A zebrafish-based acoustic motor response (AMR) assay to evaluate chemical-induced developmental neurotoxicity.

Behavioral assays using early-developing zebrafish (Danio rerio) offer a valuable supplement to the in vitro battery adopted as new approach methodologies (NAMs) for assessing risk of chemical-induced developmental neurotoxicity. However, the behavioral assays primarily adopted rely on visual stimulation to elicit behavioral responses, known as visual motor response (VMR) assays. Ocular deficits resulting from chemical exposures can, therefore, confound the behavioral responses, independent of effects on the nervous system. This highlights the need for complementary assays employing alternative forms of sensory stimulation. In this study, we investigated the efficacy of acoustic stimuli as triggers of behavioral responses in larval zebrafish, determined the most appropriate data acquisition mode, and evaluated the suitability of an acoustic motor response (AMR) assay as means to assess alterations in brain activity and risk of chemical-induced developmental neurotoxicity. We quantified the motor responses of 120 h post-fertilization (hpf) larvae to acoustic stimuli with varying patterns and frequencies, and determined the optimal time intervals for data acquisition. Following this, we examined changes in acoustic and visual motor responses resulting from exposures to pharmacological agents known to impact brain activity (pentylenetetrazole (PTZ) and tricaine-s (MS-222)). Additionally, we examined the AMR and VMR of larvae following exposure to two environmental contaminants associated with developmental neurotoxicity: arsenic (As) and cadmium (Cd). Our findings indicate that exposure to a 100 Hz sound frequency in 100 ms pulses elicits the strongest behavioral response among the acoustic stimuli tested and data acquisition in 2 s time intervals is suitable for response assessment. Exposure to PTZ exaggerated and depressed both AMR and VMR in a concentration-dependent manner, while exposure to MS-222 only depressed them. Similarly, exposure to As and Cd induced respective hyper- and hypo-activation of both motor responses. This study highlights the efficiency of the proposed zebrafish-based AMR assay in demonstrating risk of chemical-induced developmental neurotoxicity and its suitability as a complement to the widely adopted VMR assay.

Superfast Lombard response in free-flying, echolocating bats.

Acoustic cues are crucial to communication, navigation, and foraging in many animals, which hence face the problem of detecting and discriminating these cues in fluctuating noise levels from natural or anthropogenic sources. Such auditory dynamics are perhaps most extreme for echolocating bats that navigate and hunt prey on the wing in darkness by listening for weak echo returns from their powerful calls in complex, self-generated umwelts.1,2 Due to high absorption of ultrasound in air and fast flight speeds, bats operate with short prey detection ranges and dynamic sensory volumes,3 leading us to hypothesize that bats employ superfast vocal-motor adjustments to rapidly changing sensory scenes. To test this hypothesis, we investigated the onset and offset times and magnitude of the Lombard response in free-flying echolocating greater mouse-eared bats exposed to onsets of intense constant or duty-cycled masking noise during a landing task. We found that the bats invoked a bandwidth-dependent Lombard response of 0.1-0.2 dB per dB increase in noise, with very short delay and relapse times of 20 ms in response to onsets and termination of duty-cycled noise. In concert with the absence call time-locking to noise-free periods, these results show that free-flying bats exhibit a superfast, but hard-wired, vocal-motor response to increased noise levels. We posit that this reflex is mediated by simple closed-loop audio-motor feedback circuits that operate independently of wingbeat and respiration cycles to allow for rapid adjustments to the highly dynamic auditory scenes encountered by these small predators.

Analyzing the Effects of Age, Time of Day, and Experiment on the Basal Locomotor Activity and Light-Off Visual Motor Response Assays in Zebrafish Larvae.

