There is no funding source for this study.

The study protocol was approved by the institutional review board of Istanbul University Faculty of Medicine. Informed consent was obtained from patients for this study.
1. Preoperative procedures
NOTE: Preoperative evaluation is similar to any other medically intractable epilepsy patient. Routine scalp electroencephalography (EEG) monitoring and video-EEG monitoring, interictal and ictal single photon emission computed tomography (SPECT), magnetic resonance imaging (MRI), neuropsychological test (NPT), ophthalmological assessment with perimetry, and endocrinological assessment should be completed.
<ol>
	<li>Under general endotracheal anesthesia, place the patient supine with the head flexed on a three-pronged Mayfield head clamp. 
	NOTE: The patient can be placed on gel-based modifications if younger than 18 months.</li>
	<li>Plan the incision on Kocher&#39;s point, which is 3 cm lateral to the midline and 1 cm anterior to the coronal suture. The coronal suture can be outlined by palpation. 
	NOTE: The entry point can be adjusted using the intraoperative ultrasonography (iUSG) system for an optimal trajectory to the HH interface and normal tissue interface. Optic or frameless electromagnetic neuronavigation systems are alternatives to iUSG for achieving proper trajectory.</li>
	<li>Set the iUSG system with a burr-hole probe before beginning the primary surgical procedure. Most of the cases of HHs have normal-sized ventricles. The ventricle size can be seen in preoperative MRI.</li>
	<li>Adjust the 30&#176; rigid endoscope system according to the surgeon&#39;s preferred position. The neuroendoscope has an outer diameter of 2.7 mm with two working channels. The sheath of the neuroendoscope has an outer diameter of 3.8 mm and a stylet.</li>
	<li>Set other instruments, such as a monopolar coagulation electrode, a fiberoptic light guide, and the endovision system.</li>
	<li>Disinfect the surgical site with swabs soaked in commercially available povidone-iodine solution at least 10x. Drape the periauricular region with sterile blankets.</li>
	<li>Adjust the white balance and camera clarity options. Any sterile white dressing and sterile written material can be used for the check.</li>
</ol>
2. Surgical technique
<ol>
	<li>Make an approximately 3 cm vertical skin incision on Kocher&#39;s point using a 20-number blade. After passing the skin, connective tissue, and galea, incise the periosteum. Place the automatic retractor covering the skin, subcutaneous tissue, and the periosteum to expose the bone. Enter the right ventricle since it is the nondominant hemisphere unless there is anatomical difficulty.</li>
	<li>Open a 14 mm diameter burr hole. The size is 14 mm due to using iUSG, which can only fit for its burr-hole probe.</li>
	<li>Expand the burr-hole medially or laterally according to the ultrasonographic image, visualizing the appropriate trajectory to the HH.</li>
	<li>Irrigate the field with isotonic saline for a clear visualization of the coronal section of the ventricles. Introduce the sheath with its stylet at the level of the foramen of Monro in coronal view.</li>
	<li>Remove the stylet from the sheath and then introduce the endoscope.</li>
	<li>Under direct visualization, advance the endoscope through the foramen of Monro. Visualize the HH protruding from the floor and the lateral wall of the third ventricle. Direct vision usually appreciates the limits of the protruding HH and the normal tissue.</li>
	<li>Coagulate the lesion by monopolar cautery introduced from the working channel. Remove the lesion with microforceps. Keep dissecting until the pial and arachnoid membrane are reached. Complete resection and disconnection can be confirmed by postoperative MRI.</li>
	<li>Achieve hemostasis by irrigation with isotonic saline solution or monopolar coagulation. Massive bleeding usually does not occur; in case of occurrence, it may necessitate leaving external ventricular drainage (EVD) or converting to open microscopic surgery.</li>
	<li>After hemostasis, complete the procedure by removing the endoscopic system. Suture the subcutaneous tissue with 3-0 Vicryl and the skin with 3-0 prolene.</li>
</ol>
3. Postoperative procedures and follow-up
<ol>
	<li>Begin oral intake at 6 h postoperatively. Mobilize the patients on the next day of the operation.</li>
	<li>Monitor the patient immediately after surgery for early complications, such as transient memory loss, weight gain, thalamic and hypothalamic infarction, diabetes insipidus, pituitary insufficiency, and visual disturbance. 
	NOTE: The endoscope can cause damage to the fornix, optic chiasm and tract, and hypothalamus. The monopolar cautery can cause similar destruction through the thermal effect.</li>
	<li>Monitor the patient for intake and output balance. Ask the patient and the relatives to write down every patient&#39;s fluid intake and calculate the urine output. If the patient has pituitary insufficiency, hydrocortisone replacement therapy should be applied.</li>
	<li>Continue antiepileptic drugs (AED) till adequate follow-up has been established. AED can be reduced according to seizure outcome status and control electroencephalograms (EEG).</li>
	<li>Upon discharge, follow up the patient in the 2nd week, 1st month, 3rd month and 6th month.</li>
</ol>

