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Prediction of movement intentions from electromyographic (EMG) signals is typically performed with a pattern recognition approach, wherein a short dataframe of raw EMG is compressed into an instantaneous feature-encoding that is meaningful for classification. However, EMG signals are time-varying, implying that a frame-wise approach may not sufficiently incorporate temporal context into predictions, leading to erratic and unstable prediction behavior. Objective: We demonstrate that sequential prediction models and, specifically, temporal convolutional networks are able to leverage useful temporal information from EMG to achieve superior predictive performance. Methods: We compare this approach to other sequential and frame-wise models predicting 3 simultaneous hand and wrist degrees-of-freedom from 2 amputee and 13 non-amputee human subjects in a minimally constrained experiment. We also compare these models on the publicly available Ninapro and CapgMyo amputee and non-amputee datasets. Results: Temporal convolutional networks yield predictions that are more accurate and stable $(p than frame-wise models, especially during inter-class transitions, with an average response delay of 4.6 ms $(p and simpler feature-encoding. Their performance can be further improved with adaptive reinforcement training. Significance: Sequential models that incorporate temporal information from EMG achieve superior movement prediction performance and these models allow for novel types of interactive training. Conclusions: Addressing EMG decoding as a sequential modeling problem will lead to enhancements in the reliability, responsiveness, and movement complexity available from prosthesis control systems.

Controlling multi-articulated prosthetic hands with surface electromyography can be challenging for users. Sonomyography, or ultrasound-based sensing of muscle deformation, avoids some of the problems of electromyography and enables classification of multiple motion patterns in individuals with upper limb loss. Because sonomyography has been previously studied only in individuals with transradial limb loss, the purpose of this study was to assess the feasibility of an individual with transhumeral limb loss using this modality for motion classification. A secondary aim was to compare motion classification performance between electromyography and sonomyography. A single individual with transhumeral limb loss created two datasets containing 11 motions each (individual flexion of each finger, thumb abduction, power grasp, key grasp, tripod, point, pinch, wrist pronation). Electromyography or sonomyography signals associated with every motion were acquired and cross-validation accuracy was computed for each dataset. While all motions were usually predicted successfully with both electromyography and sonomyography, the cross-validation accuracies were typically higher for sonomyography. Although this was an exploratory study, the results suggest that controlling an upper limb prosthesis using sonomyography may be feasible for individuals with transhumeral limb loss.

ObjectiveA major challenge for controlling a prosthetic arm is communication between the device and the user’s phantom limb. We show the ability to enhance amputees’ phantom limb perception and improve movement decoding through targeted transcutaneous electrical nerve stimulation (tTENS).ApproachTranscutaneous nerve stimulation experiments were performed with four amputee participants to map phantom limb perception. We measured myoelectric signals during phantom hand movements before and after amputees received sensory stimulation. Using electroencephalogram (EEG) monitoring, we measure the neural activity in sensorimotor regions during phantom movements and stimulation. In one participant, we also tracked sensory mapping over 2 years and movement decoding performance over 1 year.Main resultsResults show improvements in the amputees’ ability to perceive and move the phantom hand as a result of sensory stimulation, which leads to improved movement decoding. In the extended study with one amputee, we found that sensory mapping remains stable over 2 years. Remarkably, sensory stimulation improves within-day movement decoding while performance remains stable over 1 year. From the EEG, we observed cortical correlates of sensorimotor integration and increased motor-related neural activity as a result of enhanced phantom limb perception.SignificanceThis work demonstrates that phantom limb perception influences prosthesis control and can benefit from targeted nerve stimulation. These findings have implications for improving prosthesis usability and function due to a heightened sense of the phantom hand.

