Electrophysiological Demonstration of Motor Reorganization in Healthy Hemispheres of Patients with Intractable Epilepsy due to Early Unilateral Brain Damage

Electrophysiological Demonstration of Motor Reorganization in Healthy Hemispheres of Patients with Intractable Epilepsy due to Early Unilateral Brain Damage | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Electrophysiological Demonstration of Motor Reorganization in Healthy Hemispheres of Patients with Intractable Epilepsy due to Early Unilateral Brain Damage Cihan İşler, Emine Taşkıran, Gülçin Baş, Bengi Gül Türk, Çiğdem Özkara, and 1 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4270427/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Background: The functional reorganization of motor functions is a sign of adaptive brain plasticity to brain damage and understanding its mechanisms may be a key role to many treatment models for brain damage in childhood and even in adults. Our aim is to show an electrophysiological evidence of brain plasticity regarding motor functions in early brain damaged patients. Methods: We retrospectively analyzed four patients with some extremity motor functions shifting to unusual brain areas who were diagnosed with childhood epilepsy and underwent epilepsy surgery. We analyzed their clinical and surgical data particularly including intraoperative neuromonitorization (IONM) results. Results: Patients’ preoperative data showed some motor representation of extremities was located somewhere else than the expected brain areas due to perinatal damage. In first patient right hand presentation was shifted to the right hemisphere and in second patient right hand was represented on both hemispheres. In the remaining two patients, all the motor functions of epileptogenic hemisphere were shifted to the contralateral side. IONM proved the neuroplasticity of the patients with previously crossed motor functions and was in line with preoperative functional Magnetic Resonance Imaging data. Conclusion: Brain plasticity can alter the motor reorganization of the healthy hemisphere by taking upon the functions of the pathological hemisphere. Neural plasticity epilepsy hemsipheretomy intraoperative neuromonitorization Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 Figure 7 Figure 8 Introduction Brain plasticity is the capacity of the central nervous system (CNS) to change structurally and functionally to gain its normal functions during normal brain development, or to gain new functions in response to experience or trauma [8,15]. The ability of CNS to undergo plasticity involves the regulation of neural circuit formation or synaptic connections at genetic, cellular, and molecular levels [7,8,12,15]. While the normal brain development occurs primarily during prenatal and postnatal periods and to a lesser degree adolescence and adulthood, a multilayered, versatile and an overlapping mechanism takes place controlled by intrinsic homeostatic mechanisms with the influence of extrinsic environmental experiences [7,8,12,15]. Although brain plasticity is a natural process and can be adaptive and evolutionary advantageous event of the CNS as in developmental, reactive, and adaptive plasticity, in some cases plasticity becomes a liability for the person in question causing epilepsy and disorders such as Tuberous sclerosis complex or Rett syndrome [9,27]. The maladaptive outcomes of plasticity are devastating and unwelcomed such as in childhood brain disorders, but plasticity is still an intriguing and promising research area to help CNS to regain its lost functions following injuries or in cases of congenital disorders. For example, in the case of adaptive plasticity such as in learning and memory formation, the system responds to normal developmental changes in the internal and external environment and adopts a functionally appropriate phenotype [2,16,17,25]. Or, in the case of reactive plasticity, a functional reorganization takes place in response to brain injury or lesion [3,20,23]. Reorganization of corticospinal tract (CST) following injury as in cerebral palsy (CP) or unilateral ischemia shows the potential of brain plasticity to alter motor reorganization of CNS and through this to prevent the development of motor deficits or to maintain a life with minimal deficits. Similar to individuals with CP or other patients who have suffered early brain damage, epilepsy patients in childhood with early brain damage may benefit from this motor reorganization too, like our cases which will be discussed hereafter. An epilepsy patient with a unilateral brain damage or lesion can undergo functional hemispherotomy surgery in which subcortical connections from a portion of brain to other areas are disconnected, and the patient hereby naturally will be expected to have contralateral motor palsy due to the disconnection of CST. However, it does not always work out this way and in some patients, motor deficit may not develop, or just a mild paralysis observed, which can be attributed to motor reorganization. Data related to motor or other functions’ reorganization of CNS in literature is relatively conducted from the results of functional Magnetic Resonance Imaging (fMRI) and/or Transcranial Magnetic Stimulation (TMS) studies [1,6,19]. We hereby present four cases of epilepsy patients with unilateral early brain damage and pre-operative evidence of motor reorganization at various levels. Through these surgeries we aimed to show the electrophysiological evidence of motor reorganization by intraoperative neuromonitoring (IONM). Methods Patients who underwent epilepsy surgery due to unilateral drug-resistant hemispheric or multilobar lesions with neural plasticity documented by IONM between 2017 and 2022 were retrospectively analyzed. All patients or their legal representatives gave their legal informed consent for the procedure and the study was approved by the local institutional review board (IRB). Intraoperative neuromonitoring Bilateral muscles were selected for IONM in order to assess the motor shift. At least one face muscle (usually orbicularis oris), bilateral hyoglossus, distal muscles of the upper and lower extremities (abductor policis brevis, extensor digitorum, adductor hallucis brevis, and tibialis anterior) and proximal muscles (biceps, deltoid, quadriceps) were selected for the registration of motor evoked potentials (MEP) in all cases. Scalp electrodes for stimulation (C1, C2, C3, C4, Cz for motor) and recording (C3’, C4’, Cz’, and Fz for sensorial evoked potential (SEP)) were placed according to the international Electroencephalography (EEG) 10-20 system. MEP monitoring was obtained, if possible, from both scalp (transcranial) and direct cortical stimulation via the strip electrode. Transcranial (tc) MEP responses were obtained by electrical stimulation with screw electrodes (C1/C2 and/or C3/Cz points for left hemisphere; C2/C1 and/or C4/Cz for right hemisphere). Monopolar high-frequency short train stimulation technique was used for mapping and monitoring, with anodal in cortical, and cathodal in subcortical stimulation [28]. In our settings, it consisted of 5-6 stimuli, each stimulus with 0.5 millisecond[7] duration, 3-4 ms interstimulus interval, 250-333 Hz. for monitoring and mapping. For these cases, muscle MEP responses were recorded bilaterally to the cortical electrical stimulations while using the minimal stimulus intensity to avoid stimulation of the subcortical deep structures. Bilateral tresholds for each muscle group were compared. Tc electrical stimulation for baseline MEP recordings were performed in all patients before the beginning of the surgery. Following the duratomy, SEPs were recorded by stimulating the median and tibial nerves using a 4- or 8- contact strip electrode positioned perpendicular to the central sulcal orientation. Phase reversal response was sought to accurately localize the electrophysiological central sulcus. This step was followed by direct cortical(dc) motor mapping by monopolar cortical stimulation. Maximal cortical stimulation amplitude was set to 25 mA. Baseline MEP response thresholds were recorded. Compared to baseline threshold, an increase of more than 5 mA in dc MEP and/or a decrease in amplitude of more than 50% in tc MEP were considered as the warning criteria for MEP monitoring [18]. Anesthesia Total intravenous anesthesia (TIVA) consisted of a combination of propofol and remifentanil was administered. Neuromuscular blockade was only used at the induction phase with short acting agents. During MEP monitoring, a protective handmade mouth pad was placed into mouth of the patient to prevent tongue and teeth damage. Surgery and Follow up All patients were operated on with IONM under TIVA. Optical neuronavigation device (StealthStation S7 and S8, Medtronic) was also used to adjust skin incision and craniotomy. All patients were examined pre-operatively and post-operatively. Follow-ups were at first month, third month, six month and first year after surgery at least. Results Case 1 First patient was with no known perinatal history but with right hand spastic paresis, incompetency with fine motor movements and with a muscle strength of 4/5 in proximal part of right upper extremity, 3/5 in hand, and very mild paresis in right lower extremity. Patient’s seizures began when 8 years old as tonic contractions in right hand. Cranial