Evaluation of the distortion of EEG signals caused by a hole in the skull mimicking the fontanel in the skull of human neonates

Evaluation of the distortion of EEG signals caused by a hole in the skull mimicking the fontanel in the skull of human neonates
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  Evaluation of the distortion of EEG signals caused by a hole in the skullmimicking the fontanel in the skull of human neonates Lars Flemming a,b, * , Yaozhi Wang a , Arvind Caprihan c , Michael Eiselt d ,Jens Haueisen b , Yoshio Okada a a  Biomedical Research and Integrative NeuroImaging (BRaIN Imaging) Center, Department of Neurology MSC 10-5620,School of Medicine, University of New Mexico, Albuquerque, NM 87131, USA b  Department of Neurology, Biomagnetic Center Jena, Friedrich-Schiller-University, D-07740 Jena, Germany c  MIND Institute, School of Medicine, University of New Mexico, Albuquerque, NM 87131, USA d  Department of Pathophysiology, Friedrich-Schiller-University, D-07740 Jena, Germany Accepted 19 January 2005 AbstractObjective : Interpretation of Electroencephalography (EEG) signals from newborns is in some cases difficult because the fontanels andopen sutures produce inhomogeneity in skull conductivity. We experimentally determined how EEG is influenced by a hole mimicking theanterior fontanel since distortion of EEG signals is important in neurological examinations during the perinatal period. Methods : Experiments were carried out on 10 anesthetized farm swine. The fontanel was mimicked by a hole (12 ! 12 mm) in the skull.The hole was filled with 3 types of medium differing in conductivity (air, 0 S/m; sucrose–agar, 0.017 S/m; saline–agar, 1.28 S/m). Threepositions of the snout were stimulated with a concentric bipolar electrode to activate cortical areas near the middle, the edge, and the outsideof the hole. The somatic-evoked potential (SEP) was recorded by a 4 ! 4 electrode array with a 4 mm grid spacing. It was placed on the 4quadrants of a 28 ! 28 mm measurement area on a saline-soaked filter paper over the skull, which served as artificial scalp. Results : The SEP over the hole was clearly stronger when the hole was filled with sucrose– or saline–agar as compared to air, althoughparadoxically the leakage current was stronger for the sucrose– than saline–agar. The current leaking from the hole was strongly related toposition of the active tissue. It was nearly negligible for sources 6–10 mm away from the border of the hole. The distortion was different for 3components of the SEP elicited by each stimulus, probably indicating effects of source distance relative to the hole. Conclusions : EEG is strongly distorted by the presence of a hole/fontanel with the distortion specifically dependent on both conductivityof the hole and source location. Significance : The distortion of the EEG is in contrast to the lack of distortion of magnetoencephalography (MEG) signals shown byprevious studies. In studying brain development with EEG, the infant’s head and sources should be modeled accurately in order to relate thesignals to the underlying activity. MEG may be particularly advantageous over EEG for studying brain functions in infants since it isrelatively insensitive to skull defects. q 2005 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved. Keywords:  Electroencephalography; Magnetoencephalography; Evoked response; Somatosensory; Fontanel; Pig; Newborn; Infant 1. Introduction Brain functions of human infants, including pre-term andterm babies, have been traditionally evaluated with EEG aspart of a neurological examination. The evaluation is usefulin infants with risk factors such as complications duringlabor and delivery (Sunshine, 1997). EEG is also useful forstaging the development of the nervous system, sincedifferences in the functional organization of certainbrain regions are already present in newborns (Eiseltet al., 2001), and for differential diagnosis of seizuresfrom non-seizures in the paroxysmal motor behavior Clinical Neurophysiology 116 (2005) 1141–$30.00 q 2005 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved.doi:10.1016/j.clinph.2005.01.007 *  Corresponding author. Address: Department of Neurology, Biomag-netic Center Jena, Friedrich-Schiller-University, D-07740 Jena, Germany. E-mail address: (L. Flemming).  (De Weerd, 1995; Tharp, 1997). However, neonatal EEGmonitoring is still in need of development, particularly inrelating EEG signals to the underlying brain functions.Interpretation of the underlying physiology and patho-physiology is complicated by the presence of the fontanelsand sutures in the skull. The anterior and posterior fontanelsare present at the bregma and the lambda. The skull is notpresent within the fontanels. The brain below the fontanelsis protected by the dura, which is thicker within the opening.The fontanels and sutures are squeezed together duringdelivery, but become larger during the first months and theneventually close. The anterior fontanel may be large enoughto admit an adult’s thumb. The posterior fontanel is closedwithin the first 2 month. The anterior fontanel stays open aslong as 16 months or, in abnormal cases, even for severalyears. The sutures can be quite wide near the fontanels. Themean width of the coronal and lambdoidal sutures at theirmidpositions is 3–4 mm for infants between 0 and 60 daysafter birth (Eramie and Ringertz, 1976). The sutures maystay unfused for several years (Hansman, 1966). EEGsignals may be profoundly affected by the fontanels andsutures, which are effectively skull defects, since theyrepresent areas of high conductivity relative to the skull.Volume currents might be affected by these openings in theskull. Thus, it is necessary to evaluate the effect of theseskull openings on EEG in order to accurately inferphysiological functions in human infants.This report describes distortions of the somatosensory-evoked potentials (SEPs) by a hole in the skull of neonatalpigs. Although the EEG signal distortion by skull defectscan be studied using mathematical models of the head asdiscussed later, we chose to study the problem in anexperimental preparation since such study is rare andempirical assessment always provides a solid foundation forfuture modeling studies. Our results may be useful forinterpreting distortions of EEG signals in humans arisingfrom skull defects like the fontanels and sutures in humaninfants, since the head of the piglet is large and the scalp andskull are comparable to those of human infants in thickness.The neonatal farm swine of 1–3 weeks of age has a skullthickness of 2–3 mm near the vertex, similar to the thicknessin human newborns (Hansman, 1966). Unlike humanneonates, the piglets do not have a fontanel and the suturesare nearly closed at birth. A square hole was, therefore,created in the skull to mimic a fontanel. The SEP distortionwas evaluated as a function of distance of active tissue fromthe hole and for 3 different conductivities of the hole. 2. Materials and methods 2.1. Preparation The protocol used in this study was approved by theAnimal Use Committees of the Albuquerque VeteransAffairs Medical Center and the University of New MexicoSchool of Medicine. Animals were treated according to theNational Institute of Health ‘Guide for the Care and Use of Laboratory Animals, Revised 1996’.Experiments were carried out on 10 farm swine ( Susscrofa ). The weight ranged between 8 and 16 kg and the agebetween 4 and 6 weeks. Pigs were chosen because of theirlarge gyrencephalic brain resembling to some extent thehuman brain. By 3–5 weeks of age, the neocortex of the pighas a well-established 6-layer structure (Craner, 1988).Piglets were sedated and anesthetized with a combinationof ketamine plus xylazine. Initially, the anesthetic agent wasinjected in the gluteal muscle and later in the right cephalicvein. The catheter placed in the right femoral artery wasused for monitoring the blood pressure and for blood gasanalysis. The same catheter was used for the continuousinjection of 0.9% sodium chloride solution (about 5 ml/kgper h). This fluid substitution was necessary to maintainblood volume and blood pressure within physiologicalvalues under the artificial ventilation.Tracheostomy for artificial ventilation was performedafter sedation. The ventilation rate was varied between 14and 18/min and the volume between 150 and 220 ml tomaintain physiological conditions according to the bloodgas parameters of pCO 2  (30–44 mmHg) and pO 2  (90–120 mmHg). During the surgery an anesthetic level of 12 mg/kg per h ketamine plus 1.2 mg/kg per h xylazine wasmaintained. Lidocaine (1%) was used for each surgicalapproach and for the pressure point of the ear bars of ahead holder. The scalp was removed and a square hole of 12 ! 