PUBLICATION
Engineering brain activity patterns by neuromodulator polytherapy for treatment of disorders
- Authors
- Ghannad-Rezaie, M., Eimon, P.M., Wu, Y., Yanik, M.F.
- ID
- ZDB-PUB-190615-2
- Date
- 2019
- Source
- Nature communications 10: 2620 (Journal)
- Registered Authors
- Yanik, Mehmet Faith
- Keywords
- none
- MeSH Terms
-
- Algorithms
- Animals
- Animals, Genetically Modified
- Behavior, Animal/drug effects
- Brain/cytology
- Brain/diagnostic imaging
- Brain/drug effects
- Brain/physiology
- Brain Mapping/methods
- Disease Models, Animal
- Drug Evaluation, Preclinical/methods
- Drug Synergism
- Drug Therapy, Combination/methods
- Epilepsies, Myoclonic/drug therapy*
- Epilepsies, Myoclonic/genetics
- Epilepsies, Myoclonic/pathology
- High-Throughput Screening Assays/methods
- Humans
- Microscopy, Confocal/methods
- Models, Biological*
- Nerve Net/diagnostic imaging
- Nerve Net/drug effects*
- Nerve Net/physiology
- Nervous System Physiological Phenomena/drug effects*
- Neurons/drug effects
- Neurons/physiology
- Neurotransmitter Agents/pharmacology*
- Neurotransmitter Agents/therapeutic use
- Zebrafish
- PubMed
- 31197165 Full text @ Nat. Commun.
Citation
Ghannad-Rezaie, M., Eimon, P.M., Wu, Y., Yanik, M.F. (2019) Engineering brain activity patterns by neuromodulator polytherapy for treatment of disorders. Nature communications. 10:2620.
Abstract
Conventional drug screens and treatments often ignore the underlying complexity of brain network dysfunctions, resulting in suboptimal outcomes. Here we ask whether we can correct abnormal functional connectivity of the entire brain by identifying and combining multiple neuromodulators that perturb connectivity in complementary ways. Our approach avoids the combinatorial complexity of screening all drug combinations. We develop a high-speed platform capable of imaging more than 15000 neurons in 50ms to map the entire brain functional connectivity in large numbers of vertebrates under many conditions. Screening a panel of drugs in a zebrafish model of human Dravet syndrome, we show that even drugs with related mechanisms of action can modulate functional connectivity in significantly different ways. By clustering connectivity fingerprints, we algorithmically select small subsets of complementary drugs and rapidly identify combinations that are significantly more effective at correcting abnormal networks and reducing spontaneous seizures than monotherapies, while minimizing behavioral side effects. Even at low concentrations, our polytherapy performs superior to individual drugs even at highest tolerated concentrations.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping