrist flexion-extension with external auditory cues. In Experiment 1, coordination was performed in either in-phase (simultaneous flexion and extension) or anti-phase (asymmetrical flexion and extension between the limbs) in one of three sensory conditions: no vision, normal vision or augmented vision. Cycle frequency was increased within each trial across seven cycle frequencies (0.75-2 Hz). In Experiment 2, coordination was initiated in either phase pattern and participants were cued to make an intentional switch between phases in the middle of trials. Trials were performed at one of two cycle frequencies (1 or 2 Hz) and one of two sensory conditions: no vision or normal vision. Healthy age-matched control participants were also investigated in both experiments for the occurrence of motor blocks that were measured using automated detection from a computer algorithm. The results from Experiment 1 indicated that increasing cycle frequency resulted in more ULMB in individuals with PD during continuous coordinated movement, regardless of dopaminergic status, phase pattern or sensory condition. Experiment 2 also confirmed an increased occurrence of ULMB with increased cycle frequency. Furthermore, a large amount of ULMB were observed when initiating anti-phase coordination at 2 Hz, as well as after both externally-cued switches and in 'catch trials' with distracting auditory cues when no switch was required. Dopamine replacement was not found to influence the frequency of ULMB in either experiment. Therefore, ULMB likely result from non-hypodopaminergic impairments associated with PD. Specifically, ULMB may be caused by an inability to shift attentional control under increased cognitive demand that could be associated with hypoactivation in motor and prefrontal areas.

Using ecological whole body kinematics to evaluate effects of medication adjustment in Parkinson disease.

BACKGROUND: Functional motor impairments including mobility are major reasons for clinical intervention and medication adjustment in symptomatic therapy for Parkinson's disease (PD). Outcome measures used to assess the impact of medication are mostly based on patients' memory or diaries which, considering the gaps between visits, are neither objective nor very reliable. OBJECTIVE: Investigating the feasibility of using movement features extracted from ecological whole-body kinematics recordings to measure the quantitative and qualitative changes in multiple aspects of mobility after medication changes in PD. METHODS: Eleven patients with PD (PwPD) performed mobility tasks in their own home, wearing a full body wireless inertial sensing based motion capture system. Three scripted walking tasks (walking, fast walking, and walk turns) were examined at baseline and two weeks after medication changes. Clinical scales, including investigator-rated clinical global impression of improvement (CGI-I), were collected at both visits. RESULTS: Out of 59 recorded body joint variables, five were identified as pertinent. Changes were represented in vector space as a plot of mean versus peak amplitude. Regression analysis was used to predict clinical improvement or worsening based on these vector features. The predictors were able to explain (>98.5% of variance) patients' clinical global impression of improvement, thus correctly predicting 5 cases of improvement and 2 cases of worsening. CONCLUSIONS: This study provided a method of extracting clinically meaningful reports from ecological kinematic data showing changes after drug adjustments. The results are presented using a novel concept called change space that may be more understandable for clinical staff.

Effectiveness of BoNT A in Parkinson's disease upper limb tremor management.

OBJECTIVE: One the greatest challenges of BoNT A therapy for tremor lies in the complexity and variation of components involved in tremor movement, and the lack of objective measures to determine these components. This 3 month open-label single injection study aims to couple clinician best judgment with kinematics to improve effect of BoNT A (incobotulinumtoxinA) injection in 7 patients with upper limb Parkinson's disease (PD) tremor. METHODS: Injection was guided with clinical and kinematic assessment of tremor using angular wrist position in 3 degrees of freedom: flexion/extension, pronation/supination, and radial/ulnar deviation. Overall tremor severity and change were measured by linear finger acceleration. RESULTS: Kinematic data from static and functional tasks demonstrate no improvement at one month post-injection, but significant improvement at two and three months. Clinical scales across UPDRS Items 20 (1, 2, 3 months post) and 21 (2 months), and spiral drawings (3 months) showed significant improvement from baseline, while line drawings did not. CONCLUSIONS: This study suggests injection of BoNT A as a viable focal management option for upper limb PD tremor. In addition to clinical judgment, objective quantification of tremor dynamics by kinematics may be a feasible assessment and guidance tool which can be used to optimize injection conditions for focal tremor therapy. Kinematic analysis of tremor across a variety of joints in all degrees of movement may provide important insight into tremor dynamics, allowing optimized, targeted focal therapy.