The study was approved by the IRB of Peking University First Hospital, and written informed consent was obtained from all participants.
NOTE: All children with intractable epilepsy who underwent frontal disconnection at the Pediatric Epilepsy Center of Peking University First Hospital from January 1, 2017, to March 1, 2022, were included and analyzed. Those who met the clinical and radiological criteria of MOGHE and whose MRI suggested that the epileptogenic lesion was confined to the frontal lobe were included. The histopathological diagnostic criteria for MOGHE have been previously described6. Semiology, ictal and interictal electroencephalography (EEG), magnetic resonance imaging (MRI), interictal 18fluorodeoxyglucose positron emission tomography (PET), and developmental assessment were performed for preoperative evaluation. Children over 7 years of age were evaluated by the Wechsler Intelligence Scale-IV, and children under 7 years of age were evaluated by the Griffith Developmental Assessment Scale. The outcome of epilepsy was evaluated by the ILAE classification, and patients with an ILAE 1 were considered seizure-free8. Semiology was divided into 3 groups (focal, spasm/generalized seizure, and mixed type). Interictal EEG was divided into focal (regional discharge), multifocal (several unilateral hemispheric regional discharges), and diffuse (contralateral involved). Ictal EEG was divided into focal (regional onset), diffuse (unilateral hemispheric onset or nonlocalizing EEG), and focal/diffuse (coexistence of 2 patterns)9. Based on the typing of MOGHE by Hartlieb et al.7, the MRI findings of the 8 patients were also classified as type 1 (Figure 1A, B) or type 2. Figure 1 shows representative intraoperative photos and pre-and postoperative images of frontal disconnection in patient 8.
1. Positioning
<ol>
	<li>Administer general anesthesia to the patient using standard techniques.</li>
	<li>Locate the Sylvian fissure, coronal suture, and central sulcus according to anatomical landmarks as a reference for drawing surgical incision lines. Make a &#34;7&#34;-shaped skin incision 1.0 cm off the midline and 2-3 cm anterior to the coronal suture. Ensure that the posterior margin of the incision includes the precentral gyrus and extends down to the pterygoid region (Figure 1D)</li>
	<li>Place the patient supine with the head turned to the opposite side. Place a shoulder pad under the shoulder to help the head turn.</li>
	<li>Maintain sterile conditions throughout the procedure by sterilely preparing the skin and draping the surgical area.</li>
</ol>
2. Opening
<ol>
	<li>Incise the scalp and muscles. Take care to cut the muscles in layers.</li>
	<li>Separate the scalp and periosteum with a scalpel. 
	NOTE: Preservation of the periosteum reduces postoperative subcutaneous hydrops.</li>
	<li>Drill three 1 cm holes using a high-speed drill of 1 cm diameter and mill down the bone flap with a 1 mm wide milling cutter. 
	NOTE: Adequate exposure of the sphenoid ridge is required to facilitate subsequent disconnection of the frontal base.</li>
	<li>Use bone wax, gelatin sponge, and bipolar cautery to achieve hemostasis.</li>
	<li>Drill 4-5 1 mm holes in the bone margin and suspend the dura to avoid epidural hematoma.</li>
	<li>Cut open the dura 0.5 cm away from the bone margin. Expose the precentral gyrus, the posterior part of the inferior frontal gyrus, and the beginning of the lateral fissure. (Figure 1E)</li>
</ol>
3. Frontal disconnection procedures
<ol>
	<li>Use the stereotactic system software for surgical planning before surgery. Import the 3D T1, flair weighted images, and PET data into the software for registration and 3D reconstruction10. 
	NOTE: The precentral sulcus was delineated by a 3D coregistration. Intraoperative mapping of the central gyrus was not performed (Figure 1C).</li>
	<li>Select the area with the most severe abnormality on preoperative imaging for histological examination.</li>
	<li>Resect the posterior part of the inferior frontal gyrus to fully expose the 1 and 2 short gyri of the insula. 
	NOTE: In children under 5 years of age with suspected frontal MOGHE, preservation of the speech area is not considered in order to maximize the extent of disconnection of the epileptogenic zone.</li>
	<li>Disconnect the base of the frontal lobe and the fibers along the anterior insula to the sphenoid ridge and then to the midline. 
	NOTE: The anterior cerebral artery and the olfactory triangle are landmarks of the posterior boundary of the disconnection. The gyrus rectus is located medial to the olfactory nerve, and the disconnection of the base of the frontal lobe needs to reach the midline pia. The contralateral brain tissue must be well preserved.</li>
	<li>Dissect the gray and white matter along the precentral sulcus. The boundary of disconnection at the midline is the cerebral falx, and down to the cingulate gyrus, disconnect it accordingly.
	<ol>
		<li>When performing intrafrontal disconnection along the precentral sulcus, disconnect the white matter under the bottom of the sulcus slightly forward to make the pyramidal tract intact.</li>
		<li>On the other hand, because MOGHE is a white matter lesion with blurred gray-white matter boundaries, perform a sufficiently deep resection/disconnection to achieve the highest chance of seizure freedom.</li>
	</ol>
	</li>
	<li>Incise the corpus callosum to open the ipsilateral ventricles, dissect the arcuate fibers completely along the top of the ventricles to the anterior horn, and then meet the frontal base disconnection line. 
	NOTE: The entire anterior lateral ventricle is completely open so far.</li>
	<li>Disconnect the anterior corpus callosum to the anterior commissure within the lateral ventricles, where the posterior portion of the frontobasal disconnection reaches the level of the callosal disconnection.</li>
	<li>Expose the anterior cerebral artery, which can be an anatomical landmark in the disconnection of the corpus callosum. Finally, resect the paraterminal gyrus and posterior gyrus rectus behind the anterior cerebral artery with suction. 
	NOTE: The frontobasal disconnection should be complete, including the paraterminal gyrus and posterior gyrus rectus; otherwise, the seizure outcome will be greatly affected. Frontal disconnection is frequently accompanied by resection of the 1 or/and 2 insular short gyri according to the preoperative evaluation, thereby facilitating a more comprehensive excision of the epileptogenic zone. The photos after disconnection and postoperative MRI are shown in Figure 1. Resection of the 1 and 2 short insular gyri should be actively considered, especially if preoperative MRI and PET suggest abnormalities.</li>
</ol>
4. Closure
<ol>
	<li>Suture the dura with 4-0 absorbable sutures to achieve a tight closure.</li>
	<li>Place an epidural drain for 2 days.</li>
	<li>Fix the bone using 3 absorbable cranial bone locks.</li>
	<li>Close the subcutaneous layer with 4-0 subcuticular sutures.</li>
	<li>Suture the skin with a stapler.</li>
</ol>

