The authors wish to thank Aisha Dar, Vanathy Niranjan, and Dr. Umar Dar for technical assistance with rTMS delivery and data collection. The authors also wish to acknowledge the generous support of the Toronto General and Western Hospital Foundation, the Buchan Family Foundation, and the Ontario Brain Institute in funding this work.

This study was approved by the Research Ethics Board at the University Health Network.
1. Subject Selection
<ol>
	<li>Conduct an initial assessment on a prospective patient. The inclusion criteria included the presence of a current depressive episode that is resistant to at least 1 adequate trial of medication, and a Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, (DSM-5) diagnosis of MDD as established by the assessing psychiatrist. Confirm the diagnosis with a standardized Mini Mental State Examination (MINI).</li>
	<li>Ensure that patients are on a stable medication or are washed out of their medication routine for at least 4 weeks prior to their first rTMS treatment session. Do not alter this medication regiment throughout rTMS treatment to help disambiguate the cause of any observed clinical improvement or deterioration.</li>
	<li>Exclude patients who may have a potential contraindication to rTMS or MRI, including seizure history, cardiac arrhythmia, implanted or foreign devices/metal particulates, unstable medical conditions, or pregnancy. Patients with comorbid post-traumatic stress disorder, obsessive-compulsive disorder, other anxiety disorders, attention deficit hyperactivity disorder, bulimia nervosa or binge eating disorder, or moderate Cluster B personality features are also suitable for this treatment and need not be excluded. Patients with bipolar disorder rather than MDD may also be suitable for this treatment. Patients with psychotic disorders, active substance use, a primary diagnosis of borderline or antisocial personality disorder, or persistent depressive disorder (dysthymia) may be less suitable for treatment and may require exclusion.</li>
</ol>
2. Acquiring Magnetic Resonance Images
<ol>
	<li>Acquire patients&#8217; MRIs at any time prior to treatment. Here, use a 3 Tesla scanner with an 8-channel phased-array head coil (refer to Table of Materials), or any scanner capable of created a 3D representation of a patient&#8217;s brain.</li>
	<li>Adhering to local site protocol, acquire a T1-weighted fast spoiled gradient-echo anatomical scan. Use the following parameters: TE = 12 msec, TI = 300 msec, flip angle = 20&#176;, 116 sagittal slices, thickness = 1.5 mm, no gap, 256 x 256 matrix, FOV 240 mm. This scan will be used for real-time rTMS neuronavigation during motor thresholding and treatment sessions.</li>
</ol>
3. Preprocessing Anatomical Scans for Real-time Neuronavigation
<ol>
	<li>Prepare for MRI guidance using a neuronavigation system. 
	Note: The following steps employ the Visor 2.0 neuronavigation system (refer to Table of Materials), but other navigation systems such as the Brainsight TMS Navigation, StealthStation, Aimnav, and NBS System 4 use similar procedures.</li>
	<li>Segment anatomical MRIs into its scalp and brain components. Register the two segments into standard stereotactic space, such as Talairach and Tournoux space19.</li>
	<li>Place target markers by selecting the following points on the MRI: Nasion; Left and right ear, targeting the tragus; Anterior commissure; Posterior commissure; Interhemispheric point (point between the two hemispheres); the anterior most point of the brain; the posterior most point of the brain; the superior most point of the brain; and the left and right most point of the brain.</li>
	<li>Reconstruct the surfaces of the patient&#8217;s scalp and brain in standard space to create a three-dimensional surface-based head model &#8211; this image will be used to identify stereotactic scalp coordinates overlying the dmPFC (Talairach and Tournoux coordinate X0, Y+60, Z+60) for optimal coil vertex placement during treatment. 