The recent availability of commercial platforms for behavioral analyses in zebrafish larvae based on video-tracking technologies has exponentially increased the number of studies analyzing different behaviors in this model organism to assess neurotoxicity. Among the most commonly used assays in zebrafish larvae are basal locomotor activity (BLA) and visual motor responses (VMRs). However, the effect of different intrinsic and extrinsic factors that can significantly alter the outcome of these assays is still not well understood. In this work, we have analyzed the influence of age (5-8 days post-fertilization), time of day (8:00, 10:00, 12:00, 14:00; 16:00, 18:00, and 20:00 h), and experiment (three experiments performed at different days) on BLA and VMR results (4004 analyses for each behavior) in 143 larvae. The results from both behaviors were adjusted to a random-effects linear regression model using generalized least squares (GLSs), including in the model the effect of the three variables, the second-way interactions between them, and the three-way interaction. The results presented in this manuscript show a specific effect of all three intrinsic factors and their interactions on both behaviors, supporting the view that the most stable time period for performing these behavioral assays is from 10:00 am to 04:00 pm, with some differences depending on the age of the larva and the behavioral test.

Long-Term Follow-Up of the LEAP Study: Early Versus Delayed Levodopa in Early Parkinson's Disease.

BACKGROUND AND OBJECTIVE: The Levodopa in EArly Parkinson's disease study showed no effect of earlier versus later levodopa initiation on Parkinson's disease (PD) progression over 80 weeks. We now report the effects over 5 years. METHODS: The Levodopa in EArly Parkinson's disease study randomly assigned patients to levodopa/carbidopa 300/75 mg daily for 80 weeks (early start) or to placebo for 40 weeks followed by levodopa/carbidopa 300/75 mg daily for 40 weeks (delayed start). Follow-up visits were performed 3 and 5 years after baseline. We assessed the between-group differences in terms of square root transformed total Unified Parkinson's Disease Rating Scale score at 3 and 5 years with linear regression. We compared the prevalence of dyskinesia, prevalence of wearing off, and the levodopa equivalent daily dose. RESULTS: A total of 321 patients completed the 5-year visit. The adjusted square root transformed total Unified Parkinson's Disease Rating Scale did not differ between treatment groups at 3 (estimated difference, 0.17; standard error, 0.13; P = 0.18) and 5 years (estimated difference, 0.24; standard error, 0.13; P = 0.07). At 5 years, 46 of 160 patients in the early-start group and 62 of 161 patients in the delayed-start group experienced dyskinesia (P = 0.06). The prevalence of wearing off and the levodopa equivalent daily dose were not significantly different between groups. CONCLUSIONS: We did not find a difference in disease progression or in prevalence of motor complications between patients with early PD starting treatment with a low dose of levodopa 40 weeks earlier versus 40 weeks later over the subsequent 5 years. © 2024 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Distinguishing reflex from non-reflex responses elicited by transcutaneous spinal stimulation targeting the lumbosacral cord in healthy individuals.

Transcutaneous spinal stimulation (TSS) studies rely on the depolarization of afferent fibers to provide input to the spinal cord; however, this has not been routinely ascertained. Thus, we aimed to characterize the types of responses evoked by TSS and establish paired-pulse ratio cutoffs that distinguish posterior root reflexes, evoked by stimulation of afferent nerve fibers, from motor responses, evoked by stimulation of efferent nerve fibers. Twelve neurologically intact participants (six women) underwent unipolar TSS (cathode over T11-12 spinal processes, anode paraumbilically) while resting supine. In six participants, unipolar TSS was repeated 2-3 months later and also compared to a bipolar TSS configuration (cathode 2.5 cm below T11-12, anode 5 cm above cathode). EMG signals were recorded from 16 leg muscles. A paired-pulse paradigm was applied at interstimulus intervals (ISIs) of 25, 50, 100, 200, and 400 ms. Responses were categorized by three assessors into reflexes, motor responses, or their combination (mixed responses) based on the visual presence/absence of paired-pulse suppression across ISIs. The paired-pulse ratio that best discriminated between response types was derived for each ISI. These cutoffs were validated by repeating unipolar TSS 2-3 months later and with bipolar TSS. Unipolar TSS evoked only reflexes (90%) and mixed responses (10%), which were mainly recorded in the quadriceps muscles (25-42%). Paired-pulse ratios of 0.51 (25-ms ISI) and 0.47 (50-ms ISI) best distinguished reflexes from mixed responses (100% sensitivity, > 99.2% specificity). These cutoffs performed well in the repeated unipolar TSS session (100% sensitivity, > 89% specificity). Bipolar TSS exclusively elicited reflexes which were all correctly classified. These results can be utilized in future studies to ensure that the input to the spinal cord originates from the depolarization of large afferents. This knowledge can be applied to improve the design of future neurophysiological studies and increase the fidelity of neuromodulation interventions.

