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LIPUS-induced neurogenesis:A potential therapeutic strategy for cognitive dysfunction in traumatic brain injury

Wenzhu Wang, Zihan Li, Yitong Yan, Shuo Wu, Xinyu Yao, Chen Gao, Lanxiang Liu, Yan Yu

Experimental Neurology 2024, 371, 114588 · 10.1016/j.expneurol.2023.114588

rodenttraumatic brain injurybehaviourinvasive electrophysiologyhistology molecularcellular imaging

Abstract

Traumatic brain injury (TBI) precipitates cellular membrane degeneration, phospholipid degradation, neuronal demise, impaired brain electrical activity, and compromised neuroplasticity, ultimately leading to acute and chronic brain dysfunction. Low-intensity pulsed ultrasound (LIPUS) is an emerging brain therapy with the characteristics of non-invasive, high spatial resolution, and high stimulation depth. Herein, we established a controlled cortical impact model to investigate the potential reparative mechanisms of LIPUS in TBI, employing a multi-faceted research methodology encompassing behavioral assessments, immunofluorescence, neuroelectrophysiology, scratch detection of primary cortical neurons, metabolomics and transcriptomics. Our findings demonstrate that LIPUS promotes hippocampal neurogenesis following brain injury, accomplished through the elevation of phosphatidylcholine levels in the hippocampus of TBI mice. Consequently, LIPUS enhances neural electrical activity and augments neural plasticity within the CA1 subregion of the hippocampus, effectively restoring neuronal function and cognitive capabilities in TBI mice. These findings shed light on the promising role of LIPUS in TBI brain rehabilitation, offering new perspectives and theoretical foundations for future studies in this domain.

Abstract via europepmc.

SpeciesC67BL/6 N mice (as stated in text)
Subjectsnot reported animals
Sessions per subjectnot reported
Randomisednot reported
Blindingnot reported
Sham / controlnone
Auditory controlnot reported
Readout timingoffline
Anaesthesianot reported
Readoutsbehaviour, invasive electrophysiology, histology molecular, cellular imagingNeurological Severity Score (NSS); Y-maze spontaneous alternation; hippocampal CA1 local field potential power (delta/theta/alpha/beta/gamma bands); BrdU+/NeuN+ and Dcx immunofluorescence; hippocampal RNA-seq and non-targeted metabolomics; scratch-wound migration and neurite outgrowth in primary cortical neurons
Direction of effectexcitatoryLIPUS increased hippocampal neurogenesis (BrdU+/NeuN+, Dcx), restored CA1 delta/theta LFP power, increased phosphatidylcholine levels, and improved neurological score and Y-maze alternation in TBI mice relative to the untreated TBI model group.
Adverse eventsnot reported

Exposures

Exposure 1: LIPUS treatment following controlled cortical impact TBI

Target: whole brain or unfocused — “unfocused ultrasound transducer applied over the head (effects assessed in hippocampal CA1)
Device: other named manufacturer · Dukon · DK-102T

Pulse timing
Waveformnot reported
Fundamental frequency (kHz)800✓✓
Pulse duration (ms)not reported
Pulse repetition frequency (Hz)not reported
Duty cycle (%)not reported
Sonication duration (s)600✓✓
Pressure and intensity, by domain
Free-field pressure (kPa)not reported
Free-field Isppa (W/cm²)not reported
Free-field Ispta (W/cm²)not reported
In-situ estimatenot reported
In-situ pressure (kPa)not reported
In-situ Isppa (W/cm²)not reported
In-situ Ispta (W/cm²)not reported
Isppa, domain unspecified (W/cm²)3✓✓
Protocol, in the paper’s words

LIPUS delivered via an unfocused transducer with an active area of 3.5 cm^2 for a total stimulation duration of 10 min daily; per the Figure 2 legend, treatment was applied for one week following TBI.

Flags from extraction

  • n_subjectsPaper states a total of 60 mice were purchased for the whole study, but the number specifically exposed to LIPUS (vs sham-operated/TBI-model-only) is only given per-experiment (e.g., n=6, n=3-6, n=3-4 mice per group) and never summed as one LIPUS-exposed total.
  • n_sessions_per_subjectTotal number of treatment days is not stated in the Methods (only '10 min daily'); the 'one-week' duration is stated only in the Figure 2 legend.
  • exposures[0].target.termsMethods do not state where on the head the unfocused transducer was placed or its targeting relative to the craniotomy/hippocampus; effects were assessed in hippocampal CA1 but sonication is described only as unfocused.
  • exposures[0].timing.waveformDevice is described with a pulsed intensity metric (ISPPA) but no PRF or duty cycle is given, so continuous vs pulsed cannot be determined from the text.
  • speciesText states 'C67BL/6 N', which is likely a typographical error for the common strain C57BL/6N; recorded verbatim as written.