Adjusting to an amputation can often times be difficult for the body. Post-surgery, amputees not only have to incur expensive rehabilitation treatment costs, but also have to wait for up to several months before receiving a properly fitted prosthesis. We developed a mixed-reality training environment where amputees can train, at their own time and convenience, and interact with holographic objects, while also receiving tactile and proprioceptive feedback. We incorporate positional information through inertial sensors, touch and proprioception information through vibrational feedback, all integrated into an augmented-reality (AR) environment viewed through the Microsoft HoloLens TM. Training tasks were designed to account for limb rotation and object relocation in a three-dimensional space with a correct palm orientation essential for an intuitive grasp and release of objects. Our results showed an improved performance in training time, overshoot and completion rate with vibratory feedback (of both touch and proprioception) over without feedback. Furthermore, EMG activity was analyzed to estimate the muscular effort during each task.

Myoelectric signals can be used to predict the intended movements of an amputee for prosthesis control. However, untrained effects like limb position changes influence myoelectric signal characteristics, hindering the ability of pattern recognition algorithms to discriminate among motion classes. Despite frequent and long training sessions, these deleterious conditional influences may result in poor performance and device abandonment. Goal: We present a robust sparsity-based adaptive classification method that is significantly less sensitive to signal deviations resulting from untrained conditions. Methods: We compare this approach in the offline and online contexts of untrained upper-limb positions for amputee and able-bodied subjects to demonstrate its robustness compared against other myoelectric classification methods. Results: We report significant performance improvements ( $p ) in untrained limb positions across all subject groups. Significance: The robustness of our suggested approach helps to ensure better untrained condition performance from fewer training conditions. Conclusions: This method of prosthesis control has the potential to deliver real-world clinical benefits to amputees: better condition-tolerant performance, reduced training burden in terms of frequency and duration, and increased adoption of myoelectric prostheses.

The formation of smoking induced-DNA adducts is a critical factor in the induction of human lung cancer. As derivates of benzene and polyaromatic hydrocarbons (PAHs) are important compounds of tobacco smoke, in DNA isolated from human lung and blood mononuclear cells (MNCs) from 38 lung cancer patients, we used the (32)P-postlabeling assay to detect polyphenol associated DNA adducts. Two DNA adducts were detected in blood MNCs and lung tissue that co-chromatographed with DNA modifications from HL60 cells treated with combinations of benzene metabolites (e.g., hydroquinone and benzenetriol). These adducts were designated polyphenol-associated DNA adducts. Relative adduct levels for polyphenolic adducts were five-fold higher than aromatic adducts in both lung and MNCs. A significant correlation was observed between levels of polyphenol adducts and total duration of cigarette smoking in lung (r=0.34; P0.04) and MNCs (r=0.7; P0.04), but no correlation between levels of polyphenol adducts and pack-years consumption of cigarettes nor time since quitting smoking in former smokers. Long term former smokers and the one non-smoker in the study had detectable levels of polyphenol adducts. Surprisingly, the levels of polyphenol adducts in MNCs were highly correlated with aromatic adduct levels (r=0.84; P0.001). Individual aromatic adducts in MNCs also correlated with polyphenol adducts. Total polyphenol adduct levels had a correlation with aromatic DNA adduct levels in lung tissue (r=0.46; P0.01). To our knowledge these results are the only comparison of adducts in MNCs with lung tissue, and the only data set indicating that blood MNCs are a valid surrogate for lung adduct DNA burden.

We have investigated the formation of DNA adducts and oxidative base damage produced by copper sulfate activation of dopamine and 6-hydroxydopamine. In the presence of 10 microM copper sulfate both 100 microM dopamine and 100 microM 6-hydroxydopamine formed three similar DNA adducts with relative adduct levels of 8.36 +/- 2.23 x 10(-8) and 7.98 +/- 2.53 x 10(-8), respectively. The levels of 8-hydroxy-2'-deoxyguanosine produced by these incubations were 5.2 +/- 0.03, 32.6 +/- 2.4, and 0.01 pmol/microg DNA for dopamine, 6-hydroxydopamine, and control incubations, respectively, representing a 520- to 3260-fold increase in the level of this base oxidation product. The use of specific chelators and catalase demonstrated that the reduction of Cu2+ to Cu1+ and the formation of a peroxide plays an important role in the activation of dopamine and 6-hydroxydopamine to form adducts and oxidative base damage. Our results suggest that the oxidation of dopamine by transition metals present in the brain may lead to the formation of both DNA adducts and oxidative base damage in dopaminergic cells. We propose that these processes may contribute to the observed loss of dopaminergic neurons in patients with Parkinson's disease.