ADHD and the avoidance of mental effort: the role of response inhibition and avoidance motivation.

OBJECTIVE: The tendency of people with ADHD to avoid tasks that require mental effort impacts their academic achievement. Findings in the literature suggest that children with ADHD find cognitive tasks more effortful and uncomfortable than their typically developing peers. However, neuropsychological processes contributing to this remain unclear. The present study investigated whether the relationship between prepotent motor response inhibition and avoiding mental effort is mediated by the ability to resist avoidance motivation and whether this proposed mediation mechanism is contingent on ADHD diagnosis. METHOD: 40 children with ADHD and 40 gender and age-matched typically developing peers participated in the study. They completed the Cognitive Effort Avoidance Measure, the Go/No-go Task, and the Reinforcement Sensitivity Theory-Personality Questionnaire-Children. Mediation and moderated mediation analyses were employed to test the hypotheses. RESULTS: Children with ADHD scored lower in response inhibition and resisting avoidance motivation. Poorer scores in these variables were associated with a higher avoidance rate. Moreover, the ability to resist avoidance motivation completely mediated the relationship between response inhibition and avoidance rate only among children with ADHD. CONCLUSION: Findings imply that poorer response inhibition led to an increase in avoidance motivation among children with ADHD, which becomes challenging to regulate effectively due to an impairment in the ability to resist avoidance motivation. Theoretical and clinical implications are discussed.

Assessment of acute toxicity of crude extract rich in carotenoids from Cantaloupe melon (Cucumis melo L.) and the gelatin-based nanoparticles using the zebrafish (Danio rerio) model.

Cantaloupe melon is known for its carotenoid-rich orange pulp. However, carotenoids are sensitive to oxygen, light, and heat, potentially reducing their benefits. Nanoencapsulation can preserve these benefits but raises concerns about toxicity. We aimed to assess the safety and bioactive potential of crude extract-rich carotenoids (CE) and nanoparticles based on gelatin loaded with CE (EPG) by investigating parameters such as cardio or neurotoxicity, especially acute toxicity. EPG was obtained by O/W emulsification and characterized by different methods. Zebrafish embryos were exposed to CE and EPG at 12.5 mg/L and 50 mg/L for 96h and were investigated for survival, hatching, malformations, and seven days post fertilization (dpf) larvae's visual motor response. Adult fish underwent behavioral tests after acute exposure of 96h. CE and EPG showed no acute toxicity in zebrafish embryos, and both improved the visual motor response in 7dpf larvae (p = 0.01), suggesting the potential antioxidant and provitamin A effect of carotenoids in cognitive function and response in the evaluated model. Adult fish behavior remained with no signs of anxiety, stress, swimming pattern changes, or sociability that would indicate toxicity. This study highlights the safety and potential benefits of carotenoids in zebrafish. Further research is needed to explore underlying mechanisms and long-term effects.

Acute effect of levodopa on orthostatic hypotension and its association with motor responsiveness in Parkinson's disease: Results of acute levodopa challenge test.

OBJECTIVE: Levodopa administration can induce or worsen orthostatic hypotension (OH) in patients with Parkinson's disease (PD). Understanding of acute OH post levodopa (AOHPL) is important for rational drug use in PD patients. Primary objective of this study was to investigate the incidence of AOHPL in PD patients. The secondary objectives were a) hemodynamic character of AOHPL; b) risk factors of AOHPL; c) relationship between motor responsiveness and blood pressure (BP) change. METHODS: 490 PD inpatients underwent acute levodopa challenge test (LCT). Supine-to-standing test (STS) was done 4 times during LCT, including before levodopa and every hour post levodopa intake within 3 h. Patients were classified into two groups, AOHPL and non-AOHPL. A comprehensive set of clinical features scales was assessed, including both motor (e.g., motor response, wearing-off) and nonmotor symptoms (e.g., autonomic dysfunction, neuropsychology). RESULTS: 33.1% PD patients had OH before drug, 50.8% the same subjects had AOHPL during levodopa effectiveness. PD patients who had better response to levodopa likely to have lower standing mean artery pressure (MAP) and severer systolic BP drop after levodopa intake. BP increased when the motor performance worsened and vice versa. Beneficial response was a risk factors of AOHPL (OR = 1.624, P = 0.017). CONCLUSIONS: AOHPL was very common in PD patients. We suggested that PD patients with risk factors should monitor hemodynamic change during LCT to avoid AOHPL following the introduction or increase of oral levodopa. The fluctuations of BP were complicated and multifactorial, likely caused by the process of PD and levodopa both.

