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| Open AccessRobust compression and detection of epileptiform patterns in ECoG using a real-time spiking neural network hardware framework
Costa et al. designed a modular spiking neural network in a neuromorphic device with heterogeneous silicon neurons that remotely detects epileptiform discharges and High Frequency Oscillations in intra-operative EEG during epilepsy surgery in real-time.
- Filippo Costa
- , Eline V. Schaft
- & Johannes Sarnthein
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Article
| Open AccessMultisensory flicker modulates widespread brain networks and reduces interictal epileptiform discharges
Repetitive audio-visual stimulation, or sensory flicker, can modulate oscillations in a non-invasive manner. Here the authors demonstrate the potential of flicker in individuals with epilepsy undergoing intracranial seizure monitoring.
- Lou T. Blanpain
- , Eric R. Cole
- & Annabelle C. Singer
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| Open AccessIdentification of four biotypes in temporal lobe epilepsy via machine learning on brain images
Brain imaging-based disease progression modelling is a promising technique for disease stratification. Here the authors characterize distinct ‘trajectories’ of brain atrophy in temporal lobe epilepsy and identify four subtypes with distinct neuroanatomical signatures.
- Yuchao Jiang
- , Wei Li
- & Dongmei An
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Article
| Open AccessIdentification of gene regulatory networks affected across drug-resistant epilepsies
Epilepsy is a chronic, heterogeneous disease with an urgent need for novel therapies. Here, the authors show a systematic comparison of the global molecular signature of refractory epilepsies elucidating the key mechanisms of the disease pathology.
- Liesbeth François
- , Alessia Romagnolo
- & Eleonora Aronica
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Article
| Open AccessTransient targeting of hypothalamic orexin neurons alleviates seizures in a mouse model of epilepsy
Epileptic seizures need better treatments. Here, the authors show that seizure intensity is predicted and controlled by pre-seizure activity of hypothalamic orexin cells, and can be reduced by a hypothalamic deep brain stimulation.
- Han-Tao Li
- , Paulius Viskaitis
- & Denis Burdakov
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| Open AccessAcetylcholine receptor based chemogenetics engineered for neuronal inhibition and seizure control assessed in mice
Traditional systematic anti-seizure treatments alter brain-wide activity and often carry significant side effects. The authors engineered an inhibitory, acetylcholine receptor-based, chemogenetic tool to suppress targeted neurons, enabling control of chronic seizures in mice.
- Quynh-Anh Nguyen
- , Peter M. Klein
- & Ivan Soltesz
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Article
| Open AccessPhox2b-expressing neurons contribute to breathing problems in Kcnq2 loss- and gain-of-function encephalopathy models
Kcnq2 disfunction can cause developmental and epileptic encephalopathy (DEE). Here, authors show loss or gain of Kcnq2 function in Phox2b-expressing neurons disrupts breathing, thus identifying these cells as a likely basis for DEE breathing problems.
- J. Soto-Perez
- , C. M. Cleary
- & D. K. Mulkey
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| Open AccessWake slow waves in focal human epilepsy impact network activity and cognition
Slow waves in sleep are crucial for homeostatic regulation of brain function. Here the authors show similar slow wave activity occurs during wakefulness in people with epilepsy to counter the impact of abnormal, epileptic, brain activity.
- Laurent Sheybani
- , Umesh Vivekananda
- & Matthew C. Walker
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| Open AccessTargeted suppression of mTORC2 reduces seizures across models of epilepsy
A loss of neuronal network resilience results in epilepsy. In this study, the authors show that inhibition of mTORC2 suppresses seizures in animal models with multiple aetiologies, thus enhancing neuronal resilience to the pathological hypersynchrony associated with epilepsy.
- James Okoh
- , Jacqunae Mays
- & Mauro Costa-Mattioli
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Article
| Open AccessDaily rhythm in cortical chloride homeostasis underpins functional changes in visual cortex excitability
Ionic levels in neurons provide the potential energy for all neuronal communication. Here the. authors show a very large modulation of [Cl-]i neocortical pyramidal cells, from day to night, with marked effects on cortical excitability and processing.