<ol>
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A., Killory, B. D., Nakaji, P., Rekate, H. L. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Surgical+approaches+to+hypothalamic+hamartomas.">Surgical approaches to hypothalamic hamartomas.</a> Neurosurg Focus. 30 (2), E2 (2011).</li><li>Choi, J. U., 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=Endoscopic+disconnection+for+hypothalamic+hamartoma+with+intractable+seizure.+Report+of+four+cases.">Endoscopic disconnection for hypothalamic hamartoma with intractable seizure. Report of four cases.</a> J Neurosurg. 100, 506-511 (2004).</li><li>Shim, K. W., 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=Treatment+modality+for+intractable+epilepsy+in+hypothalamic+hamartomatous+lesions.">Treatment modality for intractable epilepsy in hypothalamic hamartomatous lesions.</a> Neurosurgery. 62 (4), 847-856 (2008).</li><li>Shim, K. W., Park, E. K., Kim, D. S. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Endoscopic+treatment+of+hypothalamic+hamartomas.">Endoscopic treatment of hypothalamic hamartomas.</a> J Korean Neurosurg Soc. 60 (3), 294-300 (2017).</li><li>Delalande, O., Fohlen, M. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Disconnecting+surgical+treatment+of+hypothalamic+hamartoma+in+children+and+adults+with+refractory+epilepsy+and+proposal+of+a+new+classification.">Disconnecting surgical treatment of hypothalamic hamartoma in children and adults with refractory epilepsy and proposal of a new classification.</a> Neurol Med Chir (Tokyo). 43 (2), 61-68 (2003).</li><li>Valdueza, J. 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=Hypothalamic+hamartomas:+with+special+reference+to+gelastic+epilepsy+and+surgery.">Hypothalamic hamartomas: with special reference to gelastic epilepsy and surgery.</a> Neurosurgery. 34 (6), 949-958 (1994).</li><li>Chibbaro, 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=Pure+endoscopic+management+of+epileptogenic+hypothalamic+hamartomas.">Pure endoscopic management of epileptogenic hypothalamic hamartomas.</a> Neurosurg Rev. 40 (4), 647-653 (2017).</li><li>Ng, Y. 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=Endoscopic+resection+of+hypothalamic+hamartomas+for+refractory+symptomatic+epilepsy.">Endoscopic resection of hypothalamic hamartomas for refractory symptomatic epilepsy.</a> Neurology. 70, 1543-1548 (2008).</li><li>Bourdillon, P., 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=Surgical+treatment+of+hypothalamic+hamartomas.">Surgical treatment of hypothalamic hamartomas.</a> Neurosurg Rev. 44 (2), 753-762 (2021).</li><li>Feiz-Erfan, 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=Surgical+strategies+for+approaching+hypothalamic+hamartomas+causing+gelastic+seizures+in+the+pediatric+population:+transventricular+compared+with+skull+base+approaches.">Surgical strategies for approaching hypothalamic hamartomas causing gelastic seizures in the pediatric population: transventricular compared with skull base approaches.</a> J Neurosurg. 103, 325-332 (2005).</li><li>Dorfm&#252;ller, G., Fohlen, M., Bulteau, C., Delalande, O. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Surgical+disconnection+of+hypothalamic+hamartomas.">Surgical disconnection of hypothalamic hamartomas.</a> Neurochirurgie. 54, 315-319 (2008).</li><li>Ng, Y. 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=Endoscopic+resection+of+hypothalamic+hamartomas+for+refractory+symptomatic+epilepsy.">Endoscopic resection of hypothalamic hamartomas for refractory symptomatic epilepsy.</a> Neurology. 70 (17), 1543-1548 (2008).</li><li>Rosenfeld, J. V., Freeman, J. L., Harvey, A. S. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Operative+technique:+The+anterior+transcallosal+transseptal+interforniceal+approach+to+the+third+ventricle+and+resection+of+hypothalamic+hamartomas.">Operative technique: The anterior transcallosal transseptal interforniceal approach to the third ventricle and resection of hypothalamic hamartomas.</a> J Clin Neurosci. 11 (7), 738-744 (2004).</li><li>Rosenfeld, J. V., Feiz-Erfan, I. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Hypothalamic+hamartoma+treatment:+surgical+resection+with+the+transcallosal+approach.">Hypothalamic hamartoma treatment: surgical resection with the transcallosal approach.</a> Semin Pediatr Neurol. 14 (2), 88-98 (2007).</li><li>Ng, Y. 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=Transcallosal+resection+of+hypothalamic+hamartoma+for+intractable+epilepsy.">Transcallosal resection of hypothalamic hamartoma for intractable epilepsy.</a> Epilepsia. 47 (7), 1192-1202 (2006).</li><li>Castinetti, F., Brue, T., Morange, I., Carron, R., R&#233;gis, J. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Gamma+Knife+radiosurgery+for+hypothalamic+hamartoma+preserves+endocrine+functions.">Gamma Knife radiosurgery for hypothalamic hamartoma preserves endocrine functions.</a> Epilepsia. 58, 72-76 (2017).</li><li>Akai, T., Okamoto, K., Iizuka, H., Kakinuma, H., Nojima, T. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Treatments+of+hamartoma+with+neuroendoscopic+surgery+and+stereotactic+radiosurgery:+a+case+report.">Treatments of hamartoma with neuroendoscopic surgery and stereotactic radiosurgery: a case report.</a> Minim Invasive Neurosurg. 45 (4), 235-239 (2002).</li><li>Abla, A. 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=Gamma+Knife+surgery+for+hypothalamic+hamartomas+and+epilepsy:+patient+selection+and+outcomes.">Gamma Knife surgery for hypothalamic hamartomas and epilepsy: patient selection and outcomes.</a> J Neurosurg. 113, 207-214 (2010).</li><li>Selch, M. 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The authors report no conflict of interest concerning the materials or methods used in this study.

In 2003, Delalande classified HHs into four subtypes. Type 1 HHs are small peduncular lesions attached to the tuber cinereum, type 2 HHs are lesions protruding to the third ventricle, type 3 lesions are the combination of type 1 and type 2 HHs, and type 4 HHs are large lesions with a broad attachment to both mammillary bodies and hypothalamus and have an extension to the interpeduncular cistern8. Depending on the location of the HH, various open surgery approaches have been described. For HHs near...

Hypothalamic hamartomas (HHs) are non-neoplastic, heterotrophic tissues that contain neuronal and glial tissue in an abnormal distribution. Incidence rates of HHs are 1 in 50,000-1,000,000 people with male predominance1. HHs present different clinical symptoms, such as precocious puberty, cognitive impairment, behavioral changes, and various types of seizures, most characteristically, gelastic seizures. Mostly gelastic seizures, as well as other seizure types, are extremely refractory to antiepileptic drugs (AEDs)2,3.
Based on their morphology and relation to the hypothalamus, there are several classifications for HHs. The symptoms and the severity depend mainly on the size, location, attachment type, and degree of hypothalamic displacement. Seizures and behavioral, cognitive, and hormonal problems mostly originate from sessile HHs. Pedunculated HHs mainly cause precocious puberty4,5,6.
Seizures can be controlled surgically either by resection or disconnection of the lesion. Most favorable outcomes were obtained from near-total or total resections4. The main goal is to prevent the spreading of the epileptic burst and thus stop secondary generalized seizures. Open surgery, either pterional, transcallosal, or transventricular approach, leads to good surgical outcomes; however, the complication rate is high, up to 30%. Laser and radiofrequency thermocoagulation-based disconnection surgeries, stereotactic radiosurgery, and focused ultrasound are also described as alternatives to open surgery. The treatment approach should be selected individually since the hypothalamic area, and close structures are critical5,6,7.
The possibility that an endoscopic approach could achieve HH resection was first described in 20038. Other authors have also shown the feasibility of endoscopic resection and disconnection surgeries for HH. These studies led us to believe that, especially in sessile intrahypothalamic HHs, a full-endoscopic approach is feasible7,9,10,11. Surgical indications are mainly medically intractable gelastic seizures, neurobehavioral deterioration, and intractable endocrinopathy. Potential risk factors for surgery are mainly memory loss, endocrinopathy, behavioral and cognitive problems, and vision loss. With recent technological advancements in neuroendoscopy and surgical instruments, this study aimed to describe our technique of full-endoscopic approach for HH resection3,12,13.
CASE PRESENTATION: 
A 15-year-old boy was born at term by normal vaginal delivery. The patient had first seizures 7 years ago. Perinatal history was unremarkable. First seizures were characterized by gelastic seizures; however, after 2 years, the seizures changed character, becoming tonic type. The seizure frequency was 9-10 times per day. Neurological examination revealed moderate mental retardation and no neurological deficit. From the beginning of the seizures, the patient was administered carbamazepine, valproic acid, phenobarbital, lamotrigine, levetiracetam, and clobazam in different combinations. But there was no improvement in his condition. Magnetic resonance imaging (MRI) revealed a hamartoma of the right hypothalamus. A routine scalp electroencephalography (EEG) showed active epileptogenic focus in the right frontocentral and temporal regions. During video-EEG, 10 seizures were recorded. The electrographic discharge showed a right-sided origin. Ictal and interictal single-photon emission computed tomography (SPECT) and positron emission tomography (PET) were noncontributory. Neuropsychological tests (NPT) were not performed, as the patient was not cooperative. The patient did not have endocrinological issues such as precocious puberty, and all hormonal parameters were within normal range. Since the patient had medically intractable seizures and moderate mental retardation, surgical resection of the HH was decided.
The patient did not have any complications after surgery, nor did he experience diabetes insipidus (DI) or any other endocrinopathies. The ophthalmological exam was normal, and there was no central hyperphagia or fever. The patient was discharged on postoperative Day 5. In the 25th month after surgery, he was followed up seizure-free, Engel class 1. A control MRI 2 years postoperatively showed no recurrence of the HH. The patient and his relatives stated that the patient had a better educational level and cognition; however, testing regarding neurocognition was not applied.