Posterior cingulate cortex spontaneous activity associated with motor response inhibition in patients with obsessive-compulsive disorder: A resting-state fMRI study.

Recent evidence suggests that broad brain regions, not limited to the fronto-striato-thalamo-cortical circuit, play an important role in motor response inhibition. However, it is still unclear which specific key brain region is responsible for impaired motor response inhibition observed in obsessive-compulsive disorder (OCD). We calculated the fractional amplitude of low-frequency fluctuations (fALFF) and measured response inhibition ability using the stop-signal task in 41 medication-free patients with OCD and 49 healthy control (HC) participants. We explored the brain region that shows different association between the fALFF and the ability of motor response inhibition. Significant differences in fALFF associated with the ability of motor response inhibition were identified in dorsal posterior cingulate cortex (PCC). There was a positive correlation between increased fALFF in the dorsal PCC and impaired motor response inhibition in OCD. In the HC group, there was a negative correlation between the two variables. Our results suggest that the magnitude of resting-state blood oxygen level-dependent oscillation of the dorsal PCC is a key brain region for the underlying mechanisms of impaired motor response inhibition in OCD. Future studies should examine whether this characteristic of dorsal PCC affects other large-scale networks responsible for motor response inhibition of OCD.

Electrophysiological evidence of discontinuities in the propagation of lexical decision processes across the motor hierarchy.

This research assessed the propagation of decisional effects across multiple electrophysiological indexes related to motor-response implementation within a lexical decision task, a paradigmatic case of a 2-alternative choice task on linguistic stimuli. By co-registering electroencephalographic and electromyographic data, we focused on the lexicality effect (i.e., the difference between responses to words and nonwords), and we tracked its influence across indexes of motor-response planning (indexed by effector-selective lateralization of beta-frequency desynchronizations), programming (indexed by the lateralized readiness potential) and execution (indexed by the chronometric durations of muscular responses). In addition, we explored corticomuscular coherence as the potential physiological underpinning of a continuous mapping of information between stimulus evaluation and response channels. The results revealed lexicality effects only on indexes of motor planning and execution, with no reliable involvement of the other measures. This pattern is discussed with reference to the hypothesis of multiple decisional components exerting different influences across the motor-hierarchy.

The Simultaneous Assessment of Time and Motion Response during Dual Tasks.

Measurement of reaction time in clinical settings is generally employed to assess cognitive abilities by having a subject perform standard simple tests. In this study, a new method of measuring response time (RT) was developed using a system composed of LEDs that emit light stimuli and are equipped with proximity sensors. The RT is measured as the time taken by the subject to turn off the LED target by moving the hand towards the sensor. Through an optoelectronic passive marker system, the associated motion response is assessed. Two tasks of 10 stimuli each were defined: simple reaction time and recognition reaction time tasks. To validate the method implemented to measure RTs, the reproducibility and repeatability of the measurements were estimated, and, to test the method's applicability, a pilot study was conducted on 10 healthy subjects (6 females and 4 males, age = 25 ± 2 years), reporting, as expected, that the response time was affected by the task's difficulty. Unlike commonly used tests, the developed method has proven to be adequate for the simultaneous evaluation of the response in terms of time and motion. Furthermore, thanks to the playful nature of the tests, this method could also be used for clinical and pediatric applications to measure the impact of motor and cognitive impairments on RT.

Comparison of the prognostic validity of three simplified consciousness assessment scales with the Glasgow Coma Scale.