MRI revealed wide atrophy and encephalomalacia in left hemisphere (Fig. 1a). EEG findings were consistent with diffuse suppression in the left hemisphere and epileptiform activity in the occipital region. According to fMRI speech and right upper extremity motor functions of the patient were represented at the right hemisphere (Fig. 1b), whereas the right lower extremity motor functions remained in the left hemisphere (Fig. 1d). With Phase I investigations a functional hemispheretomy was indicated for intractable seizures. However, due to the preserved motor functions in the left hemisphere, a modification of left functional hemispherotomy that spares the motor cortex and its projection fibers was planned. IONM and neuronavigation were both applied during the surgery. Tc MEP was not optimal due to wide surgical incision and inability to place stimulation electrodes on the scalp in the appropriate positions. IONM findings: Suboptimal tc electrical stimulation of the left hemisphere elicited muscle MEP responses only in the right lower extremity before the beginning of the surgery (Fig. 2a,b). Phase reversal on SEP responses was not detected through a strip electrode perpendicular to the sulci by stimulation of the right median nerve. However, when the right tibial nerve stimulated, phase reversal was observed on SEP responses between two consecutive contacts. Afterwards, cortical motor mapping was initiated using anodal stimulation at 10mA over the exposed cortex. The right lower extremity motor representation was found to be localized within the precentral gyrus in close proximity to the midline at 20 mA (Fig. 2d,e). The stimulation amplitude was gradually increased to a maximum of 25 mA, at which point epileptic after-discharges were observed on EEG. However, the motor representation of the right upper extremity was not found within the exposed cortical area. Cortical motor thresholds for the muscles of the right lower extremity remained stable during the surgery. The right tibial SEP disappeared while the left did not (Fig. 2c). During white matter dissection, safe distance from the CST were regularly checked with cathodal stimulation. Even with stimulation of the CST with higher amplitude did not reveal any motor response from the right upper extremity which clearly proved total shift of the right upper extremity motor functions to the contralateral hemisphere. Immediately after the operation, the patient’s hemiparesis was increased on the right extremities compared to the pre-operative condition. An early post-operative cranial MRI was taken for routine control. Motor muscle strength was 2/5 in right proximal upper extremity and 1/5 in right hand on postoperative first day, whereas left extremities were similar to pre-operative motor strength. Up to postoperative seventh day, muscle strength was gradually increased on the right, and the patient was discharged as ambulatory without assistance. On postoperative third month, patient’s motor functions were back to basal condition. The pathology sent from the temporal lobe reported as Focal Cortical Dysplasia Type 1b. In last follow-up in 2023, patient’s muscle strength of the right upper and lower extremities was exactly same as the pre-operative condition. Patient’s fMRI (Fig. 1c and 1e) and Diffusion Tensor Tractography (DTT) (Fig. 1f) results on postoperative fifth year has showed the right hand and foot representation remained at the same locations and seizure outcome was Engel Class IA and ILAE Class I at the sixth post-operative year. Case 2 The second patient was with no known perinatal history. Seizures started at the age of 11 as focal to bilateral tonic-clonic seizures, and the patient was diagnosed to have Methylenetetrahydrofolate reductase (MTHFR) deficiency at that time. The patient had a motor muscle strength of 4/5 in the right upper extremity. Cranial MRI showed sequalae encephalomalacia areas in the left inferior frontal gyrus, insular cortex and superior temporal gyrus extending to external and internal capsule (Fig. 3a). EEG results showed diffuse suppression in the left hemisphere and neuronal hyperexcitability in the left frontocentral region. fMRI findings revealed that right hand presentation were on both hemispheres’ cortex (Fig. 3b) and right foot representation was in the left hemisphere (Fig. 3c). Due to possible perinatal damage in left hemisphere related to the hand area and the motor deficit of right upper extremity, no final decision could be made whether the right hand presentation was shifted to the right hemisphere or is represented by both hemispheres. After the phase I investigations, a left sided functional hemispherotomy that spares the motor, especially the related hand region, cortex and its projection fibers was decided to be performed to the patient due to the preserved motor functions on the left hemisphere (Fig. 4c). IONM findings: In this case, we were able to perform tc stimulation. MEP responses from the muscles on the right upper extremity with tc stimulation of the left hemisphere before the beginning of the surgery were obtained which showed that there was a representation of right upper extremity in the left hemiphere. Central sulcus localization was defined between the 2nd and 3rd contacts of the strip electrode (Fig. 4a) by phase reversal technique by median SEP after opening the dura (Fig. 4d). Cortical motor mapping showed the right upper extremity responses on the exposed cortical area in the left hemisphere. (Fig. 4b and 4e). The subcortical motor stimulus threshold from the resection cavity to the CST was 5 mA and it was obtained from right upper extremity muscles as well. At the end of the surgery, tc MEP responses of the right upper extremity muscles were lost, and amplitude decreased more than 50% while staying at the same threshold on dc MEP. The patient woke up with a mild worsened paresis in right upper extremity (4/5) and right hand (3/5) than before. On postoperative first day, a cranial MRI was taken for routine control. Up to postoperative tenth day, muscle strength was gradually increased, and the patient was discharged with physical therapy recommendation. On postoperative third month, patient’s motor functions were back to basal values. The pathological diagnosis of the parenchyma with encephalomalacia was subpial gliosis compatible with chronic ischemia. In last follow-up in 2023, patient’s only deficit was in right upper extremity with a muscle strength of 4/5, and incompetency in fine motor movements. fMRI results postoperatively on fifth year showed right hand (Fig. 3d) and foot (Fig. 3e) representation stayed the same. Follow-up time was six years with Engel Class IA and ILAE Class I outcomes. Case 3 The third patient was a patient with epilepsy with oral automatism seizures in sleep. There was no previous history of perinatal or postnatal injury recorded. The patient had right hemiparesis more prominently in hand and foot with a muscle strength of 4/5, 3/5 in foot, spasticity in hand and foot. Cranial MRI results had showed wide polymicrogyria and cortical dysplasia in left frontal and insular lobe extending to the central sulcus (Fig. 5a,b). fMRI showed right hand and foot motor activity was traced mostly in right hemisphere’s precentral gyrus and a little on the medial face of left hemisphere’s paracentral lobule (Fig. 5c,d,e ). Interictal Positron Emission Tomography (PET)-MR results had showed bilateral hypometabolism in mesial temporal lobes which was more prominent on the left. EEG results had showed continuous epileptiform activity in both frontocentral and frontotemporal areas which was more prominent on the left also. Due to inconsistencies between PET-MR and EEG and other cranial imaging during Phase I studies, the epilepsy team decided for Phase II to determine the following treatment. The patient underwent Stereoelectroencephalography (SEEG) of the left hemisphere (Fig. 5f,g,h). During SEEG monitorization, functional mapping with deep-brain electrodes was performed and no motor or speech functions were affected. After seven days with SEEG monitorization phase II studies showed that the seizures originated from the polymicrogyric precentral gyrus on the left hemisphere and the patient underwent left lesionectomy carried out with IONM and neuronavigation. IONM findings: MEP responses on the right extremities were not obtained from tc stimulation of the left hemisphere. However, tc stimulation of the right hemisphere via C2/C1 and C4/Cz points at the low stimulus intensity (120 and 130V) elicited bilateral MEP responses with similar latency. When stimulus threshold was increased to 300V to the left hemisphere via C1/C2, MEP responses obtained from the right extremities. However, those responses were thought to be originated from the stimulation of deep CST. Following the dural opening, cortical motor mapping was negative, meaning that no MEP responses were obtained from the exposed cortical area. The surgery went without any complication. MEP and SEP monitoring remained stable during the surgery. At the immediate post-operative period, the motor examination was the same as pre-operative findings. A routine cranial MRI was taken on the postoperative first day (Fig. 6a, b). The pathological diagnosis was polymicrogyria. Last follow-up revealed still seizure freedom (Engel IA and ILAE I) at post-operative