We have investigated the formation of DNA adducts in the bone marrow and white blood cells of male B6C3F1 mice treated with benzene using P1-enhanced 32P-postlabeling. No adducts were detected in the bone marrow of controls or mice treated with various doses of benzene once a day. After twice-daily treatment for 1 to 7 days with benzene, 440 mg/kg, one major (no. 1) and up to two minor DNA adducts were detected in both the bone marrow and white blood cells. The relative adduct levels in these cells ranged from 0.06 to 1.46 x 10(-7). a significant correlation (r2 = 0.95) between levels of adducts in bone marrow and white blood cells was observed. After a 7-day treatment with benzene, 440 mg/kg twice a day, the number of cells per femur decreased from 1.6 x 10(7) to 0.85 x 10(7), indicating myelotoxicity. In contrast, administration of benzene once a day produced only a small decrease in bone marrow cellularity. The observed induction of toxicity in bone marrow was paralleled by formation of DNA adducts. In vitro treatment of bone marrow with hydroquinone (HQ) for 24 hr produced the same DNA adducts as found after treatment of mice with benzene, suggesting that HQ is the principal metabolite of benzene leading to DNA adduct formation in vivo. Using P-postlabeling the principal DNA adduct formed in vivo was compared with N2-(4-hydroxyphenyl)-2'-deoxyguanosine-3'-phosphate. The results of this comparison demonstrated that the DNA adduct formed in vivo co-chromatographs with N2-(4-hydroxyphenyl)-2'-deoxyguanosine-3'-phosphate. These studies indicate that metabolic activation of benzene leads to the formation of DNA adducts in bone marrow and white blood cells and suggest that measurement of DNA adducts in white blood cells may be an indicator of biological effect following benzene exposure. Images Figure 1. A Figure 1. B Figure 1. C Figure 1. D Figure 2. Figure 3. A Figure 3. B Figure 4. A Figure 4. B

We have investigated the influence of peroxides on DNA adduct formation in HL-60 cells treated with polyphenolic metabolites of benzene. Treatment of HL-60 cells with 50 microM hydroquinone (HQ), 500 microM catechol (CAT) or 200 microM 1,2,4-benzenetriol (BT) resulted in adduct levels of 0.27, 0.21 and 0.21 x 10(-7), respectively. Addition of 50-250 microM H2O2 or 250 microM cumene hydroperoxide to HL-60 cells increased DNA adduct formation 2.7-10-fold following treatment with HQ or CAT but had no effect on adduct formation by BT. Treatment of HL-60 cells with the combinations of HQ plus either BT or phorbol myristate acetate (PMA) potentiated DNA adduct formation by 2.5-4-fold. Significant elevations of cellular H2O2 levels occurred after treatment of HL-60 cells with either PMA, CAT or BT. These results indicate that cellular levels of H2O2 regulate the peroxidase dependent activation of benzene metabolites to form DNA adducts.

We investigated whether hepatic DNA adducts, erythrocytic micronuclei, wet weight, developmental stage, wet weight at metamorphosis, and time to metamorphosis changed in larval Xenopus laevis exposed to varied doses of benzo[a]pyrene (B[a]P). Using 32P-postlabeling, we observed relative DNA adduct levels of 0 to 13.7 × 10−7 following continuous exposure to 0 to 496 nM B[a]P for 12 days and relative levels of 0 to 10 × 10−7 after exposure to 248 nM B[a]P over a range of 0 to 16 days. Mean numbers of micronuclei were 1.7, 6.3, and 16.4 1000 red blood cells after exposure to 0, 31, and 248 nM B[a]P, respectively, for 14 days. Micronuclei also ranged from 1.3 to 120.5 1000 red blood cells following exposure to 248 nM B[a]P over a range of 0 to 16 days. Comparatively, levels of both DNA adducts and micronuclei were greatly reduced in animals exposed previously to 31 and 248 nM B[a]P, but assayed at metamorphosis. Larvae exposed to 248 nM B[a]P for 14 days took approximately 4 days longer to metamorphose than unexposed larvae. This increased time to metamorphosis was associated with increased DNA adducts and micronuclei in larvae exposed to 248 nM B[a]P. However, DNA adducts and micronuclei also increased in larvae exposed to 31 nM B[a]P, while time to metamorphosis did not. Larval wet weight was reduced by as much as 44% immediately following exposure to B[a]P. However, there was no effect of exposure on wet weight at metamorphosis. Exposed animals were up to 2 developmental stages younger than unexposed animals in one experiment, but differences among exposed and unexposed animals were less distinct in a second experiment. These studies suggest that DNA adducts and micronuclei can be sensitive measures of sublethal DNA damage, as well as possible short-term indicators of indirect effects on fitness in amphibians.