- Enrico Pracucci
- , Robert T. Graham
- & Gian-Michele Ratto
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| Open AccessDevelopmental atlas of phase-amplitude coupling between physiologic high-frequency oscillations and slow waves
It remains unclear how cortical high-frequency oscillations (HFOs) and their relation with slow waves change with age. Here, the authors found that while HFO rate widely decreases over time, its coupling with slow waves strengthens in the occipital lobe during childhood.
- Kazuki Sakakura
- , Naoto Kuroda
- & Eishi Asano
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| Open AccessIctogenesis proceeds through discrete phases in hippocampal CA1 seizures in mice
Predicting seizure onsets may allow for seizure prevention in patients. Here, authors show two distinct phases that always preceded temporal lobe seizures in mice, with activity confined within these two phases failing to progress into a seizure.
- John-Sebastian Mueller
- , Fabio C. Tescarollo
- & Hai Sun
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| Open AccessReversal of cell, circuit and seizure phenotypes in a mouse model of DNM1 epileptic encephalopathy
One third of all epilepsies are treatment-resistant. Here, the authors show in a genetic model of epilepsy that a repurposed drug can correct cell defects, brain circuits and seizure-like events by accelerating endocytosis.
- Katherine Bonnycastle
- , Katharine L. Dobson
- & Michael A. Cousin
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| Open AccessMechanisms underlying pathological cortical bursts during metabolic depletion
Disruption to the brain’s oxygen supply triggers pathological dynamics and brain injuries. Here, the authors develop a model of coupled metabolic-neuronal activity that generates burst suppression patterns similar to those of infants after birth asphyxia.
- Shrey Dutta
- , Kartik K. Iyer
- & James A. Roberts
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Article
| Open AccessGenome-wide identification and phenotypic characterization of seizure-associated copy number variations in 741,075 individuals
Here, the authors perform a meta-analysis in 26,699 people with seizures and 492,324 controls to identify 25 genome-wide significant copy-number variants. The discovered loci point to known disease genes and associations with clinical annotations.
- Ludovica Montanucci
- , David Lewis-Smith
- & Dennis Lal
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Article
| Open AccessKv7/KCNQ potassium channels in cortical hyperexcitability and juvenile seizure-related death in Ank2-mutant mice
Seizures can occur in autism spectrum disorders (ASD). Here, the authors report that mice lacking the ASD related Ank2 gene show abnormal behaviours, and juvenile seizure related death, through impaired Kv7 potassium channel function.
- Hyoseon Oh
- , Suho Lee
- & Eunjoon Kim
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Article
| Open AccessAberrant survival of hippocampal Cajal-Retzius cells leads to memory deficits, gamma rhythmopathies and susceptibility to seizures in adult mice
Cajal-Retzius neurons number drastically decreases during postnatal life. Here, authors show that their programmed death is required for the construction of functional hippocampal circuits and memory with aberrant survival leading to gamma rhythmopathies and susceptibility to seizures.
- Martina Riva
- , Stéphanie Moriceau
- & Alessandra Pierani
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Article
| Open AccessChemogenetic attenuation of cortical seizures in nonhuman primates
Pharmacological and surgical treatments of epilepsy can have unsatisfactory outcomes, so a more targeted and on-demand approach is desirable. Here, the authors demonstrate the usage of inhibitory chemogenetics in male nonhuman primates to attenuate the magnitude and spread of cortical seizures and subsequent body convulsions.
- Naohisa Miyakawa
- , Yuji Nagai
- & Takafumi Minamimoto
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Article
| Open AccessDecreased but diverse activity of cortical and thalamic neurons in consciousness-impairing rodent absence seizures
Absence seizures impair consciousness by an unknown neuronal mechanism. Here, the authors find that a rat absence seizure model’s behavior and hemodynamics recapitulate previously reported characteristics of human absence seizures, and uncover four distinct patterns of neuronal activity in cortex and thalamus during consciousness-impairing seizures.
- Cian McCafferty
- , Benjamin F. Gruenbaum
- & Hal Blumenfeld
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| Open AccessClosed-loop direct control of seizure focus in a rodent model of temporal lobe epilepsy via localized electric fields applied sequentially
Direct stimulation of the focus of a seizure may have potential for the treatment of epilepsy. Here the authors demonstrate in a rat model a sequential narrow-field stimulation method for terminating seizures.
