Gentagne Transcranial magnetisk stimulation til den ensidige halvkugle af Rat Brain
Summary
We applied repetitive transcranial magnetic stimulation (rTMS) to the unilateral hemisphere of rat brain, by placing a 25-mm figure-8 coil 1 cm lateral to the vertex on the biauricular line and angulating the coil by 45°. An in-house water cooling system was used for rTMS for more than 20 min.
Abstract
Previous rodent models of repetitive transcranial magnetic stimulation (rTMS) adopted whole-brain stimulation instead of unilateral hemispheric rTMS, which is unlike the protocols used for human subjects. We report a successful application of rTMS to the unilateral hemisphere of rat brain. The rTMS was delivered with a low-frequency (1 Hz), high-frequency (20 Hz), or sham stimulation protocol to one side of the brain by using a small 25-mm figure-8 coil. We placed the center of the coil 1 cm lateral to the vertex on the biauricular line and angulated the coil 45° to the ground to minimize a potential direct effect of rTMS on the contralateral cortex. We also used an in-house water cooling system to enable repetitive magnetic stimulation for more than 20 min, even at a 20-Hz stimulation frequency. Increases in the transcriptions of immediate early genes (Arc, Junb, and Egr2) were greater after rTMS than after sham stimulation. After 5 consecutive days of 20-min 1-Hz rTMS, bdnf mRNA expression was significantly higher in stimulated cortex than in contralateral side. The model presented herein will elucidate the molecular mechanisms of rTMS by allowing analysis of the inter-hemispheric difference in its effect.
Introduction
Gentagne transkraniel magnetisk stimulation (rTMS), et værktøj til ikke-invasiv brain stimulation og Neuromodulation, er blevet anvendt i behandlingen af forskellige tilstande, såsom central smerte 1,2, depression 3, migræne 4, og endda slagtilfælde 5-7. Hurtigt skiftende elektrisk strøm gennem spolerne på hovedet inducerer et elektrisk felt på hjernebarken og en resulterende neuronal aktivering. Den ophidselse af hjernebarken kan moduleres af rTMS, der kan vare i mere end 30 minutter efter stimuleringen er afsluttet.
Foreslåede mekanismer for rTMS eftervirkning indbefatter langtidspotensering / depression-lignende effekt 8, forbigående ændring i ionisk ligevægt 9, og metaboliske ændringer 10. Desuden Di Lazzaro et al. antyder, at intermitterende theta-burst stimulation påvirker de excitatoriske synaptiske input til pyramideformet tract neuroner, både i den stimuleredeog den kontralaterale hemisfære 11.
Væsentlige begrænsninger har dog forhindret forskere fra oversætte på bænk beviser til kliniske situationer. Først i tidligere dyreforsøg blev rTMS anvendt til hel-hjerne stimulation 12. Hel-brain stimulation er helt forskellig fra de protokoller, der anvendes i humane undersøgelser 9. Det andet problem er relateret til stimuleringen varighed. Dette er i det mindste delvis skyldes, at et effektivt kølesystem var utilgængelig for små spoler i fortiden.
I de senere år er skelsættende artikler publiceret foreslår måder til at overvinde disse vanskeligheder i den rTMS eksperiment på den lille dyrehjerne. Ved disse dyremodeller, blev det afsløret, at rottehjernen viser også lignende corticale excitabilitet ændringer som i human som reaktion på lavfrekvente rTMS 13. Vigtigere, cellulære og molekylære mekanismer i rTMS i stigende being undersøgt med dyremodeller for rTMS. Et eksempel herpå er, at en særskilt type hæmmende interneuron er kendt for at være mest følsomme over for intermitterende theta burst stimulation 14. Gnavermodeller af rTMS dermed giver nye muligheder for at udforske meget-søgte spørgsmål om de molekylære fundament for rTMS-inducerede ændringer. Hvis der kan bruges små dyremodeller af rTMS i flere laboratorier, kan det i høj grad fremskynde og styrke forskningen på dette område.
Vi beskriver nu, hvordan man anvender rTMS til den ensidige halvkugle af rotte hjerne, en udvidelse af det tidligere arbejde 15. Stimulation-fremkaldte ændringer blev vurderet ved hjælp af mikro-positronemissionstomografi (PET) og mRNA microarrays at studere rTMS-inducerede ændringer i den stimulerede hjernebarken.