MOGHE and Epilepsy: Outcomes of Frontal Disconnection Surgery 

<ol>
	<li>Oegema, R., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=International+consensus+recommendations+on+the+diagnostic+work-up+for+malformations+of+cortical+development.">International consensus recommendations on the diagnostic work-up for malformations of cortical development.</a> Nat Rev Neurol. 16 (11), 618-635 (2020).</li><li>Najm, I., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=The+ilae+consensus+classification+of+focal+cortical+dysplasia:+An+update+proposed+by+an+ad+hoc+task+force+of+the+ILAE+diagnostic+methods+commission.">The ilae consensus classification of focal cortical dysplasia: An update proposed by an ad hoc task force of the ILAE diagnostic methods commission.</a> Epilepsia. 63 (8), 1899-1919 (2022).</li><li>Coras, R., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Proliferative+oligodendroglial+hyperplasia+in+epilepsy+(poghe):+A+novel+diagnostic+entity.">Proliferative oligodendroglial hyperplasia in epilepsy (poghe): A novel diagnostic entity.</a> Epilepsia. 54, 318-318 (2013).</li><li>Schurr, J., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Mild+malformation+of+cortical+development+with+oligodendroglial+hyperplasia+in+frontal+lobe+epilepsy:+A+new+clinico-pathological+entity.">Mild malformation of cortical development with oligodendroglial hyperplasia in frontal lobe epilepsy: A new clinico-pathological entity.</a> Brain Pathol. 27 (1), 26-35 (2017).</li><li>Garganis, K., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Temporal+lobe+&amp;#34;plus&amp;#34;+epilepsy+associated+with+oligodendroglial+hyperplasia+(MOGHE).">Temporal lobe &amp;#34;plus&amp;#34; epilepsy associated with oligodendroglial hyperplasia (MOGHE).</a> Acta Neurol Scand. 140 (4), 296-300 (2019).</li><li>Liu, X. Y., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Clinical+characteristics+and+surgical+outcomes+in+children+with+mild+malformation+of+cortical+development+and+oligodendroglial+hyperplasia+in+epilepsy.">Clinical characteristics and surgical outcomes in children with mild malformation of cortical development and oligodendroglial hyperplasia in epilepsy.</a> Epilepsia Open. 8 (3), 898-911 (2023).</li><li>Hartlieb, T., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Age-related+MR+characteristics+in+mild+malformation+of+cortical+development+with+oligodendroglial+hyperplasia+and+epilepsy+(MOGHE).">Age-related MR characteristics in mild malformation of cortical development with oligodendroglial hyperplasia and epilepsy (MOGHE).</a> Epilepsy Behav. 91, 68-74 (2019).</li><li>Wieser, H. G., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Proposal+for+a+new+classification+of+outcome+with+respect+to+epileptic+seizures+following+epilepsy+surgery.">Proposal for a new classification of outcome with respect to epileptic seizures following epilepsy surgery.</a> Epilepsia. 42 (2), 282-286 (2001).</li><li>Wang, Y., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Disconnection+surgery+in+pediatric+epilepsy:+A+single+center's+experience+with+185+cases.">Disconnection surgery in pediatric epilepsy: A single center's experience with 185 cases.</a> Neurosurgery. 93 (6), 1251-1258 (2023).</li><li>Wang, Y., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Seizure+and+cognitive+outcomes+of+posterior+quadrantic+disconnection:+A+series+of+12+pediatric+patients.">Seizure and cognitive outcomes of posterior quadrantic disconnection: A series of 12 pediatric patients.