Neural correlates of single-vessel haemodynamic responses in vivo.

Neural activation increases blood flow locally. This vascular signal is used by functional imaging techniques to infer the location and strength of neural activity. However, the precise spatial scale over which neural and vascular signals are correlated is unknown. Furthermore, the relative role of synaptic and spiking activity in driving haemodynamic signals is controversial. Previous studies recorded local field potentials as a measure of synaptic activity together with spiking activity and low-resolution haemodynamic imaging. Here we used two-photon microscopy to measure sensory-evoked responses of individual blood vessels (dilation, blood velocity) while imaging synaptic and spiking activity in the surrounding tissue using fluorescent glutamate and calcium sensors. In cat primary visual cortex, where neurons are clustered by their preference for stimulus orientation, we discovered new maps for excitatory synaptic activity, which were organized similarly to those for spiking activity but were less selective for stimulus orientation and direction. We generated tuning curves for individual vessel responses for the first time and found that parenchymal vessels in cortical layer 2/3 were orientation selective. Neighbouring penetrating arterioles had different orientation preferences. Pial surface arteries in cats, as well as surface arteries and penetrating arterioles in rat visual cortex (where orientation maps do not exist), responded to visual stimuli but had no orientation selectivity. We integrated synaptic or spiking responses around individual parenchymal vessels in cats and established that the vascular and neural responses had the same orientation preference. However, synaptic and spiking responses were more selective than vascular responses--vessels frequently responded robustly to stimuli that evoked little to no neural activity in the surrounding tissue. Thus, local neural and haemodynamic signals were partly decoupled. Together, these results indicate that intrinsic cortical properties, such as propagation of vascular dilation between neighbouring columns, need to be accounted for when decoding haemodynamic signals.

Structural and Functional Imaging of the Retina in Central Retinal Artery Occlusion - Current Approaches and Future Directions.

Central retinal artery occlusion (CRAO) is a form of acute ischemic stroke which affects the retina. Intravenous thrombolysis is emerging as a compelling therapeutic approach. However, it is not known which patients may benefit from this therapy because there are no imaging modalities that adequately distinguish viable retina from irreversibly infarcted retina. The inner retina receives arterial supply from the central retinal artery and there is robust collateralization between this circulation and the outer retinal circulation, provided by the posterior ciliary circulation. Fundus photography can show canonical changes associated with CRAO including a cherry-red spot, arteriolar boxcarring and retinal pallor. Fluorescein angiography provides 2-dimensional imaging of the retinal circulation and can distinguish a complete from a partial CRAO as well as central versus peripheral retinal non-perfusion. Transorbital ultrasonography may assay flow through the central retinal artery and is useful in the exclusion of other orbital pathology that can mimic CRAO. Optical coherence tomography provides structural information on the different layers of the retina and exploratory work has described its utility in determining the time since onset of ischemia. Two experimental techniques are discussed. 1) Retinal functional imaging permits generation of capillary perfusion maps and can assay retinal oxygenation and blood flow velocity. 2) Photoacoustic imaging combines the principles of optical excitation and ultrasonic detection and - in animal studies - has been used to determine the retinal oxygen metabolic rate. Future techniques to determine retinal viability in clinical practice will require rapid, easily used, and reproducible methods that can be deployed in the emergency setting.

National Institutes of Health StrokeNet Training Core.

Background and Purpose- The National Institutes of Health (NIH) StrokeNet provides a nationwide infrastructure to advance stroke research. Capitalizing on this unique opportunity, the NIH StrokeNet Training Core (NSTC) was established with the overarching goal of enhancing the professional development of a diverse spectrum of professionals who are embedded in the stroke clinical trials network of the NIH StrokeNet. Methods- This special report provides a descriptive account of the rationale, organization, and activities of the NSTC since its inception in 2013. Current processes and their evolution over time for facilitating training of NIH StrokeNet trainees have been highlighted. Data collected for monitoring training are summarized. Outcomes data (publications and grants) collected by NSTC was supplemented by publicly available resources. Results- The NSTC comprises of cross-network faculty, trainees, and education coordinators. It helps in the development and monitoring of training programs and organizes educational and career development activities. Trainees are provided directed guidance towards their mandated research projects, including opportunities to present at the International Stroke Conference. The committee has focused on developing sustainable models of peer-to-peer interaction and cross-institutional mentorships. A total of 124 professionals (43.7% female, 10.5% underrepresented minorities) have completed training between 2013 and 2018, of whom 55% were clinical vascular neurologists. Of the total, 85% transitioned to a formal academic position and 95% were involved in stroke research post-training. Altogether, 1659 indexed publications have been authored or co-authored by NIH StrokeNet Trainees, of which 58% were published during or after their training years. Based on data from 109 trainees, 33% had submitted 72 grant proposals as principal or co-principal investigators of which 22.2% proposals have been funded. Conclusions- NSTC has provided a foundation to foster nationwide training in stroke research. Our data demonstrate strong contribution of trainees towards academic scholarship. Continued innovation in educational methodologies is required to adapt to unique training opportunities such as the NIH StrokeNet.

Corticospinal tract lesion load: An imaging biomarker for stroke motor outcomes.

OBJECTIVE: The aim of this work was to investigate whether an imaging measure of corticospinal tract (CST) injury in the acute phase can predict motor outcome at 3 months in comparison to clinical assessment of initial motor impairment. METHODS: A two-site prospective cohort study followed up a group of first-ever ischemic stroke patients using the Upper-Extremity Fugl-Meyer (UE-FM) Scale to measure motor impairment in the acute phase and at 3 months. A weighted CST lesion load (wCST-LL) was calculated by overlaying the patient's lesion map on magnetic resonance imaging with a probabilistic CST constructed from healthy control subjects. Regression models were fit to assess the predictive value of wCST-LL and compared with initial motor impairment. RESULTS: Seventy-six patients (37 from cohort 1 and 39 from cohort 2) completed the study. wCST-LL as well as assessment of motor impairment (UE-FM) in the acute phase correlated with motor impairment (UE-FM) at 3 months in both cohort 1 (R(2) = 0.69 vs. R(2) = 0.67; p = 0.43) and cohort 2 (R(2) = 0.69 vs. R(2) = 0.62; p = 0.25). In the severely impaired subgroup (defined as UE-FM ≤ 10 at baseline), wCST-LL correlated with outcomes significantly better than clinical assessment (R(2) = 0.47 vs. R(2) = 0.11; p = 0.03). In the nonseverely impaired subgroup, stroke patients recovered approximately 70% of their maximal recovery potential. All stroke patients in both cohorts had poor motor outcomes at 3 months (defined as UE-FM ≤ 25) when wCST-LL was ≥ 7.0 cc (positive predictive value was 100%). INTERPRETATION: wCST-LL, an imaging biomarker determined in the acute phase, can predict poststroke motor outcomes at 3 months, especially in patients with severe impairment at baseline.

An artery-specific fluorescent dye for studying neurovascular coupling.

We demonstrate that Alexa Fluor 633 hydrazide (Alexa Fluor 633) selectively labels neocortical arteries and arterioles by binding to elastin fibers. We measured sensory stimulus-evoked arteriole dilation dynamics in mouse, rat and cat visual cortex using Alexa Fluor 633 together with neuronal activity using calcium indicators or blood flow using fluorescein dextran. Arteriole dilation decreased fluorescence recorded from immediately underlying neurons, representing a potential artifact during neuronal functional imaging experiments.

Revisiting Transcranial Light Stimulation as a Stroke Therapeutic-Hurdles and Opportunities.

Near-infrared laser therapy, a special form of transcranial light therapy, has been tested as an acute stroke therapy in three large clinical trials. While the NEST trials failed to show the efficacy of light therapy in human stroke patients, there are many lingering questions and lessons that can be learned. In this review, we summarize the putative mechanism of light stimulation in the setting of stroke, highlight barriers, and challenges during the translational process, and evaluate light stimulation parameters, dosages and safety issues, choice of outcomes, effect size, and patient selection criteria. In the end, we propose potential future opportunities with transcranial light stimulation as a cerebroprotective or restorative tool for future stroke treatment.

Numerical and experimental evaluation of low-intensity transcranial focused ultrasound wave propagation using human skulls for brain neuromodulation.