<table border="1" fo:keep-together.within-page="1" fo:keep-with-next.within-page="always">
	<tbody>
		<tr>
			<td>Burr-hole probe of intraoperative ultrasound system</td>
			<td>Hitachi</td>
			<td>UST-52114P</td>
			<td>Aloka Linear UST-52114P, Frequency Range: 8 &#8211; 3 MH, Scan Angle: 90&#176; FOV</td>
		</tr>
		<tr>
			<td>Fiberoptic light guide</td>
			<td>RiwoSpine</td>
			<td>806635231</td>
			<td>80663523 fiber light cable &#216; 3.5 mm, TL 2.3 m, 
			8095.09 adaptor endoscope side, 
			8095.07 adaptor projector side</td>
		</tr>
		<tr>
			<td>Intraoperative Ultrasound system</td>
			<td>Hitachi</td>
			<td></td>
			<td>Hitachi Arietta 70, Tokyo, Japan</td>
		</tr>
		<tr>
			<td>Microforceps</td>
			<td>RiwoSpine</td>
			<td>89240.3023</td>
			<td></td>
		</tr>
		<tr>
			<td>Monopolar-coagulating electrode</td>
			<td>RiwoSpine</td>
			<td>8922095000</td>
			<td></td>
		</tr>
		<tr>
			<td>Rigid neuroendoscope</td>
			<td>Karl Storz</td>
			<td>8921092051</td>
			<td>30&#176; Hopkins pediatric telescope, outside diameter 2.7 mm</td>
		</tr>
		<tr>
			<td>Sheath for the telescope</td>
			<td>Karl Storz</td>
			<td>892209510</td>
			<td>3.8 mm outside diameter with two working channels</td>
		</tr>
	</tbody>
</table>

full-endoscopic surgery for hypothalamic hamartoma resection

Hypothalamic hamartomas (HH) are rare developmental anomalies of the inferior hypothalamus that often cause refractory epilepsy, including gelastic seizures. Surgical resection is an effective method to treat drug-resistant epilepsy and endocrinopathy in a suitable patient group. Open surgery, endoscopic surgery, ablative procedures, and stereotactic radiosurgery can be utilized. In this study, we aimed to describe the full-endoscopic approach for HH resection. The technique involves the use of an intraoperative ultrasonography (USG) system, a 30&#176; rigid endoscope system that has an outside diameter of 2.7 mm with two working channels, a stylet that has an outer diameter of 3.8 mm, a monopolar coagulation electrode, a fiberoptic light guide, and the endovision system. Microforceps and monopolar electrocautery are the two main surgical instruments for HH removal. The protocol is easy to apply after a particular learning curve has been passed and shorter than open surgical approaches. It leads to less blood loss. Full-endoscopic surgery for HH is a minimally invasive technique that can be applied safely and effectively with good seizure and endocrinological outcomes. It provides low surgical site pain and early mobilization.

An example of a patient treated by a full-endoscopic approach for HH resection has been presented. The preoperative MRI, intraoperative endoscopic view, and postoperative MRI have been shown in Figure 1, Figure 2, and Figure 3. There was minimal blood loss during the procedure, so it could not be measured. The procedure is short for a surgeon experienced in neuroendoscopy. For the represented case, the operation dur...

Read this Scientific Article Protocol about Full-Endoscopic Surgery for Hypothalamic Hamartoma Resection at JoVE.com

Full-Endoscopic Surgery for Hypothalamic Hamartoma Resection

Hypothalamic hamartomas are rare, non-neoplastic congenital malformations mainly arising from the inferior hypothalamus or tuber cinereum. Surgical treatment is one of the most effective options, and the surgical approach must be precisely determined for each patient. Here, we describe the full-endoscopic technique for resecting hypothalamic hamartomas.

