Short-term low intensity PMF does not improve functional or histological outcomes in a rat model of transient focal cerebral ischemia

Stimulation with pulsed magnetic fields (PMF) is a non-invasive technique that can modulate neural activity and has the potential to facilitate functional recovery and tissue preservation/repair following brain injury. The effect of low intensity (8 mT) PMF on functional recovery and infarct tissue volume was assessed in a middle cerebral artery occlusion model of transient focal ischemia in Spontaneously Hypertensive rats. Rats received a combination of PMF protocols, including high and low frequencies and recovery was monitored over eight days. PMF treatment had no effect on functional recovery or infarct volume. Infarcted tissue accounted for ≈8% of total brain volume, encompassing both cortical and subcortical structures. The microglial and astrocytic response to PMF treatment was monitored and there was no change in glial scarring, however there was increased macrophage infiltration in animals that received chronic high (6-9 Hz) and low (1 Hz) stimulation. There was no effect of PMF on the degree of cell death observed within the ischemic core, with no TUNEL positive cells observed in the non-infarcted tissue. No detrimental side-effects of PMF were observed, indicating that low-intensity PMF may have limited safety concerns for future human and animal studies.

[1]  J. Rothwell,et al.  Low‐frequency repetitive transcranial magnetic stimulation suppresses specific excitatory circuits in the human motor cortex , 2008, The Journal of physiology.

[2]  T. Jones,et al.  Behavioral and neuroplastic effects of focal endothelin-1 induced sensorimotor cortex lesions , 2004, Neuroscience.

[3]  R. Swanson,et al.  Astrocytes and Brain Injury , 2003, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[4]  Julie Duque,et al.  Transcallosal inhibition in chronic subcortical stroke , 2005, NeuroImage.

[5]  M. Sofroniew,et al.  Astrocytes: biology and pathology , 2009, Acta Neuropathologica.

[6]  B. Brew,et al.  Microglia, macrophages, perivascular macrophages, and pericytes: a review of function and identification , 2004, Journal of leukocyte biology.

[7]  R. P. Stroemer,et al.  Neurological sequelae and long-term behavioural assessment of rats with transient middle cerebral artery occlusion , 2000, Journal of Neuroscience Methods.

[8]  K. Ikoma,et al.  Repetitive transcranial magnetic stimulation of the unaffected hemisphere in a patient who was forced to use the affected hand. , 2008, American journal of physical medicine & rehabilitation.

[9]  Katsunori Ikoma,et al.  Inhibition of the unaffected motor cortex by 1 Hz repetitive transcranical magnetic stimulation enhances motor performance and training effect of the paretic hand in patients with chronic stroke. , 2008, Journal of rehabilitation medicine.

[10]  N. Knuckey,et al.  Magnesium treatment and spontaneous mild hypothermia after transient focal cerebral ischemia in the rat , 2008, Brain Research Bulletin.

[11]  L. Pitts,et al.  Rat middle cerebral artery occlusion: evaluation of the model and development of a neurologic examination. , 1986, Stroke.

[12]  C. Kleinschnitz,et al.  Rodent models of focal cerebral ischemia: procedural pitfalls and translational problems , 2009, Experimental & Translational Stroke Medicine.

[13]  E. Khedr,et al.  Long‐term effect of repetitive transcranial magnetic stimulation on motor function recovery after acute ischemic stroke , 2010, Acta neurologica Scandinavica.

[14]  P. Carmeliet,et al.  Protective Role of Reactive Astrocytes in Brain Ischemia , 2008, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[15]  Á. Pascual-Leone,et al.  Ethical guidelines for rTMS research. , 1997, IRB.

[16]  W. Paulus,et al.  Safety aspects of chronic low-frequency transcranial magnetic stimulation based on localized proton magnetic resonance spectroscopy and histology of the rat brain. , 2003, Journal of psychiatric research.

[17]  A. Nitta,et al.  Alterations in hippocampal GAP-43, BDNF, and L1 following sustained cerebral ischemia , 2002, Brain Research.

[18]  J. Crawley,et al.  Bone marrow transplantation prolongs life span and ameliorates neurologic manifestations in Sandhoff disease mice. , 1998, The Journal of clinical investigation.

[19]  Gaby S. Pell,et al.  Modulation of cortical excitability induced by repetitive transcranial magnetic stimulation: Influence of timing and geometrical parameters and underlying mechanisms , 2011, Progress in Neurobiology.

[20]  Kortaro Tanaka,et al.  Enhanced Expression of Iba1, Ionized Calcium-Binding Adapter Molecule 1, After Transient Focal Cerebral Ischemia In Rat Brain , 2001, Stroke.

[21]  D. Howells,et al.  Stimulation of axonal sprouting by trophic factors immobilized within the wound core , 2008, Brain Research.

[22]  David W Howells,et al.  Different Strokes for Different Folks: The Rich Diversity of Animal Models of Focal Cerebral Ischemia , 2010, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[23]  J. Liepert,et al.  Lesion-induced and training-induced brain reorganization. , 2004, Restorative neurology and neuroscience.

[24]  Abraham Zangen,et al.  Long-Term Effects of Repetitive Transcranial Magnetic Stimulation on Markers for Neuroplasticity: Differential Outcomes in Anesthetized and Awake Animals , 2011, The Journal of Neuroscience.

[25]  Klaus Martiny,et al.  Transcranial Low Voltage Pulsed Electromagnetic Fields in Patients with Treatment-Resistant Depression , 2010, Biological Psychiatry.

