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Table 1 Overview of preclinical transcranial magnetic stimulation (TMS) studies

From: Electrical stimulation methods and protocols for the treatment of traumatic brain injury: a critical review of preclinical research

References

Main focus

Impairment

Animal model

Stimulation protocol

Stimulation time frame

Yoon YS et al. [138]

Effects of rTMS and EES on TBI

Motor function

51 male Sprague–Dawley rats (21 died from TBI), Marmarou’s weight drop (450 g from 1 m, diffuse, mild TBI, medial impact), awake and immobilized during TMS

90% of max. device output, 10 Hz, 3 s stim and 6 s pause, for 10 min

Twice per day, day 1–14 post-injury

Yoon KJ et al. [152]

rTMS for behavioral recovery

Motor function, brain metabolism, cell death

20 adult male Sprague–Dawley rats, lateral FPI (3.5–4 atm pressure, severe TBI), awake and immobilized during TMS

80% of RMT, 10 Hz, 15 trains of 2 s, 1 s inter-train interval

10 sessions over 2 weeks, beginning on 4th day post-injury

Lu H et al. [153]

rTMS for pediatric TBI

Motor function

26 juvenile Sprague–Dawley rats, CCI over left primary somatosensory cortex (severity unclear), TMS under 2% isoflurane

25% of max. device output, 20 Hz, 9 trains of 100 pulses, 55 s inter-train interval, for 9 min

Twice per week, starting 9 post-injury, for 4 weeks

Lu X et al. [156]

rTMS for neuromodulation and neurogenesis

Loss of brain parenchyma, reduced brain metabolism, neurological impairment

38 adult Sprague–Dawley rats, Feeney’s weight drop (moderate TBI, right hemisphere), awake and immobilized during TMS

60% of max. device output, 5 Hz, 36 trains of 25 pulses, 15 s inter-train interval, 900 pulses/day, figure-of-eight coil

From 2 days post-injury until 1 day before sacrificed (7/14/28 days after TBI)

Verdugo-Diaz et al. [157]

Treatment with intermediate frequency rTMS

Mortality, general behavioral changes

97 male Wistar rats, Marmarou’s weight drop (motor cortex, severe TBI), awake and immobilized during TMS (animals trained for immobilization)

50% of max. device output (120% of RMT), 2 Hz, 15 min per day, figure-of-eight coil

Starting 1 day post-injury, for 7 consecutive days

Shin et al. [154]

Therapy with rTMS and environmental enrichment

motor function

97 male Sprague–Dawley rats, CCI (4 m/s, moderate TBI, right hemisphere), MEP assessment under isoflurane, electrophysiological recordings under urethane, fMRI under sedation, rTMS under 2% isoflurane

10 Hz, 7 cycles of 4 s, 26 s between cycles, figure-of-eight coil, (stim. intensity unclear)

Starting 1 day post-injury, daily, for 6 days

Sekar et al. [155]

Low-field magnetic stimulation (LFMS, rTMS variant) treatment after TBI

Cognitive and motor functions

48 male C57BL/6 mice, weight drop (60 g from 1 m, closed head trauma, repetitive TBI, once daily for 3 consecutive days, severity unclear), awake and immobilized during TMS

40 Hz, 6 ms pulses, 80 trains of 2 s, 8 s pause, magn. field changes between uniform and linear gradient every 2 min, for 20 min

Once per day, following recovery from rightening reflex after TBI, for 3 days and once on day 4

Qian et al. [158]

Investigation of cellular mechanisms caused by rTMS treatment

General overview

45 male Sprague–Dawley rats, Feeney's weight drop (20 g × 30 cm impact force, moderate TBI), awake and immobilized during rTMS

30% of motor threshold, 40 Hz, 40 trains of 1 s, in 15 s intervals

Starting 4 days post-injury, once daily, for 2 weeks, five times per week

References

Stimulus location

Tests

Acquired parameters

Persistent effects

Main findings

Yoon YS et al. [138]