DNA adduct formation was examined in HL-60 cells treated with the benzene metabolites p-benzoquinone (p-BQ), hydroquinone (HQ), catechol (CAT), and 1,2,4-benzenetriol (BT). p-BQ was 13-fold more effective at forming DNA adducts than HQ, which was 7-9-fold more effective than CAT and BT. The DNA adduct formed in human bone marrow (HBM) treated with HQ was the same as that in HL-60 cells. Combination treatment of HL-60 cells with HQ and either CAT or BT increased DNA adduct formation 2.2–6.4-fold. In vitro activation of HQ by myeloperoxidase produced the same DNA adduct in purified DNA as in HL-60 cells and HBM treated with HQ. Reaction of calf thymus DNA with p-BQ produced three adducts. The DNA adduct formed in HL-60 cells treated with p-BQ did not correspond to any of the principal adducts formed in DNA reacted with p-BQ. These results suggest that peroxidase enzymes activate benzene metabolites to form DNA adducts in HBM.

We have examined DNA adduct formation in HL-60 cells and human bone marrow treated with either hydroquinone or p-benzoquinone and have found that these treatments produce the same DNA adduct in both cell types. The DNA adduct level from these treatments varied from 0.05 to 7.5 adducts per 10(7) nucleotides as a function of treatment time and concentration for both compounds. Reaction of calf thymus DNA with p-benzoquinone produced three adducts as detected by 32P-postlabeling. These adducts have been identified as (3'-hydroxy)-3,N4-benzetheno-2'-deoxycytidine-3'-phosphate; (3'-hydroxy)-1,N6-benzetheno-2'-deoxyadenosine-3'-phosphate; and (3'-hydroxy)-1,N2-benzetheno-2'-deoxyguanosine-3'-phosphate. The DNA adduct formed in HL-60 cells did not correspond to any of the principal adducts formed in DNA reacted with p-benzoquinone, suggesting that cellular environment modifies DNA adduct production by p-benzoquinone. These studies demonstrate that DNA adduct formation occurs in human bone marrow treated with benzene metabolites and suggest that P1-enhanced 32P-postlabeling may be used to detect DNA adducts resulting from benzene exposure. Images FIGURE 1. FIGURE 3. A FIGURE 3. B FIGURE 3. C FIGURE 4. A FIGURE 4. B FIGURE 6.

We have examined DNA adduct formation and cytotoxicity in HL-60 cells treated with either hydroquinone (HQ) or p-benzoquinone (p-BQ). Treatment of HL-60 cells with either HQ or p-BQ produced the same DNA adduct. The DNA adduct level varied from 0.05 to 10 adducts per 10(7) nucleotides as a function of treatment time and concentration for both compounds. To achieve the same DNA adduct level required higher concentrations and longer treatment times with HQ compared to p-BQ. p-BQ was also more cytotoxic to HL-60 cells than HQ. Reaction of calf thymus DNA with a p-BQ/HQ mixture produced five adducts as detected by 32P-postlabeling. Two isomers of (hydroxy)-1,N2-benzetheno-2'- deoxyguanosine-3'-phosphate were isolated from the reaction of 2'-deoxyguanosine-3'-phosphate with a p-BQ/HQ mixture and one of the isomers was identified as adduct no. 1 of the DNA reaction. The DNA adduct formed in HL-60 cells treated with HQ or p-BQ did not correspond to any of the principal adducts formed in DNA reacted with p-BQ/HQ. This result suggests that cellular mechanisms modify DNA adduct formation by HQ and p-BQ.