</a> Br J Neurosurg. 34 (6), 677-682 (2020).</li><li>Gaballa, A., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Clinical+characteristics+and+postoperative+seizure+outcome+in+patients+with+mild+malformation+of+cortical+development+and+oligodendroglial+hyperplasia.">Clinical characteristics and postoperative seizure outcome in patients with mild malformation of cortical development and oligodendroglial hyperplasia.</a> Epilepsia. 62 (12), 2920-2931 (2021).</li><li>Barba, C., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Clinical+features,+neuropathology,+and+surgical+outcome+in+patients+with+refractory+epilepsy+and+brain+somatic+variants+in+the+slc35a2+gene.">Clinical features, neuropathology, and surgical outcome in patients with refractory epilepsy and brain somatic variants in the slc35a2 gene.</a> Neurology. 100 (5), e528-e542 (2023).</li><li>Garganis, K., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Frontal+lobe+epilepsy+and+mild+malformation+with+oligodendroglial+hyperplasia:+Further+observations+on+electroclinical+and+imaging+phenotypes,+and+surgical+perspectives.">Frontal lobe epilepsy and mild malformation with oligodendroglial hyperplasia: Further observations on electroclinical and imaging phenotypes, and surgical perspectives.</a> Epileptic Disord. 25 (3), 343-359 (2023).</li><li>Willard, A., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Seizure+outcome+after+surgery+for+mri-diagnosed+focal+cortical+dysplasia:+A+systematic+review+and+meta-analysis.">Seizure outcome after surgery for mri-diagnosed focal cortical dysplasia: A systematic review and meta-analysis.</a> Neurology. 98 (3), e236-e248 (2022).</li><li>Kalbhenn, T., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Operative+posterior+disconnection+in+epilepsy+surgery:+Experience+with+29+patients.">Operative posterior disconnection in epilepsy surgery: Experience with 29 patients.</a> Epilepsia. 60 (9), 1973-1983 (2019).</li><li>Devlin, A. M., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Clinical+outcomes+of+hemispherectomy+for+epilepsy+in+childhood+and+adolescence.">Clinical outcomes of hemispherectomy for epilepsy in childhood and adolescence.</a> Brain. 126 (Pt 3), 556-566 (2003).</li><li>Marras, C. E., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Hemispherotomy+and+functional+hemispherectomy:+Indications+and+outcome.">Hemispherotomy and functional hemispherectomy: Indications and outcome.</a> Epilepsy Res. 89 (1), 104-112 (2010).</li><li>Castagno, S., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Seizure+outcomes+of+large+volume+temporo-parieto-occipital+and+frontal+surgery+in+children+with+drug-resistant+epilepsy.">Seizure outcomes of large volume temporo-parieto-occipital and frontal surgery in children with drug-resistant epilepsy.</a> Epilepsy Res. 177, 106769 (2021).</li><li>Kamalboor, H., Alhindi, H., Alotaibi, F., Althubaiti, I., Alkhateeb, M. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Frontal+disconnection+surgery+for+drug-resistant+epilepsy:+Outcome+in+a+series+of+16+patients.">Frontal disconnection surgery for drug-resistant epilepsy: Outcome in a series of 16 patients.</a> Epilepsia Open. 5 (3), 475-486 (2020).</li></ol>

The authors have nothing to disclose.

