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The photos are truly the stuff of nightmares: Swarms of desert locusts blocking out the sun, blanketing fields, and devouring crops in East Africa, the Middle East, and South Asia. Its the worst outbreak those regions have seen in decades. The locusts were already becoming a crisis, threatening food security and livelihoods in Kenya and Ethiopia by the time the novel coronavirus began crossing borders in late January.

Since then the situation has only gotten worse a wet spring created the right conditions for the bugs to keep multiplying.

Scientists dont know what causes locusts to flock together in the first place. The creature has a mysterious split personality. Locusts can be solitary antisocial, independent, relatively benign. But under certain conditions, which are not fully understood, they can become gregarious traveling together in masses that rival the size of cities, with more than a hundred million bugs packed into each square mile. Right now, the best available method to control the swarms is spraying pesticides, which can be dangerous for ecosystems and human health, depending on what chemicals are used. But if scientists can figure out why locusts become gregarious, that could unlock better options.

A new study published in Nature on Wednesday documents a significant breakthrough on that front. Researchers at the Chinese Academy of Sciences in Beijing identified a specific chemical substance, or pheromone, released by the migratory locust that attracts others to its side. The migratory locust is a different species than the desert locust currently making headlines, but it is a similarly destructive pest and experts told Grist that the discovery will be directly relevant to developing new methods to stave off both species.

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There is a lot of overlap in the chemistry of the two locust species, said Baldwyn Torto, a scientist at the International Centre of Insect Physiology and Ecology in Kenya, who said the species have similar biology and behavior. (Torto was not involved in the new research.)

The study found that all the locusts examined solitary and gregarious, young and old, male and female, in the lab and in the field were attracted to a pheromone known as 4-vinylanisole, or 4VA. The chemical is released mainly by gregarious locusts, and the more locusts they stuck together in a cage, the more each bug let loose. Even though solitary locusts did not emit 4VA on their own, when the researchers put just four or five solitary locusts together, they began to produce the pheromone, too.

The results indicate that scientists could measure 4VA emissions to monitor populations and predict swarms, or use 4VA lures to attract the bugs to a concentrated area where they could be killed with pesticides. Monitoring the build up of locust populations is absolutely key to their effective control, said Stephen Rogers, a research associate at the University of Cambridge who was not involved in the study. Incipient swarms can be nipped in the bud before numbers become overwhelming.

The team behind the new study made a second discovery that experts said could be even more helpful: It identified the specific receptor in the locusts antenna that detects 4VA. That knowledge could be used to develop a treatment that inhibits the receptor, essentially blinding the locust to its own pheromone.

I hate seeing those pictures of the planes going and people spraying the pesticides because those kill everything, said Leslie Vosshall, a molecular neurobiologist at The Rockefeller University, who reviewed the study before it was published. If instead, you could have these planes that are spraying molecule X, it would be really selective, it wouldnt kill anything. It just turns this receptor off or prevents the receptor from finding the pheromone. At least on paper, that would have a huge effect.

The study described one other possibility for mitigating swarms. Using gene editing, mutant locusts that lack the special receptor for 4VA could be bred and released into the wild. But neither Vosshall or Rogers felt that path would be worth pursuing anytime soon.

One of the major issues with locusts is that they affect livelihoods in regions of the world where life is already precarious and difficult, Rogers said. And high-tech solutions tend to be expensive.

The new study is not going to help with the current outbreak in Africa and the Middle East, as no one has studied whether the desert locust is attracted to 4VA, but experts agreed it presents a blueprint for scientists to find out what does seduce that cursed species.

The way that humanity tackles this pandemic parallels how it might fight climate change. Sign up for our semi-weekly newsletter,Climate in the Time of Coronavirus.

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Whats that smell? Scientists discover what makes locusts swarm. - Grist

Physiology

Dissociation of broadband high-frequency activity and neuronal firing in the neocortex – Science Advances

August 12, 2020 medical

INTRODUCTION

Broadband high-frequency activity (BHA; 70 to 150 Hz), also known as high gamma, a key analytic signal in human intracranial recordings, is often assumed to reflect local neural firing [multiunit activity (MUA)]. Accordingly, BHA has been used to study neuronal population responses reflecting auditory (1, 2), visual (35), language (6), mnemonic (710), and cognitive control (11, 12). BHA is arguably the electrophysiological measure best correlated with the blood oxygenation leveldependent (BOLD) signal in functional magnetic resonance imaging (fMRI) (13, 14). However, beyond the fact that BHA correlates with neuronal spiking (13, 1517), its precise physiology remains unknown; specifically, the neuronal populations and physiological processes generating BHA have not been identified. Here, we show that BHA can be dissociated from MUA in the primary visual and auditory cortex. Analyzing laminar multielectrode data recorded in monkeys, we found a bimodal distribution of stimulus-evoked BHA across the layers of cortex: an early-deep and late-superficial response. The early-deep BHA had a clear spatial (laminar) and temporal association with local MUA; however, the spatiotemporal overlap of MUA with the late-superficial BHA signal was much less clear. In many cases, particularly in V1 (70%), supragranular sites showed a strong BHA in lieu of any detectable increase in MUA. Because of volume conduction, BHAs from both the early-deep and the late-superficial generators contribute to the field potential (FP) at the pial surface, but the contribution is weighted toward the superficial BHA. Although both BHA components volume conduct to the pial surface, the strongest generators of BHA are in the superficial cortical layers. The origins of BHA include a mixture of the neuronal action potential firing and dendritic processes separable from firing. It is likely that, as typically recorded, BHA signals emphasize the latter processes to a greater extent than previously recognized.

We investigated the neural mechanisms generating BHA signal and their relationship to MUA in the neocortex by analyzing FP and concomitant MUA signals recorded with laminar multielectrodes in macaque primary visual (V1: two animals, 104 experimental sessions with whole-screen flashes, 49 sessions with free viewing) and auditory (A1: two animals, 26 experimental sessions with broadband noise, 26 sessions with best frequency tone) cortices. We used first and second derivative (current source density or CSD) analyses of the laminar FP profiles, along with a concomitant MUA to localize the neuronal generators of BHA and to determine their spatiotemporal relationship to neuronal firing. Figure 1 displays representative laminar activity profiles recorded from primary visual (Fig. 1, A, B, and E) and auditory (Fig. 1, C, D, and F) cortices. The notion that BHA directly reflects neuronal firing raises the obvious prediction that BHA and MUA should have the same spatial and temporal distributions across cortical layers. Contrary to this prediction, however, the spatiotemporal profiles of BHA and MUA were reliably different. We observed two temporally and spatially distinct BHA components, including the early-deep BHA localized to the granular and infragranular layers and the late-superficial BHA observed in the supragranular layers (Fig. 1, E and F). Early-deep BHA had clear spatiotemporal overlap with granular and infragranular MUA. However, the spatiotemporal association between late-superficial BHA and MUA was much less clear. Late-superficial BHA often had little or no MUA concomitant, particularly in V1.

Color maps show a CSD superimposed with FPs (left) and a BHA (color map) superimposed with MUA (line plots) profiles (right) in V1 (A) and A1 (C) from a representative session. (A) presents data from V1 recordings during diffuse flash stimulation. (C) shows data from A1 recordings during presentation of broadband noise (100-ms duration). x axes indicate time relative to stimulus onset. y axes represent cortical depth with increasing numbers from superficial to deep layers. Vertical lines indicate sensory events. (B and D) Line plots show the distribution of MUA-BHA cross-correlation coefficients calculated across trials for each penetration of V1 (B) and A1 (D). Box plot presents distribution of the lags obtained from the cross-correlations. Positive values indicate that MUA leads BHA. Shading in the line plot reflects SEM. Central mark and edges in box plots show median and 25th and 75th percentiles. (E and F) show maps of z statistics calculated across trials (n = 137 and 84) for individual V1 (E) and A1 (F) penetration. The statistics values are obtained from a nonparametric pairwise test on MUA (left) and BHA (middle) relative to the prestimulus baseline. Nonsignificant time points are masked (P < 0.05; controlled for multiple comparisons across channels and time with the Benjamini and Yekutieli procedure). Right panels show an overlap (yellow) between the BHA (green) and MUA (red) statistic masks.

Consistent with earlier work (13, 1517), we found that MUA and BHA were correlated at all cortical depths in both V1 and A1 (all Spearmans rho, >0.76; all P < 0.01). We used cross-correlation between BHA and MUA at supragranular, granular, and infragranular layers to test whether the relation between these two signals changes across cortical depth. The cross-correlation coefficient profiles were nonuniform across layers (Fig. 1, B and D). Specifically, the coefficients in the supragranular layers peaked later, relative to those in deeper layers [median lags in V1 supragranular, granular, and infragranular layers were 9, 1, and 2.5 ms; while median lags in A1 supragranular, granular, and infragranular layers were 3.25, 0.5, and 0.25 ms; both Kruskal-Wallis (KW) tests, P < 0.01; Fig. 1, B and D]. This suggests that the relationship between BHA and MUA might vary rather than being constant across cortical depth. To understand this divergence, we quantified the laminar/temporal distributions of both signals, which confirmed the above impressions about the changing association between BHA and MUA across cortical depth.

We tested laminar distributions of BHA and MUA across four different experiments in two cortical areas, V1 and A1. First, we used diffused light flash stimulation (V1-DF), which weakly activates the supragranular layers of V1 relative to patterned stimulation (18); this contrast has been known for decades [see, e.g., (19)]. We selected these nonoptimal stimuli because we expected the dissociation to be strongest under these conditions, where activation of the superficial layers is relatively weak. We observed that BHA and MUA distributions were both nonuniform across V1 cortical depth (both KW tests, P < 0.001, n = 104), yet they differed markedly (Fig. 2, A to D). BHA was strongest in layers where neural firing was sparse to undetected. It was more pronounced in the supragranular than both granular and infragranular layers (all Wilcoxon tests; P < 0.001). MUA displayed the opposite pattern: It was decreased in the supragranular compared to both granular and infragranular layers (both Wilcoxon tests; P < 0.001). BHA magnitude (P = 0.03) unlike MUA (P = 0.14) did differ across the granular and infragranular layers. Seventy percent of all V1 penetrations with diffused light flash stimulation showed a strong supragranular BHA in lieu of any detectable MUA increase. The fact that the BHA and MUA have a differing laminar/temporal distributions accords with the view that these signals reflect different aspects of neural activity.