Hypothalamic hamartomas (HH) are rare developmental anomalies of the inferior hypothalamus that often cause refractory epilepsy, including gelastic ...

full-endoscopic-surgery-for-hypothalamic-hamartoma-resection

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JoVE Journal

Neuroscience

182 Views.  Istanbul University. Hypothalamic hamartomas are rare, non-neoplastic congenital malformations mainly arising from the inferior hypothalamus or tuber cinereum. Surgical treatment is one of the most effective options, and the surgical approach must be precisely determined for each patient. Here, we describe the full-endoscopic technique for resecting hypothalamic hamartomas.

Video: Full-Endoscopic Surgery for Hypothalamic Hamartoma Resection

Rodent Stereotaxic Surgery and Animal Welfare Outcome Improvements for Behavioral Neuroscience

Stereotaxic surgery for the implantation of cannulae into specific brain regions has for many decades been a very successful experimental technique to investigate the effects of locally manipulated neurotransmitter and signaling pathways in awake, behaving animals. Moreover, the stereotaxic implantation of electrodes for electrophysiological stimulation and recording studies has been instrumental to our current understanding of neuroplasticity and brain networks in behaving animals. Ever-increasing knowledge about optimizing surgical techniques in rodents1-4, public awareness concerning animal welfare issues and stringent legislation (e.g., the 2010 European Union Directive on the use of laboratory animals5) prompted us to refine these surgical procedures, particularly with respect to implementing new procedures for oxygen supplementation and the continuous monitoring of blood oxygenation and heart rate levels during the surgery as well as introducing a standardized protocol for post-surgical care. Our observations indicate that these modifications resulted in an increased survival rate and an improvement in the general condition of the animals after surgery (e.g. less weight loss and a more active animal). This video presentation will show the general procedures involved in this type of stereotaxic surgery with special attention to our several modifications. We will illustrate these surgical procedures in rats, but it is also possible to perform this type of surgery in mice or other small laboratory animals by using special adaptors for the stereotaxic apparatus6.

Stereotaxic surgery on rodents allows for targeted administration of drugs or electrical stimulation and recordings in awake, behaving animals. In this video presentation we will demonstrate recent procedural refinements to this long-standing procedure that successfully improved survival rate and reduced post-surgical weight loss.

Stereotaxic surgery for the implantation of cannulae into specific brain regions has for many decades been a very successful experimental technique to ...

Imaging Calcium Responses in GFP-tagged Neurons of Hypothalamic Mouse Brain Slices

Despite an enormous increase in our knowledge about the mechanisms underlying the encoding of information in the brain, a central question concerning the precise molecular steps as well as the activity of specific neurons in multi-functional nuclei of brain areas such as the hypothalamus remain. This problem includes identification of the molecular components involved in the regulation of various neurohormone signal transduction cascades. Elevations of intracellular Ca2+ play an important role in regulating the sensitivity of neurons, both at the level of signal transduction and at synaptic sites.
New tools have emerged to help identify neurons in the myriad of brain neurons by expressing green fluorescent protein (GFP) under the control of a particular promoter. To monitor both spatially and temporally stimulus-induced Ca2+ responses in GFP-tagged neurons, a non-green fluorescent Ca2+ indicator dye needs to be used. In addition, confocal microscopy is a favorite method of imaging individual neurons in tissue slices due to its ability to visualize neurons in distinct planes of depth within the tissue and to limit out-of-focus fluorescence. The ratiometric Ca2+ indicator fura-2 has been used in combination with GFP-tagged neurons1. However, the dye is excited by ultraviolet (UV) light. The cost of the laser and the limited optical penetration depth of UV light hindered its use in many laboratories. Moreover, GFP fluorescence may interfere with the fura-2 signals2. Therefore, we decided to use a red fluorescent Ca2+ indicator dye. The huge Stokes shift of fura-red permits multicolor analysis of the red fluorescence in combination with GFP using a single excitation wavelength. We had previously good results using fura-red in combination with GFP-tagged olfactory neurons3. The protocols for olfactory tissue slices seemed to work equally well in hypothalamic neurons4. Fura-red based Ca2+ imaging was also successfully combined with GFP-tagged pancreatic &beta;-cells and GFP-tagged receptors expressed in HEK cells5,6. A little quirk of fura-red is that its fluorescence intensity at 650 nm decreases once the indicator binds calcium7. Therefore, the fluorescence of resting neurons with low Ca2+ concentration has relatively high intensity. It should be noted, that other red Ca2+-indicator dyes exist or are currently being developed, that might give better or improved results in different neurons and brain areas.

In this protocol, we update recent progress in imaging Ca2+ signals of GFP-tagged neurons in brain tissue slices using a red fluorescent Ca2+ indicator dye.

Despite an enormous increase in our knowledge about the mechanisms underlying the encoding of information in the brain, a central question concerning the ...

Functional Interrogation of Adult Hypothalamic Neurogenesis with Focal Radiological Inhibition

The functional characterization of adult-born neurons remains a significant challenge. Approaches to inhibit adult neurogenesis via invasive viral delivery or transgenic animals have potential confounds that make interpretation of results from these studies difficult. New radiological tools are emerging, however, that allow one to noninvasively investigate the function of select groups of adult-born neurons through accurate and precise anatomical targeting in small animals. Focal ionizing radiation inhibits the birth and differentiation of new neurons, and allows targeting of specific neural progenitor regions. In order to illuminate the potential functional role that adult hypothalamic neurogenesis plays in the regulation of physiological processes, we developed a noninvasive focal irradiation technique to selectively inhibit the birth of adult-born neurons in the hypothalamic median eminence. We describe a method for Computer tomography-guided focal irradiation (CFIR) delivery to enable precise and accurate anatomical targeting in small animals. CFIR uses three-dimensional volumetric image guidance for localization and targeting of the radiation dose, minimizes radiation exposure to nontargeted brain regions, and allows for conformal dose distribution with sharp beam boundaries. This protocol allows one to ask questions regarding the function of adult-born neurons, but also opens areas to questions in areas of radiobiology, tumor biology, and immunology. These radiological tools will facilitate the translation of discoveries at the bench to the bedside.

The function of adult-born mammalian neurons remains an active area of investigation. Ionizing radiation inhibits the birth of new neurons. Using computer tomography-guided focal irradiation (CFIR), three-dimensional anatomical targeting of specific neural progenitor populations can now be used to assess the functional role of adult neurogenesis.

The functional characterization of adult-born neurons remains a significant challenge. Approaches to inhibit adult neurogenesis via invasive viral ...

Endoscopic Endonasal Trans-sphenoidal Approach: Minimally Invasive Surgery for Pituitary Adenomas

Endoscopic endonasal trans-sphenoidal surgery has become the gold standard for the surgical treatment of pituitary adenomas and many other pituitary lesions. Refinements in surgical techniques, technological advancements, and incorporation of neuronavigation have rendered this surgery minimally invasive. The complication rates of this surgery are very low while excellent results are consistently obtained through this approach.
This paper focuses on the step-by-step surgical approach to pituitary adenomas, which is based on personal experience, and details the results obtained with this minimally invasive surgery.

The aim of this paper is to describe the different steps of the endoscopic endonasal approach to the sella turcica.

Endoscopic endonasal trans-sphenoidal surgery has become the gold standard for the surgical treatment of pituitary adenomas and many other pituitary ...

Live Images of GLUT4 Protein Trafficking in Mouse Primary Hypothalamic Neurons Using Deconvolution Microscopy

Type 2 diabetes mellitus (T2DM) is a global health crisis which is characterized by insulin signaling impairment and chronic inflammation in peripheral tissues. The hypothalamus in the central nervous system (CNS) is the control center for energy and insulin signal response regulation. Chronic inflammation in peripheral tissues and imbalances of certain chemokines (such as CCL5, TNF&#945;, and IL-6) contribute to diabetes and obesity. However, the functional mechanism(s) connecting chemokines and hypothalamic insulin signal regulation still remain unclear.
In vitro primary neuron culture models are convenient and simple models which can be used to investigate insulin signal regulation in hypothalamic neurons. In this study, we introduced exogeneous GLUT4 protein conjugated with GFP (GFP-GLUT4) into primary hypothalamic neurons to track GLUT4 membrane translocation upon insulin stimulation. Time-lapse images of GFP-GLUT4 protein trafficking were recorded by deconvolution microscopy, which allowed users to generate high-speed, high-resolution images without damaging the neurons significantly while conducting the experiment. The contribution of CCR5 in insulin regulated GLUT4 translocation was observed in CCR5 deficient hypothalamic neurons, which were isolated and cultured from CCR5 knockout mice. Our results demonstrated that the GLUT4 membrane translocation efficiency was reduced in CCR5 deficient hypothalamic neurons after insulin stimulation.

This protocol describes a technique for observation of real-time Green Fluorescence Protein (GFP) tagged Glucose Transporter 4 (GLUT4) protein trafficking upon insulin stimulation and characterization of the biological role of CCR5 in the insulin&#8211;GLUT4 signaling pathway with Deconvolution Microscopy.

