Industry-Scale Orchestrated Federated Learning for Drug Discovery

To apply federated learning to drug discovery we developed a novel platform in the context of European Innovative Medicines Initiative (IMI) project MELLODDY (grant n{\deg}831472), which was comprised of 10 pharmaceutical companies, academic research labs, large industrial companies and startups. The MELLODDY platform was the first industry-scale platform to enable the creation of a global federated model for drug discovery without sharing the confidential data sets of the individual partners. The federated model was trained on the platform by aggregating the gradients of all contributing partners in a cryptographic, secure way following each training iteration. The platform was deployed on an Amazon Web Services (AWS) multi-account architecture running Kubernetes clusters in private subnets. Organisationally, the roles of the different partners were codified as different rights and permissions on the platform and administrated in a decentralized way. The MELLODDY platform generated new scientific discoveries which are described in a companion paper.Comment: 9 pages, 4 figures, to appear in AAAI-23 ([IAAI-23 track] Deployed Highly Innovative Applications of AI

A large, curated, open-source stroke neuroimaging dataset to improve lesion segmentation algorithms.

Accurate lesion segmentation is critical in stroke rehabilitation research for the quantification of lesion burden and accurate image processing. Current automated lesion segmentation methods for T1-weighted (T1w) MRIs, commonly used in stroke research, lack accuracy and reliability. Manual segmentation remains the gold standard, but it is time-consuming, subjective, and requires neuroanatomical expertise. We previously released an open-source dataset of stroke T1w MRIs and manually-segmented lesion masks (ATLAS v1.2, N = 304) to encourage the development of better algorithms. However, many methods developed with ATLAS v1.2 report low accuracy, are not publicly accessible or are improperly validated, limiting their utility to the field. Here we present ATLAS v2.0 (N = 1271), a larger dataset of T1w MRIs and manually segmented lesion masks that includes training (n = 655), test (hidden masks, n = 300), and generalizability (hidden MRIs and masks, n = 316) datasets. Algorithm development using this larger sample should lead to more robust solutions; the hidden datasets allow for unbiased performance evaluation via segmentation challenges. We anticipate that ATLAS v2.0 will lead to improved algorithms, facilitating large-scale stroke research

Signatures intracellulaires et extracellulaires des potentiels d'action initiés dans l'axone

The action potential is considered one of the major signaling events in the brain.Although it has been studied for years, many questions remain unanswered. The present work is dedicated to the study of action potential generation, its impact on extracellular field and local network establishment. We considered three questions: Firstly, (i) we asked why mammalian neurons often have characteristically sharp onset in the somatic recordings of action potentials. We show that the Critical Resistive Coupling Hypothesis is sufficient to explain how the action potential is initiated in the axon initial segment to provide for the ‘kink’ in the soma, while the Back propagation Hypothesis is not sufficient to explain it. Next, (ii)we asked how the placement of the axon initial segment might affect the extracellular field. We show that the impact of the axon initial segment position on the shape and amplitude ofextracellular action potential depends on the distance between the recording site andthe axon and on its position along the soma–axon initial segment axis. Finally, (iii)we inquired if a single action potential might have an effect on the network activity. Weshow that a single action potential from a single pyramidal neuron in the hippocampus can trigger sharp-wave ripple activity consisting of the firing of multiple interneurons.Altogether, our results show that action potentials are complex events shaped by the biochemistry of the neuronal membrane and morphology of the axon. In addition these features strongly modulate the neuron’s impact on the extracellular field and network activity.Le potentiel d'action est un des événements de signalisation majeurs du cerveau. Ce travail est dédié à l'étude de la génération du potentiel d'action, et son impact dans le potentiel extracellulaire ainsi que dans le réseau local. Pour ce faire nous avons abordé trois questions principales. Premièrement, nous nous sommes intéressés à comprendre pourquoi les potentiels d'action ont souvent un début brutal dans les enregistrements somatiques des neurones de mammifères. Nous avons montré que l'hypothèse du couplage résistive critique explique comment le potentiel d'action est initié dans le segment initial de l'axone pour fournir le 'kink' dans le soma. Deuxièmement, nous avons évalué l'impact de la position du segment initial sur le potentiel extracellulaire. De façon importante, nous démontrons que l’impact de la position du segment initial axonal dans la forme et l’amplitude du potentiel d’action dépend de la distance entre le site d’enregistrement et l’axone, et de sa position par rapport à l’axe soma-segment initial axonal.Finalement, nous avons exploré l’impact d’un seul potentiel d’action dans l’activité de réseau, car cet effet est souvent questionné. Nos montrons qu’un seul potentiel d’action d’un neurone pyramidal hippocampique peut commencer l’activité «sharp-wave ripple” qui consiste en l’activation de multiple interneurones. L’ensemble de nos résultats montre que les potentiels d’action sont des événements complexes modelés par la biochimie de le membrane neuronale et la morphologie de l’axone. De plus, ces caractéristiques neuronales modulent fortement leur impact dans le champ extracellulaire et l’activité de réseau