MOGHE is a new white matter entity predominantly at the GM/WM boundaries but shows no cortical layer disorganization as is typical for FCDs2. The untypical semiology and extensive EEG make it very difficult to determine the location of the epileptogenic zone using traditional methods of anatomo-electro-clinical evaluation, which creates difficulties in surgical decision-making. Previous studies reported that patients with MOGHE achieved good outcomes after wide resection6<s...

Malformation of cortical development (MCD) is an important cause of drug-resistant epilepsy and developmental delay in young children. There are many types of MCD, among which FCD is the most common type1. According to the latest updated FCD classification in 2022, MOGHE is described and classified as a predominantly white matter lesion in contrast to juxta-cortical localized FCD2 that was primarily described as proliferative&#8195;oligodendroglial&#8195;hyperplasia&#8195;with&#8195;epilepsy&#8195;(POGHE) in 20133 and first proposed in 20174. MOGHE is defined by an increase in heterotopic neurons in the white matter and deep cortical layers above 2200 Olig2-immunoreactive cells/mm2 in specimen2,4,5.
Clinically, MOGHE is most commonly observed in the frontal lobe, and epileptic spasms are the most common initial seizure type6. The interictal EEG pattern was usually multifocal or widespread in young children6. In younger children, MRI showed an increased laminar signal at the gray-white matter junction. In older children, reduced subcortical T2/FLAIR signals and blurring at the gray-white matter transition were observed7. An accurate delineation of MOGHE is very difficult in clinical practice. Therefore, the traditional concept and strategy of preoperative evaluation to determine the extent of the epileptogenic zone by comprehensive anatomo-electro-clinical evaluation is difficult to implement. Herein, a pediatric cohort with MOGHE in the frontal lobe was analyzed to extend the knowledge of surgical treatment for MOGHE.

<table border="1" fo:keep-together.within-page="1" fo:keep-with-next.within-page="always">
	<tbody>
		<tr>
			<td>Absorbable cranial bone lock</td>
			<td>Braun Inc.</td>
			<td>FF016</td>
			<td></td>
		</tr>
		<tr>
			<td>Drainage</td>
			<td>Branden Inc.</td>
			<td>Fr12</td>
			<td></td>
		</tr>
		<tr>
			<td>High-speed drill</td>
			<td>Stryker</td>
			<td>5400-050-000</td>
			<td></td>
		</tr>
		<tr>
			<td>Microscope</td>
			<td>Leica Inc.</td>
			<td>M525F40</td>
			<td></td>
		</tr>
		<tr>
			<td>NIHON KOHDAN EEG system</td>
			<td>NIHON KOHDAN Inc.</td>
			<td>EEG-1200C</td>
			<td>EEG&#160;</td>
		</tr>
		<tr>
			<td>Philips PET-CT system</td>
			<td>Philips Inc.</td>
			<td>Gemini GXL</td>
			<td>PET-CT</td>
		</tr>
		<tr>
			<td>Sinovation Stereotactic system</td>
			<td>Sinovation Inc.</td>
			<td>SR1</td>
			<td>3D construction</td>
		</tr>
	</tbody>
</table>

frontal disconnection for treating mild malformation of cortical development with oligodendroglial hyperplasia in epilepsy (moghe) in the frontal lobe