[26]  S. Rossi,et al.  Safety, ethical considerations, and application guidelines for the use of transcranial magnetic stimulation in clinical practice and research , 2009, Clinical Neurophysiology.

[27]  P. Pasqualetti,et al.  Interhemispheric Asymmetries of Motor Cortex Excitability in the Postacute Stroke Stage: A Paired-Pulse Transcranial Magnetic Stimulation Study , 2003, Stroke.

[28]  C. Epstein,et al.  Magnetic brain stimulation and brain size: relevance to animal studies. , 1992, Electroencephalography and clinical neurophysiology.

[29]  N. Knuckey,et al.  Lack of Neuroprotection of Inhibitory Peptides Targeting Jun/JNK after Transient Focal Cerebral Ischemia in Spontaneously Hypertensive Rats , 2011, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[30]  E. Khedr,et al.  Short- and long-term effect of rTMS on motor function recovery after ischemic stroke. , 2010, Restorative neurology and neuroscience.

[31]  G. Donnan,et al.  Macrophages and Microglia Produce Local Trophic Gradients That Stimulate Axonal Sprouting Toward but Not beyond the Wound Edge , 2002, Molecular and Cellular Neuroscience.

[32]  Jean Théberge,et al.  Low-frequency pulsed electromagnetic field exposure can alter neuroprocessing in humans , 2010, Journal of The Royal Society Interface.

[33]  S. Dunlop,et al.  Transcranial pulsed magnetic field stimulation facilitates reorganization of abnormal neural circuits and corrects behavioral deficits without disrupting normal connectivity , 2012, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[34]  J. Liepert,et al.  Improvement of dexterity by single session low-frequency repetitive transcranial magnetic stimulation over the contralesional motor cortex in acute stroke: a double-blind placebo-controlled crossover trial. , 2007, Restorative neurology and neuroscience.

[35]  Hung-Yi Chen,et al.  Magnesium treatment and spontaneous mild hypothermia after transient focal cerebral ischemia in the rat , 2009, Brain Research Bulletin.

[36]  M. Murray,et al.  Macrophages, microglia, and astrocytes are rapidly activated after crush injury of the goldfish optic nerve: A light electron microscopic analysis , 1995, The Journal of comparative neurology.

[37]  K. Furie,et al.  Heart disease and stroke statistics--2007 update: a report from the American Heart Association Statistics Committee and Stroke Statistics Subcommittee. , 2008, Circulation.

[38]  R. Goodman,et al.  Electromagnetic fields and cells , 1993, Journal of cellular biochemistry.

[39]  Y. Z. Huang,et al.  Theta‐burst repetitive transcranial magnetic stimulation suppresses specific excitatory circuits in the human motor cortex , 2005, The Journal of physiology.

[40]  P. Weinstein,et al.  Reversible middle cerebral artery occlusion without craniectomy in rats. , 1989, Stroke.

[41]  M. Hallett,et al.  Repetitive Transcranial Magnetic Stimulation–Induced Corticomotor Excitability and Associated Motor Skill Acquisition in Chronic Stroke , 2006, Stroke.

[42]  M. Hallett Transcranial Magnetic Stimulation: A Primer , 2007, Neuron.

[43]  L. Cohen,et al.  Non-invasive brain stimulation: a new strategy to improve neurorehabilitation after stroke? , 2006, The Lancet Neurology.

[44]  J. Rothwell,et al.  Therapeutic trial of repetitive transcranial magnetic stimulation after acute ischemic stroke , 2005, Neurology.

[45]  Manli Huang,et al.  Repetitive Transcranial Magnetic Stimulation-Induced Seizure of a Patient with Adolescent-Onset Depression: A Case Report and Literature Review , 2011, The Journal of international medical research.

[46]  J. Zihl,et al.  Seizure induction and magnetic brain stimulation after stroke , 1992, The Lancet.

[47]  J. Crawley Behavioral phenotyping of transgenic and knockout mice: experimental design and evaluation of general health, sensory functions, motor abilities, and specific behavioral tests 1 Published on the World Wide Web on 2 December 1998. 1 , 1999, Brain Research.

[48]  J. Rothwell,et al.  Is there a future for therapeutic use of transcranial magnetic stimulation? , 2007, Nature Reviews Neuroscience.

[49]  D. Trock Electromagnetic fields and magnets. Investigational treatment for musculoskeletal disorders. , 2000, Rheumatic diseases clinics of North America.

[50]  A. Thomlinson,et al.  Temporary colonization of the site of lesion by macrophages is a prelude to the arrival of regenerated axons in injured goldfish optic nerve , 1998, Journal of neurocytology.

[51]  P. Manganotti,et al.  Motor disinhibition in affected and unaffected hemisphere in the early period of recovery after stroke , 2002, Clinical Neurophysiology.

[52]  Y. Guo,et al.  Protective effects of repetitive transcranial magnetic stimulation in a rat model of transient cerebral ischaemia: a microPET study , 2010, European Journal of Nuclear Medicine and Molecular Imaging.

[53]  Michael Chopp,et al.  A rat model of focal embolic cerebral ischemia , 1997, Brain Research.

[54]  Geoffrey A. Donnan,et al.  Activated Macrophages and Microglia Induce Dopaminergic Sprouting in the Injured Striatum and Express Brain-Derived Neurotrophic Factor and Glial Cell Line-Derived Neurotrophic Factor , 1999, The Journal of Neuroscience.