Signatures intracellulaires et extracellulaires des potentiels d'action initiés dans l'axone

Le potentiel d'action est un des événements de signalisation majeurs du cerveau. Ce travail est dédié à l'étude de la génération du potentiel d'action, et son impact dans le potentiel extracellulaire ainsi que dans le réseau local. Pour ce faire nous avons abordé trois questions principales. Premièrement, nous nous sommes intéressés à comprendre pourquoi les potentiels d'action ont souvent un début brutal dans les enregistrements somatiques des neurones de mammifères. Nous avons montré que l'hypothèse du couplage résistive critique explique comment le potentiel d'action est initié dans le segment initial de l'axone pour fournir le 'kink' dans le soma. Deuxièmement, nous avons évalué l'impact de la position du segment initial sur le potentiel extracellulaire. De façon importante, nous démontrons que l’impact de la position du segment initial axonal dans la forme et l’amplitude du potentiel d’action dépend de la distance entre le site d’enregistrement et l’axone, et de sa position par rapport à l’axe soma-segment initial axonal.Finalement, nous avons exploré l’impact d’un seul potentiel d’action dans l’activité de réseau, car cet effet est souvent questionné. Nos montrons qu’un seul potentiel d’action d’un neurone pyramidal hippocampique peut commencer l’activité «sharp-wave ripple” qui consiste en l’activation de multiple interneurones. L’ensemble de nos résultats montre que les potentiels d’action sont des événements complexes modelés par la biochimie de le membrane neuronale et la morphologie de l’axone. De plus, ces caractéristiques neuronales modulent fortement leur impact dans le champ extracellulaire et l’activité de réseau.The action potential is considered one of the major signaling events in the brain.Although it has been studied for years, many questions remain unanswered. The present work is dedicated to the study of action potential generation, its impact on extracellular field and local network establishment. We considered three questions: Firstly, (i) we asked why mammalian neurons often have characteristically sharp onset in the somatic recordings of action potentials. We show that the Critical Resistive Coupling Hypothesis is sufficient to explain how the action potential is initiated in the axon initial segment to provide for the ‘kink’ in the soma, while the Back propagation Hypothesis is not sufficient to explain it. Next, (ii)we asked how the placement of the axon initial segment might affect the extracellular field. We show that the impact of the axon initial segment position on the shape and amplitude ofextracellular action potential depends on the distance between the recording site andthe axon and on its position along the soma–axon initial segment axis. Finally, (iii)we inquired if a single action potential might have an effect on the network activity. Weshow that a single action potential from a single pyramidal neuron in the hippocampus can trigger sharp-wave ripple activity consisting of the firing of multiple interneurons.Altogether, our results show that action potentials are complex events shaped by the biochemistry of the neuronal membrane and morphology of the axon. In addition these features strongly modulate the neuron’s impact on the extracellular field and network activity

The basis of sharp spike onset in standard biophysical models.