BACKGROUND: Low-intensity transcranial focused ultrasound (tFUS) has gained considerable attention as a promising noninvasive neuromodulatory technique for human brains. However, the complex morphology of the skull hinders scholars from precisely predicting the acoustic energy transmitted and the region of the brain impacted during the sonication. This is due to the fact that different ultrasound frequencies and skull morphology variations greatly affect wave propagation through the skull. PURPOSE: Although the acoustic properties of human skull have been studied for tFUS applications, such as tumor ablation using a multielement phased array, there is no consensus about how to choose a single-element focused ultrasound (FUS) transducer with a suitable frequency for neuromodulation. There are interests in exploring the magnitude and dimension of tFUS beam through human parietal bone for modulating specific brain lobes. Herein, we aim to investigate the wave propagation of tFUS on human skulls to understand and address the concerns above. METHODS: Both experimental measurements and numerical modeling were conducted to investigate the transmission efficiency and beam pattern of tFUS on five human skulls (C3 and C4 regions) using single-element FUS transducers with six different frequencies (150-1500 kHz). The degassed skull was placed in a water tank, and a calibrated hydrophone was utilized to measure acoustic pressure past it. The cranial computed tomography scan data of each skull were obtained to derive a high-resolution acoustic model (grid point spacing: 0.25 mm) in simulations. Meanwhile, we modified the power-law exponent of acoustic attenuation coefficient to validate numerical modeling and enabled it to be served as a prediction tool, based on the experimental measurements. RESULTS: The transmission efficiency and -6 dB beamwidth were evaluated and compared for various frequencies. An exponential decrease in transmission efficiency and a logarithmic decrease of -6 dB beamwidth with an increase in ultrasound frequency were observed. It is found that a >750 kHz ultrasound leads to a relatively lower tFUS transmission efficiency (<5%), whereas a <350 kHz ultrasound contributes to a relatively broader beamwidth (>5 mm). Based on these observations, we further analyzed the dependence of tFUS wave propagation on FUS transducer aperture size. CONCLUSIONS: We successfully studied tFUS wave propagation through human skulls at different frequencies experimentally and numerically. The findings have important implications to predict tFUS wave propagation for ultrasound neuromodulation in clinical applications, and guide researchers to develop advanced ultrasound transducers as neural interfaces.

In vivo Measurements of Electric Fields During Cranial Electrical Stimulation in the Human Brain.

Cranial electrical stimulation (CES) has been applied at various current levels in both adults and children with neurological conditions with seemingly promising but somewhat inconsistent results. Stimulation-induced spatial electric fields (EFs) within a specific brain region are likely a significant contributing factor for the biological effects. Although several simulation models have been used to predict EF distributions in the brain, these models actually have not been validated by in vivo CES-induced EF measurements in the live human brain. This study directly measured the CES-induced voltage changes with implanted stereotactic-electroencephalographic (sEEG) electrodes in twenty-one epilepsy participants (16 adults and 5 children) and then compared these measured values with the simulated ones obtained from the personalized models. In addition, we further investigated the influence of stimulation frequency, intensity, electrode montage and age on EFs in parts of participants. We found both measured voltages and EFs obtained in vivo are highly correlated with the predicted ones in our cohort (Voltages: r = 0.93, p < 0.001; EFs: r = 0.73, p < 0.001). In white matter and gray matter, the measured voltages linearly increased when the stimulation intensity increased from 5 to 500 µA but showed no significant changes (averaged coefficient of variation <4.10%) with changing stimulation frequency from 0.5 to 200 Hz. Electrode montage, but not age, significantly affects the distribution of the EFs (n = 5, p < 0.01). Our in vivo measurements demonstrate that the individualized simulation model can reliably predict the CES-induced EFs in both adults and children. It also confirms that the CES-induced EFs highly depend on the electrode montages and individual anatomical features.

Effect of Low Intensity Transcranial Ultrasound Stimulation on Neuromodulation in Animals and Humans: An Updated Systematic Review.

Background: Although low-intensity transcranial ultrasound stimulation (LI-TUS) has received more recognition for its neuromodulation potential, there remains a crucial knowledge gap regarding the neuromodulatory effects of LI-TUS and its potential for translation as a therapeutic tool in humans. Objective: In this review, we summarized the findings reported by recently published studies regarding the effect of LI-TUS on neuromodulation in both animals and humans. We also aim to identify challenges and opportunities for the translation process. Methods: A literature search of PubMed, Medline, EMBASE, and Web of Science was performed from January 2019 to June 2020 with the following keywords and Boolean operators: [transcranial ultrasound OR transcranial focused ultrasound OR ultrasound stimulation] AND [neuromodulation]. The methodological quality of the animal studies was assessed by the SYRCLE's risk of bias tool, and the quality of human studies was evaluated by the PEDro score and the NIH quality assessment tool. Results: After applying the inclusion and exclusion criteria, a total of 26 manuscripts (24 animal studies and two human studies) out of 508 reports were included in this systematic review. Although both inhibitory (10 studies) and excitatory (16 studies) effects of LI-TUS were observed in animal studies, only inhibitory effects have been reported in primates (five studies) and human subjects (two studies). The ultrasonic parameters used in animal and human studies are different. The SYRCLE quality score ranged from 25 to 43%, with a majority of the low scores related to performance and detection bias. The two human studies received high PEDro scores (9/10). Conclusion: LI-TUS appears to be capable of targeting both superficial and deep cerebral structures to modulate cognitive or motor behavior in both animals and humans. Further human studies are needed to more precisely define the effective modulation parameters and thereby translate this brain modulatory tool into the clinic.

Transcranial Direct Current Stimulation for Poststroke Motor Recovery: Challenges and Opportunities.

There has been a renewed research interest in transcranial direct current stimulation (tDCS) as an adjunctive tool for poststroke motor recovery as it has a neuro-modulatory effect on the human cortex. However, there are barriers towards its successful application in motor recovery as several scientific issues remain unresolved, including device-related issues (ie, dose-response relationship, safety and tolerability concerns, interhemispheric imbalance model, and choice of montage) and clinical trial-related issues (ie, patient selection, timing of study, and choice of outcomes). This narrative review examines and discusses the existing challenges in using tDCS as a brain modulation tool in facilitating recovery after stroke. Potential solutions pertinent to using tDCS with the goal of harnessing the brains plasticity are proposed.

Mesenchymal Stem Cell Therapy in Stroke: A Systematic Review of Literature in Pre-Clinical and Clinical Research.

Exogenous stem cell therapy (SCT) has been recognized recently as a promising neuroregenerative strategy to augment recovery in stroke survivors. Mesenchymal stem cells (MSCs) are the primary source of stem cells used in the majority of both pre-clinical and clinical studies in stroke. In the absence of evidence-based guidelines on the use of SCT in stroke patients, understanding the progress of MSC research across published studies will assist researchers and clinicians in better achieving success in translating research. We conducted a systematic review on published literature using MSCs in both pre-clinical studies and clinical trials between 2008 and 2017 using the public databases PubMed and Ovid Medline, and the clinical trial registry ( www.clinicaltrials.gov ). A total of 78 pre-clinical studies and eight clinical studies were identified. While majority of the pre-clinical and clinical studies demonstrated statistically significant effects, the clinical significance of these findings was still unclear. Effect sizes could not be measured mainly due to reporting issues in pre-clinical studies, thus limiting our ability to compare results across studies quantitatively. The overall quality of both pre-clinical and clinical studies was sub-optimal. By conducting a systematic review of both pre-clinical and clinical studies on MSCs therapy in stroke, we assessed the quality of current evidence and identified several issues and gaps in translating animal studies to human trials. Addressing these issues and incorporating changes into future animal studies and human trials may lead to better success of stem cells-based therapeutics in the near future.

Evidence of transcranial direct current stimulation-generated electric fields at subthalamic level in human brain in vivo.

BACKGROUND: Transcranial direct current stimulation (tDCS) is a promising brain modulation technique for several disease conditions. With this technique, some portion of the current penetrates through the scalp to the cortex and modulates cortical excitability, but a recent human cadaver study questions the amount. This insufficient intracerebral penetration of currents may partially explain the inconsistent and mixed results in tDCS studies to date. Experimental validation of a transcranial alternating current stimulation-generated electric field (EF) in vivo has been performed on the cortical (using electrocorticography, ECoG, electrodes), subcortical (using stereo electroencephalography, SEEG, electrodes) and deeper thalamic/subthalamic levels (using DBS electrodes). However, tDCS-generated EF measurements have never been attempted. OBJECTIVE: We aimed to demonstrate that tDCS generates biologically relevant EF as deep as the subthalamic level in vivo. METHODS: Patients with movement disorders who have implanted deep brain stimulation (DBS) electrodes serve as a natural experimental model for thalamic/subthalamic recordings of tDCS-generated EF. We measured voltage changes from DBS electrodes and body resistance from tDCS electrodes in three subjects while applying direct current to the scalp at 2 mA and 4 mA over two tDCS montages. RESULTS: Voltage changes at the level of deep nuclei changed proportionally with the level of applied current and varied with different tDCS montages. CONCLUSIONS: Our findings suggest that scalp-applied tDCS generates biologically relevant EF. Incorporation of these experimental results may improve finite element analysis (FEA)-based models.

