Goetz, S. | Search bioRxiv

bioRxiv2018

Design of Transcranial Magnetic Stimulation Coils with Optimal Trade-off between Depth, Focality, and Energy

BackgroundTranscranial magnetic stimulation (TMS) is a noninvasive brain stimulation technique used for research and clinical applications. Existent TMS coils are limited in their precision of spatial targeting (focality), especially for deeper targets.\n\nObjectiveThis paper presents a methodology for designing TMS coils to achieve optimal trade-off between the depth and focality of the induced electric field (E-field), as well as the energy required by the coil.\n\nMethodsA multi-objective optimization technique is used for computationally designing TMS coils that achieve optimal trade-offs between stimulation focality, depth, and energy (fdTMS coils). The fdTMS coil winding(s) maximize focality (minimize stimulated volume) while reaching a target at a specified depth and not exceeding predefined peak E-field strength and required coil energy. Spherical and MRI-derived head models are used to compute the fundamental depth-focality trade-off as well as focality-energy trade-offs for specific target depths.\n\nResultsAcross stimulation target depths of 1.0-3.4 cm from the brain surface, the stimulated volume can be theoretically decreased by 42%-55% compared to existing TMS coil designs. The stimulated volume of a figure-8 coil can be decreased by 36%, 44%, or 46%, for matched, doubled, or quadrupled energy. For matched focality and energy, the depth of a figure-8 coil can be increased by 22%.\n\nO_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=153 SRC=\"FIGDIR/small/300616_fig8.gif\" ALT=\"Figure 8\">\nView larger version (14K):\norg.highwire.dtl.DTLVardef@af0b5org.highwire.dtl.DTLVardef@4118d8org.highwire.dtl.DTLVardef@1c61f80org.highwire.dtl.DTLVardef@3e23fa_HPS_FORMAT_FIGEXP M_FIG O_FLOATNOFigure 8.C_FLOATNO Energy, W, vs. spread, S1/2, curves for hand knob stimulation for a conventional figure-8 coil and optimized fdTMS coil on a 32 x 32 cm square plane.\n\nC_FIG ConclusionComputational design of TMS coils could enable more selective targeting of the induced E-field. The presented results appear to be the first significant advancement in the depth-focality trade-off of TMS coils since the introduction of the figure-8 coil three decades ago, and likely represent the fundamental physical limit.\n\nDECLARATION OF INTERESTThe fdTMS technology described in this paper is subject to a provisional patent application by Duke University with the authors as inventors. Additionally: L.J.G. is inventor on a patent pertaining to the design of focal multicoil TMS systems. S.M.G. is inventor on patents and patent applications; he has received royalties from Rogue Research, TU Muenchen, and Porsche; furthermore, he has been provided with research support and patent fee reimbursement from Magstim Co. A.V.P. is inventor on patents and patent applications, and has received research and travel support as well as patent royalties from Rogue Research; research and travel support, consulting fees, as well as equipment loan from Tal Medical / Neurex; patent application and research support from Magstim; and equipment loans from MagVenture, all related to technology for transcranial magnetic stimulation.

bioengineering↗

bioRxiv2018

Spinocerebellar ataxia type 11-associated alleles of Ttbk2 dominantly interfere with ciliogenesis and cilium stability.

Spinocerebellar ataxia type 11 (SCA11) is a rare, dominantly inherited human ataxia characterized by atrophy of Purkinje neurons in the cerebellum. SCA11 is caused by mutations in the gene encoding the Serine/Threonine kinase Tau tubulin kinase 2 (TTBK2) that result in premature truncations of the protein. We previously showed that TTBK2 is a key regulator of the assembly of primary cilia in vivo. However, the mechanisms by which the SCA11-associated mutations disrupt TTBK2 function, and whether they interfere with ciliogenesis were unknown. In this work, we present evidence that SCA11-associated mutations are dominant negative alleles and that the resulting truncated protein (TTBK2SCA11) interferes with the function of full length TTBK2 in mediating ciliogenesis. A Ttbk2 allelic series revealed that upon partial reduction of full length TTBK2 function, TTBK2SCA11 can interfere with the activity of the residual wild-type protein to decrease cilia number and interrupt cilia-dependent Sonic hedgehog (SHH) signaling. Our studies have also revealed new functions for TTBK2 after cilia initiation in the control of cilia length, trafficking of a subset of SHH pathway components, including Smoothened (SMO), and cilia stability. These studies provide a molecular foundation to understand the cellular and molecular pathogenesis of human SCA11, and help account for the link between ciliary dysfunction and neurodegenerative diseases.\n\nAuthor SummaryDefects in primary cilia structure and function are linked to a number of recessive genetic disorders, now collectively referred to as ciliopathies. Most of the characteristics of these disorders arise from disruptions to embryonic development, with the requirements for primary cilia in adult tissues being less well-defined. We previously showed that a kinase associated with an adult-onset neurodegenerative condition is required for cilium assembly and ciliary signaling during development. Here, we show that the human disease-associated mutations act as mild dominant negatives, interfering with the function of the full length protein in cilia formation and ciliary signaling.

cell biology↗