- Wonok Kang
- , Chanyang Ju
- & Sung-Min Park
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| Open AccessActivated astrocytes attenuate neocortical seizures in rodent models through driving Na+-K+-ATPase
Neocortical epilepsy is resistant to current treatments. Zhao et al. report that optogenetic stimulation of astrocytes effectively attenuates seizures via driving Na+-K+-ATPase, indicating a potential treatment strategy for intractable epilepsy.
- Junli Zhao
- , Jinyi Sun
- & Yi Wang
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Article
| Open AccessMolecular architecture of the glycogen- committed PP1/PTG holoenzyme
Glycogen metabolism is tightly regulated. Here the authors describe the 3D structure of the PP1/PTG protein complex, which plays a prominent role in the activation of glycogen synthesis and in the pathogenesis of Lafora disease, the most severe form of pediatric progressive epilepsy.
- Marta Stefania Semrau
- , Gabriele Giachin
- & Graziano Lolli
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Article
| Open AccessDiscrete subicular circuits control generalization of hippocampal seizures
The subiculum is known to contribute to seizures in epilepsy. Here the authors investigate the circuit mechanism by which the subiculum contributes to initiation and propagation of hippocampal seizures in a mouse model.
- Fan Fei
- , Xia Wang
- & Yi Wang
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| Open AccessMapping effective connectivity of human amygdala subdivisions with intracranial stimulation
The amygdala is known to be engaged in emotional and autonomic function, yet the detailed functional connectivity of the human amygdala remains unclear. Here, the authors examine effective connectivity in the amygdala of patients with epilepsy using direct focal electrical stimulation.
- Masahiro Sawada
- , Ralph Adolphs
- & Hiroyuki Oya
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Article
| Open AccessRaptor downregulation rescues neuronal phenotypes in mouse models of Tuberous Sclerosis Complex
Karalis et al show that genetic reduction of the mTORC1 component Raptor improves multiple phenotypes in mouse models of TSC. Their findings suggest that Raptor could be a potential therapeutic target for treating the neurological aspects of TSC.
- Vasiliki Karalis
- , Franklin Caval-Holme
- & Helen S. Bateup
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Article
| Open AccessStructural network alterations in focal and generalized epilepsy assessed in a worldwide ENIGMA study follow axes of epilepsy risk gene expression
Epilepsy is a brain network disorder with associated genetic risk factors. Here, the authors show that spatial patterns of transcriptomic vulnerability co-vary with structural brain network alterations in focal and generalized epilepsy.
- Sara Larivière
- , Jessica Royer
- & Boris C. Bernhardt
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| Open AccessTiming is everything: structural insights into the disease-linked Kv3 channels controlling fast action-potential firing in the brain
Kv3 channels enable neurons to fire at very high frequencies (>100 Hz) which is fundamental to brain development and our ability to make sense of the world at large. Cryo-EM and structure-function studies by Chi et al. now uncover Kv3 channel gating mechanisms and support new precision medicine approaches for CNS diseases.
- Martin J. Gunthorpe
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| Open AccessCryo-EM structure of the human Kv3.1 channel reveals gating control by the cytoplasmic T1 domain
Here, Chi et al. report cryo-EM structures of the human Kv3.1a channel, revealing a unique arrangement of the cytoplasmic T1 domain, which allows the interactions with the C-terminal axonal targeting motif and key components of the gating machinery. These findings provide insights into the functional relevance of previously unknown interdomain interactions in Kv3 channels and may guide the design of new pharmaceutical drugs.
- Gamma Chi
- , Qiansheng Liang
- & Katharina L. Dürr
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| Open AccessBrain-wide reconstruction of inhibitory circuits after traumatic brain injury
Traumatic brain injury is often followed by changes in neural connectivity. This study describes how inputs to a population of inhibitory neurons change to favor local over long-range connectivity in a mouse model of traumatic brain injury.
- Jan C. Frankowski
- , Alexa Tierno
- & Robert F. Hunt
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Article
| Open AccessMicrovascular stabilization via blood-brain barrier regulation prevents seizure activity
The mechanisms underlying epilepsy development are not well understood. Here the authors show that loss of a key component of the so called blood-brain barrier drives seizures in mice and is also lost in humans with treatment resistant epilepsy
- Chris Greene
- , Nicole Hanley
- & Matthew Campbell
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| Open AccessGain-of-function and loss-of-function GABRB3 variants lead to distinct clinical phenotypes in patients with developmental and epileptic encephalopathies
Genetic variants of γ-aminobutyric acid (GABAA) receptors are associated with early onset epilepsies. Here, the authors show that functional loss or gain-of-function defines clinical outcomes, with gain-of-function variants unexpectedly more severe.