Type 2 diabetes mellitus (T2DM) is a global health crisis which is characterized by insulin signaling impairment and chronic inflammation in peripheral ...

Role of Diffusion MRI Tractography in Endoscopic Endonasal Skull Base Surgery

Endoscopic endonasal surgery has gained a prominent role in the management of complex skull base tumors. It allows the resection of a large group of benign and malignant lesions through a natural anatomical extra-cranial pathway, represented by the nasal cavities, avoiding brain retraction and neurovascular manipulation. This is reflected by the patients' prompt clinical recovery and the low risk of permanent neurological sequelae, representing the main caveat of conventional skull base surgery. This surgery must be tailored to each specific case, considering its features and relationship with surrounding neural structures, mostly based on preoperative neuroimaging. Advanced MRI techniques, such as tractography, have been rarely adopted in skull base surgery due to technical issues: lengthy and complicated processes to generate reliable reconstructions for inclusion in the neuronavigation system. 
This paper aims to present the protocol implemented in the institution and highlights the synergistic collaboration and teamwork between neurosurgeons and the neuroimaging team (neurologists, neuroradiologists, neuropsychologists, physicists, and bioengineers) with the final goal of selecting the optimal treatment for each patient, improving the surgical results and pursuing the advancement of personalized medicine in this field.

We present a protocol to integrate diffusion MRI tractography in patient work-up to endoscopic endonasal surgery for a skull base tumor. The methods for adopting these neuroimaging studies in the pre- and intra-operative phases are described.

Endoscopic endonasal surgery has gained a prominent role in the management of complex skull base tumors. It allows the resection of a large group of ...

Detection of G Protein-coupled Receptor Expression in Mouse Vagal Afferent Neurons using Multiplex In Situ Hybridization

This study describes a protocol for the multiplex in situ hybridization (ISH) of the mouse jugular-nodose ganglia, with a particular emphasis on detecting the expression of G protein-coupled receptors (GPCRs). Formalin-fixed jugular-nodose ganglia were processed with the RNAscope technology to simultaneously detect the expression of two representative GPCRs (cholecystokinin and ghrelin receptors) in combination with one marker gene of either nodose (paired-like homeobox 2b, Phox2b) or jugular afferent neurons (PR domain zinc finger protein 12, Prdm12). Labeled ganglia were imaged using confocal microscopy to determine the distribution and expression patterns of the aforementioned transcripts. Briefly, Phox2b afferent neurons were found to abundantly express the cholecystokinin receptor (Cck1r) but not the ghrelin receptor (Ghsr). A small subset of Prdm12 afferent neurons was also found to express Ghsr and/or Cck1r. Potential technical caveats in the design, processing, and interpretation of multiplex ISH are discussed. The approach described in this article may help scientists in generating accurate maps of the transcriptional profiles of vagal afferent neurons.

Detection of G Protein-coupled Receptor Expression in Mouse Vagal Afferent Neurons using Multiplex In Situ Hybridization

Multiplex in situ hybridization (ISH) was employed to simultaneously visualize the transcripts for two G protein-coupled receptors and one transcription factor in the entire vagal ganglionic complex of the adult mouse. This protocol could be used to generate accurate maps of the transcriptional profiles of vagal afferent neurons.

This study describes a protocol for the multiplex in situ hybridization (ISH) of the mouse jugular-nodose ganglia, with a particular emphasis on detecting ...

Surgery and Behavioral Testing in the Tibial Neuroma Transposition Model in Rats

The tibial neuroma transposition (TNT) is a rat model in which allodynia at the neuroma site (tibial nerve) can be independently evaluated from allodynia at the plantar surface of the hind paw innervated by the intact sural nerve. This TNT model is suitable to test therapies for neuroma pain, such as the potential superiority of certain surgical therapies that are already used in the clinic, or to evaluate new drugs and their effect on both pain modalities in the same animal. In this model, a distal lesion (neurotmesis) is made in the tibial nerve, and the proximal nerve end is transposed and fixed subcutaneously and pretibially to enable assessments of the neuroma site with a 15 g Von Frey monofilament. To assess allodynia over the sural nerve, Von Frey monofilaments can be used via the up-down method on the plantar lateral region of the hind paw. After cutting the tibial nerve, mechanical hypersensitivity develops at the neuroma site within 1 week after surgery and persists at least until 12 weeks after surgery. Allodynia at the sural innervated plantar surface develops within 3 weeks after surgery compared to the contralateral limb. At 12 weeks, a neuroma forms on the proximal end of the severed tibial nerve, indicated by dispersion and swirling of axons. For the TNT model surgery, multiple critical (micro)surgical steps need to be followed, and some surgery practice under terminal anesthesia is advised. Compared to other neuropathic pain models, such as the spared nerve injury model, allodynia over the neuroma site can be independently tested from sural nerve hypersensitivity in the TNT model. However, the neuroma site can be tested only in rats, not in mice. The tips and directions provided in this protocol can help research groups working on pain successfully implement the TNT model in their facility.