Mobile health as a viable strategy to enhance stroke risk factor control: A systematic review and meta-analysis.

BACKGROUND: With the rapid growth worldwide in cell-phone use, Internet connectivity, and digital health technology, mobile health (mHealth) technology may offer a promising approach to bridge evidence-treatment gaps in stroke prevention. We aimed to evaluate the effectiveness of mHealth for stroke risk factor control through a systematic review and meta-analysis. METHODS: We searched PubMed from January 1, 2000 to May 17, 2016 using the following keywords: mobile health, mHealth, short message, cellular phone, mobile phone, stroke prevention and control, diabetes mellitus, hypertension, hyperlipidemia and smoking cessation. We performed a meta-analysis of all eligible randomized control clinical trials that assessed a sustained (at least 6months) effect of mHealth. RESULTS: Of 78 articles identified, 13 met eligibility criteria (6 for glycemic control and 7 for smoking cessation) and were included for the final meta-analysis. There were no eligible studies for dyslipidemia or hypertension. mHealth resulted in greater Hemoglobin A1c reduction at 6months (6 studies; 663 subjects; SMD: -0.44; 95% CI: [-0.82, -0.06], P=0.02; Mean difference of decrease in HbA1c: -0.39%; 95% CI: [-0.74, -0.04], P=0.03). mHealth also lead to relatively higher smoking abstinence rates at 6months (7 studies; 9514 subjects; OR: 1.54; 95% CI: [1.24, 1.90], P<0.0001). CONCLUSIONS: Our meta-analysis supports that use of mHealth improves glycemic control and smoking abstinence rates.

Safety and tolerability of transcranial direct current stimulation to stroke patients - A phase I current escalation study.

BACKGROUND AND OBJECTIVE: A prior meta-analysis revealed that higher doses of transcranial direct current stimulation (tDCS) have a better post-stroke upper-extremity motor recovery. While this finding suggests that currents greater than the typically used 2 mA may be more efficacious, the safety and tolerability of higher currents have not been assessed in stroke patients. We aim to assess the safety and tolerability of single session of up to 4 mA in stroke patients. METHODS: We adapted a traditional 3 + 3 study design with a current escalation schedule of 1¼2¼2.5¼3¼3.5¼4 mA for this tDCS safety study. We administered one 30-min session of bihemispheric montage tDCS and simultaneous customary occupational therapy to patients with first-ever ischemic stroke. We assessed safety with pre-defined stopping rules and investigated tolerability through a questionnaire. Additionally, we monitored body resistance and skin temperature in real-time at the electrode contact site. RESULTS: Eighteen patients completed the study. The current was escalated to 4 mA without meeting the pre-defined stopping rules or causing any major safety concern. 50% of patients experienced transient skin redness without injury. No rise in temperature (range 26°C-35 °C) was noted and skin barrier function remained intact (i.e. body resistance >1 kΩ). CONCLUSION: Our phase I safety study supports that single session of bihemispheric tDCS with current up to 4 mA is safe and tolerable in stroke patients. A phase II study to further test the safety and preliminary efficacy with multi-session tDCS at 4 mA (as compared with lower current and sham stimulation) is a logical next step. ClinicalTrials.gov Identifier: NCT02763826.

Transcranial Direct Current Stimulation Post-Stroke Upper Extremity Motor Recovery Studies Exhibit a Dose-Response Relationship.