third year. fMRI on the post-operative third year showed right hand (Fig. 6c) and foot (Fig. 6d) representation was still in the right hemisphere as before the surgery. Case 4 The patient was presented with staring, jerking movements or focal to bilateral tonic-clonic seizures. Medical history was uneventful except for seizures which started when 2 months old. Patient had also no previous history of perinatal injury that was recorded, however had spastic right hemiparesis with a muscle strength of 4/5, more prominent in distal extremities. Cranial MRI was consistent with encephalomalacia as a sequelae of stroke in the left medial cerebral artery watershed area (Fig. 7a). fMRI showed that motor representation of right extremities was found on the right hemisphere (Fig. 7c and 7e). EEG revealed epileptiform activity related to the left hemisphere motor network and burn-out phenomena on the right hemisphere. After Phase I epilepsy studies, the patient underwent left periinsular functional hemispherotomy with the aid of IONM and neuronavigation. IONM findings: MEP responses from the left upper extremity were obtained at 80V by tc stimulation of the right hemisphere, whereas responses from the right upper extremity (ipsilateral response) and bilateral lower extremities appeared at 100V and 150V, respectively. MEP responses of the right extremities were not obtained by tc electrical stimulation of the left hemisphere within normal limits of the stimulation. However, bilateral upper and lower extremity responses by stimulation of the left hemisphere were elicited at 250V which is higher than normal limits, can be explained by subcortical deep white matter stimulation of the right hemisphere. SEP responses of the left extremities were recorded on the right hemisphere whereas SEP responses of the right extremities were not elicited. Following the dural opening, cortical motor mapping was negative on the exposed cortex of the left hemisphere. Resection was accompanied by intermittent subcortical stimulation. The subcortical deep white matter stimulation interestingly showed responses from the left extremities at 18 mA (Fig. 8a), while stimulation with 20 mA at the same location revealed bilateral motor responses from all extremities (Fig. 8b). This finding let us to conclude that, as a result of neuroplastical process the fibers of the shifted motor function were located lateral to the native corticospinal fibers on the right hemisphere. Tc MEP and SEP recordings were similar to the baseline recordings at the end of the surgery. After the surgery, motor examination was the same as before the surgery. On the post-operative third day, a routine cranial MRI was taken (Fig. 7b). The pathological diagnosis was cortical lacunae formation in subpial areas and surrounding gliosis. fMRI on post-operative first year showed that right hand (Fig. 7d) and foot (Fig. 7f) presentation is on right hemisphere. Last follow-up was at the first year after the surgery with an Engel IA and ILAE I seizure outcome. Discussion We hereby present four cases of epilepsy patients with unilateral early brain damage and per-operative evidence of motor reorganization at various levels. The two last cases were shown to have complete shift of motor functions to the contralateral hemisphere according to pre-operative studies. Therefore, their surgeries (hemsipheretomy and lesionectomy, respectively) did not cause any change in their neurological examination post-operatively. In the second case, right hand presentation was on both hemispheres and in the first case, right hand presentation was shifted to the right hemisphere. In order to protect the motor functions of the patients, a modified functional hemispherotomy with sparing motor cortex and its projections was performed as epilepsy surgery after which both patients had temporary change in their motor functions that returned to pre-operative status within three months. Interestingly, Case 1 who initially presented with a pre-operative motor deficit in the right upper extremity, experienced an additional transient motor deficit in the same extremity. This occured despite both fMRI and IONM confirming the motor representation of the right upper extremity to be shifted to the contralateral hemisphere. Thorough these surgeries we aimed to show the electrophysiological evidence of motor reorganization with intraoperative neuromonitoring (IONM) findings. The timing of the injury and the neurodevelopmental stage at that moment guides brain plasticity mechanisms. Several studies on animals and humans with TMS showed that at early stages in development the corticospinal tracts have both contralateral and ipsilateral projections [10,23,24]. When maturity is reached, the ipsilateral projections are eliminated near total and contralateral projections are strengthened [10]. A study by Eyre et al showed that, in the first 15 months after birth, thresholds and amplitudes for ipsilateral and contralateral responses did not show significant differences. However, beyond 15 months, a noteworthy decrease in the thresholds of ipsilateral responses was observed. This suggests that synaptic competition leading to the elimination of ipsilateral projections, may initiate or intensify around the 15 months after birth. Also, in this study, the finding of the small and late ipsilateral responses observed in older children and adults suggests that the persistence of a small ipsilateral corticomotoneuronal projection is potent in both children and adults [11]. Early unilateral lesions before the aforementioned competitive elimination can result in plastic reorganization of the corticospinal tract in which the ipsilateral projections from the healthy hemisphere can compete stronger than that of the contralateral pathological hemisphere and leading to healthy hemisphere to control bilateral motor functions of the body [11]. Several animal and human studies with TMS and fMRI supported these findings in children and adults with perinatal brain injuries [1,5,10,11,13,23,24,29]. TMS is currently the chosen method for stimulating motor activity in human brain due to its non-invasive and painless nature. Since the mapping accuracy of a single pulse TMS (spTMS) for determining motor area is currently debatable, its reliability is not certain and should be further investigated [4,14,21,22,26]. To our knowledge, there are no electrophysiological data using tc and/or cortical electrical stimulation in human studies. In all the patients, there was no previous recorded history of perinatal or childhood brain injury. However, their radiological data revealed unilateral congenital or acquired pathology. We conducted a comprehensive study of MEP recordings of the last two patients, examining both healthy and pathological hemispheres using tc direct stimulation, cortical and subcortical stimulation which we consider more accurate and reliable. During tc stimulation on the pathological side, MEP responses that should have been elicited in the contralateral extremities either were not obtained or were obtained with higher voltages. This suggests the possibility of originating from the stimulation of the contralateral white matter. In all patients, cortical direct electrical stimulation findings were compatible with pre-operative fMRI data. In the first case, the right upper extremity representation was not found on the left hemisphere with cortical stimulation, but lower extremity motor functions were present at expected location. In the last two cases, no motor representation belonging to the right side of the body was found on left hemisphere. Our study shows that an early impaired development of a hemisphere due to a perinatal injury or congenital anomaly, resulted that the healthy hemisphere takes upon motor functions of the pathological hemisphere. The lack of TMS system at our institution has limited us to compare our findings with TMS. However, we believe direct electrical stimulation shows more reliable results than that of the TMS and to our knowledge, this study is the first of its kind. Moreover, TMS may prove the plasticity by stimulation of the healthy hemisphere, but may not be able to show whether there are any residual functions of the pathological hemisphere. In this study, we have directly proved neural plasticity in humans by several ways: First, tc stimulations may show similar responses to TMS of the healthy hemisphere. However, both of them can be considered indirect methods. But these findings further supported by direct cortical stimulations. Second, fMRI and tractographic data were proven with direct stimulation of both cortex and projection fibers. Third, relying on electrophysiological data have proved neuroplasticity in our patients with preserved motor functions following the surgery. Conclusions In this article, we attempted to draw attention to neuroplasticity in early brain damage proved by intraoperative neuromonitorization. We believe that understanding the capacity and limitations of neuroplasticity allows extensive neurosurgical interventions without further motor complications. Declarations Competing Interests: The authors declare no competing interests. Funding: The authors did not receive support from any organization for the submitted work. Ethics Approval: This study was approved by the local institutional review board (IRB). All patients or their legal representatives gave their legal informed consent for the procedure. The authors affirm that human research participants provided informed consent for publication of the images in all figures. Credit Authorship Contribution Statement: Cihan İşler: Conceptualization, Methodology, Visualization, Resources, Writing – review and editing. Emine Taşkıran: Methodology, Writing – review and editing. Gülçin Baş: Data curation, Investigation, Visualization, Resources, Writing – original draft. Bengi Gül Türk: Validation, Writing – review and editing. Çiğdem Özkara: Validation, Writing – review and editing. Mustafa Uzan: Conceptualization, Methodology, Visualization, Resources, Writing – review and editing, Supervision. References Artzi, M., Shiran, S. 