procedure to detect the formation DNA of adducts in the white blood cells (WBC) of B6C3F1 mice treated by i.p. injection with benzene. Treatment twice a day with 440 rag/kg benzene for 1-7 days resulted in the formation of one major (adduct 1) and one minor (adduct 2) DNA adduct in the WBCs of mice. The same DNA adduct pattern was also found in the bone marrow (BM) of benzene treated mice. The relative adduct levels were dependent upon both benzene dose from 100-440 mg/kg and treatment time from 1 to 7 days. The relative adduct levels ranged between 0.11 and 133 adducts in 10 7 nucleotides for WBCs and 0.16-1.21 adducts in 10 7 nucleotides for BM. Following treatment with benzene, the levels of DNA adducts formed in WBCs were significantly correlated with the levels of DNA adducts formed in BM (r2 = 0.97, P

Using 32P-postlabeling we studied DNA adduct formation in HL-60 cells treated with the o-phenylphenol metabolites o-phenylhydroquinone (o-PHQ) and o-phenylbenzoquinone (o-PBQ). Treatment with 25-500 microM o-PHQ for 8 h produced one principal and three minor adducts with a relative distribution of 80, 10, 6 and 4%. The relative adduct levels from these treatments were 0.26-2.31 adducts/10(7) nucleotides. Treatment with 25-250 microM o-PBQ for 2 h resulted in a similar level of DNA modification and adduct distribution. Reaction of purified calf thymus DNA with o-PBQ produced one DNA adduct, which did not correspond to the major adduct produced in HL-60 cells. These results show that o-PHQ and o-PBQ can form DNA adducts. Peroxidase activation of o-phenylphenol may therefore play a role in the carcinogenic effect of this compound.

Oxidation of catecholamines may lead to the formation of o-semiquinones and o-quinones in catecholaminergic brain tissues, and these reactive molecules may form DNA or protein adducts. In this study, cultured cells were treated with dopamine (DA) for 24 h and 32P-postlabelling was used to detect DA-DNA adducts. In HL-60 cells, 250 microM DA induced 8.5 DNA adducts/10(8) nucleotides; adduct formation was dose-dependent up to 500 microM DA. Addition of H2O2 increased the relative adduct levels 7- to 13-fold, but no adducts were detected when DA and ascorbic acid were added simultaneously. In human glioblastoma cell lines U87, U251, SF-763 and SF-767, 1000 microM DA produced 0.98-2.31 adducts/10(8) nucleotides. These results suggest that the formation of DNA adducts by DA may contribute to the development of certain neurodegenerative diseases such as Parkinson's disease.

Using P1 nuclease enhanced 32P postlabeling, we investigated DNA adduct formation in HL-60 promyelocytic leukemia cells treated with the benzene metabolites hydroquinone, catechol, and 1,2,4-benzenetriol. Comparison of the slopes of the dose-response curves showed that hydroquinone was 7-9 times more effective than 1,2,4,-benzenetriol and catechol at inducing DNA adducts. Comparison of hydroquinone with catechol showed a good correlation between adduct formation and cytotoxicity. Similar comparisons of hydroquinone and 1,2,4,-benzenetriol suggest that cellular processes in addition to DNA adduct formation contributed to cytotoxicity. In cells treated with the combination of hydroquinone and either catechol or 1,2,4,-benzenetriol, DNA adduct formation was 3-6 times greater than the sum of adduct formation produced by single-agent treatments. Treatment with hydroquinone and 1,2,4,-benzenetriol produced DNA adducts not detected after treatment with either metabolite alone. The synergistic interaction of benzene metabolites in the production of DNA adducts may play an important role in the genotoxic effects of benzene in vivo.