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• W4213303739 abstract "Article Figures and data Abstract Editor's evaluation Introduction Results Discussion Materials and methods Data availability References Decision letter Author response Article and author information Metrics Abstract Cognitive operations are widely studied by measuring electric fields through EEG and ECoG. However, despite their widespread use, the neural circuitry giving rise to these signals remains unknown because the functional architecture of cortical columns producing attention-associated electric fields has not been explored. Here, we detail the laminar cortical circuitry underlying an attention-associated electric field measured over posterior regions of the brain in humans and monkeys. First, we identified visual cortical area V4 as one plausible contributor to this attention-associated electric field through inverse modeling of cranial EEG in macaque monkeys performing a visual attention task. Next, we performed laminar neurophysiological recordings on the prelunate gyrus and identified the electric-field-producing dipoles as synaptic activity in distinct cortical layers of area V4. Specifically, activation in the extragranular layers of cortex resulted in the generation of the attention-associated dipole. Feature selectivity of a given cortical column determined the overall contribution to this electric field. Columns selective for the attended feature contributed more to the electric field than columns selective for a different feature. Last, the laminar profile of synaptic activity generated by V4 was sufficient to produce an attention-associated signal measurable outside of the column. These findings suggest that the top-down recipient cortical layers produce an attention-associated electric field that can be measured extracortically with the relative contribution of each column depending upon the underlying functional architecture. Editor's evaluation By combining rare EEG and laminar recordings in monkeys, Westerberg and colleagues studied the neural correlates of the well-known attention-related N2pc signal and found that it is due to the activation of extra-granular layers of cortex. Further, this effect was stronger for columns that were more feature selective. These findings are extremely important and a unique contribution to the literature on the neurobiology of attention. https://doi.org/10.7554/eLife.72139.sa0 Decision letter Reviews on Sciety eLife's review process Introduction Research into extracortical electric fields provides fundamental insights into the mechanisms of human perception, cognition, and intention. For instance, event-related potential (ERP) components like the N2pc (Eimer, 1996; Luck and Hillyard, 1994; Woodman and Luck, 1999) and Pd (Hickey et al., 2009) reliably index selective attention in humans and monkeys, alike. However, the interpretation of these extracortical measures of attention is severely limited by uncertainty about the exact neural processes that generate these signals (Nunez and Srinivasan, 2006). Understanding what brain processes an electric field indicates requires knowing how it is generated (e.g., Cohen, 2017). One avenue to localize neural generators of electric fields is through inverse source localization (Michel et al., 2004; Grech et al., 2008). However, the results are indefinite and cannot offer conclusive answers. Moreover, these methods do not allow for the probing of the underlying neural circuitry. For example, most EEG signals are hypothesized to be generated by interlaminar interactions in cortical columns (Nunez and Srinivasan, 2006). Columnar microcircuits are ubiquitous across the brain (Douglas et al., 1989; Douglas and Martin, 1991), having a well-defined anatomical structure (Mountcastle, 1997; Kaas, 2012) and consistent physiological activation pattern (Bastos et al., 2012 but see Godlove et al., 2014). The canonical cortical microcircuit offers a framework in which to interpret columnar dynamics in sensory or cognitive tasks, yet the relationship between this functional architecture and electric fields related to cognition commonly measured in humans is unexplored. Electric fields measured at the surface of the brain (ECoG) and scalp (EEG) are theorized to be generated by dipoles in cortex. However, measuring current dipoles requires sampling electrical potentials across all the layers of the cerebral cortex. Such laminar neurophysiological measurements are rare and unsystematic in humans. Work in rodents has uncovered intriguing insights into cortical laminar microcircuits underlying evoked EEG signals, but all of these were limited to sensory responses (Jellema et al., 2004; Bruyns-Haylett et al., 2017; Nass et al., 2021). Fortunately, macaque monkeys produce homologues of the attention-associated EEG signals (N2pc: Woodman et al., 2007; Cohen et al., 2009; Purcell et al., 2013; Pd: Cosman et al., 2018). Laminar neurophysiological measurements (Schroeder et al., 