BACKGROUND: Various tools simpler than the Glasgow Coma Scale (GCS) have been proposed for the assessment of consciousness. In this study, the validity of three coma scales [Simplified Motor Scale, Modified GCS Motor Response, and AVPU (alert, verbal, painful, unresponsive)] is evaluated for the recognition of coma and the prediction of short- and long-term mortality and poor outcome. The predictive validity of these scales is also compared to the GCS. METHODS: Patients treated in the Department of Neurosurgery and the Intensive Care Unit in need of consciousness monitoring were assessed by four raters (two consultants, a resident and a nurse) using the GCS. The corresponding values of the simplified scales were estimated. Outcome was recorded at discharge and at 6 months. Areas Under the Receiver Operating Characteristic Curve (AUCs) were calculated for the prediction of mortality and poor outcome, and the identification of coma. RESULTS: Eighty-six patients were included. The simplified scales showed good overall validity (AUCs > 0.720 for all outcomes of interest), but lower than the GCS. For the identification of coma and the prediction of long-term poor outcome, the difference was significant (p < 0.050) for all the ratings of the most experienced rater. The validity of these scales was comparable to the GCS only in predicting in-hospital mortality, but without this being consistent for all raters. CONCLUSION: The simplified scales showed inferior validity than the GCS. Their potential role in clinical practice needs further investigation. Thus, the replacement of the GCS as the main scale for consciousness assessment cannot be currently supported.

Long-term behavioral alterations following embryonic alcohol exposure in three zebrafish populations.

Fetal alcohol exposure may lead to a condition known as fetal alcohol spectrum disorder (FASD), which comprises a set of consequences, including cognitive and behavioral impairments. Although zebrafish has been applied as a reliable model for studying FASD, there is no approach to the disorder's ontogeny and population differences. Here, we evaluated the behavioral outcomes of AB, Outbred (OB), and Tübingen (TU) zebrafish populations embryonically exposed to alcohol throughout the development to the adult stage. We exposed 24hpf eggs to 0 %, 0.5 %, or 1.0 % alcohol for 2 h. Fish were let grow and locomotor and anxiety-like behaviors were tested in a novel tank at larval - 6dpf, juvenile - 45dpf, and adult- 90dpf stages. At 6dpf, both AB and OB treated with 1.0 % alcohol showed hyperactivity, while 0.5 % and 1.0 % TU fish exhibited hypolocomotion. At 45dpf, AB and TU fish maintained the larval pattern of locomotion. At the adult stage - 90dpf, both AB and TU populations showed increased locomotor activity and anxiogenic responses, while the OB population did not show altered behavior. Our results show for the first time that zebrafish populations exhibit behavioral differences in response to embryonic alcohol exposure and that it varies along animals' ontogeny. AB fish showed the most consistent behavioral pattern through developmental stages, TU fish showed behavioral changes only in adulthood, and OB population showed high interindividual variability. These data reinforce that different populations of zebrafish are better adapted to translational studies, offering reliable results in contrast to domesticated OB populations obtained from farms, which exhibit more variable genomes.

Multisensory integration augmenting motor processes among older adults.

Objective: Multisensory integration enhances sensory processing in older adults. This study aimed to investigate how the sensory enhancement would modulate the motor related process in healthy older adults. Method: Thirty-one older adults (12 males, mean age 67.7 years) and 29 younger adults as controls (16 males, mean age 24.9 years) participated in this study. Participants were asked to discriminate spatial information embedded in the unisensory (visual or audial) and multisensory (audiovisual) conditions. The responses made by the movements of the left and right wrists corresponding to the spatial information were registered with specially designed pads. The electroencephalogram (EEG) marker was the event-related super-additive P2 in the frontal-central region, the stimulus-locked lateralized readiness potentials (s-LRP) and response-locked lateralized readiness potentials (r-LRP). Results: Older participants showed significantly faster and more accurate responses than controls in the multisensory condition than in the unisensory conditions. Both groups had significantly less negative-going s-LRP amplitudes elicited at the central sites in the between-condition contrasts. However, only the older group showed significantly less negative-going, centrally distributed r-LRP amplitudes. More importantly, only the r-LRP amplitude in the audiovisual condition significantly predicted behavioral performance. Conclusion: Audiovisual integration enhances reaction time, which associates with modulated motor related processes among the older participants. The super-additive effects modulate both the motor preparation and generation processes. Interestingly, only the modulated motor generation process contributes to faster reaction time. As such effects were observed in older but not younger participants, multisensory integration likely augments motor functions in those with age-related neurodegeneration.