(A to D) present V1 data from recordings during diffuse flash stimulation (V1-DF; n = 104 experiments in two animals). (E to H) Data from V1 recordings during free-viewing exploration of visual images [V1-FV; n = 49, same two animals as in (A to D)]. Line plots show the time course of BHA (A and E) and MUA (C and G) response across supragranular, granular, and infragranular (red, green, and blue lines) layers. x axes indicate time relative to stimulus (A, C) or fixation onset (E, G). y axes represent signal change from baseline (i.e., normalized BHA/MUA). Box plots present BHA (B and F) and MUA (D and H) distributions averaged across time after stimulus onset (B and D) and across the entire pre- and postfixation epoch (F and H). Supragranular, granular, and infragranular (S, G, and I) layers are plotted as separate box plots. Box plots indicate 25th percentile, median, and 75th percentile; whiskers extend to extreme values not considered outliers, while outliers are marked with crosses. Shading in line plots reflects SEM. Note the consistently different laminar distributions of BHA and MUA in both experiments. Despite different stimuli, levels of firing, and BHA magnitude across experiments, BHA in the supragranular layers is enhanced relative to that in the granular and infragranular layers, while MUA in supragranular is sparse compared to granular and infragranular. Note also that in the free viewing (E to H), there is substantial saccadic modulations of MUA and BHA across all layers, with a clear pattern of MUA suppression around the time of the saccade (perisaccadic suppression) and MUA increase at the end of the saccade (onset of fixation). Arrows in (A and E) indicate early (solid line) and late (dashed line) BHA components.

To test whether the observed dissociation generalizes across types of visual stimuli and task, we examined BHA-MUA dissociation in experimental data collected during free viewing of natural scenes in the same V1 penetrations (V1-FV; see Materials and Methods). It is noteworthy that natural scene viewing produces a much more effective activation of the superficial layers of the primary visual cortex (20). There are multiple differences in BHA and MUA morphology elicited by active (i.e., fixation locked) as compared to passive (stimulus locked) visual input. For example, both BHA and MUA decrease during saccade and rebound after saccade termination (Fig. 2, E to H). Despite these differences in both BHA and MUA morphology, we continue to observe the laminar dissociation between BHA and MUA. Both BHA and MUA show nonuniform distributions across layers (both KW tests, P < 0.001, n = 49), with superficial layers showing strongest BHA (all Wilcoxon tests, z > 5.7, P < 0.001) and weakest MUA (all Wilcoxon test, z > 6.0, P < 0.001).

Next, we sampled from A1 during presentation of broadband noise (A1-BBN; see Materials and Methods) to test whether these effects generalize to other areas of the sensory cortex. Despite differing temporal patterns of BHA signals in V1 and A1, key aspects of laminar dissociation between BHA and MUA generalize to A1. As in V1, event-related BHA and MUA were both observed across all three laminar compartments (Fig. 3, A to D), and both had a nonuniform laminar distribution (both KW tests, P < 0.001, n = 26). Critically, BHA was stronger in the supragranular layers compared to granular and infragranular layers (both Wilcoxon tests, P < 0.001). In contrast, supragranular MUA was weaker than granular and infragranular layers MUA (both Wilcoxon tests, P < 0.001). The poststimulus time interval during which BHA was increased from baseline was more sustained in the supragranular than in the granular and infragranular layers (73.5-, 18.7-, and 20.0-ms median supragranular, granular, infragranular, respectively; both Wilcoxon tests, P < 0.001). In contrast, the poststimulus time interval during which MUA was increased from baseline was shorter in the superficial, as compared to deeper layers (15.5-, 42.5-, and 45.5-ms median supragranular, granular, and infragranular, respectively; both Wilcoxon tests, P < 0.001). Neither BHA nor MUA durations differed between granular and infragranular layers (both Wilcoxon tests, P > 0.84). While the spatiotemporal pattern of BHA and MUA differences in A1 largely parallels with that observed in V1, there are noteworthy A1-V1 differences. BHA in V1 during both passive (stimulus locked) and active (i.e., fixation locked) visual input had two elements (early and late) with confined laminar spread; the early component was limited to deep layers, while the late component was limited to supragranular layers. In A1, we observed larger temporal separation between early and late BHA components (median of 33 ms). As in V1, the late BHA component in A1 is largely limited to the superficial layers. However, unlike the early-deep component in V1, the early BHA component in A1 extends up into the supragranular layers. We quantified this by directly comparing the BHA magnitude in A1 across layers in early (0- to 30-ms poststimulus) and late (31 to 100 ms) time window. Differential laminar distribution was noted for the magnitude of the late (KW test, P < 0.001) but not the early BHA (KW test, P = 0.76). In contrast, MUA was decreased in the supragranular layers compared to granular and infragranular layers during both time windows (all Wilcoxon tests, P < 0.001).

(A to D) presents data from A1 recordings during presentation of broadband noise (A1-BBN; duration, 100 ms; n = 26, two animals). (E to H) shows data from A1 recordings during presentation of best frequency tones [A1-BFT; 100-ms duration; n = 26, same two animals as in (A to D)]. Line plots show the time course of BHA (A and E) and MUA (C and G) response across supragranular, granular, and infragranular (red, green, and blue lines) layers. x axes indicate time relative to stimulus (A, C, E, G). y axes represent signal change from baseline (i.e., normalized BHA/MUA). Box plots present BHA (B and F) and MUA (D and H) distributions averaged across time after stimulus onset. Supragranular, granular, and infragranular (S, G, and I) layers are plotted as separate box plots. Box plots indicate 25th percentile, median, and 75th percentile; whiskers extend to extreme values not considered outliers, while outliers are marked with crosses. Shading in line plots reflects SEM. Note the consistently different laminar distributions of BHA and MUA in both experiments. Despite different stimuli (i.e., broadband noise and best frequency tones), BHA in the supragranular layers is enhanced relative to that in the granular and infragranular layers, while MUA in supragranular is sparse compared to granular and infragranular. Arrows in (A and E) indicate early (solid line) and late (dashed line) BHA components.

To test whether these results further generalize to other auditory stimuli, we analyzed data from the local best frequency tone response for each site within the same penetrations in A1 (A1-BFT; n = 26 sessions, two animals). For each individual penetration, we compared MUA responses across a set of 14 pure tones from 354 to 32 kHz (see Materials and Methods). We defined the best frequency tone as the one that elicited the largest magnitude MUA response in the layer L4 [e.g., (21, 22)]. Subsequently, we aggregated laminar BHA and MUA responses elicited by these best tone frequencies. This analysis reproduced our initial finding of nonuniform laminar distribution of BHA and MUA (KW test, both BHA and MUA, P < 0.01), with BHA being, again, strongest in the superficial layers (all Wilcoxon test, z > 3.3, P < 0.01) and MUA being weakest in the superficial layers (all Wilcoxon test, z > 2.9, P < 0.001; Fig. 3, E to H).

Next, we evaluated the extent to which these two BHA components (deep versus superficial) contribute to the BHA recorded on the pial surface [i.e., electrocorticographic (ECoG)like signal; Fig. 4, A to D]. We reasoned that a signal from the cortical depth that explains most of the variance in the pial surface BHA would indicate a major laminar generator of surface BHA. To quantify the contribution of generators from different depths to the pial surface BHA, we used a standard method of tracing continuous FP from a neural source (generator) to the cortical surface [(22, 23); see Materials and Methods]. On the basis of both the magnitude of supragranular BHA and the proximity of supragranular current generators to the pial surface of cortex, we predicted that the supragranular layers should provide the largest contribution to BHA signal at the cortical surface. To quantify this, we estimated the percentage of variance explained (adjusted R2) by four linear regression models, including the data from either individual layers (Fig. 4) or all layers together (fig. S8). We used a linear regression model because it has been shown that volume conduction itself is linear at a macroscopic scale (2325). For both V1 and A1 experiments, most of the variance was explained by supragranular BHA (see Fig. 4, E to H; KW test, P < 0.05). We also observed that BHA from deep layers could explain some significant portion of variance, particularly in V1 passive viewing. The amount of variance explained by supragranular layers reached 15, 25, 12, and 20% (for V1-DF, V1-FV, A1-BBN, and A1-BFT, respectively), while it peaked at about 5% for granular and infragranular layers in all four experiments. Thus, while the BHA from all laminar compartments contributes to the pial surface BHA, the supragranular layers appear to be the major source.

(A to D) BHA recorded from pial surface, supragranular, granular, and infragranular layers (gray, red, green, and blue, respectively) of (A) V1 during whole-screen flash stimulation (n = 31 experiments). (B) Presentation of broadband noise during A1 recordings (n = 24), (C) free viewing of visual images during V1 recordings (n = 18), and (D) presentation of best frequency pure tones during A1 recordings (n = 24). y axes represent signal change from baseline (i.e., normalized BHA). (E to H) Portions of the amount of variance (adjusted R2) in the pial surface BHA signal explained by each of three different models, containing laminar BHA from either supragranular (red), granular (green), or infragranular (blue) layers as predictors. Colored markers over panels represent cortical depth, which explains most of the variance (KW test across distributions of adjusted R2 values).

