Gaby S. Pell

Modulation of cortical excitability induced by repetitive transcranial magnetic stimulation: Influence of timing and geometrical parameters and underlying mechanisms

Transcranial magnetic stimulation (TMS) is a non-invasive brain stimulation technique that activates neurons via generation of brief pulses of high-intensity magnetic field. If these pulses are applied in a repetitive fashion (rTMS), persistent modulation of neural excitability can be achieved. The technique has proved beneficial in the treatment of a number of neurological and psychiatric conditions. However, the effect of rTMS on excitability and the other performance indicators shows a considerable degree of variability across different sessions and subjects. The frequency of stimulation has always been considered as the main determinant of the direction of excitability modulation. However, interactions exist between frequency and several other stimulation parameters that also influence the degree of modulation. In addition, the spatial interaction of the transient electric field induced by the TMS pulse with the cortical neurons is another contributor to variability. Consideration of all of these factors is necessary in order to improve the consistency of the conditioning effect and to better understand the outcomes of investigations with rTMS. These user-controlled sources of variability are discussed against the background of the mechanisms that are believed to drive the excitability changes. The mechanism behind synaptic plasticity is commonly accepted as the driver of sustained excitability modulation for rTMS and indeed, plasticity and rTMS share many characteristics, but definitive evidence is lacking for this. It is more likely that there is a multiplicity of mechanisms behind the action of rTMS. The different mechanisms interact with each other and this will contribute to the variability of rTMS-induced excitability changes. This review investigates the links between rTMS and synaptic plasticity, describes their similarities and differences, and highlights a neglected contribution of the membrane potential. In summary, the principal aims of this review are (i) to discuss the different experimental and subject-related factors that contribute to the variability of excitability modulation induced by rTMS, and (ii) to discuss a generalized underlying mechanism for the excitability modulation.

Long-Term Effects of Repetitive Transcranial Magnetic Stimulation on Markers for Neuroplasticity: Differential Outcomes in Anesthetized and Awake Animals

Long-term effects of repetitive transcranial magnetic stimulation (rTMS) have been associated with neuroplasticity, but most physiological studies have evaluated only the immediate effects of the stimulation on neurochemical markers. Furthermore, although it is known that baseline excitability state plays a major role in rTMS outcomes, the role of spontaneous neural activity in metaplasticity has not been investigated. The first aim of this study was to evaluate and compare the long-term effects of high- and low-frequency rTMS on the markers of neuroplasticity such as BDNF and GluR1 subunit of AMPA receptor. The second aim was to assess whether these effects depend on spontaneous neural activity, by comparing the neurochemical alterations induced by rTMS in anesthetized and awake rats. Ten daily sessions of high- or low-frequency rTMS were applied over the rat brain, and 3 d later, levels of BDNF, GluR1, and phosphorylated GluR1 were assessed in the hippocampus, prelimbic cortex, and striatum. We found that high-frequency stimulation induced a profound effect on neuroplasticity markers; increasing them in awake animals while decreasing them in anesthetized animals. In contrast, low-frequency stimulation did not induce significant long-term effects on these markers in either state. This study highlights the importance of spontaneous neural activity during rTMS and demonstrates that high-frequency rTMS can induce long-lasting effects on BDNF and GluR1 which may underlie the clinical benefits of this treatment in neuroplasticity-related disorders.

Motor cortex activation by H-coil and figure-8 coil at different depths. Combined motor threshold and electric field distribution study.

OBJECTIVE To compare the ability of an H-coil and figure-8 coil to stimulate different motor cortex regions. METHODS The resting (rMT) and active (aMT) motor thresholds were measured for the right hand APB and leg AHB muscles in 10 subjects, using an H-coil and a figure-8 coil. The electric field distribution induced by the coils was measured in a head model. The combination of the hand and leg MTs with the field measurements was used to determine the depth of hand and leg motor areas via the intersection points. RESULTS The rMT and aMT of both APB and AHB were significantly lower for the H-coil. The ratio and difference between the leg and hand rMT and aMT were significantly lower for the H-Coil. Electric field measurements revealed significantly more favorable depth profile and larger volume of stimulation for the H-coil. The averaged intersection for the APB was at a distance from coil of 1.83±0.54cm and at an intensity of 97.8±21.4V/m, while for the AHB it was at a distance of 2.73±0.44cm and at an intensity of 118.6±21.3V/m. CONCLUSION The results suggest a more efficient activation of deeper motor cortical regions using the H-coil. SIGNIFICANCE The combined evaluation of MTs by H- and figure-8 coils allows measurement of the individual depth of different motor cortex regions. This could be helpful for optimizing stimulation parameters for TMS treatment.

