title: Prolonged stimulation with low-intensity ultrasound induces delayed increases in spontaneous hippocampal culture spiking activity.
abstract: Ultrasound is a promising neural stimulation modality, but an incomplete understanding of its range and mechanism of effect limits its therapeutic application. We investigated the modulation of spontaneous hippocampal spike activity by ultrasound at a lower acoustic intensity and longer time scale than has been previously attempted, hypothesizing that spiking would change conditionally upon the availability of glutamate receptors. Using a 60-channel multielectrode array (MEA), we measured spontaneous spiking across organotypic rat hippocampal slice cultures (N = 28) for 3 min each before, during, and after stimulation with low-intensity unfocused pulsed or sham ultrasound (spatial-peak pulse average intensity 780 μW/cm2) preperfused with artificial cerebrospinal fluid, 300 μM kynurenic acid (KA), or 0.5 μM tetrodotoxin (TTX) at 3 ml/min. Spike rates were normalized and compared across stimulation type and period, subregion, threshold level, and/or perfusion condition using repeated-measures ANOVA and generalized linear mixed models. Normalized 3-min spike counts for large but not midsized, small, or total spikes increased after but not during ultrasound relative to sham stimulation. This result was recapitulated in subregions CA1 and dentate gyrus and replicated in a separate experiment for all spike size groups in slices pretreated with aCSF but not KA or TTX. Increases in normalized 18-sec total, midsized, and large spike counts peaked predominantly 1.5 min following ultrasound stimulation. Our low-intensity ultrasound setup exerted delayed glutamate receptor-dependent, amplitude- and possibly region-specific influences on spontaneous spike rates across the hippocampus, expanding the range of known parameters at which ultrasound may be used for neural activity modulation. © 2016 Wiley Periodicals, Inc.
authors.affiliation: Department of East-West Medical Science, Graduate School of East-West Medical Science, Kyung Hee University, Yongin, Republic of Korea.
authors.forename: Hyun-Bum
authors.initials: HB
authors.lastname: Kim
authors.affiliation: Department of East-West Medicine, Graduate School of East-West Medical Science, Kyung Hee University, Yongin, Republic of Korea.
authors.forename: Kelley M
authors.initials: KM
authors.lastname: Swanberg
authors.affiliation: Department of Biomedical Engineering, Kyung Hee University, Yongin, Republic of Korea.
authors.forename: Hee-Sok
authors.initials: HS
authors.lastname: Han
authors.affiliation: Biometrics Team, CTO Future IT Laboratory, LG Electronics Umyeon R&D Campus, Seocho-gu, Republic of Korea.
authors.forename: Jung-Chae
authors.initials: JC
authors.lastname: Kim
authors.affiliation: Division of Polar Logistics, Korea Polar Research Institute, Incheon, Republic of Korea.
authors.forename: Jun-Woo
authors.initials: JW
authors.lastname: Kim
authors.affiliation: School of Electrical Engineering, Hanyang University, Ansan, Republic of Korea.
authors.forename: Sungon
authors.initials: S
authors.lastname: Lee
authors.affiliation: Center for Neuroscience and Functional Connectomics, Brain Science Institute, Korea Institute of Science and Technology, Seoul, Republic of Korea.
authors.forename: C Justin
authors.initials: CJ
authors.lastname: Lee
authors.affiliation: Department of East-West Medicine, Graduate School of East-West Medical Science, Kyung Hee University, Yongin, Republic of Korea.
authors.forename: Sungho
authors.initials: S
authors.lastname: Maeng
authors.affiliation: Department of Biomedical Engineering, Kyung Hee University, Yongin, Republic of Korea.
authors.forename: Tae-Seong
authors.initials: TS
authors.lastname: Kim
authors.affiliation: Department of East-West Medicine, Graduate School of East-West Medical Science, Kyung Hee University, Yongin, Republic of Korea.
authors.forename: Ji-Ho
authors.initials: JH
authors.lastname: Park
mesh_terms: D000200:Action Potentials / Q000187:drug effects / Q000502:physiology*; D000818:Animals; D000831:Animals, Newborn; D004307:Dose-Response Relationship, Radiation; D018683:Excitatory Amino Acid Agents / Q000494:pharmacology; D006624:Hippocampus / Q000166:cytology*; D066298:In Vitro Techniques; D008839:Microelectrodes; D009474:Neurons / Q000187:drug effects / Q000502:physiology*; D009924:Organ Culture Techniques; D051381:Rats; D017470:Receptors, Glutamate / Q000378:metabolism; D026941:Sodium Channel Blockers / Q000494:pharmacology; D013696:Temperature; D013779:Tetrodotoxin / Q000494:pharmacology; D013997:Time Factors; D014465:Ultrasonics / Q000379:methods*
chemical_list: D018683:Excitatory Amino Acid Agents; D017470:Receptors, Glutamate; D026941:Sodium Channel Blockers; D013779:Tetrodotoxin
keywords: electrophysiology; hippocampus; multielectrode array; spike detection; spontaneous activity; unfocused pulsed ultrasound