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Two types of ipsilateral reorganization in congenital hemiparesis: a TMS and fMRI study. Brain , 125 (Pt 10), 2222-2237. https://doi.org/10.1093/brain/awf227 Stein, M., Federspiel, A., Koenig, T., Wirth, M., Strik, W., Wiest, R., Brandeis, D., & Dierks, T. (2012). Structural plasticity in the language system related to increased second language proficiency. Cortex , 48 (4), 458-465. https://doi.org/10.1016/j.cortex.2010.10.007 Su, B., Jia, Y., Zhang, L., Li, D., Shen, Q., Wang, C., Chen, Y., Gao, F., Wei, J., Huang, G., Liu, H., & Wang, L. (2022). Reliability of TMS measurements using conventional hand-hold method with different numbers of stimuli for tibialis anterior muscle in healthy adults. Front Neural Circuits , 16 , 986669. https://doi.org/10.3389/fncir.2022.986669 Tamura, Y., Ueki, Y., Lin, P., Vorbach, S., Mima, T., Kakigi, R., & Hallett, M. (2009). Disordered plasticity in the primary somatosensory cortex in focal hand dystonia. Brain , 132 (Pt 3), 749-755. https://doi.org/10.1093/brain/awn348 Taniguchi, M., Cedzich, C., & Schramm, J. (1993). Modification of cortical stimulation for motor evoked potentials under general anesthesia: technical description. Neurosurgery , 32 (2), 219-226. https://doi.org/10.1227/00006123-199302000-00011 Umeda, T., & Funakoshi, K. (2014). Reorganization of motor circuits after neonatal hemidecortication. Neurosci Res , 78 , 30-37. https://doi.org/10.1016/j.neures.2013.08.011 Additional Declarations No competing interests reported. Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-4270427","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":292571948,"identity":"4de09df7-5370-4794-a19f-560a44c4d473","order_by":0,"name":"Cihan İşler","email":"","orcid":"","institution":"İstanbul University-Cerrahpaşa Cerrahpaşa Faculty of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Cihan","middleName":"","lastName":"İşler","suffix":""},{"id":292571949,"identity":"a4f0b239-f1dc-4d6f-b401-ca7e05242a15","order_by":1,"name":"Emine Taşkıran","email":"","orcid":"","institution":"İstanbul University-Cerrahpaşa Cerrahpaşa Faculty of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Emine","middleName":"","lastName":"Taşkıran","suffix":""},{"id":292571950,"identity":"dde503f4-eb9b-458c-b2fd-7771d0718a21","order_by":2,"name":"Gülçin Baş","email":"","orcid":"","institution":"İstanbul University-Cerrahpaşa Cerrahpaşa Faculty of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Gülçin","middleName":"","lastName":"Baş","suffix":""},{"id":292571951,"identity":"1b4ed760-beaf-46e5-9ee2-abb2ab6c6a74","order_by":3,"name":"Bengi Gül Türk","email":"","orcid":"","institution":"İstanbul University-Cerrahpaşa Cerrahpaşa Faculty of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Bengi","middleName":"Gül","lastName":"Türk","suffix":""},{"id":292571952,"identity":"e3c60d0c-18bc-4abf-b511-e17cda918b5b","order_by":4,"name":"Çiğdem Özkara","email":"","orcid":"","institution":"İstanbul University-Cerrahpaşa Cerrahpaşa Faculty of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Çiğdem","middleName":"","lastName":"Özkara","suffix":""},{"id":292571953,"identity":"165c76a5-be8c-4d82-bd89-a22fc0d8b2e6","order_by":5,"name":"Mustafa Uzan","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAAqElEQVRIiWNgGAWjYLCCDwZgyoB4HYwz4FoSiNTCzMNAihaD84efPbYpOCzPwN68TYLxxz0itBw4Zm6cY3DYsIHnWJkEQ0IxEVoONphJA7UkMEjkmAG1EOEyg8Ps36QtQFrk3xCr5RiPmTQD2BYeIrVInuEpk+wxSDds40krtkhII0IL3/nj2yR+/LGW52c/vPHGBxsitMABG4ggRcMoGAWjYBSMAjwAAHp8Lz9NcFOGAAAAAElFTkSuQmCC","orcid":"","institution":"İstanbul University-Cerrahpaşa Cerrahpaşa Faculty of Medicine","correspondingAuthor":true,"prefix":"","firstName":"Mustafa","middleName":"","lastName":"Uzan","suffix":""}],"badges":[],"createdAt":"2024-04-15 14:38:20","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-4270427/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-4270427/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":55323840,"identity":"8b7b98b5-6e8b-4168-aec3-afbac54ef76f","added_by":"auto","created_at":"2024-04-25 16:46:29","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":10210173,"visible":true,"origin":"","legend":"\u003cp\u003ePre-operative and post-operative imaging of the first case. Pre-operative coronal T2-weighted Cranial MR images showing wide atrophia and encephalomalacia on the left hemisphere (a). Pre-operative (b) and post-operative (c) fMRI showing right hand motor representation on the right hemisphere’s precentral gyrus whereas right foot representation is still on the left hemisphere’s precentral gyrus, near to the midline at both pre- (d) and post-operative (e) fMRI. Post-operative DTI showing corticospinal tract in the left hemisphere remained intact (f).\u003c/p\u003e","description":"","filename":"Figure1.png","url":"https://assets-eu.researchsquare.com/files/rs-4270427/v1/500a359a878f6df4f27d9628.png"},{"id":55323843,"identity":"1c428337-6acc-421d-b3f2-31bb61e0236b","added_by":"auto","created_at":"2024-04-25 16:46:29","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":12834332,"visible":true,"origin":"","legend":"\u003cp\u003eIONM screenshots of the case 1. Transcranial electrical stimulation of the left hemisphere elicited muscle MEP responses only in the right lower extremity (a), while transcranial stimulation of the right hemisphere elicited MEP responses from the left upper and lower extremities (b). Bilateral tibial SEP recordings at baseline (lower row; green) and at the end of surgery (upper row; pink) that demonstrates loss of right tibial SEP recording on the left hemisphere (c). Direct cortical stimulation on the left hemisphere elicited motor responses (yellow waves) of the right lower extremity only (d). Snapshot of the neuronavigation screen showing the most lateral stimulation point that elicited MEP response. (e). Recordings at baseline are shown green (lower row) and final response in pink (upper row) Abbreviations: L:left, R:right, TRAP: trapezius muscle, EDC: extensor digitorum communis muscle, APB: abductor pollicis brevis muscle, QUAD: quadriceps femoris muscle, TIBIALIS: Tibialis anterior muscle, AH: adductor hallucis muscle.\u003c/p\u003e","description":"","filename":"Figure2.png","url":"https://assets-eu.researchsquare.com/files/rs-4270427/v1/67808878c8f2cfab1967370a.png"},{"id":55323849,"identity":"40fbe5c5-5f99-4bcc-a6d7-f96c451595cd","added_by":"auto","created_at":"2024-04-25 16:46:30","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":7790143,"visible":true,"origin":"","legend":"\u003cp\u003ePre-operative and post-operative imaging of the second case. Pre-operative axial T2-weighted Cranial MRI images showing \u0026nbsp;sequalae encephalomalacia areas in the left inferior frontal gyrus, insular cortex and superior temporal gyrus extending to external and internal capsule (a). Pre-operative fMRI showing right hand motor representation on both hemispheres’ precentral gyrus (b) whereas right foot representation is on left hemisphere’s reciprocal area midline (c). Post-operative fMRI showing right hand motor representation on both hemispheres’ precentral gyrus (d) whereas right foot representation is on both hemispheres, still (e).\u003c/p\u003e","description":"","filename":"Figure3.png","url":"https://assets-eu.researchsquare.com/files/rs-4270427/v1/cb8792402e85d94c71b071b6.png"},{"id":55323847,"identity":"9e447990-c0df-4620-9269-b988a04cb4f7","added_by":"auto","created_at":"2024-04-25 16:46:30","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":929188,"visible":true,"origin":"","legend":"\u003cp\u003eIONM and peri-operative images of the second case. Phase reversal responses (d) showing central sulcus is between second and third contact of the cortical strip electrode (a). Direct cortical stimulation on the left hemisphere showing right upper extremity responses on the exposed cortex (e) which was marked on left cortex (b). \u0026nbsp;The resection margins at the end of the surgery (c). Abbreviations: R: right, L: left, ORB ORIS: orbicularis oris, MASS: masseter muscles, HIPO: hypoglosus muscle, TRPZ: trapezius muscle, DLT: deltoid muscle, BCP: biceps muscle, EDC: extensor digitorum muscle, APB: abductor pollicis brevis muscle, VL: quadriceps femoris muscle, TA: tibialis anterior muscle, GAST: gastrocnemius muscle, AH: adductor hallucis muscle.