To test whether the spatial dissociation between BHA and MUA noted in monkeys could be observed in humans, we used a small dataset from similar laminar probes implanted in a to-be-resected tissue of the prefrontal cortex (PFC) of two patients with pharmacoresistant epilepsy during rest (Fig. 5). In short, spatial distributions of BHA and MUA were notably similar to those observed in monkeys with strongest BHA in the superficial electrodes and MUA in the deeper electrodes. As in our monkey data, we found nonuniform distributions across cortical depth for both BHA and MUA (both KW tests, P < 0.001). There was also a differential distribution of BHA and MUA across cortical depth that was similar to that observed in monkeys: BHA (Fig. 5, A and B) was strongest in the superficial channels as compared to middle and deep channels (both Wilcoxon tests, P < 0.001), whereas MUA (Fig. 5, C and D) was strongest in the middle channels as compared to superficial and deep (both Wilcoxon tests, P < 0.001). This is consistent with our results from nonhuman primates, showing that the main generators of BHA are localized in supragranular layers, whereas the strongest local population neuronal firing is observed in deeper layers. These data were recorded from only two patients during rest (n = 960 and 2532 segments for a duration of 1 s, resulting in a total of 16 and 42.20 min of data) and should be interpreted with caution. However, the data do suggest that BHA and MUA might dissociate in the human neocortex in a manner similar to that we observed in the nonhuman primate neocortex.

Line plots show example traces from simultaneous BHA (A and B) and MUA (C and D) recordings during rest in two patients with epilepsy implanted with linear probes in a to-be-resected tissue. Signals were assigned into three a priori depths (1, 150 to 900 m; 2, 1050 to 1800 m; and 3, 1950 to 2850 m) based on known thickness of the cortex (see Materials and Methods). The whole resting data were segmented into 1-s-long intervals (100-ms-long intervals at side of epoch were removed after filtering to avoid contamination of edge effects). The laminar distribution of BHA and MUA was quantified by testing for nonuniformity of BHA and MUA across depths (see Materials and Methods). Box plots present results aggregated across all BHA (A and B) and MUA (C and D) epochs in each patient separately. Box plots indicate 25th percentile, median, and 75th percentile; whiskers extend to extreme values not considered outliers. Outliers are shown as + signs.

Laminar activity profile recordings in rodents suggest that the most prominent current sink in the supragranular layers, which corresponds to the location generating the late-superficial BHA in our study, reflects the Ca2+-dependent spiking in the apical dendrites of pyramidal neurons (26). The synaptically evoked Ca2+ signal is largely mediated by the N-methyl-d-aspartate (NMDA) receptors (27), which regulate several processes, including neural plasticity (28) and dynamic shifts in neural excitability (29). The effect of NMDA-mediated enhancement of excitability is strongest in the supragranular layers (29), consistent with the preferential expression of NMDA receptors there (30). The laminar distribution of NMDA receptors and the time course of the NMDA-mediated depolarization (slower and primarily supragranular) suggest that the later superficial BHA signal may have a strong NMDA dependence, further dissociating BHA from neuronal firing. To address this possibility, we examined the effects of systemic administration of the noncompetitive NMDA antagonist phencyclidine (PCP) on auditory responses in A1 (n = 8 experiments, one animal). During control recordings (i.e., before PCP), stimulation elicited a sharp and transient increase in both BHA and MUA (Fig. 6). To test the overall effect of PCP on BHA and MUA, we averaged each signal across time within a 150-ms poststimulus window and compared the magnitude of these averaged responses before and after PCP administration (see Fig. 6). After PCP administration, BHA was significantly attenuated across all layers (all Wilcoxon tests, P < 0.01), while MUA showed no detectable difference between control and PCP (all Wilcoxon tests, P > 0.26) at any cortical depth. While there is no significant impact on the MUA, both early and late BHA components are attenuated by the PCP. It is also noteworthy that the early BHA component is attenuated, while the late component is abolished. Albeit based on data from only one subject, the effects of NMDA blockade are robust and provide a pharmacological dissociation between BHA and MUA. Previous studies found enhanced [e.g., (31)] and suppressed (32) BHA after NMDA-antagonist administration. These differential effects might be attributed to the complex influence that NMDA-antagonists have on the stimulus-elicited response (32). Lazarewicz et al. (32) found that an NMDA-antagonist (ketamine) simultaneously enhanced prestimulus and poststimulus gamma activity, while the relative response to stimulus was decreased. The current findings point to a pharmacological dissociation with low doses of an NMDA-antagonist affecting BHA relative response to stimulus while keeping MUA intact.

(A and B) Box plots present BHA (A) and MUA (B) averaged within the 150-ms-long poststimulus time window before (control) and after systemic administration of PCP (n = 8). Box plots indicate 25th percentile, median, and 75th percentile; whiskers extend to extreme values not considered outliers. (C to F) Line plots show the time course of BHA (C and E) recorded from supragranular, granular, and infragranular (red, green, and blue lines) layers of A1 before (C) and after (E) systemic administration of PCP. (D and F) Concomitant MUA recordings from the same supragranular, granular, and infragranular (red, green, and blue lines) layers before (D) and after (F) systemic administration of PCP. x axis indicates time relative to stimulus onset. y axis represents signal change from baseline, averaged over the 50-ms interval before the stimulus (normalized BHA/MUA). Shading reflects SEM.

BHA is a critical mesoscopic signal commonly used to bridge the gap between human electrophysiology and single-unit studies in animals. Moreover, BHA is the closest neural correlate to the BOLD fMRI signal, linking neuroimaging and neurophysiology. On the basis of influential earlier studies, a prevalent view on human electrophysiology is that BHA is a simple reflection of MUA. Across experiments in V1 and A1, we identified spatial, temporal, and pharmacological dissociations between BHA and MUA. Our results suggest that BHA and MUA index different aspects of the neural activity with divergent features across layers of the neocortex. BHA had two spatially and temporally distinct components, i.e., early deep and late superficial, observed in granular-infragranular and supragranular layers, respectively. There is a substantial spatial and temporal correspondence between MUA and the early-deep BHA component. In contrast, the MUA correlate of late-superficial BHA is much weaker and often undetectable. BHA appears to be NMDA mediated, with low doses of noncompetitive NMDA antagonist (PCP) decreasing BHA while leaving MUA intact. Our regression analyses show that, although the BHA from all laminar compartments volume conducts to the pial surface, the main generators of BHA are localized in the supragranular layers where, as shown by numerous prior studies, firing is sparse [(22, 33, 34); for review, see (35)]. This is important because it suggests that the BHA recorded at the pial surface (e.g., with an ECoG electrode) likely overrepresents signals generated in supragranular layers, while the more robust event-related spiking activity is observed in the granular and infragranular layers and often precedes activation, as indexed by BHA. The results of laminar recording experiments in rodents (26) indicate that the large, late-superficial component may be generated by Ca2+ influx during apical dendritic spiking of pyramidal cells. The vulnerability of the largest (late superficial) component of BHA signal to NMDA receptor blockade in our experiments suggests that this component may index the same process.

Several critical implications of our findings for the interpretation of the BHA signal merit further emphasis. First, BHA as recorded from the pial surface of the cortex reflects relatively modest contributions from neuronal firing. Our pharmacological findings (Fig. 6) link to those of Suzuki and Larkum (26) in pointing to an underlying NMDA-mediated process generating BHA. One possibility is that BHA originates from calcium-dependent spikes that are long-lasting (10 to 100 ms) nonsynaptic events triggered by NMDA receptormediated excitatory postsynaptic potentials (36) that have been suggested to be a mechanism for associating information carried by feedforward and feedback pathways (37).

The current finding that the supragranular BHA is the largest contributor to the pial surface signal suggests that the BHA as typically measured in ECoG may contain a substantial representation of input from cortical feedback pathways. The median of 33-ms (interquartile range of 3 ms) onset-to-onset difference between early and late supragranular BHA signals in A1 is much longer than expected for a conduction delay within a direct monosynaptic connection between granular and supragranular layers (35). One possible explanation is that the early BHA reflects feedforward signal propagating to L4 and then to extragranular layers, whereas the late-superficial BHA reflects feedback from higher auditory areas to A1, which provides a strong input to the supragranular layers. In feedback pathways, predictions and contextual information originating in extragranular layers of higher-order areas are projected to and modulate lower cortical areas. Because feedforward and feedback pathways encode different information (33), bias toward feedback circuits in ECoG-derived BHA might favor predictive and contextual information.

The idea that BHA reflects an integrative process separable from the typical action potential may help to interpret several currently unexplained observations. Niessing et al. (14) used recordings from V1 of anesthetized cats to show that BHA is a better correlate of BOLD fMRI than MUA. Both BOLD and BHA encode stimulus intensity at a finer rate than MUA. This is puzzling under the assumption of BHA being a direct consequence of spiking neurons. The current results help to understand this discrepancy by suggesting that BHA (and consequently BOLD fMRI) might reflect dendritic processes subthreshold to neural firing. This interpretation would predict that the correlation between the magnitude of BHA and firing, rather than being constant, depends on the effectiveness of a stimulus in driving the cortex. For stimuli that are more effective in eliciting action potentials, correspondence between BHA and MUA will be stronger than for stimuli that are less effective. In support of this, Nir et al. (15) showed that coupling between firing rates of individual neurons and BHA varies across time rather than being stable. Furthermore, they also showed that the level of spike-BHA coupling depends on the degree of firing rate correlations between neighboring neurons. Similarly, Smith et al. (38) observed changing correlation between BHA and MUA during epileptic seizure. In support of the subthreshold view, Rich and Wallis (17) found that the BHA in the orbitofrontal cortex, although correlated with firing, diverged from MUA on several dimensions, carried more information, and was more sensitive to spatiotemporal changes than neural firing. The current findings suggest that BHA primarily reflects a dendritic process that is separable from neural firing. Our findings also suggest that using BHA as a proxy for neural firing overestimates the onset latency and duration of firing. This outcome introduces important caveats into the interpretation of the BHA signal, but it remains clear that the signal, particularly in the deeper layers, still has a strong relationship to neuronal firing. Improved understanding of the additional neuronal contributions to BHA makes it a richer, more useful index of brain activation. While it is unlikely, it is also possible that BHA and MUA might be generated by two distinct mechanisms operating at the same time at the same cortical depths.

The current findings provide an additional step toward the understanding that in supragranular layers, neural codes could entail dense subthreshold synaptic inputs accompanied by sparse firing (35). It has been clear for some time that the firing in superficial layers is sparse compared to those in the deeper layers. For example, Sakata and Harris (34) studied the population activity in the rat auditory cortex during spontaneous and sensory-evoked stimulation. Both conditions exhibited a sparse, spatially localized activity in the layer 2/3 pyramidal cells, with a densely distributed activity in the larger layer 5 pyramidal cells and putative interneurons. Recordings from pyramidal neurons in primary somatosensory barrel cortex, both under anesthesia and in awake animals, also revealed low spontaneous and evoked firing in layer 2/3 compared to much higher firing rates in layer 5 pyramidal neurons (39, 40). Another study that looked at the barrel cortex in awake head-restrained mice during object localization found superficial layers (layer 2/3) firing was about 20 times weaker than firing rates in deeper layers (41). Similarly, in A1 of nonhuman primates, neuronal firing is typically reduced in the superficial, relative to the middle and deep layers during both spontaneous and stimulus-evoked recordings [e.g., (21, 42)]. A relative paucity of firing in superficial layers is observed in primary somatosensory cortex during stimulation (43) and in resting spontaneous activity (44). Similarly, Bastos et al. (45) observed a weaker superficial firing, as compared to layer 4 in macaque prefrontal cortex (PFC) (see the Supplementary Materials). Self et al. (46) also show weaker supragranular MUA in response to full-screen, high-contrast checkerboard stimulation and during spontaneous recordings in V1. A detailed review of possible mechanisms leading to sparser firing in the superficial layers relative to deeper layers is beyond the scope of our manuscript. However, the fact that layer 2/3 pyramidal neurons appear to require substantially more excitatory synaptic input to drive them to action potential threshold compared to L5 pyramids (35) points to one mechanistic explanation for this common observation.

Acknowledgments: Funding: B.R.A.I.N., MH111439, EYE24776, DC015780, and MH109429. Author contributions: M.L. and C.E.S. designed the study. A.B., Y.K., A.Y.F., and I.U. collected data. M.L. performed analyses. M.L. and C.E.S. wrote the manuscript. All authors contributed to the discussion and interpretation of findings and edited the manuscript. Competing interests: The authors declare that they have no competing interests. Data and materials availability: All data needed to evaluate the conclusions in the paper are present in the paper and/or the Supplementary Materials. Additional data related to this paper may be requested to the authors.

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Dissociation of broadband high-frequency activity and neuronal firing in the neocortex - Science Advances

Physiology

How to get into a positive mindset to move with the COVID times – Houston Chronicle

August 12, 2020 medical

This is a challenging moment. The way we see each other, the way we work even the way we grocery shop has been shaken up.

The pandemic hasnt only threatened obvious aspects of our lives, its had an uncanny way of bringing other problems to light, too.

Frustration, resentment and helplessness are common threads. If you feel that gloomy things often happen to you, youre not alone. Success coach Albina Rippy has a few tips that may help.

Rippy and her husband, Roger, started YogaOne, a small one-room yoga studio in Midtown, in 2008 and grew to seven locations before selling to YogaWorks in 2017. Now, Rippy leads yoga training virtually and at beautiful international destinations; runs a coaching business; and operates their retreat center in Taos, N.M. Shes a mom, too.

But none of this came without obstacles and doubt. Rippy grew up in the Soviet Union, amid its collapse. As a child, I waited in bread lines, she said in an interview with Voyage Houston. I witnessed how my familys savings became worthless because the government changed its currency, literally, overnight. I witnessed fear, desperation and hopelessness firsthand.

At 16 years old, Rippy left Kazakhstan, alone, barely speaking English, to go to school in the U.S.

She knows a thing or two about handling a challenge.

She says when seemingly unfixable circumstances yield chronic blues, its important to take a deeper look. The root of the problem isnt typically what it seems.

We blame the economy, the pandemic, our soul-crushing jobs, a mean boss, all men, all women, our upbringing, and so on, for our lack of happiness and wealth, she says.

To Rippy, this kind of finger-pointing uses a lot of energy and ultimately leaves us tired, bitter and blind to opportunities for better outcomes. A wiser approach is to turn a gentle gaze within.

Say, for example, you hate your boss and blame this person for why you didnt get a promotion. Its an understandable situation, but according to Rippy, dwelling on the other person represents a victims mindset. When we see the world from this perspective, we cement a limited view that lacks self-awareness and is incompatible with growth and possibilities.

You cannot even consider that your boss might sense your resentment and dislike, or that your mindset is causing you to have a negative attitude at work, or that on a subconscious level you are sabotaging (your own cause), Rippy says.

She adds: The moment you see this clearly, you get access to choice. You can choose to forgive your boss and yourself and let go of your grudge and resentment. You can genuinely choose positivity and love. Your choice alone will elevate your inner vibration and influence the way you see the world.

Perhaps, you will start seeing that your boss is actually trying to connect with you. Or that your bosss own challenges (a sick child or parent, difficulties in their marriage, their financial struggles, etc.) influence their inner state and that it has never been about you.

Rippy says when we take responsibility for our experiences, we uncover a magnitude of possibilities, opportunities and choices right under our noses.

Maybe softening your view of your boss paves the way for a surprising bond that leads to an even better opportunity. Maybe when youre less consumed by this persons shortcomings, your creativity surges and you take on new and deeply fulfilling projects, or start a kick butt side hustle. Maybe you just realize a vacation would serve you well. The possibilities are vast.

But heres an important qualifier: Shame is not a part of the game.

Rippy urges us not to start presuming everything imperfect is our fault. On the other hand, she says this about shifting into a next-level mindset where instead of challenges being cause for blame on anyone, theyre invitations to dig deep and find new potential.

Through challenges and trials, you grow and expand, you become strong, unstoppable, unshakable, unbreakable. This perspective gives you access to choice, power, innovation, resilience, love.

Here are a few of other strategies she suggests for moving through ups and downs:

When we dwell in the victim mindset, we are filled with resentment, grudges and blame. This is a heavy burden to carry. Furthermore, these difficult emotions take up too much of our energetic bandwidth, blocking the flow of goodness in our lives. If you want to create the life you yearn for you must let go of your resentments and free yourself. I teach an ancient Hawaiian prayer called HoOponopono (where you repeat the phrases): I love you. I am sorry. Please forgive me. Thank you.

Her favorite: Every day and in every way, I am strong, healthy, young, beautiful, charismatic, creative, resilient, kind, loving, generous, compassionate, infinitely loved, abundantly blessed and divinely guided.

I say this over and over again, as I run or work out, using all of my physiology and lots of passion, she says.

We all are very clear on what we dont want. I dont want to get sick or I dont want to lose my job or I dont want to end up alone. We have a much more challenging time identifying what we truly want. When we consciously direct our minds to focus on what we do want, our brains start filtering bringing to our attention situations, people, opportunities that will get us to where we want to go.

To Rippy, looking within and doing this work is a pathway out of the pits and to much brighter pastures.

Marci Izard Sharif is an author, yoga teacher, meditation facilitator and mother. In Feeling Matters, she writes about self-love, sharing self-care tools, stories and resources that center around knowing and being kind to yourself.

Neuroscience

Potential Impact of COVID-19 Pandemic on Global Neuroscience Antibodies and Assays Market Report PDF 2020 Key Companies Thermo Fisher, Abcam, Bio Rad,…

August 11, 2020 medical

Report is a detailed study of the Neuroscience Antibodies and Assays market, which covers all the essential information required by a new market entrant as well as the existing players to gain a deeper understanding of the market.The primary objective of this research report named Neuroscience Antibodies and Assays market is to help making reliable strategic decisions regarding the opportunities in Neuroscience Antibodies and Assays market. It offers business accounts, industry investors, and industry segments with consequential insights enhancing decision making ability.nicolas.shaw@cognitivemarketresearch.com or call us on +1-312-376-8303.

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Competitive Analysis has been done to understand overall market which will be helpful to take decisions. Major players involved in the manufacture of Neuroscience Antibodies and Assays product has been completely profiled along with their SWOT. Some of the key players include Thermo Fisher, Abcam, Bio Rad, Merck, Cell Signaling Technology, Genscript, Rockland Immunochemicals, BioLegend, Santa Cruz Biotechnology, Roche, Siemens. It helps in understanding their strategy and activities. Business strategy described for every company helps to get idea about the current trends of company. The industry intelligence study of the Neuroscience Antibodies and Assays market covers the estimation size of the market each in phrases of value (Mn/Bn USD) and volume (tons). Report involves detailed chapter on COVID 19 and its impact on this market. Additionally, it involves changing consumer behavior due to outbreak of COVID 19.

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Regional Analysis for Neuroscience Antibodies and Assays North America (United States, Canada)Europe (Germany, Spain, France, UK, Russia, and Italy)Asia-Pacific (China, Japan, India, Australia, and South Korea)Latin America (Brazil, Mexico, etc.)The Middle East and Africa (GCC and South Africa)

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Potential Impact of COVID-19 Pandemic on Global Neuroscience Antibodies and Assays Market Report PDF 2020 Key Companies Thermo Fisher, Abcam, Bio Rad,...

Neuroscience

FDA Approves TMS Therapy to Treat OCD – MD Magazine

August 11, 2020 medical

MagVenture TMS Therapy can be used as adjunctive therapy to other OCD treatments.