Malformation of cortical development is an important cause of drug-resistant epilepsy in young children. Mild malformation of cortical development with oligodendroglial hyperplasia in epilepsy (MOGHE) has been added to the last focal cortical dysplasia (FCD) classification and commonly involves the frontal lobe. The semiology at the onset of epilepsy is dominated by non-lateralizing infantile spasm; the boundaries of the malformation are usually difficult to determine by magnetic resonance imaging (MRI) and positron emission tomography (PET), and electroencephalography (EEG) findings are often widespread. Therefore, the traditional concept and strategy of preoperative evaluation to determine the extent of the epileptogenic zone by comprehensive anatomo-electro-clinical methods are difficult to implement. 
Frontal disconnection is an effective surgical method for the treatment of epilepsy, but there are few related reports. A total of 8 children with histo-pathologically confirmed MOGHE were retrospectively studied. MOGHE was located in the frontal lobe in all patients, and frontal disconnection was performed. The periinsular approach was used in the disconnective procedures, divided into several surgical steps: the partial inferior frontal gyrus resection, the frontobasal and intrafrontal disconnection, and the anterior corpus callosotomy. 
One patient presented with a short-term postoperative speech disorder, while another patient exhibited transient postoperative limb weakness. No long-term postoperative complications were observed. At 2 years after surgery, 75% of patients were seizure-free, with cognitive improvement in half of them. This finding suggested that frontal disconnection is an effective and safe surgical procedure for the treatment of MOGHE instead of extensive resection in the frontal lobe.

According to the inclusion criteria, a total of 8 eligible patients were included in the analysis. The group consisted of 8 boys. The age of onset was 4-28 months (median 6 months), and the age of surgery ranged from 17-135 months (median 38 months). The duration of epilepsy ranged from 13 to 121 months (median 32 months). The semiology of 4 patients was epileptic spasms, 3 had focal seizures, and 1 had mixed seizures. Interictal EEG indicated focal in 3 patients, multifocal in 3 patients, and diffuse in 2 patients. Icta...

Author Spotlight: Studying Clinical Characters and Epilepsy Outcomes After Frontal Disconnection in Patients with MOGHE

Here, we present a protocol to describe the epilepsy outcome and complications of 8 patients with mild malformation of cortical development with oligodendroglial hyperplasia in epilepsy (MOGHE) in the frontal lobe after frontal disconnection. The procedure is characterized by its simplicity, user-friendliness, and fewer postoperative complications.

Frontal Disconnection for Treating Mild Malformation of Cortical Development with Oligodendroglial Hyperplasia in Epilepsy (MOGHE) in the Frontal Lobe

Malformation of cortical development is an important cause of drug-resistant epilepsy in young children. Mild malformation of cortical development with ...

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653 Views.  Peking University First Hospital. Here, we present a protocol to describe the epilepsy outcome and complications of 8 patients with mild malformation of cortical development with oligodendroglial hyperplasia in epilepsy (MOGHE) in the frontal lobe after frontal disconnection. The procedure is characterized by its simplicity, user-friendliness, and fewer postoperative complications.

Video: Author Spotlight: Studying Clinical Characters and Epilepsy Outcomes After Frontal Disconnection in Patients with MOGHE

Development of an Audio-based Virtual Gaming Environment to Assist with Navigation Skills in the Blind

Audio-based Environment Simulator (AbES) is virtual environment software designed to improve real world navigation skills in the blind. Using only audio based cues and set within the context of a video game metaphor, users gather relevant spatial information regarding a building's layout. This allows the user to develop an accurate spatial cognitive map of a large-scale three-dimensional space that can be manipulated for the purposes of a real indoor navigation task. After game play, participants are then assessed on their ability to navigate within the target physical building represented in the game. Preliminary results suggest that early blind users were able to acquire relevant information regarding the spatial layout of a previously unfamiliar building as indexed by their performance on a series of navigation tasks. These tasks included path finding through the virtual and physical building, as well as a series of drop off tasks. We find that the immersive and highly interactive nature of the AbES software appears to greatly engage the blind user to actively explore the virtual environment. Applications of this approach may extend to larger populations of visually impaired individuals.

Audio-based Environment Simulator (AbES) is virtual environment software designed to improve real world navigation skills in the blind.

Audio-based Environment Simulator (AbES) is virtual environment software designed to improve real world navigation skills in the blind. Using only audio ...