12 mm cut out in the skull over the left hemisphere(Fig. 1). The location of the hole was over the rostrumregion of the primary somatosensory cortex (SI). The durawas kept intact.The level of anesthesia was reduced to 6 mg/kg per h forketamine and 0.6 mg/kg per h for xylazine duringthe measurement.  D -Tubocurarine was injected (0.3 mg/kgper h) after the surgery to avoid involuntary movementsduring the data acquisition. Body-temperature was keptconstant with a thermal jacket at 37–38  8 C. 2.2. Stimulation For the stimulation we used a concentric bipolarelectrode which was a modified 6 mm Genuine GrassAg/AgCl disc electrode with a tungsten needle in the center.The electrode was fixed on the snout with collodion after theinsertion of the needle. In Exp. 1 the concentric bipolarelectrode was placed on the right side of snout with thecentral needle electrode in the location which projected to acortical area below the hole (Fig. 1). In Exp. 2, 3 bipolarelectrodes were fixed on the right part of the snout. Thecentral needle electrodes were placed in the snout locationsthat projected to a cortical area within the skull opening,near the border, and 6–10 mm outside the hole (Fig. 7). Theplacement of the electrode on the snout was based onthe data of  Craner (1988) and Okada et al. (1999a).  L. Flemming et al. / Clinical Neurophysiology 116 (2005) 1141–1152 1142  The stimulus was a brief current pulse (50  m s, 4–7 mA)applied at 1 pulse/s. 2.3. Electrical measurement  The SEP was recorded with a 4 ! 4 Ag–AgCl electrodearray with an electrode spacing of 4 mm that was placed ona 0.9% NaCl saline-soaked filter paper covering the exposedskull. The filter paper served as an artificial scalp. Theelectrode array was moved systematically to cover an areaof 28 ! 28 mm. The reference electrode was attached to theleft ear. The measurements were carried out in anelectromagnetically shielded chamber. The custom madepreamplifier had a gain of 5 and the CyberAmp 380 of AxonInstruments had a gain of 1000. We used a high-pass filter of 0.1 Hz and a low-pass filter of 200 Hz with a sampling rateof 2 kHz and averaged the data across 30 epochs. The 60 Hznoise was removed online. The A/D converter had aresolution of 16 bits and an input range of  K 1 to C 1 V.Thus, we had a resolution of 3 nV.The SEP distribution on the artificial scalp wasmeasured sequentially under the following conditions:(1) air in the hole, (2) isotonic 3% agar containing330 mEq of sucrose (sucrose–agar), (3) isotonic 3% agarcontaining 0.9% NaCl (saline–agar), (4) again withsucrose–agar and (5) finally with air in the hole. Thesucrose and air conditions were repeated to check forpossible changes in the SEP due to changes inphysiological and extraneous conditions. In the agarconditions the sucrose– or saline–agar was poured intothe hole in liquid form with a temperature of less than38  8 C, then the skull was covered with a saline-soakedfilter paper. The SEP measurements were started 10 minlater, after allowing for the agar to gel and for itsconductivity to equilibrate. Additionally, the SEP wasmeasured on the dura beneath the hole in each conditionto monitor possible changes in the SEP directly on thecortex.The resistivities of sucrose– and saline–agar weredetermined with a variation of the classical 4-electrodemethod, by passing a constant 20 ms square-wave current toa pair of large Ag–AgCl electrode plates and measuring thepotential in the agar block at 200  m m steps along thedirection of the applied current through a hole in the top of the plate. The resistivity of sucrose–agar was 280  U m andthat of saline–agar was 0.78  U m at room temperature. Thesevalues correspond to conductivity of 0.0036 and 1.28 S/m,respectively. The resistivity of the sucrose–agar under theexperimental conditions with the saline-soaked filter paperplaced over the agar decreased with the time after placingthe filter paper, going from 199  U m at 10 min to 48  U m at80 min. We estimated that the resistivity during the SEPmeasurement was about 60–120  U m, corresponding toconductivities of 0.016–0.0083 S/m.Two experiments were carried out with each animal. Inthe first experiment, the amplitude distortion of the SEP wasdetermined for an active tissue in the middle of the skullopening (see Fig. 1), which was subjected to a maximumamplitude distortion. The SEP measurements were repeatedtwice at each of 64 locations in order to check for reliability. Fig. 1. Sixty-four-channel EEG measurement of 3 different conductivities within the hole. The position of the hole is marked by the solid square. Themeasurement covered an area of 28 ! 