1998; Maier et al., 2010; Buffalo et al., 2011; Hansen et al., 2011; Self et al., 2013; Godlove et al., 2014; Engel et al., 2016; Klein et al., 2016; Hembrook-Short et al., 2017; Nandy et al., 2017; Trautmann et al., 2019; Westerberg et al., 2019; Tovar et al., 2020; Ferro et al., 2021) and EEG (Schmid et al., 2006; Woodman et al., 2007; Sandhaeger et al., 2019) are well established in macaques. However, despite many studies linking intra- and extracortical signals (Schroeder et al., 1992; Whittingstall and Logothetis, 2009; Musall et al., 2014; Snyder and Smith, 2015), to date, little is known about the laminar origins of ERPs in primates. Here, we show that visual cortex generates dipoles through layer-specific transsynaptic currents that give rise to electric fields that track the deployment of selective attention. These dipoles were generated by the extragranular compartments of cortex, indicating these cognitive operations likely arise from top-down interactions. Moreover, functional architecture – in the form of feature columns – was associated with the relative contribution of individual, local cortical columns to the global electric field. These results are the first to our knowledge to describe laminar specificity in synaptic activations contributing to the generation of electric fields associated with cognitive processing. Results Attention task To investigate extracortical manifestations of attention-associated electric fields, we trained macaque monkeys to perform a visual search task (Figure 1A). Three macaque monkeys (designated Ca, He, and Z) performed visual search for an oddball color target (red or green), presented within an array of five or seven uniform distractors (green or red) (N sessions for each monkey: Ca 21, He 9, Z 18). A fourth monkey (P) performed visual search for an oddball shape (T or L) presented within an array of up to seven uniform distractors (L or T) (N sessions: monkey P, 22). Each animal performed well above chance (chance level for monkeys Ca, He: 16.6%; P, Z: 12.5%) (behavioral accuracy in color search: Ca 88%, He 81%, Z 85%, shape search monkey P 66%). We sampled cortical neural signals during the color pop-out search to be certain of which item received the benefit of attention in the array. We used the more difficult search data to determine the generality of our findings. Two different recording types were used, necessitating four monkeys total, as described below and summarized in Supplementary file 1. Figure 1 with 1 supplement see all Download asset Open asset EEG traces and inverse source localization for the N2pc index of attention in monkeys. (A) EEG was recorded from electrodes arranged according to the 10–20 system in monkeys performing visual search by shifting gaze to a colored oddball stimulus (monitor diagrams show two example arrays). Blue and red shading highlights mapping between visual hemifield and cerebral hemisphere. (B) Trial-averaged P5 and P6 EEG traces from monkey Z following presentation of search arrays with the target in either the right (blue) or left (red) visual hemifield as well as the difference (orange). The voltage difference between the target in the left versus right hemifields reveals the N2pc ~150 ms after array presentation. The N2pc was significant (dependent samples t test between polarizations averaged between 125 and 250 ms after array presentation (t(35) = 2.42, p = 0.02)). (C) Inverse solution of current distribution consistent with difference in voltage distribution during the N2pc (113–182 ms) when the target was in the left hemifield versus right hemifield using sLORETA. Current density is displayed over the three-dimensional (3D) boundary element model derived from a magnetic resonance scan of monkey Z. Data was clipped below the 85% maximum value for display purposes. Cyan disks indicate EEG electrode positions. Current density is concentrated beneath electrode P6 caudal to the lunate sulcus and in area V4 on the prelunate gyrus. Results are reproduced for a second monkey in Figure 1—figure supplement 1. Inverse modeling of attention-associated extracortical electric fields points to visual cortex Once animals could perform visual search, we implanted an array of electrodes approximating the human 10–20 system in monkeys P and Z (Figure 1A). Using these electrodes, we observed extracortical electric dynamics in both monkeys. An index of attention known as the N2pc manifests during visual search. The N2pc electric field indexes attention allocation in this task. The magnitude of the N2pc was largest over occipital sites (Figure 1B, Figure 1—figure supplement 1), consistent with previous reports in humans and macaques (Luck and Hillyard, 1994; Eimer, 1996; Woodman and Luck, 1999; Hopf et al., 2000; Woodman et al., 2007; Cohen et al., 2009; Purcell et al., 2013). We used sLORETA inverse modeling for source localization. Previous source estimates for the N2pc identified the human homologue of V4 (Luck and Hillyard, 1990; Luck and Hillyard, 