- Nathan L. Absalom
- , Vivian W. Y. Liao
- & Philip K. Ahring
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Article
| Open AccessVirtual intracranial EEG signals reconstructed from MEG with potential for epilepsy surgery
Dynamic network models offer insight into brain networks affected by epileptic seizures. Here the authors derive ViEEG (virtual intracranial EEG) from non-invasive MEG recordings that show brain areas involved in seizure generation in patients with epilepsy.
- Miao Cao
- , Daniel Galvis
- & Mark J. Cook
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Article
| Open AccessScn1a gene reactivation after symptom onset rescues pathological phenotypes in a mouse model of Dravet syndrome
Dravet syndrome is a devastating epileptic encephalopathy caused by Scn1a gene haploinsufficiency. Exploiting a novel knock-in mouse model, here the authors show that restoring Scn1a expression after symptom onset is sufficient to rescue main phenotypic manifestations of the syndrome.
- Nicholas Valassina
- , Simone Brusco
- & Gaia Colasante
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Article
| Open AccessDeficiency of autism risk factor ASH1L in prefrontal cortex induces epigenetic aberrations and seizures
ASH1L haploinsufficiency is strongly linked to autism, despite the unknown mechanism. Here, the authors show that ASH1L deficiency in prefrontal cortex causes the downregulation of synaptic genes, leading to seizures, which is rescued by chemogenetic and pharmacological restoration of excitation/inhibition balance.
- Luye Qin
- , Jamal B. Williams
- & Zhen Yan
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Article
| Open AccessReverse optogenetics of G protein signaling by zebrafish non-visual opsin Opn7b for synchronization of neuronal networks
Microbial rhodopsins can be used to control action potentials, while animal opsins can be used to control intracellular signaling pathways. The authors identify Opn7b as constitutively active Gi/o coupled receptor that can be deactivated by light and used to modulate neuronal activity.
- Raziye Karapinar
- , Jan Claudius Schwitalla
- & Stefan Herlitze
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Article
| Open AccessSpreading depression as an innate antiseizure mechanism
Spreading depression is a prolonged depolarization in the CNS associated with several neurological diseases. Here the authors demonstrate a reciprocal relationship between spreading depression and seizures in an animal model.
- Isra Tamim
- , David Y. Chung
- & Cenk Ayata
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Article
| Open AccessA critical period of neuronal activity results in aberrant neurogenesis rewiring hippocampal circuitry in a mouse model of epilepsy
Adult-born granule cells integrate in hippocampal circuitry and contribute to hippocampal function. Here, the authors show that a critical period of neuronal activity regulates aberrant neurogenesis to rewire hippocampal circuitry and drive seizures in a mouse model of epilepsy.
- Zane R. Lybrand
- , Sonal Goswami
- & Jenny Hsieh
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| Open AccessDysregulation of REV-ERBα impairs GABAergic function and promotes epileptic seizures in preclinical models
Rev-erbα is a known regulator of the circadian clock. Here, the authors show that Rev-erbα is also a regulator of synaptic dysfunction in preclinical models of epilepsy.
- Tianpeng Zhang
- , Fangjun Yu
- & Baojian Wu
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Article
| Open AccessHippocampal adult-born granule cells drive network activity in a mouse model of chronic temporal lobe epilepsy
The dentate gyrus is involved in synchronous discharges and seizures, but its microcircuit functional organization in TLE is unclear. Here, the authors show that interictal discharges recruit specific granule cell ensembles dominated by adult-born immature neurons.
- F. T. Sparks
- , Z. Liao
- & A. Losonczy
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Article
| Open AccessIdentification of epilepsy-associated neuronal subtypes and gene expression underlying epileptogenesis
The pathophysiology of epilepsy is unclear. Here, the authors present single-nuclei transcriptomic profiling of human temporal lobe epilepsy from patients. They identified epilepsy-associated neuronal subtypes, and a panel of dysregulated genes, predicting neuronal circuits contributing to epilepsy.