Quantitative imaging assessment of blood-brain barrier permeability in humans

The blood–brain barrier (BBB) is a functional and structural barrier separating the intravascular and neuropil compartments of the brain. It characterizes the vascular bed and is essential for normal brain functions. Dysfunction in the BBB properties have been described in most common neurological disorders, such as stroke, traumatic injuries, intracerebral hemorrhage, tumors, epilepsy and neurodegenerative disorders. It is now obvious that the BBB plays an important role in normal brain activity, stressing the need for applicable imaging and assessment methods. Recent advancements in imaging techniques now make it possible to establish sensitive and quantitative methods for the assessment of BBB permeability. However, most of the existing techniques require complicated and demanding dynamic scanning protocols that are impractical and cannot be fulfilled in some cases. We review existing methods for the evaluation of BBB permeability, focusing on quantitative magnetic resonance-based approaches and discuss their drawbacks and limitations. In light of those limitations we propose two new approaches for BBB assessment with less demanding imaging sequences: the “post-pre” and the “linear dynamic” methods, both allow semi-quantitative permeability assessment and localization of dysfunctional BBB with simple/partial dynamic imaging protocols and easy-to-apply analysis algorithms. We present preliminary results and show an example which compares these new methods with the existing standard assessment method. We strongly believe that the establishment of such “easy to use” and reliable imaging methods is essential before BBB assessment can become a routine clinical tool. Large clinical trials are awaited to fully understand the significance of BBB permeability as a biomarker and target for treatment in neurological disorders.

Glutamate-Mediated Blood-Brain Barrier Opening: Implications for Neuroprotection and Drug Delivery.

The blood–brain barrier is a highly selective anatomical and functional interface allowing a unique environment for neuro-glia networks. Blood–brain barrier dysfunction is common in most brain disorders and is associated with disease course and delayed complications. However, the mechanisms underlying blood–brain barrier opening are poorly understood. Here we demonstrate the role of the neurotransmitter glutamate in modulating early barrier permeability in vivo. Using intravital microscopy, we show that recurrent seizures and the associated excessive glutamate release lead to increased vascular permeability in the rat cerebral cortex, through activation of NMDA receptors. NMDA receptor antagonists reduce barrier permeability in the peri-ischemic brain, whereas neuronal activation using high-intensity magnetic stimulation increases barrier permeability and facilitates drug delivery. Finally, we conducted a double-blind clinical trial in patients with malignant glial tumors, using contrast-enhanced magnetic resonance imaging to quantitatively assess blood–brain barrier permeability. We demonstrate the safety of stimulation that efficiently increased blood–brain barrier permeability in 10 of 15 patients with malignant glial tumors. We suggest a novel mechanism for the bidirectional modulation of brain vascular permeability toward increased drug delivery and prevention of delayed complications in brain disorders. SIGNIFICANCE STATEMENT In this study, we reveal a new mechanism that governs blood–brain barrier (BBB) function in the rat cerebral cortex, and, by using the discovered mechanism, we demonstrate bidirectional control over brain endothelial permeability. Obviously, the clinical potential of manipulating BBB permeability for neuroprotection and drug delivery is immense, as we show in preclinical and proof-of-concept clinical studies. This study addresses an unmet need to induce transient BBB opening for drug delivery in patients with malignant brain tumors and effectively facilitate BBB closure in neurological disorders.

Commentary on: Deng et al., Electric field depth–focality tradeoff in transcranial magnetic stimulation: Simulation comparison of 50 coil designs

* Corresponding author. Tel.: þ972 8 934 4415; fax: E-mail address: azangen@bgu.ac.il (A. Zangen). 1935-861X/

Safety and Characterization of a Novel Multi-channel TMS Stimulator

e see front matter 2013 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.brs.2012.04.003 The review by Deng et al. in this edition modeling 50 theoretical and practical coils [1] is a comprehensive and important article that compares the electric field depth-focality profile of various coils using a spherical head model. The use of a spherical model facilitates the definition of a simple and universal metric framework for a convenient comparison of the depth and focality characteristics of all TMS coils. Yet, the gain in generality and simplicity of this approach comes at the expense of losing some valuable features that must be acknowledged. First, the human brain geometry is obviously significantly different from the ideal spherical form, hence the induced electric field distributionwill have different features in the two cases. In the realistic head geometry, the resulting electric field distribution will be much more sensitive to the coil position and orientation since the head surface is non-uniform and with a variable curvature. The analogousmetric definition of d1⁄2 in a realistic head should be based on the distance from the deepest point having field at or above E1⁄2, relative to its closest point on the brain surface. Second, in most practical clinical applications, a certain degree of symmetry break is required. For example, a spherically-symmetric stimulation of a cortical ring around the brain is usually undesired, but instead a complex distribution inducing suprathreshold electric field in certain targeted brain regions e including deep regions e with simultaneous minimization of the effect at other brain regions. It is imperative tominimize adverse side effects such as excessivemotor activation (which may increase the risk of seizure), facial muscle activation, and subject pain or discomfort. The degree and type of

Realistic shape head model and spherical model as methods for TMS coil characterization.