In most vertebrate neurons, spikes initiate in the axonal initial segment (AIS). When recorded in the soma, they have a surprisingly sharp onset, as if sodium (Na) channels opened abruptly. The main view stipulates that spikes initiate in a conventional manner at the distal end of the AIS, then progressively sharpen as they backpropagate to the soma. We examined the biophysical models used to substantiate this view, and we found that spikes do not initiate through a local axonal current loop that propagates along the axon, but through a global current loop encompassing the AIS and soma, which forms an electrical dipole. Therefore, the phenomenon is not adequately modeled as the backpropagation of an electrical wave along the axon, since the wavelength would be as large as the entire system. Instead, in these models, we found that spike initiation rather follows the critical resistive coupling model proposed recently, where the Na current entering the AIS is matched by the axial resistive current flowing to the soma. Besides demonstrating it by examining the balance of currents at spike initiation, we show that the observed increase in spike sharpness along the axon is artifactual and disappears when an appropriate measure of rapidness is used; instead, somatic onset rapidness can be predicted from spike shape at initiation site. Finally, we reproduce the phenomenon in a two-compartment model, showing that it does not rely on propagation. In these models, the sharp onset of somatic spikes is therefore not an artifact of observing spikes at the incorrect location, but rather the signature that spikes are initiated through a global soma-AIS current loop forming an electrical dipole

Currents at spike initiation.

<p>(A) Somatic voltage-clamp recordings. Top: somatic membrane potential, spaced by 1 mV increments from threshold (red), with one trace just below threshold. Middle: recorded currents. Bottom: membrane potential at the AIS end. (B) Top: peak current measured in somatic voltage-clamp versus holding voltage, with and without somatic Na channels, showing a discontinuity. Bottom: peak proportion of open Na channels at the distal axonal end versus holding voltage (variable m³ representing activation is shown for the first two models; variable o representing current-passing state is shown for the third model). (C) Left, Current traces experimentally measured in somatic voltage-clamp in raphé neuron (from [<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0175362#pone.0175362.ref015" target="_blank">15</a>]). Right, Peak current vs. command voltage (red; the black curve is obtained when axonal Na channels are inactivated with a prepulse). (D) Same as (C), but in a two-electrode somatic voltage-clamp of a cat motoneuron [<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0175362#pone.0175362.ref016" target="_blank">16</a>]. Voltage is relative to the resting potential.</p

Theories of spike initiation.

<p>(A) Standard account of spike initiation: spike initiation results from the interplay between Na current and K current (mostly leak) flowing through the membrane at the initiation site. (B) Top: The isopotential Hodgkin-Huxley model produces spikes with smooth onset (left), exhibiting a gradual increase in dV/dt as a function of membrane potential V (right: onset rapidness measured as the slope at 20 mV/ms = 5.6 ms^-1). Bottom: cortical neurons have somatic spikes with sharp onsets (left), with steep increase in dV/dt as a function of V (onset rapidness: 28.8 ms^-1; human cortical data from [<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0175362#pone.0175362.ref004" target="_blank">4</a>]). (C) Backpropagation hypothesis: spikes are initiated according to the conventional account, with a local axonal current loop propagating towards the soma. (D) Critical resistive coupling hypothesis: owing to the strong resistive coupling between the two sites and the soma acting as a current sink, spike initiation results from the interplay between Na current and axial current. Spikes then initiate through a global current loop encompassing AIS and soma, which behaves as an electrical dipole.</p

Active backpropagation is not necessary for sharp initiation.

<p>Left: model with simplified soma-axon geometry. Right: cortical pyramidal cell model with morphological reconstruction. (A) Axonal Na channels are moved to a single axonal location (3 different locations shown). Left: voltage traces; right: phase plots. (B) Peak Na current (left) and proportion of open axonal Na channels (right) versus holding potential in somatic voltage-clamp. (C) Onset rapidness as a function of AIS position.</p

Influence of soma size on spike initiation.

<p>(A) Somatic voltage trace and phase plot. (B) Peak Na current (left) and proportion of open axonal Na channels (right) versus holding potential in somatic voltage-clamp. (C) Membrane potential across the neuron at different instants near spike initiation. (D) Balance of currents at initiation site (bottom) near spike initiation (top and middle: voltage trace).</p

Extracellular field at spike initiation.

<p>(A)-(C), Extracellular potential (color coded) and electrical field (arrows) around the simplified neuron (white box and line), at three different times indicated in (D) and (E). (D), Intracellular voltage trace at the soma and AIS distal end. (E), Extracellular potential near the soma and AIS distal end. (F), Extracellular recording near the soma of two cortical neurons (from [<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0175362#pone.0175362.ref013" target="_blank">13</a>]). (G), Extracellular AP recording near the AIS (grey) of a cortical pyramidal cell (from [<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0175362#pone.0175362.ref014" target="_blank">14</a>]).</p