28 mm over the left somatosensory cortex (dotted square). Electrode spacing is 4 mm. Time range from K 10 to 100 ms,low-pass filter of 200 Hz, high-pass filter of 0.5 Hz, and 30 averages.  L. Flemming et al. / Clinical Neurophysiology 116 (2005) 1141–1152  1143  In the second experiment, the amplitude distortion wasdetermined as a function of distance of the active tissuefrom the hole, by activating the cortical areas 4, 7, and 10(Fig. 7). The SEP was measured only once at each electrodeposition in each condition in order to compare the SEPs asmuch as possible under stable physiological conditionsduring the entire experiment.The data from 6 out of 10 animals were used for the finalanalysis of results of Exp. 1 and data from 5 out of 10animals were used for Exp. 2 because of lack of stabilityacross the replications and incomplete set of data in theremaining animals. 2.4. MRI  After the experiment, the brain was perfused and fixedwith 4% formaldehyde under a deep anesthesia. The entirehead was stored in a 4% formaldehyde solution to preservethe shape of the brain for MRI scans. MRI images of thehead were taken on a 4 T Varian scanner. A fast spin echo,multi-slice pulse sequence (Hennig, 1988) with an effectiveecho time (TE) of 45 ms and 16 averages were used. Thepulse sequence had a train of 4 echoes with the center of the k  -space being traversed in the 3rd echo. The in-planeresolution was 0.5 mm ! 0.5 mm and the slice thickness was0.5 mm giving an isotropic voxel of 0.5 mm 3 . A 16 cmquadrature /bird-cage rf coil was used. 2.5. Data processing and source localization The data were filtered with a high-pass filter of 0.3 Hzand a low-pass filter of 200 Hz. The stimulation artifact wasremoved. In the case of Experiment 1 the data from the tworeplications were averaged for the analysis.Source localization was performed at the time instant of the peak of the first cortical response after stimulation(component  c 1, see Fig. 5). A single equivalent currentdipole for the source and a boundary element method(BEM) was used to model the head. The BEM model wasbased on the MRI images of one representative animal. Itconsisted of 3 compartments representing the brain, theskull, and the scalp. The brain was modeled with 2490surface triangles (edge length of 2.5 mm), the skull with3306 surface triangles (edge length 2.5 mm), and the scalpwith 5786 surface triangles (edge length 2.0 mm). For thecompartments we assumed a homogeneous conductivity of 0.25 (brain), 0.013 (skull), and 0.25 (scalp) S/m (Haueisenet al., 1997b).For each animal, the data set of the sucrose–agarcondition was used for the source localization since theconductivity of the sucrose–agar (0.016–0.008 S/m) wasclosest to the conductivity of the skull, estimated to be0.013 S/m. The conductivity difference between thesucrose–agar and the skull was neglected. Source localiz-ation was performed with the software Curry version 4.5. 2.6. Analysis and statistics The Laplacian method was used to estimate the radialcurrent source density  I  m  in the artificial scalp (Babiloniet al., 1996, 1997; Gevins et al., 1994, 1999; He, 1999;Hjorth, 1975; Le et al., 1994; Nunez et al., 1994). Sincethere is no primary source in the artificial scalp, the potentialon the scalp follows the Laplace equation:  s V $ V f e Z 0,where  s  is the conductivity of the scalp,  f e  is thepotential on the scalp,  V f e  is the gradient of the scalppotential and  V $ is the divergence operator on the gradientof the potential. The equation can be written as: sv 2 f e  =  v  x 2 C sv 2 f e  =  v  y 2 Z K sv 2 f e  =  v  z 2 , approximating thelocal scalp surface as a plane, where  v  is the partialdifferential operator. The right-hand side can be re-writtenas:  v  J   z  /  v  z , where  J   z  is the current density along the  z -axisperpendicular to the scalp surface.  v  J   z  /  v  z  can be viewed asan effective current source density K  I  m  in units of A/m 3 thatproduces a divergence of current in the scalp.  