\u003c/p\u003e","description":"","filename":"Figure4.png","url":"https://assets-eu.researchsquare.com/files/rs-4270427/v1/6686eef4317800c89b7d59d7.png"},{"id":55323841,"identity":"a090373b-d39a-40b8-b01a-6215ba1404b4","added_by":"auto","created_at":"2024-04-25 16:46:29","extension":"png","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":13178106,"visible":true,"origin":"","legend":"\u003cp\u003ePre-operative sagittal T2-weighted (a) and axial T1-weighted (b) images of the third case showing wide polymicrogyria and cortical dysplasia in left frontal and insular lobe extending to the central sulcus. Pre-operative fMRI images of the case showing right hand presentation is on right hemisphere’s precentral gyrus (c),both hands presentationare on the right hemisphere (d) and right foot representation is mostly on right hemisphere as well (e). SEEG images that are shown in the following; peri-operative image of electrodes on neuronavigation device (f), post-operative 3D CT-scan of the patient after SEEG implantation (g) and the cut electrodes during the second surgery after opening the dura (h).\u003c/p\u003e","description":"","filename":"Figure5.png","url":"https://assets-eu.researchsquare.com/files/rs-4270427/v1/dedfd91c8e45c8ccf4772805.png"},{"id":55323844,"identity":"8106d2f3-9168-4f58-9dac-06b7bf6b41d6","added_by":"auto","created_at":"2024-04-25 16:46:30","extension":"png","order_by":6,"title":"Figure 6","display":"","copyAsset":false,"role":"figure","size":13174617,"visible":true,"origin":"","legend":"\u003cp\u003ePost-operative images of the third case. T2-weighted sagittal (a) and T1-weighted axial slices (b) of the post-operative MRI. Post-operative fMRI showing right hand presentation (c) and right foot presentation (d) are on right hemisphere.\u003c/p\u003e","description":"","filename":"Figure6.png","url":"https://assets-eu.researchsquare.com/files/rs-4270427/v1/a094198b07f7fdf4fa7fa571.png"},{"id":55323846,"identity":"28a27a95-d4cf-4ba3-a944-31898b40a61c","added_by":"auto","created_at":"2024-04-25 16:46:30","extension":"png","order_by":7,"title":"Figure 7","display":"","copyAsset":false,"role":"figure","size":24054105,"visible":true,"origin":"","legend":"\u003cp\u003eT2-weighted Cranial MRI images of the fourth case pre-operatively. There is sequelae of encephalomalacia in the left medial cerebral artery watershed area, first row axial, second row sagittal and third row coronal sections of the imaging (a). Post-operative T2-weighted images showing resection margins (b). Right hand presentation of fMRI showing it is on the right hemisphere pre-operatively (c) and post-operatively (d). Right foot presentation also is on the right hemisphere pre-operatively (e) and post-operatively (f).\u003c/p\u003e","description":"","filename":"Figure7.png","url":"https://assets-eu.researchsquare.com/files/rs-4270427/v1/9bddb3dc2a9b579c958f62fe.png"},{"id":55323845,"identity":"12376406-6a31-4bff-b003-66483d398623","added_by":"auto","created_at":"2024-04-25 16:46:30","extension":"png","order_by":8,"title":"Figure 8","display":"","copyAsset":false,"role":"figure","size":14050824,"visible":true,"origin":"","legend":"\u003cp\u003ePossible explanation for IONM findings during stimulation of the deep white matter within the surgical cavity of Case 4. \u0026nbsp;Stimulation at 18 mA elicited MEP responses from the left extremities (a), while stimulation at 20 mA at the same location revealed bilateral motor responses from all extremities(b). This observation suggests a potential organization of decussating corticospinal fibers (blue) located medially to the fibers descending without decussation (red).\u003c/p\u003e","description":"","filename":"Figure8.png","url":"https://assets-eu.researchsquare.com/files/rs-4270427/v1/deefaa6ba6c2a470a3d4012c.png"},{"id":56346870,"identity":"a5f97ef2-40e4-4234-99ec-b3f280a40d8c","added_by":"auto","created_at":"2024-05-13 02:38:34","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":8251621,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4270427/v1/b0503dc5-63db-4caa-a6ef-d953c0700b72.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Electrophysiological Demonstration of Motor Reorganization in Healthy Hemispheres of Patients with Intractable Epilepsy due to Early Unilateral Brain Damage","fulltext":[{"header":"Introduction","content":"\u003cp\u003eBrain plasticity is the capacity of the central nervous system (CNS) to change structurally and \u0026nbsp;\u0026nbsp;functionally to gain its normal functions during normal brain development, or to gain\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;new functions in response to experience or trauma\u0026nbsp;[8,15]. The ability of CNS to undergo\u0026nbsp;plasticity involves the regulation of neural circuit formation or synaptic connections at genetic, cellular, and molecular levels\u0026nbsp;[7,8,12,15]. While the normal brain development occurs\u0026nbsp;primarily during prenatal and postnatal periods and to a lesser degree adolescence and adulthood, a multilayered, versatile and an overlapping mechanism takes place controlled by\u0026nbsp;intrinsic homeostatic mechanisms with the influence of extrinsic environmental experiences\u0026nbsp;[7,8,12,15]. Although brain plasticity is a natural process and can be adaptive and evolutionary advantageous event of the CNS as in developmental, reactive, and adaptive plasticity, in some cases plasticity becomes a liability for the person in question causing epilepsy and disorders\u0026nbsp;such as Tuberous sclerosis complex or Rett syndrome\u0026nbsp;[9,27]. The maladaptive outcomes of\u0026nbsp;plasticity are devastating and unwelcomed such as in childhood brain disorders, but plasticity\u0026nbsp;is still an intriguing and promising research area to help CNS to regain its lost functions\u0026nbsp;following injuries\u0026nbsp;or in cases of congenital disorders. For example, in the case of adaptive plasticity such\u0026nbsp;as in learning and memory formation, the system responds to normal developmental changes\u0026nbsp;in the internal and external environment and adopts a functionally appropriate phenotype\u0026nbsp;[2,16,17,25]. Or, in the case of reactive plasticity, a functional reorganization takes place in response to\u0026nbsp;brain injury or lesion\u0026nbsp;[3,20,23]. Reorganization of corticospinal tract (CST) following injury as in cerebral palsy (CP) or unilateral ischemia shows the potential of brain plasticity to alter motor reorganization of CNS and through this to prevent the development of motor deficits or to maintain a life with minimal deficits.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eSimilar to individuals with CP or other patients who have suffered early brain damage, epilepsy patients in childhood with early brain damage may benefit from this motor reorganization too, like our cases which will be discussed hereafter. An epilepsy patient with a unilateral brain damage or lesion can undergo functional hemispherotomy surgery in which subcortical connections from a portion of brain to other areas are disconnected, and the patient hereby naturally will be expected to have contralateral motor palsy due to the disconnection of CST. However, it does not always work out this way and in some patients, motor deficit may not develop, or just a mild paralysis observed, which can be attributed to motor reorganization. Data related to motor or other functions\u0026rsquo; reorganization of CNS in literature is relatively conducted from the results of functional Magnetic Resonance Imaging (fMRI) and/or Transcranial Magnetic Stimulation (TMS) studies\u0026nbsp;[1,6,19].\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eWe hereby present four cases of epilepsy patients with unilateral early brain damage and pre-operative evidence of motor reorganization at various levels. Through these surgeries we aimed to show the electrophysiological evidence of motor reorganization by intraoperative neuromonitoring (IONM).\u003c/p\u003e"},{"header":"Methods","content":"\u003cp\u003ePatients who underwent epilepsy surgery due to unilateral drug-resistant hemispheric or multilobar lesions with neural plasticity documented by IONM between 2017 and 2022 were retrospectively analyzed. All patients or their legal representatives gave their legal informed consent for the procedure and the study was approved by the local institutional review board (IRB).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eIntraoperative neuromonitoring\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eBilateral muscles were selected for IONM in order to assess the motor shift. At least one face muscle (usually orbicularis oris), bilateral hyoglossus, distal muscles of the upper and lower extremities (abductor policis brevis, extensor digitorum, adductor hallucis brevis, and tibialis anterior) and proximal muscles (biceps, deltoid, quadriceps) were selected for the registration of motor evoked potentials (MEP) in all cases.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eScalp electrodes for stimulation (C1, C2, C3, C4, Cz for motor) and recording (C3\u0026rsquo;, C4\u0026rsquo;, Cz\u0026rsquo;, and Fz for sensorial evoked potential (SEP)) were placed according to the international Electroencephalography (EEG) 10-20 system. MEP monitoring was obtained, if possible, from both scalp (transcranial) and direct cortical stimulation via the strip electrode. Transcranial (tc) MEP responses were obtained by electrical stimulation with screw electrodes (C1/C2 and/or C3/Cz points for left hemisphere; C2/C1 and/or C4/Cz for right hemisphere). Monopolar high-frequency short train stimulation technique was used for mapping and monitoring, with anodal in cortical, and cathodal in subcortical stimulation\u0026nbsp;[28]. In our settings, it consisted of 5-6 stimuli, each stimulus with 0.5 millisecond[7]\u0026nbsp;duration, 3-4 ms interstimulus interval, 250-333 Hz. for monitoring and mapping. For these cases, muscle MEP responses were recorded bilaterally to the cortical electrical stimulations while using the minimal stimulus intensity to avoid stimulation of the subcortical deep structures. Bilateral tresholds for each muscle group were compared.