Network Analysis of the Default Mode Network Using Functional Connectivity MRI in Temporal Lobe Epilepsy

Functional connectivity MRI (fcMRI) is an fMRI method that examines the connectivity of different brain areas based on the correlation of BOLD signal fluctuations over time. Temporal Lobe Epilepsy (TLE) is the most common type of adult epilepsy and involves multiple brain networks. The default mode network (DMN) is involved in conscious, resting state cognition and is thought to be affected in TLE where seizures cause impairment of consciousness. The DMN in epilepsy was examined using seed based fcMRI. The anterior and posterior hubs of the DMN were used as seeds in this analysis. The results show a disconnection between the anterior and posterior hubs of the DMN in TLE during the basal state. In addition, increased DMN connectivity to other brain regions in left TLE along with decreased connectivity in right TLE is revealed. The analysis demonstrates how seed-based fcMRI can be used to probe cerebral networks in brain disorders such as TLE.

The Default Mode Network (DMN) in Temporal Lobe Epilepsy (TLE) is analyzed in the resting state of the brain using seed-based functional connectivity MRI (fcMRI).

Functional connectivity MRI (fcMRI) is an fMRI method that examines the connectivity of different brain areas based on the correlation of BOLD signal ...

Tumor Treating Field Therapy in Combination with Bevacizumab for the Treatment of Recurrent Glioblastoma

A novel device that employs TTF therapy has recently been developed and is currently in use for the treatment of recurrent glioblastoma (rGBM). It was FDA approved in April 2011 for the treatment of patients 22 years or older with rGBM. The device delivers alternating electric fields and is programmed to ensure maximal tumor cell kill1.
Glioblastoma is the most common type of glioma and has an estimated incidence of approximately 10,000 new cases per year in the United States alone2. This tumor is particularly resistant to treatment and is uniformly fatal especially in the recurrent setting3-5. Prior to the approval of the TTF System, the only FDA approved treatment for rGBM was bevacizumab6. Bevacizumab is a humanized monoclonal antibody targeted against the vascular endothelial growth factor (VEGF) protein that drives tumor angiogenesis7. By blocking the VEGF pathway, bevacizumab can result in a significant radiographic response (pseudoresponse), improve progression free survival and reduce corticosteroid requirements in rGBM patients8,9. Bevacizumab however failed to prolong overall survival in a recent phase III trial26. A pivotal phase III trial (EF-11) demonstrated comparable overall survival between physicians&#8217; choice chemotherapy and TTF Therapy but better quality of life were observed in the TTF arm10.
There is currently an unmet need to develop novel approaches designed to prolong overall survival and/or improve quality of life in this unfortunate patient population. One appealing approach would be to combine the two currently approved treatment modalities namely bevacizumab and TTF Therapy. These two treatments are currently approved as monotherapy11,12, but their combination has never been evaluated in a clinical trial. We have developed an approach for combining those two treatment modalities and treated 2 rGBM patients. Here we describe a detailed methodology outlining this novel treatment protocol and present representative data from one of the treated patients.

A novel methodology that is employed for the treatment of recurrent glioblastomas is described. This treatment approach employs the application of alternating electric tumor treating fields (TTFields), known as TTF Therapy in combination with bevacizumab, a targeted agent that is currently FDA approved as monotherapy.

A novel device that employs TTF therapy has recently been developed and is currently in use for the treatment of recurrent glioblastoma (rGBM). It was FDA ...

Collection and Extraction of Saliva DNA for Next Generation Sequencing

The preferred source of DNA in human genetics research is blood, or cell lines derived from blood, as these sources yield large quantities of high quality DNA. However, DNA extraction from saliva can yield high quality DNA with little to no degradation/fragmentation that is suitable for a variety of DNA assays without the expense of a phlebotomist and can even be acquired through the mail. However, at present, no saliva DNA collection/extraction protocols for next generation sequencing have been presented in the literature. This protocol optimizes parameters of saliva collection/storage and DNA extraction to be of sufficient quality and quantity for DNA assays with the highest standards, including microarray genotyping and next generation sequencing.

DNA extraction from saliva can provide a readily available source of high molecular weight DNA, with little to no degradation/fragmentation. This protocol provides optimized parameters for saliva collection/storage and DNA extraction to be of sufficient quality and quantity for downstream DNA assays with high quality requirements.

The preferred source of DNA in human genetics research is blood, or cell lines derived from blood, as these sources yield large quantities of high quality ...