BACKGROUND Currently available TMS stimulators have a single channel operating a single coil. OBJECTIVE To outline and present physical and physiological benefits of a novel convenient multi-channel stimulator, comprising five channels, where the stimulation parameters of each channel are independently controllable. METHODS Simultaneous and sequential operation of various channels was tested in healthy volunteers. Paired pulses schemes with various inter-stimulus intervals (ISIs) were studied for the hand APB and the leg AH muscles. Energy consumption and coil heating rates with simultaneous operation of 4 channels was compared to a single figure-8 coil. RESULTS Repetitive operation of separate channels with different stimulation parameters is demonstrated. The operations of various channels can be combined simultaneously or sequentially to induce multiple pulses with ISIs of μs resolution. A universal pattern of inhibition and facilitation as a function of ISI was found, with some dependence on coils configurations and on pulse widths. A strong dependence of the induced inhibition on the relative orientation of the conditioning and test pulses was discovered. The ability of this method to induce inhibition in shallow brain region but not in deeper region, thus focusing the effect in the deep brain region, is demonstrated. A significant saving in energy consumption and a reduction in coil heating were demonstrated for several channels operated simultaneously compared to a standard single channel figure-8 coil. CONCLUSIONS The multi-channel stimulator enables the synchronized induction of different excitability modulations to different brain regions using different stimulation patterns in various channels. Multiple pulses operation with coils with various depth profiles can increase the focality of TMS effect in deep brain regions.

Network Meta-analysis in Mental Health Research

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Reply to "On the stimulation depth of transcranial magnetic stimulation coils"

Network Meta-analysis in Mental Health Research To the Editor The network meta-analysis of various repetitive transcranial magnetic stimulation (rTMS) modalities in major depressive disorder by Brunoni et al1 is fairly comprehensive, given the limited criteria for article selection used in this analysis. Such an approach could enhance understanding of rTMS efficacy and tolerability; however, if not implemented with great care, it can also lead to distorted conclusions. Unfortunately, this review1 includes several methodological issues and errors. Specifically, the conclusions are compromised by the inclusion of sparse nodes with a single study (3 of 8 nodes); the grouping of different interventions into a single node (1 θ-burst stimulation node comprising 3 routes of administration); the grouping of very different sham conditions into a single node (diverse sham techniques and patients with or without concomitant antidepressants); and by placing emphasis on the ranking of treatments, rather than on their effects and uncertainty.2,3 Regarding ranking, modalities with a large proportion of studies with an active but no sham comparator are likely to show greater effectiveness. For example, the response and remission rates of bilateral rTMS (the intervention ranked second best) vs active comparator (58.7% and 38.0%, respectively; references 48, 53, and 75 in the Brunoni et al study1) are doubled compared with studies of bilateral rTMS vs sham control (24.2% and 17.9%, respectively; references 36-37, 50, 52, 54, 56, 82, 86, 92, and 94 in the Brunoni et al study1). In accordance, the intervention ranked highest (priming low-frequency rTMS) was informed by evidence from 2 studies without a sham arm at all, while the 3 interventions ranked lowest were each informed only by evidence from a single sham-controlled study. In addition, critical errors in this review include inclusion of data obtained after complete randomization was not maintained (references 60 and 90, the 2 largest studies for highfrequency rTMS, in the Brunoni et al study1), inclusion of data not consistent with the authors’ definition of intention to treat and primary end point (references 90 and 107 in the Brunoni et al study1), errors in calculation of some of the pairwise values relative to the original published data (eg, references 5, 48, 57, 84, and 103 in the Brunoni et al study1), and attribution of sham condition to trials, which included a pharmacological (ie, active) intervention (references 40 and 68 in the Brunoni et al study1), which produces bias against ranking of treatments that were only compared with sham without concomitant medications such as deep (H-coil) TMS. Finally, 2 treatments (low-frequency rTMS and deep [H-coil] TMS) were not included in the discussion of valid techniques based on remission scores, despite supporting pairwise values (eTable 4 in Supplement 2).1 Taken together, these issues confound interpretation of the study’s results.