Predicting the best fit based on the synergistic interaction of remifentanil and propofol at the corrected dose in elderly patients undergoing painless gastroscopy.

OBJECTIVE: To validate a response surface model for the inhibition of somatic motor response at corrected body weight (CBW) doses of remifentanil plus propofol in elderly patients and to analyze the dose-effect relationship and optimal dosing range for total intravenous anesthesia (TIVA) induction in painless gastroscopy. METHODS: We designed a prospective, open-ended, randomized, parallel group study. A total of 300 elderly patients undergoing painless gastroscopy were randomized to receive remifentanil (0-0.5 µg/kg) and propofol (0.8-2.2 mg/kg) dosing based on CBW. Gastroscopy was performed at the drug's peak effect time. The somatic motor response to gastroscopic stimulation and the adverse reactions at different points were recorded. The somatic motor response was used as the basic element in the subsequent RSM analysis. Model parameters and 95% confidence intervals were fitted by MATLAB software. RESULTS: The CBW doses of remifentanil and propofol showed synergistic inhibitory effects on motor response to noxious stimulation and attenuated adverse reactions. The 50% effective doses of remifentanil and propofol for inhibiting the motor response were 1.754 µg/kg and 2.048 mg/kg, respectively. CONCLUSION: Remifentanil or propofol alone could not inhibit the somatic motor response at weight-adjusted doses among elderly patients. A combination of remifentanil and propofol showed a synergistic interaction in suppressing the motor response and adverse reactions in elderly patients. Preinjection of remifentanil could reduce the needed dose of propofol.

Neuroelectric indices of motor response preparation are selectively associated with physical activity among adults with obesity.

Previous work has demonstrated that physical activity and weight status are associated with attentional inhibition (indexed with the P3 component of event-related potentials). However, there is limited knowledge on the neural underpinnings of motor response planning and activation. This study investigated the effect of weight status on relationships between moderate-to-vigorous physical activity (MVPA) and the lateralized readiness potential (LRP), a neuroelectric index of motor response planning and activation. Adults (N = 165 [98 females]) wore ActiGraph wGT3X+ accelerometers to measure physical activity. Behavioral outcomes were recorded during the modified Eriksen Flanker task to assess attentional inhibition. EEG recordings were taken to elucidate response- (LRP-R) and stimulus-locked (LRP-S) LRPs, and P3. Participants were separated into groups based on the BMI cutoff of 30 kg/m2 (i.e., non-obese [n = 88], obese [n = 77]). Independent t-tests and ANCOVA were conducted to determine differences between groups. Regression analyses within each group were conducted to determine relationships between MVPA and LRP and P3 amplitude and latencies. There was no difference in MVPA between weight groups after adjustment for age and sex, although the non-obese group had significantly higher incongruent accuracy (p = 0.007). Only in the obese group, MVPA was positively associated with LRP-R incongruent (ß = 0.014, p = 0.029) and LRP-S congruent (ß = 0.013, p = 0.008) amplitude, and inversely associated with LRP-S incongruent (ß = -0.488, p = 0.017) and P3 congruent (ß = 0.013, p = 0.008) fractional area latency. MVPA was associated with pre-motor planning and activation only among persons with obesity. Future work should study the impact of physical activity on neuroelectric indices of motor responses in people with obesity.

Effect of Opicapone on Levodopa Pharmacokinetics in Patients with Fluctuating Parkinson's Disease.