This protocol describes the tibial neuroma transposition model, which entails a lesion of the tibial nerve with subsequent transposition of the proximal nerve end toward a subcutaneous pretibial or lateral position. Behavioral testing of neuroma pain and plantar hyperalgesia is quantified using Von Frey monofilaments.

The tibial neuroma transposition (TNT) is a rat model in which allodynia at the neuroma site (tibial nerve) can be independently evaluated from allodynia ...

Hypothalamic Kisspeptin Neurons as a Target for Whole-Cell Patch-Clamp Recordings

Kisspeptins are essential for the maturation of the hypothalamic-pituitary-gonadal (HPG) axis and fertility. Hypothalamic kisspeptin neurons located in the anteroventral periventricular nucleus and rostral periventricular nucleus, as well as the arcuate nucleus of the hypothalamus, project to gonadotrophin-releasing hormone (GnRH) neurons, among other cells. Previous studies have demonstrated that kisspeptin signaling occurs through the Kiss1 receptor (Kiss1r), ultimately exciting GnRH neuron activity. In humans and experimental animal models, kisspeptins are sufficient for inducing GnRH secretion and, consequently, luteinizing hormone (LH) and follicle stimulant hormone (FSH) release. Since kisspeptins play an essential role in reproductive functions, researchers are working to assess how the intrinsic activity of hypothalamic kisspeptin neurons contributes to reproduction-related actions and identify the primary neurotransmitters/neuromodulators capable of changing these properties. The whole-cell patch-clamp technique has become a valuable tool for investigating kisspeptin neuron activity in rodent cells. This experimental technique allows researchers to record and measure spontaneous excitatory and inhibitory ionic currents, resting membrane potential, action potential firing, and other electrophysiological properties of cell membranes. In the present study, crucial aspects of the whole-cell patch-clamp technique, known as electrophysiological measurements that define hypothalamic kisspeptin neurons, and a discussion of relevant issues about the technique, are reviewed.

Here, we present a protocol to perform a whole-cell patch-clamp on brain slices containing kisspeptin neurons, the primary modulator of gonadotrophin-releasing hormone (GnRH) cells. By adding knowledge about kisspeptin neuron activity, this electrophysiological tool has served as the basis for significant advancements in the neuroendocrinology field over the last 20 years.

Kisspeptins are essential for the maturation of the hypothalamic-pituitary-gonadal (HPG) axis and fertility. Hypothalamic kisspeptin neurons located in ...

Hormonal, Metabolic, and Electrical Regulation of Isolated Hypothalamic Neurons

Isolation of Targeted Hypothalamic Neurons for Studies of Hormonal, Metabolic, and Electrical Regulation

The hypothalamus regulates fundamental metabolic processes by controlling functions as varied as food intake, body temperature, and hormone release. As the functions of the hypothalamus are controlled by specific subsets of neuronal populations, the ability to isolate them provides a major tool for studying metabolic mechanisms. In this regard, the neuronal complexity of the hypothalamus poses exceptional challenges. 
For these reasons, new techniques, such as Magnetic-Activated Cell Sorting (MACS), have been explored. This paper describes a new application of magnetic-activated cell sorting (MACS) using microbead technology to isolate a targeted neuronal population from prenatal mice brains. The technique is simple and guarantees a highly pure and viable primary hypothalamic neuron culture with high reproducibility. The hypothalamus is gently dissociated, neurons are selectively isolated and separated from glial cells, and finally, using a specific antibody for a cell surface marker, the population of interest is selected. 
Once isolated, targeted neurons can be used to investigate their morphological, electrical, and endocrine characteristics and their responses in normal or pathological conditions. Furthermore, given the variegated roles of the hypothalamus in regulating feeding, metabolism, stress, sleep, and motivation, a closer look at targeted and region-specific neurons may provide insight into their tasks in this complex environment.

Author Spotlight: Hypothalamic Neural Mechanism Insights 

Here we present a protocol to grow specific hypothalamic cell subtypes in culture. The cells can be selected based on opportune/unique membrane markers and used in many applications, including immunofluorescence, electrophysiological, and biochemical assays.

The hypothalamus regulates fundamental metabolic processes by controlling functions as varied as food intake, body temperature, and hormone release. As ...