\u003c/p\u003e\n\u003cp\u003eTc electrical stimulation for baseline MEP recordings were performed in all patients before the \u0026nbsp; \u0026nbsp;\u0026nbsp;beginning of the surgery. Following the duratomy, SEPs were recorded by stimulating the median and tibial nerves using a 4- or 8- contact strip electrode positioned perpendicular to the central sulcal orientation. Phase reversal response was sought to accurately localize the electrophysiological central sulcus. This step was followed by direct cortical(dc) motor mapping by monopolar cortical stimulation. Maximal cortical stimulation amplitude was set to 25 mA. Baseline MEP response thresholds were recorded.\u003c/p\u003e\n\u003cp\u003eCompared to baseline threshold, an increase of more than 5 mA in dc MEP and/or a decrease in amplitude of more than 50% in tc MEP were considered as the warning criteria for MEP monitoring\u0026nbsp;[18].\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAnesthesia\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eTotal intravenous anesthesia (TIVA) consisted of a combination of propofol and remifentanil was administered. Neuromuscular blockade was only used at the induction phase with short acting agents. During MEP monitoring, a protective handmade mouth pad was placed into mouth of the patient to prevent tongue and teeth damage.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eSurgery and Follow up\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll patients were operated on with IONM under TIVA. Optical neuronavigation device (StealthStation S7 and S8, Medtronic) was also used to adjust skin incision and craniotomy. All patients were examined pre-operatively and post-operatively. Follow-ups were at first month, third month, six month and first year after surgery at least.\u0026nbsp;\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003e\u003cstrong\u003eCase 1\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eFirst patient was with no known perinatal history \u0026nbsp; but with right hand spastic paresis, incompetency with fine motor movements and with a muscle strength of 4/5 in proximal part of right upper extremity, 3/5 in hand, and very mild paresis in right lower extremity. Patient\u0026rsquo;s seizures began when 8 years old as tonic contractions in right hand. Cranial MRI revealed wide atrophy and encephalomalacia in left hemisphere (Fig. 1a). EEG findings were consistent with diffuse suppression in the left hemisphere and epileptiform activity in the occipital region. According to \u0026nbsp; fMRI speech and right upper extremity motor functions of the patient were represented at the right hemisphere (Fig. 1b), whereas the right lower extremity motor functions remained in the left hemisphere (Fig. 1d).\u003c/p\u003e\n\u003cp\u003eWith Phase I investigations a functional hemispheretomy was indicated for intractable seizures. However, due to the preserved motor functions in the left hemisphere, a modification of left functional hemispherotomy that spares the motor cortex and its projection fibers was planned.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eIONM and neuronavigation were both applied during the surgery. Tc MEP was not optimal due to wide surgical incision and inability to place stimulation electrodes on the scalp in the appropriate positions.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eIONM findings: Suboptimal tc electrical stimulation of the left hemisphere elicited muscle MEP responses only in the right lower extremity before the beginning of the surgery (Fig. 2a,b). Phase reversal on SEP responses was not detected through a strip electrode perpendicular to the sulci by stimulation of the right median nerve. However, when the right tibial nerve stimulated, phase reversal was observed on SEP responses between two consecutive contacts. Afterwards, cortical motor mapping was initiated using anodal stimulation at 10mA over the exposed cortex. The right lower extremity motor representation was found to be localized within the precentral gyrus in close proximity to the midline at 20 mA (Fig. 2d,e). The stimulation amplitude was gradually increased to a maximum of 25 mA, at which point epileptic after-discharges were observed on EEG. However, the motor representation of the right upper extremity was not found within the exposed cortical area. Cortical motor thresholds for the muscles of the right lower extremity remained stable during the surgery. The right tibial SEP disappeared while the left did not (Fig. 2c). During white matter dissection, safe distance from the CST were regularly checked with cathodal stimulation. Even with stimulation of the CST with higher amplitude did not reveal any motor response from the right upper extremity which clearly proved total shift of the right upper extremity motor functions to the contralateral hemisphere.\u003c/p\u003e\n\u003cp\u003eImmediately after the operation, the patient\u0026rsquo;s hemiparesis was increased on the right extremities compared to the pre-operative condition. An early post-operative cranial MRI was taken for routine control. Motor muscle strength was 2/5 in right proximal upper extremity and 1/5 in right hand on postoperative first day, whereas left extremities were similar to pre-operative motor strength. Up to postoperative seventh day, muscle strength was gradually increased on the right, and the patient was discharged as ambulatory without assistance. On postoperative third month, patient\u0026rsquo;s\u0026nbsp;motor functions were back to basal condition. The pathology sent from the temporal lobe reported as\u0026nbsp;Focal Cortical Dysplasia Type 1b. In last follow-up in 2023, patient\u0026rsquo;s muscle strength of the right upper and lower extremities was exactly same as the pre-operative condition. Patient\u0026rsquo;s fMRI (Fig. 1c and 1e) and Diffusion Tensor Tractography (DTT) (Fig. 1f) results on postoperative fifth year has showed the right hand and foot representation remained at the same locations and seizure outcome was Engel Class IA and ILAE Class I at the sixth post-operative year.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCase 2\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe second patient was with no known perinatal history. Seizures started at the age of 11 as focal to bilateral tonic-clonic seizures, and the patient was \u0026nbsp; diagnosed to have Methylenetetrahydrofolate reductase (MTHFR) deficiency at that time. The patient had a motor muscle strength of 4/5 in the right upper extremity. Cranial MRI showed sequalae encephalomalacia areas in the left inferior frontal gyrus, insular cortex and superior temporal gyrus extending to external and internal capsule (Fig. 3a). EEG results showed diffuse suppression in the left hemisphere and neuronal hyperexcitability in the left frontocentral region. fMRI findings revealed that right hand presentation were on both hemispheres\u0026rsquo; cortex (Fig. 3b) and right foot representation was in the left hemisphere (Fig. 3c). Due to possible perinatal damage in left hemisphere related to the hand area and the motor deficit of right upper extremity, no final decision could be made whether the right hand presentation was shifted to the right hemisphere or is represented by both hemispheres.\u003c/p\u003e\n\u003cp\u003eAfter the phase I investigations, a left sided functional hemispherotomy that spares the motor, especially the related hand region, cortex and its projection fibers was decided to be performed to the patient due to the preserved motor functions on the left hemisphere (Fig. 4c).\u003c/p\u003e\n\u003cp\u003eIONM findings: In this case, we were able to perform tc stimulation. MEP responses from the muscles on the right upper extremity with tc stimulation of the left hemisphere before the beginning of the surgery were obtained which showed that there was a representation of right upper extremity in the left hemiphere. \u0026nbsp; Central sulcus localization was defined between the 2nd and 3rd contacts of the strip electrode (Fig. 4a) by phase reversal technique by median SEP after opening the dura (Fig. 4d). Cortical motor mapping showed the right upper extremity responses on the exposed cortical area in the left hemisphere. (Fig. 4b and 4e). The subcortical motor stimulus threshold from the resection cavity to the CST was 5 mA and it was obtained from right upper extremity muscles as well. At the end of the surgery, tc MEP responses of the right upper extremity muscles were lost, and amplitude decreased more than 50% while staying at the same threshold on dc MEP.