Multi-electrode Array Recordings of Human Epileptic Postoperative Cortical Tissue

Epilepsy, affecting about 1% of the population, comprises a group of neurological disorders characterized by the periodic occurrence of seizures, which disrupt normal brain function. Despite treatment with currently available antiepileptic drugs targeting neuronal functions, one third of patients with epilepsy are pharmacoresistant. In this condition, surgical resection of the brain area generating seizures remains the only alternative treatment. Studying human epileptic tissues has contributed to understand new epileptogenic mechanisms during the last 10 years. Indeed, these tissues generate spontaneous interictal epileptic discharges as well as pharmacologically-induced ictal events which can be recorded with classical electrophysiology techniques. Remarkably, multi-electrode arrays (MEAs), which are microfabricated devices embedding an array of spatially arranged microelectrodes, provide the unique opportunity to simultaneously stimulate and record field potentials, as well as action potentials of multiple neurons from different areas of the tissue. Thus MEAs recordings offer an excellent approach to study the spatio-temporal patterns of spontaneous interictal and evoked seizure-like events and the mechanisms underlying seizure onset and propagation. Here we describe how to prepare human cortical slices from surgically resected tissue and to record with MEAs interictal and ictal-like events ex vivo.

We here describe how to perform multi-electrode array recordings of human epileptic cortical tissue. Epileptic tissue resection, slice preparation and multi-electrode array recordings of interictal and ictal events are demonstrated in detail.

Epilepsy, affecting about 1% of the population, comprises a group of neurological disorders characterized by the periodic occurrence of seizures, which ...

Network Analysis of Foramen Ovale Electrode Recordings in Drug-resistant Temporal Lobe Epilepsy Patients

Approximately 30% of epilepsy patients are refractory to antiepileptic drugs. In these cases, surgery is the only alternative to eliminate/control seizures. However, a significant minority of patients continues to exhibit post-operative seizures, even in those cases in which the suspected source of seizures has been correctly localized and resected. The protocol presented here combines a clinical procedure routinely employed during the pre-operative evaluation of temporal lobe epilepsy (TLE) patients with a novel technique for network analysis. The method allows for the evaluation of the temporal evolution of mesial network parameters. The bilateral insertion of foramen ovale electrodes (FOE) into the ambient cistern simultaneously records electrocortical activity at several mesial areas in the temporal lobe. Furthermore, network methodology applied to the recorded time series tracks the temporal evolution of the mesial networks both interictally and during the seizures. In this way, the presented protocol offers a unique way to visualize and quantify measures that considers the relationships between several mesial areas instead of a single area.

This protocol describes a procedure to track the evolution of mesial network measures in temporal lobe epilepsy (TLE) patients. It is based on the combination of intracranial recordings with a novel numerical technique for data analysis. Specifically, we present a protocol for network analyses of foramen ovale recordings.

Approximately 30% of epilepsy patients are refractory to antiepileptic drugs. In these cases, surgery is the only alternative to eliminate/control ...

Balloon-based Injury to Induce Myointimal Hyperplasia in the Mouse Abdominal Aorta

The use of animal models is essential for a better understanding of MH, one major cause for arterial stenosis.In this article, we demonstrate a murine balloon denudation model, which is comparable with established vessel injury models in large animals. The aorta denudation model with balloon catheters mimics the clinical setting and leads to comparable pathobiological and physiological changes. Briefly, after performing a horizontal incision in the aorta abdominalis, a balloon catheter will be inserted into the vessel, inflated, and introduced retrogradely. Inflation of the balloon will lead to intima injury and overdistension of the vessel. After removing the catheter, the aortic incision will be closed with single stiches. The model shown in this article is reproducible, easy to perform, and can be established quickly and reliably. It is especially suitable for evaluating expensive experimental therapeutic agents, which can be applied in an economical fashion. By using different knockout-mouse strains, the impact of different genes on MH development can be assessed.

This article demonstrates a murine model to study the development of myointimal hyperplasia (MH) after aortic balloon injury.

The use of animal models is essential for a better understanding of MH, one major cause for arterial stenosis.In this article, we demonstrate a murine ...