I  m  is positivewhen the positive charge is entering the scalp (currentsource) and negative when the positive charge is leaving thescalp(current sink). We estimated  I  m  from a discrete versionof the left-hand side:  s {4 V  (  x 0 ,  y 0 ) K V  ( h ,  y 0 ) K V  ( K h ,  y 0 ) K V  (  x 0 , h ) K V  (  x 0 , K h )}/  h 2 , where  V  (  x ,  y ) are the potentialsmeasured at 5 positions centered at position  x Z  x 0  and  y Z  y 0 (He, 1999). The inter-electrode distance  h Z d  x Z d  y  was4 mm in this study. The value of   s  for the artificial scalp(filter paper soaked with saline) was assumed to be thesame as that of the extracellular conductivity of the brain,0.25 S/m because of the tortuosity produced by the fibers inthe paper. The Laplacian estimate should be applicable evenwhen the underlying geometry of the skull and brain isinhomogeneous as it is the case in the present preparationsince the Laplace equation is locally valid and the artificialscalp is homogeneous.A within-subject repeated ANOVA test was used for thestatistical analyses of both experiments. In the firstexperiment, we determined the effects of the conductivityof the hole, separately on 3 components of the SEPproduced by an active cortical tissue within the hole. Inthe second experiment, we investigated the effect of distance of the active area from the hole and conductivitiesof the hole on the SEP. The Wilcoxon test was also used forthe second experiment. 3. Results 3.1. Experiment 1 The circle in the inset of  Fig. 1 shows the estimatedsource location in the rostrum region (shaded areadelineated by the circular coronal sulcus) of the SI cortexactivated by the snout stimulation. This area was within thesquare 12 ! 12 mm hole created in the skull. The SEPmeasurements were carried out within the dashed square  L. Flemming et al. / Clinical Neurophysiology 116 (2005) 1141–1152 1144  area. The SEP over the hole was larger in the sucrose1–agarcondition compared to the air1 condition in which the holewas filled with a non-conducting medium (namely air).Similarly, the SEP over the hole in the saline–agar conditionwas stronger than in the air condition. The SEP patterns inthe sucrose2–agar and air2 conditions were similar to thesucrose1–agar and air1 conditions, indicating good repro-ducibility of the data.Fig. 2 shows difference maps of the SEPs between thesucrose and air conditions and between the saline and airconditions. The SEPs in air conditions 1 and 2 wereaveraged and the averaged SEP was subtracted from theSEPs in the sucrose and saline conditions. The SEPs werestronger over the hole in the sucrose– and saline–agarconditions as compared to the air condition. In contrast thedifference waves were close to zero at the edges of themeasurement area indicatingthat the effects ofthe hole wereconfined within the area of measurements. The largestdifferences were seen above the hole where the active tissuewas located.These results suggest that the current leaking from thehole was stronger when the hole was filled witha conducting medium. The radial current leaking from thehole can be directly estimated by the Laplacian derivation of the potentials. Fig. 3 shows the Laplacian derivation of thedifference waves in the 3 conditions. This analysisdemonstrates several interesting features. First, the currentclearly leaks through the hole. Second, the amount of current leak is somewhat counter intuitively larger in thesucrose condition than in the saline condition. Third, thepolarity of the waveform is opposite just outside the hole ascompared to the waveforms inside the hole, indicating thatthe current leaking through the intact skull just outside thehole was weaker in the saline– and sucrose–agar conditionscompared to the air condition. This last result is consistentwith the fact that the current leak was stronger in the hole inthese conditions compared to the control condition of thehole filled with air.The Laplacian derivations of the srcinal SEP data inthe 3 conditions provide results that are consistent with theresults from the difference data. Fig. 4 shows the Laplacianof the SEP data in the air, and in the sucrose–agar andsaline–agar conditions averaged across the two replications.In the air condition, the current leaking through the hole was Fig. 2. Difference maps of the 64-channel EEG measurement shown in Fig. 1. Measurement of air1 and air2 were averaged and subtracted from the othermeasurements. The position of the hole is marked by a square. Time range, filters, etc. See Fig. 1.Fig. 3. Laplacian derivation maps of the difference maps shown in Fig. 2. The position of the hole is marked by a square. Time range, filters, etc. See Fig. 1.  L. Flemming et al. / Clinical Neurophysiology 116 (2005) 1141–1152  1145
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