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364.8 Introduction S. Dietrich , W. L. Neuhuber , C. Scherzinger ,R. Ringler 1,2 2 1 3 cerboMed GmbH, Erlangen, Germany Institute of Anatomy, Department I, University of Erlangen, Germany Dept. of Medical Physics, Clinical Center Nuremberg, Nuremberg, Germany 1) 2) 3) Methods ! ! ! ! ! 12 subjects - 11 males, 1 female (27.1 ± 5.1 years, ) electrical stimulation of: N. Vagus, N. mentalis and N. trigeminus mean ± SD individual threshold determination for each stimulation site and subject fMRI BOLD imaging with standard block design data evaluation with Brain Voyager QX® (Brain Innovations, Netherlands, www.brainvoyager.com) Subjects and stimulation fMRI data evaluation and statistical analysis Conclusions fMRI of N. vagus, facialis and trigeminus stim ! Transcutaneous nerve stimulation is a safe method to stimulate cranial nerves without the risks of invasive techniques BOLD fMRI results could be obtained for transcutaneous non- invasive stimulation of N. vagus, N. trigeminus and N. facialis ! transcutaneous nerve stimulation - t-VNS 1) Pre-processing of the fMRI-EPI data by: 3D-motion correction with a trilinear interpolation Slice scan time correction with a sinc interpolation Temporal smoothing, by a) linear trend removal, b) high pass filter 2) 3) Transformation of each subject 3D-MPRAGE data set toTailarach space 4) GLM multi study with z-transformation 5) Statistical significance of activated clusters by p < 0.005 6) Anatomical assignment of activated areas by averaged brain analysis with “Tailarach Daemon” in combination with standard anatomical atlas ! ! ! Coregistration of functional EPI experiment to individual 3D-MPRAGE data set [voxel size: mm³] 1x1x1 Comparison of stimulation sides Acknowledgement Supported by cerboMed GmbH, Germany, Grant Mr002 Non-invasive electrical nerve stimulation of Ramus auricularis nervi vagi, N. facialis and N. mentalis results in nerve-specific brainstem and cerebral activations examined by BOLD fMRI email: [email protected] [email protected] Society for Neuroscience, 38 Annual Meeting, 2008, Washington th Experimental protocol Anatomical setup: Application of electrical, non-painful stimuli to a) N. vagus at the inner side of the tragus b) N. facialis close to the stylomastoid foramen c) origin of the N. mentalis above the mental foramen fMRI - experimental setup: Application of electrical stimuli in a block design with 4 stimulus periods of 30 sec and alternating rest periods of 60 sec EPI-Parameters: TR: 5000 ms for 36 slices, voxel: 4x4x3.75mm³, FOV: 256x256 TR:110 ms/slice, TE=60 ms, flip angle=90° transcutaneously Results: N. trigeminus stimulation Results: N. facialis stimulation N. mentalis stimulation leads to a prominent activation in Lobulus semilunaris inferior right, Tonsille left,bilateral Culmen ventral tegmentum (rvT), right Globus pallidus medialis Nucleus ventralis lateralis, Capsula interna, Bilateral: insula cortex, gyrus temporalis superior BA 22, Right side: Gyrus precentralis BA 6, Gyrus frontalis medialis BA 10 and BA 43 and BA 2 Gyrus postcentralis Cerebellum: Brain stem: Thalamus: Left side: BA 40 Gyrus postcentralis Electrical stimulus of the N. facialis leads to significant BOLD-activation in cerebellum und brain stem as well as subcortical and cortical brain areas. In detail: obus posterior, regio Declive (rD) and right Culmen of lobus anterior. Substantia nigra (rSN) bilateral Nucleus dorsalis medialis anterior