It wasn't me! Motor activation from irrelevant spatial information in the absence of a response

Embodied cognition postulates that perceptual and motor processes serve higher-order cognitive faculties like language. A major challenge for embodied cognition concerns the grounding of abstract concepts. Here we zoom in on abstract spatial concepts and ask the question to what extent the sensorimotor system is involved in processing these. Most of the empirical support in favor of an embodied perspective on (abstract) spatial information has derived from so-called compatibility effects in which a task-irrelevant feature either facilitates (for compatible trials) or hinders (in incompatible trials) responding to the task-relevant feature. This type of effect has been interpreted in terms of (task-irrelevant) feature-induced response activation. The problem with such approach is that incompatible features generate an array of task relevant and irrelevant activations [e.g., in primary motor cortex (M1)], and lateral hemispheric interactions render it difficult to assign credit to the task-irrelevant feature per se in driving these activations. Here, we aim to obtain a cleaner indication of response activation on the basis of abstract spatial information. We employed transcranial magnetic stimulation (TMS) to probe response activation of effectors in response to semantic, task-irrelevant stimuli (i.e., the words left and right) that did not require an overt response. Results revealed larger motor evoked potentials (MEPs) for the right (left) index finger when the word right (left) was presented. Our findings provide support for the grounding of abstract spatial concepts in the sensorimotor system

Fast HPLC-based affinity method to determine capsid titer and full/empty ratio of adeno-associated viral vectors

Recombinant adeno-associated viruses (rAAVs) are promising gene delivery vectors in the emerging field of in vivo gene therapies. To ensure their consistent quality during manufacturing and process development, multiple analytical techniques have been proposed for the characterization and quantification of rAAV capsids. Despite their indisputable capabilities for performing this task, current analytical methods are rather time-consuming, material intensive, complicated, and costly, restricting their suitability for process development in which time and sample throughput are severe constraints. To eliminate this bottleneck, we introduce here an affinity-based high-performance liquid chromatography method that allows the determination of the capsid titer and the full/empty ratio of rAAVs within less than 5 min. By packing the commercially available AAVX affinity resin into small analytical columns, the rAAV fraction of diverse serotypes can be isolated from process-related impurities and analyzed by UV and fluorescence detection. As demonstrated by both method qualification data and side-by-side comparison with AAV enzyme-linked immunosorbent assay results for rAAV8 samples as well as by experiments using additional rAAV2, rAAV8, and rAAV9 constructs, our approach showed good performance, indicating its potential as a fast, simple and efficient tool for supporting the development of rAAV gene therapies

Identification of Potential Sites for Tryptophan Oxidation in Recombinant Antibodies Using tert-Butylhydroperoxide and Quantitative LC-MS

Amino acid oxidation is known to affect the structure, activity, and rate of degradation of proteins. Methionine oxidation is one of the several chemical degradation pathways for recombinant antibodies. In this study, we have identified for the first time a solvent accessible tryptophan residue (Trp-32) in the complementary-determining region (CDR) of a recombinant IgG1 antibody susceptible to oxidation under real-time storage and elevated temperature conditions. The degree of light chain Trp-32 oxidation was found to be higher than the oxidation level of the conserved heavy chain Met-429 and the heavy chain Met-107 of the recombinant IgG1 antibody HER2, which have already been identified as being solvent accessible and sensitive to chemical oxidation. In order to reduce the time for simultaneous identification and functional evaluation of potential methionine and tryptophan oxidation sites, a test system employing tert-butylhydroperoxide (TBHP) and quantitative LC-MS was developed. The optimized oxidizing conditions allowed us to specifically oxidize the solvent accessible methionine and tryptophan residues that displayed significant oxidation in the real-time stability and elevated temperature study. The achieved degree of tryptophan oxidation was adequate to identify the functional consequence of the tryptophan oxidation by binding studies. In summary, the here presented approach of employing TBHP as oxidizing reagent combined with quantitative LC-MS and binding studies greatly facilitates the efficient identification and functional evaluation of methionine and tryptophan oxidation sites in the CDR of recombinant antibodies

Analysis of shared common genetic risk between amyotrophic lateral sclerosis and epilepsy

Because hyper-excitability has been shown to be a shared pathophysiological mechanism, we used the latest and largest genome-wide studies in amyotrophic lateral sclerosis (n = 36,052) and epilepsy (n = 38,349) to determine genetic overlap between these conditions. First, we showed no significant genetic correlation, also when binned on minor allele frequency. Second, we confirmed the absence of polygenic overlap using genomic risk score analysis. Finally, we did not identify pleiotropic variants in meta-analyses of the 2 diseases. Our findings indicate that amyotrophic lateral sclerosis and epilepsy do not share common genetic risk, showing that hyper-excitability in both disorders has distinct origins