The Pilocarpine Model of Temporal Lobe Epilepsy and EEG Monitoring Using Radiotelemetry System in Mice

Temporal lobe epilepsy (TLE) is a common neurological disorder in adulthood. For translational studies of chronic epilepsy, pilocarpine-induced status epilepticus (SE) is frequently selected to recapitulate spontaneous recurrent seizures (SRS). Here we present a protocol of SE induction by intraperitoneal (i.p.) injection of pilocarpine and monitoring of chronic recurring seizures in live animals using a wireless telemetry video and electroencephalogram (EEG) system. We demonstrated notable behavioral changes that need attention after pilocarpine injection and their correlation with hippocampal neuronal loss at 7 days and 6 weeks post-pilocarpine. We also describe the experimental procedures of electrode implantation for video and EEG recording, and analysis of the frequency and duration of chronic recurrent seizures. Finally, we discuss the possible reasons why the expected results are not achieved in each case. This provides a basic overview of modeling chronic epilepsy in mice and guidelines for troubleshooting. We believe this protocol can serve as a baseline for suitable models of chronic epilepsy and epileptogenesis.

This manuscript describes a method of inducing status epilepticus by systemic pilocarpine injection and of monitoring spontaneous recurrent seizures in live animals using a wireless telemetry video and electroencephalogram system. This protocol can be utilized for studying the pathophysiologic mechanisms of chronic epilepsy, epileptogenesis, and acute seizures.

Temporal lobe epilepsy (TLE) is a common neurological disorder in adulthood. For translational studies of chronic epilepsy, pilocarpine-induced status ...

Assessment of Static Graviceptive Perception in the Roll-Plane using the Subjective Visual Vertical Paradigm

Vestibular disorders are among the most common syndromes in medicine. In recent years, new vestibular diagnostic systems have been introduced that allow the examination of all semicircular canals in the clinical setting. Assessment methods of the otolithic system, which is responsible for the perception of linear acceleration and perception of gravity, are far less in clinical use. There are several experimental approaches for measuring the perception of gravity. The most frequently used method is the determination of the subjective visual vertical. This is usually measured with the head in an upright position. We present here an assessment method for testing otolith function in the roll plane. The subjective visual vertical is measured in the head upright position as well as with head inclination of &#177; 15&#176; and &#177; 30&#176; in the roll plane. This extended functional paradigm is an easy-to-perform clinical test of otolith function and ensures increased information content for the detection of impaired graviceptive perception.

The perception of gravity is commonly determined by the subjective visual vertical in the head upright position. The additional assessment at head tilts of &#177; 15&#176; and &#177; 30&#176; in the roll plane ensures increased information content for the detection of impaired graviceptive perception.

Vestibular disorders are among the most common syndromes in medicine. In recent years, new vestibular diagnostic systems have been introduced that allow ...

Intrathecal Application of a Fluorescent Dye for the Identification of Cerebrospinal Fluid Leaks in Cochlear Malformation

In cases of cerebrospinal fluid (CSF) leaks, reliable detection of their origins is needed to seal the leak sufficiently and prevent complications, such as meningitis. A method is presented here using intrathecal administered fluorescein in a clinical case of bilateral congenital ear malformation. A fluorescent dye is administered intrathecally to achieve intraoperative visualization of CSF leaks. The dye is applied 20 min before surgery, and concentration of 5% is used. Per every 10 kg of body weight, 0.1 mL of the fluid is applied intrathecally. The fluorescein is visualized using a fully digital microscope. The origin of the fluid leak is identified in the stapes footplate. During primary surgery, it is sealed, and cochlea implantation is performed for hearing restoration. In this specific case, 6 weeks later, the implant was explanted due to acute meningitis, and the electrode array was left as a spacer. Postoperatively, in the aural smear, &#946;-transferrin was detected. During a revision mastoidectomy, dislocated coverage of the leak was found. The stapes was removed and oval window sealed. Five days after revision surgery, no &#946;-transferrin was detected in the aural smear. During the revision of cochlea implantation 6 months later, intact coverage of the oval niche was observed. Thus, intrathecal fluorescein application proves to be a reliable tool for the detection of CSF leaks. It facilitates the orientation in malformations and complicated or unknown surgical situs. In the literature, its use is described for CSF fistulas in endonasal surgery but is rarely described in skull base and mastoid surgeries. The method has been used successfully in several cases with CSF leaks, and the results confirm the feasibility of safely accessing the origin of the leak.

Intrathecally applied fluorescein is used to achieve intraoperative visualization of CSF leaks. This protocol describes a lumbar puncture, the application of 5% fluorescein, and intraoperative visualization using a fully digital microscope.

In cases of cerebrospinal fluid (CSF) leaks, reliable detection of their origins is needed to seal the leak sufficiently and prevent complications, such ...