The US Food and Drug Administration (FDA) has approved transcranial magnetic stimulation (TMS Therapy) for adjunct treatment in adult patients with obsessive-compulsive disorder.

TMS had previously been granted approval to MagVenture for the treatment of major depressive disorder in patients who failed to experience adequate improvement from use of antidepressant medication.The company was the first to receive FDA clearance for the 3-minute Express TMSthe shortest TMS treatment now available.

Now, the out-patient procedure can be used as adjunctive to other OCD treatments that might involve pharmaceutical and behavioral therapy. Using magnetic pulses to stimulate specific areas in the brain, TMS targets its networks and deeper-lying structures that are known to be particularly affected by OCD.

The therapy was not associated with any systemic side effects.

OCD, a mental disorder characterized by obsessions and compulsions, can cause severe disruptions in ones daily life and routines and can lead to further distress and functional impairment. Although there are currently several pharmaceutical and psychological intervention options that are available for these patients, some experience limited improvement and mitigation of symptoms. Thus, the need for greater therapeutic options becomes increasingly necessary.

We have worked closely with brain researchers for well over 25 years, providing numerous TMS solutions to help advance the field of neuroscience both basic and applied, said Kerry Rome, VP of Sales for MagVenture, in a statement. Expanding the treatment options to include other indications than major depressive disorder, such as OCD, is one more important step towards helping more adult patients improve their mental health

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FDA Approves TMS Therapy to Treat OCD - MD Magazine

Neuroscience

AZTherapies Announces the Appointment of Drs. Robert Malenka, Adam Boxer, Vijay Kuchroo and Megan Levings, to Scientific Advisory Board -…

August 11, 2020 medical

BOSTON, Aug. 11, 2020 (GLOBE NEWSWIRE) -- AZTherapies, Inc., a biopharmaceutical company in advanced clinical trials to treat neuroinflammatory diseases, today announced the expansion of its Scientific Advisory Board, appointing esteemed neuroscientist Robert Malenka, M.D., Ph.D., as well as experts in the development of neuroimmunology and T-cell therapeutics, Adam Boxer, M.D., Ph.D., Vijay Kuchroo, D.V.M., Ph.D., and Megan Levings, Ph.D., who have joined the AZTherapies SAB following the companys acquisition of Smith Therapeutics in October 2019.

We are very pleased to welcome these neuro-immunology leaders to our Scientific Advisory Board, as we are all committed to advancing efforts to slow down or halt the progression of neurodegenerative diseases by targeting neuroinflammation as the main cause of progressive neural damage, and declining cognition and function, said David R. Elmaleh, Ph.D., AZTherapies Founder, CEO, and Chairman. Each of our new board members brings unique expertise relevant to our pipeline whether it be our Phase 3 program in early Alzheimers disease, our progressing candidate for the treatment of ALS and post-ischemic stroke cognitive impairment, or our novel biologic approach using specifically engineered immunosuppressive CAR-T regulatory (Treg) cells to treat neurodegenerative disease and I look forward to working together to achieve our common goals.

Philip Ashton-Rickardt, Ph.D., Senior Vice President, Immunology at AZTherapies also commented on the appointments: I am thrilled that the SAB members from Smith have agreed to stay on to support our efforts in the development of CAR-Tregs to restore a healthy balance of inflammatory and regulatory cells in the brain. Since last fall, we have continued to advance this innovative program through pre-clinical development, and now anticipate initial in vitro and in vivo proof of concept across several models of neurodegenerative disease later this year.

Dr. Malenka is Deputy Director of the Wu Tsai Neurosciences Institute and Associate Chair of the Department of Psychiatry and Behavioral Science at Stanford University, while also serving as the Pritzker Professor of Psychiatry & Behavioral Sciences. Recognized as a world leader in the field of synapse biology, his work has resulted in more than 250 scientific publications. Dr. Malenka is an elected member of both the National Academy of Sciences and the National Academy of Medicine as well as the American Academy of Arts and Sciences. He received a B.A., summa cum laude, from Harvard College and an M.D. and a Ph.D. in neuroscience from Stanford University School of Medicine.

Dr. Boxer is Endowed Professor in Memory and Aging in the Department of Neurology at the University of California, San Francisco (UCSF) and directs UCSFs Neurosciences Clinical Research Unit and the Alzheimers Disease and Frontotemporal Degeneration (FTD) Clinical Trials Program at the UCSF Memory and Aging Center. Dr. Boxers research is focused on developing new treatments and biomarkers for neurodegenerative diseases. He is the principal investigator of the Advancing Research and Treatment for Frontotemporal Lobar Degeneration Clinical Research Consortium, while also leading the FTD Treatment Study Group, which is looking to speed the development of new therapies for FTD. The author of more than 150 scientific publications, Dr. Boxer received his medical and doctorate degrees at New York University Medical Center.

Dr. Kuchroo is the Samuel L. Wasserstrom professor of neurology at Harvard Medical School, and a senior scientist at Brigham and Womens Hospital. He is also a member of the Broad Institute, and a participant in a Klarman Cell Observatory project that focuses on T cell differentiation. He is the founding director of the Evergrande Center for Immunologic Diseases at Harvard Medical School and Brigham and Womens Hospital. Dr. Kuchroo obtained his degree in Veterinary Medicine from the College of Veterinary Medicine, Hisar, India, and subsequently specialized in pathology at the University of Queensland, Brisbane Australia, where he obtained a Ph.D. He is the recipient of the Fred Z. Eager Research Prize, the Javits Neuroscience Award by the NIH, the Ranbaxy Prize in Medical Research, the Nobel Laureate Peter Doherty Lecture/Prize, and was named Distinguished Eberly Lecturer.

Dr. Levings is Professor, Department of Surgery and School of Biomedical Engineering, Faculty of Medicine at the University of British Columbia, Investigator at BC Childrens Hospital Research Institute, Lead, Childhood Diseases Research Theme, and an Associate Member of the Department of Microbiology and Immunology. She is internationally recognized in the field of human immunology and currently chairs the Federation of Clinical Immunology Societies Centers' of Excellence and is a member of the NIH-funded Immune Tolerance Network steering committee. Her research focuses on the use of T regulatory cells to replace conventional immunosuppression in the context of transplantation and autoimmunity. Dr. Levings received her BSc in biology from Simon Fraser University and her Ph.D. in genetics at the University of British Columbia.

About AZTherapiesAZTherapies is an advanced clinical-stage biopharmaceutical company developing novel small molecules and biologic therapies that aim to fundamentally change neurodegenerative disease progression, extending normal cognition and function and improving quality of life in the aging population. Our lead candidate, ALZT-OP1, is built on a multi-modal approach that recognizes neuroinflammation as a root cause of serious neurodegeneration and seeks to stop or slow the progression of disease; the ALZT-OP1 Phase 3 COGNITE trial in early Alzheimers disease is fully enrolled, with trial completion expected in late 2020 and results in the first quarter of 2021. Following our lead program, we are advancing candidates for the treatment of amyotrophic lateral sclerosis (ALS), post-ischemic stroke cognitive impairment, and are pursuing an innovative CAR-Treg program that could have broad application across a spectrum of neurodegenerative diseases. AZTherapies is a private company headquartered in Boston, Massachusetts. To learn more, please visit http://www.aztherapies.com.

Media Contact:Jennifer LaVinjlavin@aztherapies.com

Investor Contact:Brian BartlettChief Financial & Accounting Officerbrian.bartlett@aztherapies.com

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AZTherapies Announces the Appointment of Drs. Robert Malenka, Adam Boxer, Vijay Kuchroo and Megan Levings, to Scientific Advisory Board -...

Neuroscience

The first Virtual Microscope of the human brain, developed by Darmiyan, accurately measures Alzheimer’s-related abnormalities – PRNewswire

August 11, 2020 medical

"Darmiyan's AI, machine learning algorithm using unique MRI microscopic voxel analysis with macroscopic input has generated a very sensitive and specific five year prognosis for patients presenting with amnestic MCI," noted Jamshid Ghajar, MD, PhD, FACS, Moghadam Family Director of Stanford Medicine Brain Performance Center. "This technology has high test-retest reliability and can be applied to any clinical grade MRI which is a very useful clinical tool to assist doctors advising patients with early memory complaints."

"Darmiyan's vision excited me because it offers a biologically-based, objective, and sensitive method for detecting changes in the brain that may first show up as subtle changes in memory and cognition and later, as neurodegenerative disease progresses, lead to more serious cognitive and functional deficits. The promise of a new tool that can give patients and their doctors a head start in planning for and possibly even heading off the advance of dementia is exactly what is needed right now, as the aging population grows larger. With the successful conclusion of this project, Darmiyan moves a step closer to delivering on this promise," said Bradley Buchsbaum, PhD, Cognitive Neuroscience Associate Professor at University of Toronto, Senior Scientist at Baycrest Institute & Rotman Research Institute, and the Principal Investigator of the Canadian arm of Darmiyan's validation project.

Validating BrainSeeon Both Clinical-grade and Research-grade Data

The current study showed that BrainSee performs with as high accuracy on clinical-grade data (from patients who present to clinics and hospitals) as it had previously performed on research-grade data (from patients who volunteer for research or clinical trials). This makes BrainSee the first cutting-edge solution that can be easily integrated in any community clinical setting around the world, not just the high-end academic institutions.

A blind retrospective analysis was previously conducted on 411 amnestic mild cognitive impairment (aMCI) patients with research-grade input data (MRI: 3D T1, T2, DTI; plus MMSE & CDR) reporting 90+% performance accuracy. In the current third-party validation study, external investigators blind-tested BrainSee on 107 new patients with clinical-grade input data (routine clinical T1, T2, DWI; plus MMSE & estimated CDR from clinician notes).