BACKGROUND: Inhibiting catechol-O-methyltransferase extends the plasma half-life of levodopa, potentially allowing physicians to optimize the levodopa regimen in patients with Parkinson's disease (PD) experiencing motor fluctuations. OBJECTIVES: To evaluate the effects of once-daily opicapone on levodopa plasma pharmacokinetics and motor response when added to two different levodopa dosing regimens. METHODS: A total of 24 patients with PD and motor fluctuations were enrolled in an exploratory, open-label, modified cross-over trial. Participants first received levodopa/carbidopa 500/125 mg (five intakes) for 2 weeks and were then randomly assigned (1:1) to levodopa/carbidopa 400/100 mg given over either four or five daily intakes plus opicapone 50 mg for an additional 2 weeks. Levodopa 12-hour pharmacokinetics was the primary outcome (ie, excluding the effect of last/evening levodopa/carbidopa intake), with motor complications evaluated as secondary outcomes. RESULTS: Over 12-hour pharmacokinetics and compared with five-intake levodopa/carbidopa 500/125 mg without opicapone, maximal levodopa concentrations were similar or nonsignificantly higher on both levodopa/carbidopa 400/100 mg regimens plus opicapone. Despite a 100 mg lower total levodopa/carbidopa daily dose, adding opicapone 50 mg at least doubled the levodopa plasma half-life and minimal concentrations, with a significant ≈30% increase in total exposure. The levodopa fluctuation index was only significantly lower for the five intakes plus opicapone regimen (difference of -71.8%; P < 0.0001). Modifications to levodopa pharmacokinetics were associated with decreased off time and increased on time. CONCLUSIONS: Combining opicapone 50 mg with a 100 mg lower daily dose of levodopa provides higher levodopa bioavailability with avoidance of trough levels. Despite the lower levodopa dose, modifying the levodopa pharmacokinetic profile with opicapone was associated with decreased off time and increased on time. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Effect of cortical extracellular GABA on motor response.

To elucidate how the flattening of sensory tuning due to a deficit in tonic inhibition slows motor responses, we simulated a neural network model in which a sensory cortical network ([Formula: see text]) and a motor cortical network ([Formula: see text]) are reciprocally connected, and the [Formula: see text] projects to spinal motoneurons (Mns). The [Formula: see text] was presented with a feature stimulus and the reaction time of Mns was measured. The flattening of sensory tuning in [Formula: see text] caused by decreasing the concentration of gamma-aminobutyric acid (GABA) in extracellular space resulted in a decrease in the stimulus-sensitive [Formula: see text] pyramidal cell activity while increasing the stimulus-insensitive [Formula: see text] pyramidal cell activity, thereby prolonging the reaction time of Mns to the applied feature stimulus. We suggest that a reduction in extracellular GABA concentration in sensory cortex may interfere with selective activation in motor cortex, leading to slowing the activation of spinal motoneurons and therefore to slowing motor responses.

Motor Nerve Conduction Block Estimation in Demyelinating Neuropathies by Deconvolution.

A deconvolution method is proposed for conduction block (CB) estimation based on two compound muscle action potentials (CMAPs) elicited by stimulating a nerve proximal and distal to the region in which the block is suspected. It estimates the time delay distributions by CMAPs deconvolution, from which CB is computed. The slow afterwave (SAW) is included to describe the motor unit potential, as it gives an important contribution in case of the large temporal dispersion (TD) often found in patients. The method is tested on experimental signals obtained from both healthy subjects and pathological patients, with either Chronic Inflammatory Demyelinating Polyneuropathy (CIDP) or Multifocal Motor Neuropathy (MMN). The new technique outperforms the clinical methods (based on amplitude and area of CMAPs) and a previous state-of-the-art deconvolution approach. It compensates phase cancellations, allowing to discriminate among CB and TD: estimated by the methods of amplitude, area and deconvolution, CB showed a correlation with TD equal to 39.3%, 29.5% and 8.2%, respectively. Moreover, a significant decrease of percentage reconstruction errors of the CMAPs with respect to the previous deconvolution approach is obtained (from a mean/median of 19.1%/16.7% to 11.7%/11.2%). Therefore, the new method is able to discriminate between CB and TD (overcoming the important limitation of clinical approaches) and can approximate patients' CMAPs better than the previous deconvolution algorithm. Then, it appears to be promising for the diagnosis of demyelinating polyneuropathies, to be further tested in the future in a prospective clinical trial.