1994; Hopf et al., 2000). These findings are consistent with numerous reports that areas in mid-level visual cortex in monkeys produce robust attention signals (Moran and Desimone, 1985; Luck et al., 1997a; McAdams and Maunsell, 1999; Reynolds et al., 1999; Fries et al., 2001; see Roe et al., 2012 for review) across cortical layers (Engel et al., 2016; Nandy et al., 2017). Consistent with these earlier studies, the inverse model showed that current sources include V4 on the prelunate gyrus (Figure 1C, Figure 1—figure supplement 1). However, the modeled current sources also included other cortical regions, as is common for inverse solutions. Notably, the inverse solution identifies V1 to be about as strong as V4 in contributing to the N2pc, which is unlikely given current knowledge on attentional modulation for each area (Motter, 1993; Luck et al., 1997a; Kastner et al., 1999; Buffalo et al., 2011). Given the primary feature used in the search task was color, we investigated the laminar profile of attention-associated electric field generation in V4 where color is better represented (Roe et al., 2012). V4’s laminar microcircuit produces dipoles that predict the attention-associated electric field Guided by magnetic resonance imaging (MRI), linear multielectrode arrays (LMAs) were inserted into area V4 of monkeys Ca and He. LMAs were placed perpendicular to the cortical surface, spanning supragranular (L2/3), granular (L4), and infragranular (L5/6) cortical layers (Figure 2—figure supplement 1). We confirmed that attentional modulation of spiking activity could be observed during pop-out search performance consistent with previous reports (Westerberg et al., 2020a). Moreover, the laminar profile of attentional modulation matched that of attentional modulation in a different task with spiking activity in the middle layers being the most highly enhanced with attention (Figure 2; Nandy et al., 2017). Critically, while attentional modulation is present in the laminar data prior to the emergence of extracortical attention-associated fields such as the N2pc, that cross-laminar modulation persists through this interval. Figure 2 with 1 supplement see all Download asset Open asset Laminar profile of local field potential (LFP) and multiunit (MUA) attentional target selection during visual search task performance across monkeys Ca and He (n = 2). Responses were averaged across sessions (n = 30) at each of the depths (n = 15) relative to the L4/5 boundary (magenta to green). Difference between target (attended) and distractor (unattended) responses represented by the fill color corresponding to the recording channels’ laminar compartment. Top line of each trace combination is the attended condition, bottom trace is the unattended condition. Significant differences in magnitude of attention effect, averaged 150–190 ms after search array onset, across laminar compartment were detected through an ANOVA for both LFP (F(2, 442) = 22.43, p = 5.2e–10) and MUA (F(2, 442) = 3.87, p = 0.022). Note the effect of attention in the MUA was largest in the middle layers (ML2/3 = 2.68, ML4 = 3.50, ML5/6 = 2.38), consistent with previous reports (Nandy et al., 2017). Time of the N2pc as measured throughout the main text (150–190 ms following array onset) indicated with orange. Simultaneous with LMA recording, an extracortical electric signal was recorded immediately above V4 – critically the recording took place outside of the cortical column itself. Current source density (CSD) was derived from the local field potentials (LFPs) sampled across V4 layers. To relate the extracortical signal (Figure 3A) to synaptic currents estimated as CSD (Figure 3B–D), we employed information theory to capture multivariate factors and nonlinearities between signals (Shannon, 1948; Cover and Thomas, 2006). Importantly, information theory analyses are model independent (Timme and Lapish, 2018). Information theory is thus superior to standard linear models since these models cannot capture all potential relationships between signals. The relationship between the extracortical signal and CSD was assessed in four distinct steps, as illustrated by a representative session (Figure 3E–F, Figure 3—figure supplement 1). We use the interval of the N2pc to determine whether laminar circuitry in V4 can contribute to the attention-associated electric fields. This interval occurred before the median response times for each monkey contributing laminar V4 data ([median± standard deviation]: monkey Ca 227 ± 49 ms, He 225 ± 44 ms). Figure 3 with 1 supplement see all Download asset Open asset Extracortical attention-associated signal and simultaneously recorded V4 synaptic currents during representative session. (A) Extracortical event-related potential (ERP) voltages after search array presentation, averaged over all trials when the target was presented contra- (solid) or ipsilateral (dashed) to the electrode. Inset magnifies the N2pc interval defined as the difference in potentials 150–190 ms after