- Ulrich Pfisterer
- , Viktor Petukhov
- & Konstantin Khodosevich
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Article
| Open AccessD-serine mitigates cell loss associated with temporal lobe epilepsy
Temporal lobe epilepsy (TLE) can be unresponsive to treatment. Here, the authors show that treatment with D-Serine mitigates TLE and acts on neurons and glia, attenuating neuronal loss and reducing astro- and microgliosis in rodents.
- Stephen Beesley
- , Thomas Sullenberger
- & Sanjay S. Kumar
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Article
| Open AccessRobust dynamic community detection with applications to human brain functional networks
Understanding how brain networks evolve in time remains a challenge, with the potential for significant impact to human health and disease. Here, the authors introduce a new methodology to track dynamic functional networks that is robust to edge noise, and yields well-defined spatiotemporal communities that span forward and backwards in time.
- L.-E. Martinet
- , M. A. Kramer
- & E. D. Kolaczyk
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Article
| Open AccessCritical slowing down as a biomarker for seizure susceptibility
Critical slowing (associated with increased variance and autocorrelation) can precede critical state transitions. Here, the authors show critical slowing can be used as a marker in seizure forecasting algorithms.
- Matias I. Maturana
- , Christian Meisel
- & Dean R. Freestone
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Article
| Open AccessNoninvasive electromagnetic source imaging of spatiotemporally distributed epileptogenic brain sources
Noninvasive electromagnetic measurements are utilized effectively to estimate large scale dynamic brain networks. Sohrabpour et al. propose a novel electrophysiological source imaging approach to estimate the location and size of epileptogenic tissues in patients with epilepsy.
- Abbas Sohrabpour
- , Zhengxiang Cai
- & Bin He
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Article
| Open AccessA disinhibitory nigra-parafascicular pathway amplifies seizure in temporal lobe epilepsy
The neural circuits through which the substantia nigra pars reticulata (SNr) exerts its role in epilepsy control are not known. Here the authors reveal that a long-range SNr-parafascicular nucleus disinhibitory circuit participates in regulating seizures in temporal lobe epilepsy and inhibition of this circuit can alleviate severity of epileptic seizures.
- Bin Chen
- , Cenglin Xu
- & Zhong Chen
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Article
| Open AccessTransplanted interneurons improve memory precision after traumatic brain injury
The brain’s capacity to produce new neurons in response to injury is limited. Here, the authors transplant GABAergic progenitor cells and show that they synaptically incorporate into the damaged hippocampus and rescue memory problems and post-traumatic seizures caused by traumatic brain injury.
- Bingyao Zhu
- , Jisu Eom
- & Robert F. Hunt
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Article
| Open AccessIntronic ATTTC repeat expansions in STARD7 in familial adult myoclonic epilepsy linked to chromosome 2
Familial cortical myoclonic tremor (FAME) has so far been mapped to regions on chromosome 2, 3, 5 and 8 and pentameric repeat expansions in SAMD12 were identified as cause of FAME1. Here, Corbett et al. identify ATTTT/ATTTC repeat expansions in intron 1 of STARD7 in individuals with FAME2.”
- Mark A. Corbett
- , Thessa Kroes
- & Jozef Gecz
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Article
| Open AccessUnstable TTTTA/TTTCA expansions in MARCH6 are associated with Familial Adult Myoclonic Epilepsy type 3
Familial cortical myoclonic tremor with epilepsy (FAME) is a slowly progressing cortical tremor mapping to various genomic loci, including intronic expansions in SAMD12 for FAME1. Here, Florian et al. describe mixed intronic TTTTA/TTTCA expansions of various lengths in the first intron of MARCH6 as a cause of FAME3.
- Rahel T. Florian
- , Florian Kraft
- & Christel Depienne
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Article
| Open AccessEngineering brain activity patterns by neuromodulator polytherapy for treatment of disorders
Brain disorders are associated with network dysfunctions that are not addressed by conventional drug screens. Here, the authors use high-throughput functional imaging of brain activity in zebrafish larvae to study the effects of individual drugs on network connectivity and demonstrate an algorithm that predicts the most effective drug combinations to normalize both the activity patterns and the animal behavior.
- Mostafa Ghannad-Rezaie
- , Peter M. Eimon
- & Mehmet Fatih Yanik