BACKGROUND AND PURPOSE: Transcranial direct current stimulation (tDCS) has shown mixed results in post-stroke motor recovery, possibly because of tDCS dose differences. The purpose of this meta-analysis was to explore whether the outcome has a dose-response relationship with various dose-related parameters. METHODS: The literature was searched for double-blind, randomized, sham-controlled clinical trials investigating the role of tDCS (≥5 sessions) in post-stroke motor recovery as measured by the Fugl-Meyer Upper Extremity (FM-UE) scale. Improvements in FM-UE scores were compared between active and sham groups by calculating standardized mean differences (Hedge's g) to derive a summary effect size. Inverse-variance-weighted linear meta-regression across individual studies was performed between various tDCS parameters and Hedge's g to test for dose-response relationships. RESULTS: Eight studies with total of 213 stroke subjects were included. Summary Hedge's g was statistically significant in favor of the active group (Hedge's g = 0.61, p = 0.02) suggesting moderate effect. Specifically, studies that used bihemispheric tDCS montage (Hedge's g = 1.30, p = 0.08) or that recruited chronic stroke patients (Hedge's g = 1.23, p = 0.02) showed large improvements in the active group. A positive dose-response relationship was found with current density (p = 0.017) and charge density (p = 0.004), but not with current amplitude. Moreover, a negative dose-response relationship was found with electrode size (p < 0.001, smaller electrodes were more effective). CONCLUSIONS: Our meta-analysis and meta-regression results suggest superior motor recovery in the active group when compared to the sham group and dose-response relationships relating to electrode size, charge density and current density. These results need to be confirmed in future dedicated studies.

Improved blood velocity measurements with a hybrid image filtering and iterative Radon transform algorithm.

Neural activity leads to hemodynamic changes which can be detected by functional magnetic resonance imaging (fMRI). The determination of blood flow changes in individual vessels is an important aspect of understanding these hemodynamic signals. Blood flow can be calculated from the measurements of vessel diameter and blood velocity. When using line-scan imaging, the movement of blood in the vessel leads to streaks in space-time images, where streak angle is a function of the blood velocity. A variety of methods have been proposed to determine blood velocity from such space-time image sequences. Of these, the Radon transform is relatively easy to implement and has fast data processing. However, the precision of the velocity measurements is dependent on the number of Radon transforms performed, which creates a trade-off between the processing speed and measurement precision. In addition, factors like image contrast, imaging depth, image acquisition speed, and movement artifacts especially in large mammals, can potentially lead to data acquisition that results in erroneous velocity measurements. Here we show that pre-processing the data with a Sobel filter and iterative application of Radon transforms address these issues and provide more accurate blood velocity measurements. Improved signal quality of the image as a result of Sobel filtering increases the accuracy and the iterative Radon transform offers both increased precision and an order of magnitude faster implementation of velocity measurements. This algorithm does not use a priori knowledge of angle information and therefore is sensitive to sudden changes in blood flow. It can be applied on any set of space-time images with red blood cell (RBC) streaks, commonly acquired through line-scan imaging or reconstructed from full-frame, time-lapse images of the vasculature.

Towards a naturalistic brain-machine interface: hybrid torque and position control allows generalization to novel dynamics.

Realization of reaching and grasping movements by a paralytic person or an amputee would greatly facilitate her/his activities of daily living. Towards this goal, control of a computer cursor or robotic arm using neural signals has been demonstrated in rodents, non-human primates and humans. This technology is commonly referred to as a Brain-Machine Interface (BMI) and is achieved by predictions of kinematic parameters, e.g. position or velocity. However, execution of natural movements, such as swinging baseball bats of different weights at the same speed, requires advanced planning for necessary context-specific forces in addition to kinematic control. Here we show, for the first time, the control of a virtual arm with representative inertial parameters using real-time neural control of torques in non-human primates (M. radiata). We found that neural control of torques leads to ballistic, possibly more naturalistic movements than position control alone, and that adding the influence of position in a hybrid torque-position control changes the feedforward behavior of these BMI movements. In addition, this level of control was achievable utilizing the neural recordings from either contralateral or ipsilateral M1. We also observed changed behavior of hybrid torque-position control under novel external dynamic environments that was comparable to natural movements. Our results demonstrate that inclusion of torque control to drive a neuroprosthetic device gives the user a more direct handle on the movement execution, especially when dealing with novel or changing dynamic environments. We anticipate our results to be a starting point of more sophisticated algorithms for sensorimotor neuroprostheses, eliminating the need of fully automatic kinematic-to-dynamic transformations as currently used by traditional kinematic-based decoders. Thus, we propose that direct control of torques, or other force related variables, should allow for more natural neuroprosthetic movements by the user.