While all 107 patients held the same clinical diagnosis label of aMCI, BrainSee visualized and quantified microstructural differences that existed in each patient's brain, and predicted if they would convert to Alzheimer's dementia within 5 years (converter) or stay stable/ improve (non-converter). Investigators compared BrainSee's predictions against the actual clinical diagnosis five years later. The overall predictive accuracy of BrainSee was reported as 91% (Sensitivity 90%, Specificity 92%)."Such an accurate and non-invasive prognostic tool is non-existent in the market today," noted the US investigators.

The current study also included a separate analysis for evaluating BrainSee's test-retest reliability on 84 additional aMCI patients who were recruited to get two brain MRI scans on the same day: one clinical-grade and one research-grade. The test-retest reliability (consistency) of BrainSee was reported very high, with a correlation coefficient of 99.5%.

With this external validation data, the total number of aMCI patients tested by BrainSee has reached 602.

Novel Technological Advantages

"While reading brain PET scans at Stanford & NYU hospitals as a radiologist, I imagined the day when we could help clinicians visualize and evaluate brain health more comprehensively and objectively while posing less discomfort to patients. That day has come now and Darmiyan's BrainSee technology can finally bring clarity to the field of Alzheimer's through visualizing brain tissue microstructure for doctors. Darmiyan's Virtual Microscope technology unlocks the enormous informative potential of the currently underutilized brain MRI scans," said Darmiyan's Chief Medical and Technology Officer, Kaveh Vejdani, MD. "The huge advantage of MRI modality over PET is that it is safer (no radiation exposure), faster, more cost-efficient, non-invasive (does not require radiotracer injection), and much more widely available throughout the world."

According to Dr. Michael G. Harrington, FRCP, Scientific Director of Neuroscience, HMRI, "Objective measures such as Darmiyan's BrainSee that can predict cognitive decline are strongly needed to recognize and monitor potential therapies."

Meeting Today's Clinical Needs

Alexandra Papaioannou, MD, Executive Director, and George Ioannidis, PhD, Associate Scientific Director of GERAS Centre at HHS (both Professors of Medicine at McMaster University) noted that Darmiyan's non-invasive technology "could result in an important development in the Alzheimer's field" as it has "performed well in predicting disease progression" and can "improve clinicians' workflow and how patients are monitored."

David J. Mikulis, MD, Professor and Director of the JDMI (Joint Department of Medical Imaging) Functional Neuroimaging Research Lab, UHN, noted: "I was impressed by the potential of this breakthrough technology. All study investigators are optimistic that Darmiyan's solution will be successful providing a much needed predictor of disease progression. It may therefore fill a significant diagnostic gap highly valued by patients, clinicians, and clinical researchers."

"With the great help of our clinical trials sites in the US and Canada, we demonstrated that BrainSee can well integrate in the clinical workflow without imposing any limitations, such as specific MRI protocol, in the process of monitoring MCI patients," said Darmiyan's CEO Padideh Kamali-Zare, PhD. "These data support our vision to make BrainSee readily accessible for all people worldwide addressing the dire need for accurate diagnosis of Alzheimer's disease and prognosis of mild cognitive impairment in clinics and clinical trials. Localizing and quantifying early signs of brain cell distortion, in a way that is agnostic to specific protein-based biomarkers such as amyloid or tau, is key to understanding the disease pathology early on in its process and providing personalized treatments suitable for each Alzheimer's patient in the future."

About Darmiyan, Inc.

Darmiyan(based in San Francisco, CA) was incorporated in September 2016 and backed by Y-Combinator (YC) in Summer 2017. The Company has won numerous awards and recognitions including the TEDMED Hive Innovator in 2018 and CABHI Innovation Award in 2019. Darmiyan's most recent funding in 2020 was led by the global pharma giant Eisai with participation of YC and IT-Farm.

SOURCE Darmiyan

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The first Virtual Microscope of the human brain, developed by Darmiyan, accurately measures Alzheimer's-related abnormalities - PRNewswire

Neuroscience

Revisiting the industrial revolution in scientific lasers – Laser Focus World

August 11, 2020 medical

ALLAN ASHMEAD, STEVE BUTCHER, and MARCO ARRIGONI

Experience from decades of industrial laser applications, along with vertical integration leading to better components and materials, have enabled laser manufacturers to build scientific lasers with industrial reliability. At Coherent (Santa Clara, CA), investment in an immersive reliability concept called HALT/HASS long used in other reliability-critical industries has assisted in achieving this goal (HALT stands for highly accelerated life testing and HASS stands for highly accelerated stress screening). For example, in a 2014 Laser Focus Worldarticle entitled Ultrafast scientific lasers undergo an industrial revolution, Coherent noted that a one-box femtosecond oscillator was delivering levels of reliability that opened the path towards significant advances in data productivity.

Six years is a long time in a dynamic field like ultrafast lasers, so now seems like a reasonable time to assess if and how this industrial revolution has progressed, and more importantly, how it has impacted real scientific studies. This second article on the topic focuses on the more complex and challenging domain of femtosecond amplifiers.

For many years, titanium sapphire (Ti:sapphire) was the gain material of choice in virtually every ultrafast amplifier and oscillator. Today, however, ytterbium (Yb)-doped crystals or fibers are well-established alternatives to Ti:sapphire and complement its performance capabilities. Ytterbium has the advantages of being directly and efficiently pumped by laser diodes, resulting in a smaller quantum defect than Ti:sapphire. As a result, Yb lends itself to more-compact platforms.

From an applications viewpoint, the important differences are power, pulse energy, and repetition rates. Ti:sapphire amplifiers are unmatched in their ability to deliver high pulse energy. Coupled with the short pulses (less than 35 fs) of turnkey Ti:sapphire amplifiers, this translates into peak powers approaching the terawatt level. These amplifiers are therefore favored for applications requiring high fluence such as strong-field physics and high harmonic generation (HHG) for extreme ultraviolet (EUV) or attosecond-pulse generation.

The optimum performance of one-box Ti:sapphire amplifiers is at low repetition rates: 110 kHz. Ytterbium amplifiers, on the other hand, have lower pulse energy, but deliver much-higher average power (tens of watts) with extremely flexible repetition rates up to the megahertz regime. As a result, Yb amplifiers are optimum for applications requiring fast data collection with modest energy requirement (such as imaging and solid-state spectroscopy) or where high average power is critical (such as materials processing). Moreover, as a newer material, Yb amplifiers have more room for performance improvements.

This article will examine four applications, three scientific and one industrial, that highlight the impact of the industrial revolution on day-to-day performance, reliability, and productivityeither in terms of data or process throughput.

Ferroelectric materials and films can support a permanent electric dipole (meaning electrically polarized), which is why they are already widely used in electronic and photonic devices. However, more-detailed information is needed on films as thin as a few unit cells, as these could support higher density electronics and also offer the potential of custom (atomic-scale) novel ferroelectric heterostructures. A group led by Dr. Morgan Trassin and Prof. Manfred Fiebig at ETH Zurich (Switzerland) has been conducting the first in situ measurements of film polarity during the actual growth process performed by pulsed laser deposition with an excimer laser (Coherent LPX 220).

In any material where there is a break in symmetry and long-range order, irradiating with intense laser light can result in some second-harmonic generation (SHG). This effect has already been used in the past as a diagnostic with thicker ferroelectric samples. However, no one had previously demonstrated in situ harmonic generation (ISHG) during the film growth process.

SHG is highly sensitive to polarization, says Trassin. So, we reasoned that we could use the polarization dependence of the SHG signal to map the alignment of domains in a ferroelectric film. And, more importantly, we wanted to investigate the potential of ISHG to follow the polarization (or depolarization) of ultrathin films during the epitaxial deposition process. The light source for their SHG setup is a Ti:sapphire one-box amplifier (Coherent Astrella) that pumps a tunable optical parametric amplifier (OPA).

The technique has proved successful and has been capable of measuring ferroelectric polarization properties, as films are grown from zero to just a few unit cells in thickness. Based on this success, the Trassin group has applied this technique to examine the local polarization orientation, as the layers are incorporated into heterostructure model devices.

What is the impact of industrial reliability? The stability of this amplifier to changes in ambient temperature is particularly important to our work, says Trassin. We grow these films in a deposition chamber with internal temperatures up to 950C, so the temperature of our lab unavoidably varies considerably during the day (see Fig. 1). But critical amplifier output (pointing and power) parameters are thankfully unaffected.

2D spectroscopy involves measuring an optical signal as a function of pulses with two different optical frequencies and provides a wealth of data that would be impossible to obtain by any other method. The signal can be based on various different processes, including absorption, Raman, and sum/difference frequency generation. The data can be presented as two-dimensional contour graphs plotted against two frequencies, but are usually recorded as time-domain data and then Fourier-transformed in the frequency space. To ensure coherence, the three (or four) different femtosecond pulses required for these measurements are generated from a single source using a pulse shaper in what is essentially a four-wave mixing effect in the sample. The very wide spectral bandwidth of the short Ti:sapphire pulses critically enables a wide frequency range to be covered in a single set of data.

A group led by Professor Wei Xiong at the University of California, San Diego has recently used 2D spectroscopy to investigate a heterogeneous CO2 reduction catalyst, Re(diCN-bpy)(CO)3Cl, bound as a monolayer on gold surfaces. The researchers have performed experiments based on sum-frequency generation (SFG), a technique originally developed by Xiong as a graduate student in the lab of Martin Zanni. SFG vibrational signals are only generated at surfaces and phase interfaces. So, comparison with 2D spectra of the unbound catalyst (that is, in solution) enabled the Xiong group to reveal how the catalyst is bound to gold (see Fig. 2) and how its bond structure is impacted by this.FIGURE 2. Orientations of a catalyst on a gold surface determined from HD 2D SFG data and data from reflection-mode infrared spectroscopy is simulated using density functional theory (DFT). Orientation a is preferred. Blue lines represent directions of the vibrational modes.(Courtesy of Wei Xiong)

Xiong cites the operational simplicity of their one-box industrialized amplifier (Coherent Astrella) as a key benefit in these inherently challenging experiments. Just as important is the long-term stability: some of their time-resolved experiments (i.e., 3DSFG) require data runs in excess of 40 hours, during which the amplifier output must remain perfectly stable.