Protocol
Representative Results
Discussion
Det primære formål med denne undersøgelse var at indføre en dyremodel af ensidige rTMS. Selvom ensidig stimulation er en af de mest grundlæggende karakteristika ved menneskelige rTMS forskning, har mange undersøgelser ikke vedtaget det i små dyr. Men Rotenberg et al. 15 indspillede kontralaterale MEP'er med stimulering af 100% MT ved hjælp af en figur-8 spole med en udvendig lap diameter på 20 mm, mens stimulation med 112,5% og 133,3% MT produceret ipsilaterale samt kontralat…
Disclosures
The authors have nothing to disclose.
Acknowledgements
This work was supported by the Korea Research Foundation Grant funded by the Korean Government (KRF-2008-313-E00458). The authors thank Jin-Joo Lee for the technical assistance.
Materials
| Homeothermic blanket with a rectal probe | Harvard apparatus | 507222F | |
| Isoflurane (Forane sol.) | Choongwae | ||
| Propofol (Provive Inj. 1% 20ml) | Claris Lifesciences | ||
| Repetitive magnetic stimulator (Magstim Rapid2) | Magstim Company Ltd | ||
| 25 mm figure-of-8 coil | Magstim Company Ltd | 1165-00 | |
| PET-CT | GE Healthcare | ||
| QIAzol Lysis Reagent | Qiagen | (US Patent No. 5,346,994) | |
| RNeasy Lipid Tissue Mini Kit | Qiagen | 74804 | |
| RNeasy Mini Spin Columns | Qiagen | (Mat No. 1011708) | |
| Agilent 2100 Bioanalyzer | Agilent Technologies | ||
| Ambion Illumina RNA amplification kit | Ambion | ||
| Nanodrop Spectrophotometer | NanoDrop | ND-1000 | |
| Illumina RatRef-12 Expression BeadChip | Illumina, Inc. | ||
| Amersham fluorolink streptavidin-Cy3 | GE Healthcare Bio-Sciences |
References
- Lefaucheur, J. P., et al. Neurogenic pain relief by repetitive transcranial magnetic cortical stimulation depends on the origin and the site of pain. J Neurol Neurosurg Psychiatry. 75 (4), 612-616 (2004).
- Hirayama, A., et al. Reduction of intractable deafferentation pain by navigation-guided repetitive transcranial magnetic stimulation of the primary motor cortex. Pain. 122 (1-2), 22-27 (2006).
- O’Reardon, J. P., et al. Efficacy and safety of transcranial magnetic stimulation in the acute treatment of major depression: a multisite randomized controlled trial. Biol Psychiatry. 62 (11), 1208-1216 (2007).
- Brighina, F., et al. Facilitatory effects of 1 Hz rTMS in motor cortex of patients affected by migraine with aura. Exp Brain Res. 161 (1), 34-38 (2005).
- Lefaucheur, J. P. Stroke recovery can be enhanced by using repetitive transcranial magnetic stimulation (rTMS). Neurophysiol Clin. 36 (3), 105-115 (2006).
- Khedr, E. M., Ahmed, M. A., Fathy, N., Rothwell, J. C. Therapeutic trial of repetitive transcranial magnetic stimulation after acute ischemic stroke. Neurology. 65 (3), 466-468 (2005).
- Fregni, F., et al. A sham-controlled trial of a 5-day course of repetitive transcranial magnetic stimulation of the unaffected hemisphere in stroke patients. Stroke. 37 (8), 2115-2122 (2006).
- Pascual-Leone, A., Valls-Sole, J., Wassermann, E. M., Hallett, M. Responses to rapid-rate transcranial magnetic stimulation of the human motor cortex. Brain. 117 (4), 847-858 (1994).
- Ridding, M. C., Rothwell, J. C. Is there a future for therapeutic use of transcranial magnetic stimulation). Nat Rev Neurosci. 8 (7), 559-567 (2007).
- Valero-Cabre, A., Payne, B. R., Pascual-Leone, A. Opposite impact on 14C-2-deoxyglucose brain metabolism following patterns of high and low frequency repetitive transcranial magnetic stimulation in the posterior parietal cortex. Exp Brain Res. 176 (4), 603-615 (2007).