insula BA 45, BA 9, g Lobus parietalis inferior (Ba40). Cerbellum: Brain stem: Thalamus: Left: Bilateral: Right: regio Pyramis vermis (rPv) in l bilateral BA 9 in gyrus frontalis medialis, Capsula interna yrus praecentralis, gyrus occipitalis medialis, cingulate cortex, ! ! Comparison of BOLD activation pattern evidenced nerve- specific signal processing in the brain Our experimental design could supplement the current mainly descriptive anatomical understanding of cranial nerves signal processing with functional mode-of-action parameter. Comparisons of healthy functional data with pathological data could lead to better treatment options in cranial nerve disorders ! Invasive neurostimulation has proven to be effective, but its clinical use is limited by a variety of reasons such as negative side-effects or high costs. Therefore, non-invasive stimulation methods are of increased interest. Our research has focused on transcutaneous and non-invasive stimulation of N. vagus, N. facialis and N. mentalis (trigeminus). BOLD fMRI was used to detect potential nerve-specific activation cluster in the brainstem, subcortical and cortical brain areas during transcutaneous electrical nerve stimulation. Two main questions were addressed with this work: ! ! Is BOLD fMRI a feasible method to study the cerebral processing of transcutaneously applied stimuli of N. vagus, N. facialis and N. trigeminus? Does nerve-specific transcutaneous non-invasive stimulation lead to nerve-specific BOLD action cluster in the brain? 1:00 1:30 2:30 3:00 4:00 4:30 5:30 6:00 time [min] baseline stimulus baseline stimulus baseline stimulus baseline stimulus baseline Literature ! Dietrich S, Smith J, Scherzinger C, Hoffmann-Preiß K, Freitag T, Eisenkolb A, Ringler R. A novel transcutaneous vagus nerve stimulation leads to brainstem activations measured by functional MRI. Biomed Tech 2008;53(3):104-111. Most significant activation in cerebellum (regio Pyramis vermis t = 6.404, p<0.000000; Lobus posterior regio Declive right t = 5.724, p<0.000000) and right g. frontalis inferior BA 45 (t = 5.588, p<0.000000) and right g. praecentralis BA 4 (t = 5.081, p<0.000002). Most prominent clusters on a high significance level were found in Insula cortex (t = 4.685,p<0.000011), right g.temporalis superior (t = 5.274, p<0.000001), right g. praecentralis (t = 5.336, p<0.000001), right g. postcentralis (t= 6.188, p<0.000000) and right g. frontalis medialis (t = 5.945, p<0.000000). Results: N. vagus stimulation A prominent activation in contra lateral pontine tegmentum and right due to stimulation of vagal afferent fibers of the outer ear canal (RANV). : regio Nucleus dentatus rechts (rNd), regio Uvula Vermis (rUV), Lobus posterior cerebelli regio Declive (rD) bilateral) Locus coeruleus, pontine Tegmentum, Region of Nucleus subthalamicus (rNS), Nucleus ventralis lateralis of the Thalamus, dorsal parts of the Putamen, Amygdala of Gyrus parahippocampalis, regio Locus coeruleus (rLC) dorsolateral prefrontal Cortex (DLPFC) Cingulate Gyrus, Insula, Gyrus frontalis superior, S1- Cortex Cuneus located in Lobus occipitalis. Further activaed areas are Cerebellum: Right side: Bilateral: Left side: White cross: (x=8, y=-28, z=-22) regio Locus coeruleus / regio pontines Tegmentum Best Match Red circle: (x=8, y=-13, z=-5) 3rd Best Match regio Nuc. subthalamicus (rNs) Subthalamus / right (Total of N= 12 subjects) Coordinates Cerebellum r Lobus posterior rNd * 2.97 0.003801 18 -48 -32 m * rUV 2 nd 3.991 