Internal and external spatial attention examined with lateralized EEG power spectra

Several authors argued that retrieval of an item from visual short term memory (internal spatial attention) and focusing attention on an externally presented item (external spatial attention) are similar. Part of the neuroimaging support for this view may be due to the employed experimental procedures. Furthermore, as internal spatial attention may have a more induced than evoked nature some effects may not have been visible in event related analyses of the electroencephalogram (EEG), which limits the possibility to demonstrate differences. In the current study, a colored frame cued which stimulus, one out of four presented in separate quadrants, required a response, which depended on the form of the cued stimulus (circle or square). Importantly, the frame occurred either before (precue), simultaneously with (simultaneous cue), or after the stimuli (postcue). The precue and simultaneous cue condition both concern external attention, while the postcue condition implies the involvement of internal spatial attention. Event-related lateralizations (ERLs), reflecting evoked effects, and lateralized power spectra (LPS), reflecting both evoked and induced effects, were determined. ERLs revealed a posterior contralateral negativity (PCN) only in the precue condition. LPS analyses on the raw EEG showed early increased contralateral theta power at posterior sites and later increased ipsilateral alpha power at occipito-temporal sites in all cue conditions. Responses were faster when the internally or externally attended location corresponded with the required response side than when not. These findings provide further support for the view that internal and external spatial attention share their underlying mechanis

Reward anticipation modulates primary motor cortex excitability during task preparation

Task preparation has been associated with a transient suppression of corticospinal excitability (CSE) before target onset, but it is an open question to what extent CSE suppression during task preparation is susceptible to motivational factors. Here, we examined whether CSE suppression is modulated by reward anticipation, and, if so, how this modulation develops over time. We administered a cue-target delay paradigm in which 1000 ms before target onset a cue was presented indicating whether or not reward could be obtained for fast and accurate responses in a Simon task. Single-pulse transcranial magnetic stimulation was applied over left primary motor cortex (M1) during the delay period (400, 600, or 800 ms after cue onset) or 200 ms after target onset, and electromyography was obtained from the right first dorsal interosseous muscle. Behaviorally, the anticipation of reward improved performance (i.e. faster reaction times). Most importantly, during reward anticipation we observed a linear decrease of motor evoked potential amplitudes that was absent when no reward was anticipated. This suggests that reward anticipation modulates CSE during task preparation

Methohexital-Induced Changes in Spectral Power of Neuromagnetic Signals : Beta Augmentation is Smaller Over the Hemisphere Containing the Epileptogenic Focus

Previous research has suggested that methohexital, a short-term barbiturate, alters activity in the primary epileptogenic area. It can be assumed that drug-induced activation of the epileptogenic focus provides a rapid and safe method to obtain a sufficient amount of information relevant for the lateralization and localisation of the primary epileptogenic area. This study shows that methohexital changes spectral power in the beta band derived from magnetoencephalographic (MEG) signals over the hemisphere ipsilateral to the primary epileptogenic area. This effect was demonstrated for 10/13 of the investigated patients suffering from unilateral temporal lobe epilepsy (TLE). The side and location of the primary epileptogenic area of these patients (5 left TLE, 8 right TLE) was determined invasively during presurgical evaluation. During a 1-2 minute interval after intravenous bolus injection of 100 mg methohexital a clear lateralization effect in the beta band was observed, which differed maginally between fronto-central, fronto-temporal and temporo-parietal brain regions. Analyses of simultaneously recorded scalp electroencephalographic (EEG) data revealed effects consistent with those of the MEG anasysis. The reduced enhancement of beta band spectral power of MEG recordings provides a potential application for the non-invasive lateralization of the primary epileptogenic area

Panel A and B: Mean mouse trajectories for the congruent and incongruent trials as a function of proportion congruency (80% congruent: Panel A; 20% congruent: panel B).

<p>Error bars represent 95% confidence intervals. Panel C and D: Mean MT and AUC for the congruent and incongruent trials as a function of proportion congruency (i.e., ISPC effect). Error bars represent standard errors. ***<i>p</i><.001.</p

Schematic illustration of a congruent (“RED” in red ink) and an incongruent trial (“BLUE” in yellow ink) trial.

<p>Participants clicked the start button to prompt the presentation of a stimulus that indicated the correct response box. Note that all words were actually displayed in Dutch and that there was a 300ms delay between clicking the start button and stimulus presentation. In addition, after clicking the response box of their choice, participants had to wait 500ms before the start button appeared again to start the next trial.</p

Early and late indications of item-specific control in a Stroop mouse tracking study - Fig 3

<p>Mean IT (panel A and B) and MT (panel C and D) for fast and slow initiation time bins. Error bars represent standard errors. **<i>p</i><.01, ***<i>p</i><.001.</p