- Di Lazzaro, V., et al. The physiological basis of the effects of intermittent theta burst stimulation of the human motor cortex. J Physiol. 586 (16), 3871-3879 (2008).
- Post, A., Keck, M. E. Transcranial magnetic stimulation as a therapeutic tool in psychiatry: what do we know about the neurobiological mechanisms. J Psychiatr Res. 35 (4), 193-215 (2001).
- Muller, P. A., Dhamne, S. C., Vahabzadeh-Hagh, A. M., Pascual-Leone, A., Jensen, F. E., Rotenberg, A. Suppression of motor cortical excitability in anesthetized rats by low frequency repetitive transcranial magnetic stimulation. PLoS One. 9 (3), 91065 (2014).
- Funke, K., Benali, A. Modulation of cortical inhibition by rTMS – findings obtained from animal models. J Physiol. 589 (18), 4423-4435 (2011).
- Rotenberg, A., et al. Lateralization of forelimb motor evoked potentials by transcranial magnetic stimulation in rats. Clin Neurophysiol. 121 (1), 104-108 (2010).
- Beom, J., Kim, W., Han, T. R., Seo, K. S., Oh, B. M. Concurrent use of granulocyte-colony stimulating factor with repetitive transcranial magnetic stimulation did not enhance recovery of function in the early subacute stroke in rats. Neurol Sci. 36 (5), 771-777 (2015).
- Haghighi, S. S., Green, K. D., Oro, J. J., Drake, R. K., Kracke, G. R. Depressive effect of isoflurane anesthesia on motor evoked potentials. Neurosurgery. 26, 993-997 (1990).
- Fishback, A. S., Shields, C. B., Linden, R. D., Zhang, Y. P., Burke, D. The effects of propofol on rat transcranial magnetic motor evoked potentials. Neurosurgery. 37 (5), 969-974 (1995).
- Rohde, V., Krombach, G. A., Baumert, J. H., Kreitschmann-Andermahr, I., Weinzierl, M., Gilsbach, J. M. Measurement of motor evoked potentials following repetitive magnetic motor cortex stimulation during isoflurane or propofol anaesthesia. Br J Anaesth. 91 (4), 487-492 (2003).
- Lee, S. A., Oh, B. M., Kim, S. J., Paik, N. J. The molecular evidence of neural plasticity induced by cerebellar repetitive transcranial magnetic stimulation in the rat brain: a preliminary report. Neurosci Lett. 575, 47-52 (2014).
- Fu, Y. K., et al. Imaging of regional metabolic activity by (18)F-FDG/PET in rats with transient cerebral ischemia. Appl Radiat Isot. 67 (18), 1743-1747 (2009).
- Silveyra, P., Catalano, P. N., Lux-Lantos, V., Libertun, C. Impact of proestrous milieu on expression of orexin receptors and prepro-orexin in rat hypothalamus and hypophysis: actions of Cetrorelix and Nembutal. Am J Physiol Endocrinol Metab. 292 (3), 820-828 (2007).
- Zidek, N., Hellmann, J., Kramer, P. J., Hewitt, P. G. Acute hepatotoxicity: a predictive model based on focused illumina microarrays. Toxicol Sci. 99 (1), 289-302 (2007).
- Hsieh, T. H., Dhamne, S. C., Chen, J. J., Pascual-Leone, A., Jensen, F. E., Rotenberg, A. A new measure of cortical inhibition by mechanomyography and paired-pulse transcranial magnetic stimulation in unanesthetized rats. J Neurophysiol. 107 (3), 966-972 (2012).
- Salvador, R., Miranda, P. C. Transcranial magnetic stimulation of small animals: a modeling study of the influence of coil geometry, size and orientation. Conf Proc IEEE Eng Med Biol Soc. 2009, 674-677 (2009).
- Parthoens, J., Verhaeghe, J., Servaes, S., Miranda, A., Stroobants, S., Staelens, S. Performance Characterization of an Actively Cooled Repetitive Transcranial Magnetic Stimulation Coil for the Rat. Neuromodulation. , (2016).
- Toro, R., et al. Brain size and folding of the human cerebral cortex. Cereb Cortex. 18 (10), 2352-2357 (2008).