the array appeared (orange highlight). (B) Simultaneous current source density (CSD) when the target appeared in the population receptive field of the column. Dashed lines indicate boundaries between supragranular (L2/3), granular (L4), and infragranular (L5/6) layers. CSD values were interpolated and smoothed along depth for display only. Current sinks have hotter hues, and current sources, cooler. The earliest sink arises in putative L4, likely from rapid feedforward transmission, followed by intense, prolonged sinks in L2/3 accompanied by weaker source in L5/6. (C) CSD evoked by distractor in the receptive field has similar pattern. (D) Subtraction of CSD responses to target versus distractor in receptive field. The only statistically significant differences (determined through a t test across time-depth with p < 0.05, outlined by magenta line) were due to a current sink in L2/3 that arose gradually ~100 ms after array presentation. This relative sink was associated with a weak relative source in L5/6. (E) Simultaneous mutual information between CSD and the extracortical signal for L2/3 (blue), L4 (purple), and L5/6 (green). Times with significant mutual information were computed through Monte Carlo shuffle simulations (MCS). N2pc interval is highlighted. Intervals with significant mutual information persisting for at least 10 ms are indicated by horizontal bars. No mutual information with EEG was observed in L4. (F) Information transmission about target position from V4 CSD to the extracortical signal. Conventions as in E. First, we employed Monte Carlo simulations of the mutual information analysis to verify that the extracortical signal exhibited significantly enhanced information about target position during the time window of the N2pc. Second, we measured target information across the layers of V4 during the N2pc interval. This analysis revealed enhanced information in L2/3 and L5/6 but not in L4. Third, we computed the mutual information between the extracortical signal and CSD during the N2pc window, irrespective of target position. This analysis showed a significant relationship between the extracortical signal and the CSD in L2/3 and L5/6 but not in L4. Fourth, we measured the transmitted information about target location from CSD to extracortical signal during the N2pc interval (Timme and Lapish, 2018). This analysis demonstrated significant information transmission to the extracortical signal from L2/3 and L5/6, but not L4. Averaged across sessions, we observed that the electric field during the N2pc interval (Figure 4A) was associated with a consistent CSD pattern (Figure 4B). This relationship was observed in each monkey (Figure 4—figure supplement 1). Presentation of the search array in any configuration elicited an early current sink in L4, followed by a prolonged sink in L2/3 that was associated with a briefer source in L5/6. Figure 4 with 4 supplements see all Download asset Open asset Grand average demonstrating the link between V4 current source density (CSD) and the extracortical attention-associated electric field. Conventions as in Figure 3. (A) Average event-related potential (ERP) across all sessions and animals with the target contra- (solid) or ipsilateral (dashed). The N2pc interval is indicated by orange shading. (B) Average V4 CSD with the target in (top) or out of the receptive field (RF) (center) with the difference between the two at the bottom. (C) Grand average information transmission about target position from V4 layers to the extracortical signal as a function of time (left). Average +2 SEM of information transmission during the N2pc window (right). Panel below shows that information transmission from L2/3 and in L5/6 was significantly greater than that from L4 (t test p < 0.05). Timepoints with significant information transmission were assessed through Monte Carlo simulations during >75% of sessions. Intervals with significance persisting for at least 10 ms are indicated by horizontal bars, color coded for each laminar compartment (bottom). We next computed information transmission about target location from the CSD to the extracortical signal for each session (Figure 4C). All cortical layers provided significant information transmission in >75% of sessions during the N2pc window (150–190 ms following array onset). However, the magnitude of transmitted target information was significantly greater in L2/3 and L5/6 relative to L4 (L2/3-L4: t(29) = 2.15, p = 0.040; L5/6-L4: t(29) = 2.20, p = 0.036). The magnitude of information transmission was not significantly different between L2/3 and L5/6 (t(29) = 0.21, p = 0.84). Across sessions, the three other information theoretic analyses were consistent with the example session (Figure 3—figure supplement 1). Moreover, significant information transmission during the N2pc was observed in each monkey (Figure 4—figure supplement 1). To verify the results, we applied the information theoretic analysis over a longer interval (Figure 4—figure supplement 