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe patient woke up with a mild worsened paresis in right\u0026nbsp;upper extremity (4/5) and right hand (3/5) than before. On postoperative first day, a cranial MRI was taken for routine control. Up to postoperative tenth day,\u0026nbsp;muscle strength was gradually increased, and the patient was discharged with physical therapy\u0026nbsp;recommendation. On postoperative third month, patient\u0026rsquo;s motor functions were back to basal\u0026nbsp;values. The pathological diagnosis of the parenchyma with encephalomalacia was subpial\u0026nbsp;gliosis compatible with chronic ischemia. In last follow-up in 2023, patient\u0026rsquo;s only deficit was in right upper extremity with a muscle strength of 4/5, and incompetency in fine motor movements. fMRI results postoperatively on fifth year showed right hand (Fig. 3d) and foot (Fig. 3e) representation stayed the same. Follow-up time was six years with Engel Class IA and ILAE Class I outcomes.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCase 3\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe third patient was a patient with epilepsy with oral automatism seizures in sleep. There was no previous history of perinatal or postnatal injury recorded. The patient had right hemiparesis more prominently in hand and foot with a muscle strength of 4/5, 3/5 in foot, spasticity in hand and foot. Cranial MRI results had showed wide polymicrogyria and cortical dysplasia in left frontal and insular lobe extending to the central sulcus (Fig. 5a,b). fMRI showed right hand and foot motor activity was traced mostly in right hemisphere\u0026rsquo;s precentral gyrus and a little on the medial face of left hemisphere\u0026rsquo;s paracentral lobule (Fig. 5c,d,e ). Interictal Positron Emission Tomography (PET)-MR results had showed bilateral hypometabolism in mesial temporal lobes which was more prominent on the left. EEG results had showed continuous epileptiform activity in both frontocentral and frontotemporal areas which was more prominent on the left also. Due to inconsistencies between PET-MR and EEG and other cranial imaging during Phase I studies, the epilepsy team decided for Phase II to determine the following treatment. The patient underwent Stereoelectroencephalography (SEEG) of the left hemisphere (Fig. 5f,g,h). During SEEG monitorization, functional mapping with deep-brain electrodes was performed and no motor or speech functions were affected. After seven days with SEEG monitorization phase II studies showed that the seizures originated from the polymicrogyric precentral gyrus on the left hemisphere and the patient underwent left lesionectomy carried out with IONM and neuronavigation.\u003c/p\u003e\n\u003cp\u003eIONM findings: MEP responses on the right extremities were not obtained from tc stimulation of the left hemisphere. However, tc stimulation of the right hemisphere via C2/C1 and C4/Cz points at the low stimulus intensity (120 and 130V) elicited bilateral MEP responses with similar latency. When stimulus threshold was increased to 300V to the left hemisphere via C1/C2, MEP responses obtained from the right extremities. However, those responses were thought to be originated from the stimulation of deep CST. Following the dural opening, cortical motor mapping was negative, meaning that no MEP responses were obtained from the exposed cortical area. The surgery went without any complication. MEP and SEP monitoring remained stable during the surgery. At the immediate post-operative period, the motor examination was the same as pre-operative findings. A routine cranial MRI was taken on the postoperative first day (Fig. 6a, b).\u003c/p\u003e\n\u003cp\u003eThe pathological diagnosis was polymicrogyria. Last follow-up revealed still seizure freedom (Engel IA and ILAE I) at post-operative third year. fMRI on the post-operative third year showed right hand (Fig. 6c) and foot (Fig. 6d) representation was still in the right hemisphere as before the surgery.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCase 4\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe patient was presented with staring, jerking movements or focal to bilateral tonic-clonic seizures. Medical history was uneventful except for seizures which started when 2 months old. Patient had also no previous history of perinatal injury that was recorded, however had spastic right hemiparesis with a muscle strength of 4/5, more prominent in distal extremities. \u0026nbsp;Cranial MRI was consistent with encephalomalacia as a sequelae of stroke in the left medial cerebral artery watershed area (Fig. 7a). fMRI showed that motor representation of right extremities was found on the right hemisphere (Fig. 7c and 7e). EEG revealed epileptiform activity related to the left hemisphere motor network and burn-out phenomena on the right hemisphere. After Phase I epilepsy studies, the patient underwent left periinsular functional hemispherotomy with the aid of IONM and neuronavigation.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eIONM findings: MEP responses from the left upper extremity were obtained at 80V by tc stimulation of the right hemisphere, whereas responses from the right upper extremity (ipsilateral response) and bilateral lower extremities appeared at 100V and 150V, respectively. MEP responses of the right extremities were not obtained by tc electrical stimulation of the left hemisphere within normal limits of the stimulation. However, bilateral upper and lower extremity responses by stimulation of the left hemisphere were elicited at 250V which is higher than normal limits, can be explained by subcortical deep white matter stimulation of the right hemisphere. SEP responses of the left extremities were recorded on the right hemisphere whereas SEP responses of the right extremities were not elicited.\u003c/p\u003e\n\u003cp\u003eFollowing the dural opening, cortical motor mapping was negative on the exposed cortex of the left hemisphere. Resection was accompanied by intermittent subcortical stimulation. The subcortical deep white matter stimulation interestingly showed responses from the left extremities at 18 mA (Fig. 8a), while stimulation with 20 mA at the same location revealed bilateral motor responses from all extremities (Fig. 8b). This finding let us to conclude that, as a result of neuroplastical process the fibers of the shifted motor function were located lateral to the native corticospinal fibers on the right hemisphere. Tc MEP and SEP recordings were similar to the baseline recordings at the end of the surgery.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eAfter the surgery, motor examination was the same as before the surgery. On the post-operative third day, a routine cranial MRI was taken (Fig. 7b). The pathological diagnosis was\u0026nbsp;cortical lacunae formation in subpial areas and surrounding gliosis. fMRI on post-operative first year showed that right hand (Fig. 7d) and foot (Fig. 7f) presentation is on right hemisphere. Last follow-up was at the\u003csup\u003e\u0026nbsp;\u003c/sup\u003efirst year after the surgery with an Engel IA and ILAE I seizure outcome.\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eWe hereby present four cases of epilepsy patients with unilateral early brain damage and per-operative evidence of motor reorganization at various levels. The two last cases were shown to have complete shift of motor functions to the contralateral hemisphere according to pre-operative studies. Therefore, their surgeries (hemsipheretomy and lesionectomy, respectively) did not cause any change in their neurological examination post-operatively. In the second case, right hand presentation was on both hemispheres and in the first case, right hand presentation was shifted to the right hemisphere. In order to protect the motor functions of the patients, a modified functional hemispherotomy with sparing motor cortex and its projections was performed as epilepsy surgery after which both patients had temporary change in their motor functions that returned to pre-operative status within three months. Interestingly, Case 1 who initially presented with a pre-operative motor deficit in the right upper extremity, experienced an additional transient motor deficit in the same extremity. This occured despite both fMRI and IONM confirming the motor representation of the right upper extremity to be shifted to the contralateral hemisphere. Thorough these surgeries we aimed to show the electrophysiological evidence of motor reorganization with intraoperative neuromonitoring (IONM) findings.\u003c/p\u003e\n\u003cp\u003eThe timing of the injury and the neurodevelopmental stage at that moment guides brain\u0026nbsp;plasticity mechanisms. Several studies on animals and humans with TMS showed that at early stages in development the corticospinal tracts have both\u0026nbsp;contralateral and ipsilateral projections\u0026nbsp;[10,23,24]. When\u0026nbsp;maturity is reached, the ipsilateral projections are eliminated near total and contralateral\u0026nbsp;projections are strengthened\u0026nbsp;[10]. A study by Eyre \u003cem\u003eet al\u0026nbsp;\u003c/em\u003eshowed that, in the\u0026nbsp;first 15\u0026nbsp;months\u0026nbsp;after\u0026nbsp;birth,\u0026nbsp;thresholds and amplitudes for ipsilateral and contralateral responses did not show significant differences. However, beyond\u0026nbsp;15\u0026nbsp;months, a noteworthy decrease in the\u0026nbsp;thresholds of\u0026nbsp;ipsilateral\u0026nbsp;responses\u0026nbsp;was observed.