Center of the coil placed above injury site

Limb placement test, SPRT, RRT, immunohistochemistry

Limb placement changes, SPRT success rate, RRT performance time rate, c-Fos expression

Not investigated

TMS and EES resulted in significant improvement in SPRT and accelerated improvement in RRT, with particularly robust effects of EES

Yoon KJ et al. [152]

Area with largest MEP amplitude at the weaker biceps femoris after suprathreshold stim., side not stated (probably ipsilateral)

Rotarod and beam balance tests, brain MRI, magnetic resonance spectroscopy, western blot, immunohistochemistry

Motor coordination, balance ability, intact and lesioned hemispheric volume, brain metabolism, apoptotic signaling

Not investigated

rTMS did not have beneficial effects on motor recovery, enhancement of anti-apoptotic response in perilesional area

Lu H et al. [153]

Contralateral primary sensory region

Extracellular electrophysiological recordings, fMRI, open field test, forelimb and hindlimb reflex test, immunostaining

CaMKII expression (LTP), MUA responses, LFP magnitude, evoked fMRI cortical responses, behavioral tests (physiology and hyperactivity)

Long-lasting increase of excitability in non-injured cortex after 4 weeks of TMS therapy

Significant increases in evoked-fMRI cortical response, evoked synaptic activity, evoked neuronal firing and expression of neuroplasticity markers, decreased hyperactivity in behavioral tests

Lu X et al. [156]

Whole brain influenced by magnetic field (max. stim. over the center of the brain)

Behavioral tests (mNSS evaluation), hematoxylin and eosin staining, immunohistochemistry, PET examination

Behavioral recovery, relative brain parenchyma loss, cell proliferation and neurogenesis, neuron protection, cell apoptosis, metabolic activity

Not investigated

High-frequency rTMS may decrease mortality, mature neuron loss, apoptosis, improve behavioral recovery, cell proliferation and neurogenesis in the SVZ, metabolic activity in the contralateral site was not affected

Verdugo-Diaz et al. [157]

Injury site

Hunter’s 21-point behavioral-neurological scale, histology

Body weight, food intake, post-TBI bleeding and mortality, neurobehavioral score, cellular morphological changes, disruptions in hippocampal tissue architecture

Not investigated

Movement restriction prevents damage caused by TBI, intermediate-frequency rTMS slightly promotes behavioral and histologic recovery after TBI

Shin et al. [154]

Midpoint between lambda and bregma, medial located

Beam walk and challenge ladder tests, electrophysiology, evoked LFP, MEP assessment, fMRI in the contralateral cortex

Beam traversal latency, mean speed and slips from ladder, MEP amplitude, LFP magnitude, fMRI activation maps

Combination of EE and TMS led to benefits in sensorimotor function lasting up to 6 weeks

Combined therapy with TMS and EE after TBI leads to functional improvements, possibly via cortical excitability and reorganization, long-term effects probably due to EE rather than TMS

Sekar et al. [155]

Cortical and subcortical areas

RRT, open field test, novel location recognition test, immunohistochemistry, western blot

Time on rotarod, locomotor activity, cognitive function, PrPc level in plasma, GFAP, NeuN and PrPc protein levels, CLOCK and CRY2 levels

Not investigated

LFMS treatment improved motor and cognitive function in mice after repetitive TBI, restored PrPc level, decreased proteins associated with circadian rhythm, decreased GFAP levels, increased NeuN levels, and showed neuroprotective effects

Qian et al. [158]

Coil placed above ipsilateral side, close to the scalp

mNSS assessment, TEM, immunohistochemistry, western blot, RT-PCR detection

Injury severity, synaptic ultrastructure, protein expression (BDNF, TrkB, NMDAR1, P-CREB, SYN), mRNA expression levels

Not investigated

rTMS may promote recovery of neurological functions in TBI rats through enhanced SYN protein levels to promote synaptic reconstruction and affecting the expression of proteins related to LTP occurrence