Two-photon microscopy and related techniques represent a major market segment for one-box oscillators, particularly in neuroscience, and now one-box Yb amplifiers are starting to enable new neuroscience applications. The main applications here are three-photon (3P) microscopy, photostimulation of groups of neurons, and photoablation of select neurons. These all require one or more of the main Yb amplifier advantages: long output wavelength, high repetition rate, and high average power. For example, high power is needed for two-photon photostimulation of hundreds of neurons using optogenetic expression. The power requirement stems from the large number of cells to be stimulated simultaneously, as well as system losses in spatial light modulators (SLMs).

Three-photon microscopy is a relatively new technique that depends on the simultaneous absorption of three photons, a low-probability event that therefore requires the high photon flux from an amplifier rather than an ultrafast oscillator. As a scanning-imaging application, high repetition rate is also necessary to acquire many pixels. Here, a Yb amplifier is usually combined with a tunable OPA to deliver high power in the 1.3 and 1.7 m wavelength windows that yield deeper penetration into brain and other scattering tissues.

Professor Raluca Niesner at the German Rheumatism Research Center (DFRZ; Berlin, Germany) recently used a Yb amplifier (Coherent Monaco) together with an OPA (Coherent Opera-F) to perform 3P imaging inside lymph nodes. These are densely packed with cells, which causes scattering issues for two-photon microscopy.

One of the targets of my research group is improved understanding of the rogue inflammatory response that results in rheumatoid arthritis in particular, and in chronic inflammatory diseases in general, says Niesner. Preliminary studies of mouse-limb lymph nodes by Dr. Rakhymzhan in Niesners laboratory indicate that 3P excitation can deliver a dramatic increase in deep imaging capabilities, specifically a greater-than 2X increase in maximum imaging depth for 3P vs. 2P under identical conditions. Figure 3 shows typical images.FIGURE 3. Murine lymph-node z stack images, where z = 300 m, are obtained using a Coherent Monaco Opera-F combination tuned to a wavelength of 1630 nm and a LaVision Trim Scope microscope. The red image is due to 3P excitation of tdTomato (a fluorescent protein) detected at 595 (20) nm (a), the white image is due to SHG signals from collagen fibers detected at 810 (45) nm (b), and the green signal originates from THG of lipid bilayers, lipids, or other anisotropic structures and was detected at 525 (25) nm (c). The composite image combines the tdTomato and SHG signals (d).

Surely nothing illustrates the success of the industrialization of scientific ultrafast lasers more than the use of the same laser in both scientific and industrial applications. Bringing the story full circle, a brief look is taken at an industrial application that illustrates both the flexibility of Yb amplifiers and the broad benefits of the industrial revolution approach to scientific and commercial applications.

Lasers with ultrashort pulse durations have long been used in micromachining (cutting, drilling, scribing, and so on) because the short pulse duration minimizes the heat-affected zone (HAZ)the extent of surrounding material that exhibits undesirable thermal damage such as melting/resolidification or microcracking. The HAZ is minimized when the pulse duration is short compared to the thermal diffusion time in the target material, so that most of the extra heat associated with the cutting or drilling process is carried away in the ejected debris before it has time to spread into the surrounding material.

Until recently, ultrashort-pulse (USP) industrial lasers have been mostly confined to the picosecond domain, limited by the bandwidth of the neodymium (Nd)-doped gain medium. However, for some applications, even the small HAZ from picosecond lasers was problematic, indicating a need for even shorter pulse durations. Unfortunately, femtosecond amplifiers based on Ti:sapphire do not have the requisite combination of high repetition rates and high average power. The advent of Yb femtosecond amplifiers with output powers up to 60 W has thus completely changed this situation. One of the first applications to benefit has been medical device fabrication.

A standout example can be found at Motion Dynamics (Fruitport, MI), a manufacturer of difficult subassemblies for the medical market such as steerable catheter products for neurovascular interventions. They use a four-axis cutting machine (Coherent StarCut Tube) equipped with a Monaco femtosecond amplifier rated at 60 W (see Fig. 4). Chris Witham, President of Motion Dynamics says, Our products require cutting and drilling a range of different metals, including gold, where surface roughness and edge quality are critical qualities. The femtosecond laser enables us to fabricate these components in a single step, typically with no polishing or other postprocessing required.FIGURE 4. An example of a wire/spring subassembly cut with a Yb femtosecond amplifier (Coherent Monaco).(Courtesy of Motion Dynamics)

The success of the industrial revolution in ultrafast science has been clearly demonstrated in these, and many other, representative applications that are critically enabled by the reliability and stability resulting from this design and manufacturing approach.

Allan Ashmead is VP of the Research Laser Systems business unit, Steve Butcher is director of marketing for the Scientific Market, and Marco Arrigoni is director of marketing for the Advanced Systems business unit, all at Coherent, Santa Clara, CA; e-mail: allan.ashmead@coherent.com;coherent.com.

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Revisiting the industrial revolution in scientific lasers - Laser Focus World

Physiology

UO team will use zebrafish in new study of aquatic symbioses – AroundtheO

August 11, 2020 medical

A UO-led team of researchers spanning physics, neuroscience, molecular biology, ecology and evolution will use a new $325,000 grant to examine aquatic symbioses the interactions between different animal species living together.

The project is funded by a 30-month award from the Gordon and Betty Moore Foundation and involves the study of zebrafish in controlled ecosystems.

The team will leverage decades worth of pioneering research at the UO involving zebrafish and explorations of the gut microbiome, in which vast numbers of microbes contribute to both health and disease in their hosts. UO has been a leader in zebrafish research since the 1960s, when the late biologist George Streisinger established zebrafish as an ideal model for studying human development and disease.

We aim to develop new tools for studying these symbioses throughout the entire lifespan of zebrafish, which serves as a model aquatic animal and a model for phenomena relevant to all vertebrates, including humans, said Raghuveer Parthasarathy, an Alec and Kay Keith Professor in the Department of Physics, a member of the UOs Institute of Molecular Biology and Materials Science Institute, and the principal investigator on the award.

The project builds on the successes of the zebrafish group here at the UO and it pushes it to the next frontier of trying to capture the whole lifespan of the animal and its ecosystem, Parthasarathy said.

Along with Parthasarathy, the team includes Karen Guillemin, Judith Eisen and Brendan Bohannan, all professors in the Department of Biology. Guillemin is a Philip H. Knight Chair and a member of the Institute of Molecular Biology. Eisen is a member of the Institute of Neuroscience. Bohannan, the James F. and Shirley K. Rippey Chair in Liberal Arts and Sciences, is a member of the Institute of Ecology and Evolution.

The team also includes John Rawls, a professor of molecular genetics and microbiology at Duke University and the director of the Duke Microbiome Center.

Part of the Moore Foundations Symbiosis in Aquatic Systems Initiative, the project will contribute to a larger effort to equip the scientific community with new genetic tools, cultivation methods and other infrastructure to improve experimental capabilities in aquatic symbiosis research over the coming decade. Increasingly, researchers are recognizing that symbiotic bacteria are critical components in the processes that sculpt the evolution, ecology, development and physiology of animals, yet remarkably little is known about exactly how those processes play out.

The four UO researchers have worked together on previous projects as part of the UOs interdisciplinary Microbial Ecology and Theory of Animals, a National Institutes of Health-funded Center of Excellence in Systems Biology. The center is funded by a $7.6 million grant and seeks to better understand the bacteria and other microorganisms that reside in the animal gut and influence many biological functions.

Building on their earlier work studying individual biological processes, the new research will explore the entire ecosystem and lifespan of zebrafish and consider food chains, population densities and other attributes. The project will serve as a bridge between more traditional model system research and field studies, opening up new frontiers in zebrafish research, Parthasarathy said.

The project involves three main areas. Investigators will:

Were hoping to learn how can we both predict and control ecosystem constituents, things like food and bacteria and how can that give us healthy organisms throughout their lifespan, Parthasarathy said. Our approach focuses especially on better understanding nutrition and on engineering new aquatic habitats that allow controlled investigation of symbiotic interactions. We want to watch and learn from the entire process.

The UO team will be building on a strong foundation of zebrafish research. That includes groundbreaking work by Eisen examining interactions between the nervous system, immune system and bacteria in the gut, and Guillemins innovative development of specialized sterile zebrafish that allow scientists to better determine the role microbes play as animals grow.

Bohannan has conducted important research on zebrafish, tracking them throughout their life cycle to see how diet, genetics and immune response affect their microbial diversity. And Parthasarathy has employed physics to better understand how gut microbes move and interact with each other, producing stunning, high-resolution, three-dimensional images and videos of gut bacteria in zebrafish using a technique known as light sheet microscopy.

Rawls, the biologist from Duke University, studies gut bacteria in zebrafish and their role in regulating digestive physiology, innate immunity and gut-brain communication.

I think (this research) may open up a lot of ecological questions, Parthasarathy said. If we succeed, we can expand our methods to other species such as plants and algae and explore their interactions. I think there is lots of potential for growth.

The project is the latest in a string of awards to UO researchers from the Moore Foundation. Earlier this year Eisen received a $2 million grant through the same symbiosis initiative to probe the relationship between symbiotic bacteria and neural development, using zebrafish as a model organism. In January, UO biologist Kelly Sutherland received a $1.1 million grant from the foundation funding her research examining the swimming mechanisms of gelatinous marine organisms.

These awards are a testament to the exceptional research being conducted at the University of Oregon, said Provost and Senior Vice President Patrick Phillips. We are grateful to the Gordon and Betty Moore Foundation for their generous support of our researchers and their investment in these innovative and impactful projects, which support the foundations critical mission of fostering pathbreaking scientific discovery and further the UOs commitment to enriching the human condition through creative inquiry and scientific discovery.

By Lewis Taylor, University Communications

Physiology

Antibody drugs could be key tools against Covid-19. But will they matter? – STAT

August 11, 2020 medical

From the moment Covid-19 emerged as a threat, one approach to making drugs to treat or prevent the disease seemed to hold the most promise: Theyre known as monoclonal antibodies.

Now, scientists are on the brink of getting important data that may indicate whether these desperately needed therapies could be safe and effective. Clinical trials involving a pair of antibodies developed by Regeneron Pharmaceuticals will read out early results in September. A separate effort from Eli Lilly could yield data later in the fall.

Despite experts eagerness to see the data, however, there remains a debate over just how significant a role any antibody treatment might play in changing the course of the pandemic.

A lot of smart people who understand immunology and virology think antibodies will work, said Robert Nelsen, an investor at ARCH Venture Partners who is invested in Vir Biotechnology, which will start tests of its own Covid-19 antibody study this month.

Scott Gottlieb, the former commissioner of the Food and Drug Administration, is less sure antibody treatments will be significant factors in bringing the pandemic under control. Even though the development efforts have been proceeding extraordinarily fast by normal standards, the U.S. has spent billions of dollars purchasing vaccines in advance, but has done far less to shore up capacity for antibody drugs.

We may have missed a window to scale the manufacturing of antibody drugs that could have been an important bridge to a vaccine and a hedge in the event vaccines are delayed or dont work, Gottlieb, a fellow at the American Enterprise Institute and board member for Pfizer and other health care companies, told STAT. These drugs had the ability to perhaps meaningfully change the contours of this epidemic, and we just wont have enough doses to realize that goal.

Monoclonal antibodies are antibodies the kind that the body produces to neutralize invading viruses that have been genetically engineered into new medicines.

In 1975, two researchers, Georges J.F. Khler and Csar Milstein, developed the method for mass-producing them by fusing antibody-producing cells from mice with cancer cells. They shared the Nobel Prize in physiology or medicine in 1984. The first monoclonal antibody drug, for kidney transplant patients, was approved in 1986. Today, Humira, an antibody from AbbVie that treats a host of immune-related diseases, is the pharmaceutical industrys top-selling product, generating $15 billion in sales last year.

Regeneron has produced several monoclonal antibodies since being founded in 1988, including Praluent for high cholesterol, Libtayo for a type of cancer, and Dupixent for severe eczema. In 2014, the technology was also used to develop an effective treatment for Ebola.

As the Covid pandemic hit, Regenerons chief scientific officer, George Yancopoulos, assigned Christos Kyratsous, a confident, Porsche-driving scientist with a dry sense of humor, to lead a team that would search for an antibody. In early February, a non-infectious fragment of genetic code of the novel coronavirus arrived at the companys research laboratories in Tarrytown, N.Y., from China, and the company has used this starting material to produce hundreds of virus-neutralizing antibodies using genetically engineered mice, along with blood taken from survivors of Covid-19.

But getting antibodies into people has taken time. I tragically right now have a 91-year-old aunt whos trapped in a nursing home where right now theres a coronavirus outbreak, Yancopoulos said in April. And I just wish I could get them our [drug] today. Its just not ready.

Other companies are advancing their own efforts. For years, AbCellera, a Vancouver-based biotech, had been working with the National Institutes of Health and the U.S. Department of Defense to game out the response to future pandemics. In February, the NIHs National Institute of Allergy and Infectious Diseases sent the company a sample of blood from a patient who had recovered from Covid-19. AbCellera inserted the sample into a credit-card-sized device that isolates the B cells that make antibodies, and used it to find more than 550 antibodies that might work against the virus.

Adaptive Biotechnologies, AbbVie, and AstraZeneca have also rushed forward with their own antibody efforts.

Regenerons antibodies REGN10933 and REGN10987 both target the spike protein on the virus surface that helps it invade cells, but individually, each drug binds to the protein at a different, non-overlapping location. This cocktail approach aims to increase the chance that the virus can be neutralized without escaping. Its the same multidrug strategy used successfully to treat other viral diseases such as HIV and hepatitis C. Regeneron refers to the dual antibody regimen as REGN-COV2.

The first look at Regenerons data will provide results on the ability of REGN-COV2 to reduce the amount of SARS-CoV-2 virus in patients compared to placebo. Safety and other data will also be announced.

Outcomes data will come later. For the study of hospitalized Covid-19 patients, Regeneron hopes to show that the treatment can improve clinical status based on a seven-point scale ranging from hospital discharge to death. In between, the scoring system measures changes in the use of supplemental oxygen or mechanical ventilation. In the study of ambulatory Covid-19 patients, REGN-COV2 is designed to speed recovery and prevent the disease from getting worse. Unlike Regeneron, Eli Lilly and AbCellera have chosen not to use a cocktail approach, starting instead by testing a single antibody. Data from its study, however, being conducted with the NIH, arent expected to be released until October or November.

Reducing the theoretical risk of escape mutations has a real cost, and the real cost is manufacturing, meaning you will have less doses available, meaning fewer people will be treated in this critical time period, Lilly Chief Scientific Officer Daniel Skovronsky told STAT during a recent event. So my view is we go for a single antibody, which means that we can treat twice as many people if it works.

The Lilly antibody, called LY-CoV555, will be investigated in a placebo-controlled clinical trial of approximately 300 patients hospitalized with mild to moderate Covid-19. An initial efficacy assessment based on symptoms improvement, including the need for supplemental oxygen, will be conducted five days following the injections of LY-CoV555 or placebo. If these initial results show a benefit for the Lilly antibody, the study will be expanded to enroll another 700 patients, including people with severe cases of Covid-19.

Recently published animal data suggest these antibody treatments may work in humans. Monkeys exposed to SARS-CoV-2 followed one day later with injections of the Regeneron cocktail cleared the virus faster than monkeys treated with a placebo. Damage to the lungs, including cases of pneumonia, was reduced but not eliminated in the monkeys treated with the cocktail compared to the placebo group. The monkey study was released via a preprint server, meaning the data had not yet been peer-reviewed or published in a journal.

In a research note, SVB Leerink analyst Geoff Porges called the monkey data quite encouraging, but he also cautioned it may not be curative in humans on its own, citing the inconclusive pneumonia results and the challenge of treating patients early, before they might have symptoms.

If clinical development for the antibody cocktails is successful, we believe it would be most likely to complement the existing standard of care and antiviral therapies such as remdesivir, rather than displacing antivirals, said Porges.

Nelsen, the investor at ARCH Venture Partners, said: If you treat people who are very sick, you may not see anything. If you treat people earlier, you will probably see what you saw in the monkeys: a significant reduction in virus, which doesnt necessarily mean a reduction in morbidity and mortality, but it should. What you really want to do is prevent the progression of the disease.

Vir, the biotech firm that Nelsen backed, will start a clinical trial of its lead antibody candidate VIR-7831 later this month, seeking to show that it can prevent hospitalization due to Covid-19. A second antibody candidate, VIR-7832, will advance into a clinical trial later this year. Both drugs are designed to bind to a location on the spike protein that creates a high barrier to resistance. In preclinical studies, the antibodies also recruit immune cells to help kill other cells already infected by the virus, Vir said.

Similar to vaccines, antibody treatments are also being developed to prevent Covid-19 infection, particularly in people who are at high risk and who might have been exposed to the virus through close contact with an already infected person.

Once someone has come into contact with some of the disease, its too late for an active vaccine, Lillys Skovronsky said. But a passive immunization like our antibody could be valuable. When you think about the populations that are suffering the most, its the elderly, its the immunocompromised, its patients in nursing homes and long-term care facilities.

Lilly and NIAID are conducting a 2,400-patient Phase 3 study to test whether its treatment can keep nursing home patients from developing Covid-19. The antibody will be given to patients and staff at places where there has been an infection to see if it can stop them from developing the disease. To conduct the study, Lilly is deploying a fleet of recreational vehicles that can be used prepare study drug and do lab work, as well as pull trailers that can be used as on-site infusion clinics.

Regeneron and NIAID are also conducting a prevention study in 2,000 healthy adults who are household contacts with an individual with a positive Covid-19 test. Will it be possible to manufacture enough antibody? Regeneron said it is in active discussions with other parties that can add additional manufacturing capacity.

The big determinant of how fast answers will emerge will be the speed at which doctors can enroll patients in these studies, said Anita Kohli, the director of clinical research at Arizona Clinical Trials and an investigator for both Regeneron and Eli Lilly. This, she said, is harder than it sounds, especially for patients who are not so sick that they are in the hospital. I think some of the recruitment is more difficult, because youre recruiting sick people, she said. Sick people want to eat chicken soup and stay at home and not go to the clinical trials center.

One problem is that diagnostic tests are taking a long time to come back. Doctors are supposed to enroll patients in the studies within five or six days of the onset of symptoms. If testing takes two weeks to come back, patients often recover before they are enrolled. Kohlis center has begun to test patients for Covid in the hopes that some will volunteer to be in studies.

Vaccines are not going to work for everybody, she said. People are still going to get sick, theres no two ways about it. And weve got to have a treatment.

The problem, she said, is that patients are not being made aware of clinical trials for therapeutics soon enough.

People have not been directed toward clinical trials, or are not thinking about them, she said. I think thats what we need to change here. Its not that they arent very exciting, they are very exciting. They just arent talked about enough.

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Antibody drugs could be key tools against Covid-19. But will they matter? - STAT