\u0026nbsp;This suggests that synaptic competition leading to the elimination of\u0026nbsp;ipsilateral projections, may initiate or intensify around the 15 months after birth. Also, in this study, the finding of the small and late ipsilateral responses observed in older children and adults suggests that the persistence of a small ipsilateral corticomotoneuronal projection is \u0026nbsp;\u0026nbsp;potent in both children and adults\u0026nbsp;[11]. Early unilateral lesions before the aforementioned competitive elimination can result in plastic reorganization of the corticospinal tract in which the ipsilateral projections from the healthy hemisphere can compete stronger than that of the contralateral pathological hemisphere and leading to healthy hemisphere to control bilateral\u0026nbsp;motor functions of the body\u0026nbsp;[11]. Several animal and human studies with TMS and fMRI supported these findings in children and adults with perinatal brain injuries\u0026nbsp;[1,5,10,11,13,23,24,29].\u003c/p\u003e\n\u003cp\u003eTMS is currently the chosen method for stimulating motor activity in human brain due to its\u0026nbsp;non-invasive and painless nature. Since the mapping accuracy of a single pulse TMS (spTMS)\u0026nbsp;for determining motor area is currently debatable, its reliability\u0026nbsp;is not certain and should be further investigated\u0026nbsp;[4,14,21,22,26]. To our knowledge, there are no electrophysiological data using tc and/or cortical electrical stimulation in human studies.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eIn all the patients, there was no previous recorded history of perinatal or childhood brain injury. However, their radiological data revealed unilateral congenital or acquired pathology. We conducted a comprehensive study of MEP recordings of the last two patients, examining both healthy and pathological hemispheres using tc direct stimulation, cortical and subcortical stimulation which we consider more accurate and reliable. During tc stimulation on the pathological side, MEP responses that should have been elicited in the contralateral extremities either were not obtained or were obtained with higher voltages. This suggests the possibility of originating from the stimulation of the contralateral white matter.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eIn all patients, cortical direct electrical stimulation findings were compatible with pre-operative fMRI data. In the first case, the right upper extremity representation was not found on the left hemisphere with cortical stimulation, but lower extremity motor functions were present at expected location. In the last two cases, no motor representation belonging to the right side of the body was found on left hemisphere. Our study shows that an early impaired development of a hemisphere due to a perinatal injury or congenital anomaly, resulted that the healthy hemisphere takes upon motor functions of the pathological hemisphere. The lack of TMS system at our institution has limited us to compare our findings with TMS. However, we believe direct electrical stimulation shows more reliable results than that of the TMS and to our knowledge, this study is the first of its kind. Moreover, TMS may prove the plasticity by stimulation of the healthy hemisphere, but may not be able to show whether there are any residual functions of the pathological hemisphere. In this study, we have directly proved neural plasticity in humans by several ways: First, tc stimulations may show similar responses to TMS of the healthy hemisphere. However, both of them can be considered indirect methods. But these findings further supported by direct cortical stimulations. Second, fMRI and tractographic data were proven with direct stimulation of both cortex and projection fibers. Third, relying on electrophysiological data have proved neuroplasticity in our patients with preserved motor functions following the surgery.\u003c/p\u003e"},{"header":"Conclusions","content":"\u003cp\u003eIn this article, we attempted to draw attention to neuroplasticity in early brain damage proved by intraoperative neuromonitorization. We\u0026nbsp;believe that understanding the capacity and limitations of neuroplasticity allows extensive neurosurgical interventions without further motor complications.\u003c/p\u003e\n"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eCompeting Interests:\u0026nbsp;\u003c/strong\u003eThe authors declare no competing interests.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding:\u0026nbsp;\u003c/strong\u003eThe authors did not receive support from any organization for the submitted work.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics Approval:\u003c/strong\u003e This study was approved by the local institutional review board (IRB). All patients or their legal representatives gave their legal informed consent for the procedure. The authors affirm that human research participants provided informed consent for publication of the images in all figures.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCredit Authorship Contribution Statement:\u0026nbsp;\u003c/strong\u003eCihan İşler:\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003eConceptualization, Methodology, Visualization, Resources, Writing \u0026ndash; review and editing. Emine Taşkıran: Methodology, Writing \u0026ndash; review and editing. G\u0026uuml;l\u0026ccedil;in Baş: Data curation, Investigation, Visualization, Resources, Writing \u0026ndash; original draft. Bengi G\u0026uuml;l T\u0026uuml;rk: Validation, Writing \u0026ndash; review and editing. \u0026Ccedil;iğdem \u0026Ouml;zkara: Validation, Writing \u0026ndash; review and editing. Mustafa Uzan: Conceptualization, Methodology, Visualization, Resources, Writing \u0026ndash; review and editing, Supervision.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eArtzi, M., Shiran, S. I., Weinstein, M., Myers, V., Tarrasch, R., Schertz, M., Fattal-Valevski, A., Miller, E., Gordon, A. M., Green, D., \u0026amp; Ben Bashat, D. (2016). Cortical Reorganization following Injury Early in Life. \u003cem\u003eNeural Plast\u003c/em\u003e,\u003cem\u003e 2016\u003c/em\u003e, 8615872. https://doi.org/10.1155/2016/8615872 \u003c/li\u003e\n\u003cli\u003eBerken, J. A., Gracco, V. L., \u0026amp; Klein, D. (2017). Early bilingualism, language attainment, and brain development. \u003cem\u003eNeuropsychologia\u003c/em\u003e,\u003cem\u003e 98\u003c/em\u003e, 220-227. https://doi.org/10.1016/j.neuropsychologia.2016.08.031 \u003c/li\u003e\n\u003cli\u003eCastellanos, N. P., Pa\u0026uacute;l, N., Ord\u0026oacute;\u0026ntilde;ez, V. 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Reorganization of motor circuits after neonatal hemidecortication. \u003cem\u003eNeurosci Res\u003c/em\u003e,\u003cem\u003e 78\u003c/em\u003e, 30-37. https://doi.org/10.1016/j.neures.2013.08.011 \u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Neural plasticity, epilepsy, hemsipheretomy, intraoperative neuromonitorization","lastPublishedDoi":"10.21203/rs.3.rs-4270427/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4270427/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eBackground: The functional reorganization of motor functions is a sign of adaptive brain plasticity to brain damage and understanding its mechanisms may be a key role to many treatment models for brain damage in childhood and even in adults. Our aim is to show an electrophysiological evidence of brain plasticity regarding \u0026nbsp;motor functions in early brain damaged patients.\u003c/p\u003e\n\u003cp\u003eMethods: We retrospectively analyzed four patients with some extremity motor functions shifting to unusual brain areas who were diagnosed with childhood epilepsy and underwent epilepsy surgery. We analyzed their clinical and surgical \u0026nbsp;data particularly including intraoperative neuromonitorization (IONM) results.\u003c/p\u003e\n\u003cp\u003eResults: Patients’ preoperative data showed some motor representation of extremities was located somewhere else than the expected brain areas due to perinatal damage. In first patient right hand presentation was shifted to the right hemisphere and in second patient right hand was represented on both hemispheres. In the remaining two patients, all the \u0026nbsp;motor functions of epileptogenic hemisphere were shifted to the contralateral side. IONM proved the neuroplasticity of the patients with previously crossed motor functions and was in line with preoperative functional Magnetic Resonance Imaging data.\u003c/p\u003e\n\u003cp\u003eConclusion: Brain plasticity can alter the motor reorganization of the healthy hemisphere by taking upon the functions of the pathological hemisphere.\u003c/p\u003e","manuscriptTitle":"Electrophysiological Demonstration of Motor Reorganization in Healthy Hemispheres of Patients with Intractable Epilepsy due to Early Unilateral Brain Damage","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-04-25 16:46:24","doi":"10.21203/rs.3.rs-4270427/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"bcc0004a-309d-4ee1-bdec-b86462e2f85e","owner":[],"postedDate":"April 25th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2024-05-13T02:30:24+00:00","versionOfRecord":[],"versionCreatedAt":"2024-04-25 16:46:24","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-4270427","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4270427","identity":"rs-4270427","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}