2). Importantly, we found no signal differences or significant information transmission in the 100 ms pre-array baseline period as expected with baseline correction. We also evaluated the interval 200–250 ms following array presentation and found a polarization reversal in the extracortical signal likely corresponding to the Pd (Cosman et al., 2018). We observe persistent current differences in the extragranular CSD during this interval sufficient to contribute to the extracortical signal. However, we observed no statistically significant information theoretic relationship between the CSD and extracortical signal during this interval. The absence of a relationship could indicate no actual association or be a consequence of the reduced trial count due to the clipping of signals at saccade initiation. This uncertainty prevents further consideration of this interval in these data. Last, we performed two additional analyses to determine whether the observed information theoretic relationship is confounded by spurious factors. First, we measured the contribution of V4 neuron selectivity for stimulus color. We computed information transmission separately for trials with a red stimulus and with a green stimulus in the receptive field (RF). In the population average of the two calculations for each session, we observed significant information transmission during the N2pc (Figure 4—figure supplement 3). Hence, the relationship between V4 activity and the EEG does not depend on color specificity. Second, we measured the contribution of microsaccades, which have been linked to attentional modulation in V4 (Lowet et al., 2018). We computed information transmission separately for trials without microsaccades (Figure 4—figure supplement 4). In the population average of the two calculations for each session, we observed significant information transmission during the N2pc. Hence, microsaccade production was not responsible for the observed information theoretic associations between signals. The outcomes of these control analyses engender more confidence that the current dipole in V4 generated by the L2/3 CSD sink and the L5/6 CSD source contributes to the N2pc measured in the extracortical electric field. Columnar feature selectivity influences contribution to N2pc Given the columnar organization of color tuning of V4 neurons (Figure 5A; Roe et al., 2012; Zeki, 1973; Zeki, 1980; Tootell et al., 2004; Conway and Tsao, 2009; Kotake et al., 2009), we investigated the association between the N2pc and the CSD in columns with different color preferences. To quantify color selectivity through depth, we computed the response ratio between red and green stimuli (Figure 5B). Responses were measured as power in the gamma range (30–150 Hz) because this signal reflects local circuit interactions (Ray and Maunsell, 2011) and feature selectivity in visual cortex (Berens et al., 2008) and is more reliably measured than spiking activity across all LMA contacts. This analysis collapses across differences in color tuning across layers, so although the interlaminar specificity of gamma activity is not fully understood, recent work indicates that laminar gamma power can reliably reflect feature selectivity in a spatially specific fashion (Westerberg et al., 2021b). Figure 5 with 2 supplements see all Download asset Open asset Contribution of columnar feature selectivity to the N2pc. Conventions as in Figure 3. (A) Visual search array configurations used for color selectivity analyses. (B) Laminar profiles of red/green color selectivity across all sessions. The hue of each point across cortical depth signifies the value of a color selectivity index (CSI), derived from local gamma power. CSI values < 0 (>0) indicate preference for green (red). CSI is smoothed across adjacent channels for display. Sessions are sorted from left to right based on a column color selectivity index (CCSI) that estimates each column’s combined selectivity. A bar plot of session-wise CCSI is plotted below. Asterisks indicate columns with significant color-selectivity (Wilcoxon signed rank, p < 0.05). Asterisk color indicates monkey (Ca cyan; He magenta). (C) Average event-related potentials (ERPs) for trials when a red (top) or green (bottom) target or distractor appeared in the receptive field (RF) of the 17 color selective columns. Conventions as in Figure 3. (D) Difference in current source density (CSD) when the target relative to distractor appeared in the columnar population RF when a red (top) or green (bottom) stimulus appeared in the RF (n = 17). (E) Average ERP for trials when the preferred color (top) or non-preferred color (bottom) target or distractor appeared in the RF (n = 17). Conventions as in Figure 3. (F) Difference in CSD when the target relative to distractor appeared in the RF with the preferred (top) or non-preferred (bottom) color. (G) Average difference in information transmission between laminar CSD and N2pc when preferred relative to non-preferred stimulus color