0.000143 -2 -62 -27 r l st Truncus cerebri r Pons rLC/rpT * 3.273 0.001561 8 -28 -22 Subthalamus r * rNS 3 rd 3.185 0.002045 8 -13 -5 Thalamus r st l Nucleus ventralis lateralis * 1 st 3.408 0.000522 -11 -13 9 Nucleus lentiforme l Putamen * 2 nd 3.114 0.002546 -32 -8 -1 l r l Gyrus cinguli BA24 2 nd 3.122 0.002485 -6 -16 34 Insula r * BA13 + 2 nd 5.288 0.000001 34 16 6 l * BA13 + 2 nd 5.704 0.000000 -34 21 6 Lobus frontalis r DLPFC BA46 3 rd 6.290 0.000000 41 44 13 l OFC BA10 2 5.228 0.000001 -36 44 22 r Gyrus frontalis superior BA8 1 st 4.974 0.000004 4 30 44 Lobus parietalis r Kortex BA2 4 th 5.890 0.000000 52 -25 29 l st (Total of N= 12 subjects) Coordinates z Cerebellum m Lobus posterior [rPV] 3 rd 6.404 0.000000 -1 -71 -31 r Lobus posterior [rD] * 5.724 0.000000 19 -77 -31 l Lobus posterior [rD] * 4.571 0.000017 -18 -75 -31 r st r Thalamus r Nucleus dorsalis medialis * 1 st 3.576 0.000588 9 -16 6 l Nucleus dorsalis medialis * 1 st 3.331 0.001300 -10 -16 11 Insula r * BA13 + 3 rd 4.513 0.000021 38 19 -2 l * BA13 + 1 st 4.8497 0.000005 -44 12 -1 Lobus frontalis r r l r Extra-Nuclear l Capsula interna * * 4.260 0.00054 -18 9 11 Lobus occipitalis r Gyrus occipitalis medialis BA19 2 nd -4.515 0.000021 35 -83 14 Lobus limbicus r Gyrus cinguli BA32 1 st 3.499 0.000758 9 20 36 r st Abbreviations: rPV = regio Pyramis vermis, rD = regio Declive, rSN = regio Substantia nigra, BM = Best match (Total of N= 12 subjects) Coordinates z Cerebellum r Lobus posterior LSI 1 st 2.980 0.003788 19 -67 -38 l st st Truncus cerebri l Pons rvT * 2.700 0.008418 -7 -26 -31 Nucleus lentiforme r Globus pallidus medialis * 4.576 0.000017 14 -10 -3 Thalamus r Nucleus ventralis lateralis * 5 th 4.289 0.000049 15 -11 -1 l Nucleus ventralis lateralis * 6 th 4.277 0.000051 -16 -11 -1 Extra-Nuclear l Insula r * BA13 + 2 nd 4.685 0.000011 38 2 -1 l * BA13 + 2 nd 3.648 0.000462 -39 16 -1 r st l Lobus frontalis r Gyrus praecentralis BA6 2 nd 5.336 0.000001 50 -2 9 r l r Gyrus postcentralis BA43 2 nd 6.188 0.000000 53 -13 16 r Gyrus postcentralis BA2 1 st 4.555 0.000018 56 -26 37 Abbreviations: LSI = Lobulus semilunaris inferior, rvT = regio ventrales Tegmentum, BM = Best Match N. VAGUS N. FACIALIS N. TRIGEMINUS (N. mentalis) (N= 12) Cerebellum Lobus posterior rNd ↑ R rUV ↑ M rD ↑ B ↑ B rPV ↑ M Culmen ↑ R LSI ↑ R Tonsille ↑ L Lobus anterior Culmen ↑ M Truncus cerebri Pons rSN ↑ R rVT ↑ L Subthalamus rNS ↑ R Thalamus Nucl. ventralis lat. ↑ B ↑ B Nucl.dorsalis med. ↑ B Nucl. lentiforme Putamen ↑ L med. ↑ R Extra-Nuclear Capsula interna ↑ L ↑ L N. VAGUS N. FACIALIS N. TRIGEMINUS (N. mentalis) Lobus limbicus parahippocampalis ↑ L (rA) anterior ↑ (BA24) Gyrus cinguli ↑ (BA24) ↑ (BA32) Insula * ↑ (BA13) ↑ (BA13) ↑ (BA13) Lobus temporalis superior ↑ (BA22) Lobus frontalis medialis ↑ (BA46) ↑ (BA9) ↑ (BA10) [DLPFC] [↑] [R] superior/ OFC ↑ (BA10) superior ↑ (BA8) Gyrus frontalis inferior ↑ (BA45) R (BA9) praecentralis ↑ (BA4) ↑ (BA6) Lobus parietalis / S1-Kortex ↑ (BA2) ↑ (BA2) ↑ (BA43) ↑ (BA40) inferior ↑ (BA40) Lobus occipitalis Cuneus ↑ (BA19) medialis ↑ (BA19) Nucleus dentatus, rUV = regio Uvula vermis, rA = regio Amygdala, rD = regio Declive, rNS = region Nucleus subthalamicus, BA = Brodmann Area, DLPFC = dorsolateraler präfrontaler Kortex, OFC = orbitofront aler Kortex, LSI = Lobulus semilunaris inferior, rvT = regio ventrales Tegmentum, rPV = regio Pyramis vermis, rD = regio Declive, rSN = regio Substantia nigra t-VNS stimuation device, cerboMed GmbH, Erlangen, Germany