appeared in RF. Conventions as before. More information was transmitted when a stimulus of the preferred color appeared in the RF. (H) Correlation between difference in information transmission across color columns and CCSI for each session for L2/3 (blue, top), L4 (purple, center), and L5/6 (green, bottom). Spearman correlation reported in lower right of each plot with data from all 30 sessions. Color-specific information transmission scaled with magnitude of color selectivity. (I) Information transmission for columns with (solid, n = 17) and without (dashed line, n = 13) feature selectivity for L2/3 (top), L4 (middle), and L5/6 (bottom). Intervals with significant differences are plotted below at two alpha levels for a two-sample t test (filled: 0.05; unfilled: 0.1). Bars plot average with upper 95% confidence interval of information transmission during the N2pc for columns with (left) and without (right) feature selectivity. Significant differences are indicated with a bracket and p value from a two-sample t test. To identify columns with significant selectivity for either red or green, we performed Wilcoxon signed rank tests between the distribution of ratios in each column against bootstrapped null distributions. Each bootstrapped null distribution contained 15 randomly selected ratios from the full dataset (450 experimental values) from which 1000 distributions were generated. The bootstrapped distributions represent the range of possible values observed across V4, but do not capture any difference in the homogeneity of feature selectivity within a column. We found that more than half of V4 columns show selectivity for red or green stimuli (monkey Ca 12/21 [57.1%], He 5/9 [55.6%]). We computed the information transmission of target position for each color tuned column separately for trials when the preferred or the non-preferred color was in the column’s population RF. Across sessions with different target and distractor colors, we observed no difference in the amplitude of the extracortical signal during the N2pc (paired sample t(16) = 0.40, p = 0.69) (Figure 5C) nor the laminar CSD (L2/3: t(16) = –0.85, p = 0.41; L4: t(16) = 0.75, p = 0.46; L5/6: t(16) = 0.36, p = 0.72) (Figure 5D). However, information transmission during the N2pc was greater when a preferred rather than a non-preferred color was in the RF (Figure 5G). This difference was significant in L2/3 and L5/6 but not in L4 (t test across time with at least 10 ms having p < 0.05) and is evident in single sessions (Figure 5—figure supplement 1). We investigated whether the magnitude of information transmission varied with degree of color preference. In session-wise correlations of the difference in information transmission between preferred and non-preferred colors at the time of peak information transmission (160–180 ms) as a function of columnar color selectivity index (CCSI), we found a significant relationship for L2/3 (Spearman’s R = 0.50, p = 0.005) and L5/6 (R = 0.51, p = 0.004) but not L4 (Figure 5H). We also tested whether feature selective columns, on average, transmitted more information than their non-feature-selective counterparts. We found that feature selective columns, in all laminar compartments, transmitted significantly more information (Figure 5I) (two-sample t test: L2/3, p = 0.044; L4, p = 0.023; L5/6, p = 0.009). As such, we wanted to determine if this was due to a lack of attentional modulation in the non-selective columns. This was not the case, we observed that non-selective columns were modulated with attention. Attentional modulation was observed in both the CSD in L2/3 and L5/6 (one-sample t test: L2/3: t(64) = –6.01, p = 9.8e–8; L4: t(64) = –0.18, p = 0.86; L5/6: t(64) = 5.24, p = 1.9e–6) as well as across all layers in the population spiking activity (one-sample t test: L2/3: t(64) = 8.00, p = 3.7e–11; L4: t(64) = 9.66, p = 4.1e–14; L5/6: t(64) = 7.58, p = 1.8e–10) during the N2pc interval (averaged 150–190 ms following array onset) (Figure 5—figure supplement 2). Importantly, we tested whether the N2pc varied across sessions with or without color-selective columns sampled. We found no difference between N2pc polarization (150–190 ms after the array) between sessions with (n = 17) or without (n = 13) sampling of color selective columns (two sample t test: t(28) = –0.75, p = 0.46). This invariance is expected because extracortical EEG spatially integrates signals from multiple cortical columns. Translaminar currents in V4 recapitulate the N2pc CSD is computed by differentiating between LFPs to eliminate volume-conducted signals that do not arise from local circuit activity. Using an inverse procedure (i.e., summing the CSD), it is possible to estimate the LFP without contamination by vol" @default.
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• W4213303739 title "Decision letter: Laminar microcircuitry of visual cortex producing attention-associated electric fields" @default.
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