	Note: This method uses population coordinates to identify the stimulation target. Other methods to identify a stimulation target, outlined in the Discussion, include single-subject anatomy or fMRI activation maps.</li>
	<li>Register brain and scalp coordinates from stereotactic space to patient space for individualized coil placement.</li>
</ol>
4. Motor Threshold Assessment
<ol>
	<li>Seat patient in the treatment chair, adjusting the camera for an unobstructed view of the patient.</li>
	<li>Place the headband with the marker clip attached to it around the patient&#8217;s head. The marker clip should sit above bridge of nose.</li>
	<li>Preprocess the anatomical scan for the patient as described above in Step 3.</li>
	<li>Load the preprocessed anatomical scans to the neuronavigation program and turn on the camera.</li>
	<li>Using a neuronavigation pen, highlight each scalp target point on the patient. The movements made with the neuronavigation pen will be projected on the television screen in the form of red lines.</li>
	<li>Assess patients&#8217; motor thresholds, the minimum intensity needed to globally excite the motor pathway, prior to rTMS treatment. For this step, begin by having the patient&#8217;s lower limbs extended and supported from below, using a stool or a chair equipped with an extensible leg rest.</li>
	<li>For motor threshold determination, under neuronavigation, target the medial primary motor cortex. Place the coil vertex over the sagittal fissure, 0.5-1.0 cm anterior to the central sulcus. Use an angled or double-cone coil for deeper pulse penetration into medial areas. Use stimulator equipped with a fluid-cooled coil, whose windings are angled at 120&#176; to allow deeper penetration of the pulses (refer to Table of Materials).</li>
	<li>Perform motor thresholding separately for the left and right hemispheres. Orient the coil laterally to direct rTMS-evoked current flow to the desired hemisphere20. For example, to stimulate the left hemisphere, orient the coil with the handle pointing rightwards and the direction of current flow toward the left hemisphere. Observe the contralateral (right) lower limb for movements during this procedure.</li>
	<li>Determine threshold and elicited motor movement visually by the halluces longus muscle of the big toe. 
	Note: Unlike conventional motor threshold testing that targets the hand muscle, stimulating the medial wall of the motor cortex will target the toe muscle. Motor evoked potentials (MEPs) may also be used as a more accurate determination of motor threshold, however it is a much lengthier approach.
	<ol>
		<li>Begin by stimulating at 55% of maximum machine intensity, then adjust upwards or downwards in increments of ~5% depending on whether a response is observed. Reduce the increment size steadily to ~1% as the motor threshold is approached, as previously described21. Stimulate no more frequently than 0.2 Hz (once per 5 sec) to avoid inhibitory or excitatory effects over time.</li>
		<li>Once a motor threshold is established, move the vertex 1-2 cm anteriorly and posteriorly, in exploratory increments of 2-3 mm, to determine whether any alternative site offers a lower motor threshold. Use the lowest threshold achieved along this arc for each side.</li>
	</ol>
	</li>
</ol>
5. rTMS Treatment &#38; Adaptive Titration
<ol>
	<li>Perform a course of neuronavigated dmPFC-rTMS, using a total of 20-30 daily sessions over 4-6 weeks. For treatments, use the 120&#176; angled, fluid-cooled coil and the parameters listed below for dmPFC stimulation in each treatment session (refer to Table of Materials).</li>
	<li>Seat the patient in the treatment chair, adjusting the camera for an unobstructed view of the patient.</li>
	<li>Place a headband with a marker clip attached to it around the patient&#8217;s head (placed laterally so as not to block the rTMS coil placement over the medial target site) as described above. Using a camera, the neuronavigation system, will detect the marker clip and will allow for preprocessing and neuronavigation.</li>
	<li>Load the preprocessed anatomical scans to the neuronavigation program and turn on the camera.</li>
	<li>Using a neuronavigation pen, highlight each scalp target point on the patient. The movements made with the neuronavigation pen will be projected on the television screen in the form of red lines.</li>
	<li>Place the coil over the dmPFC target under MRI guidance using the neuronavigation system. For verification purposes, this point should lie close to 25% of the distance from nasion to inion. Laterally. Orient the coil laterally, with the handle pointing away from the hemisphere to be stimulated. Stimulate the left hemisphere, then re-orient the coil by 180&#176; to stimulate the right hemisphere, maintaining the vertex in the same location over the dmPFC scalp site.</li>
	<li>Ensure that the scalp site for dmFPC remains in close contact with the coil itself throughout treatment. Ensure that the patient and operator wear earplugs or other hearing protection during treatment.</li>
	<li>For 10 Hz stimulation, use a duty cycle of 5 sec on, 10 seconds off for a total of 60 trains (3,000 pulses) per hemisphere per session. Perform this protocol of the left then right hemisphere by orienting the coil laterally, as previously described20. 
	Note: The described protocol for 10 Hz rTMS is outside international safety guidelines (Rossi&#160;et al., 2009). There is evidence for its safety18,22.</li>
	<li>For TBS stimulation, use a duty cycle of 2 sec on, 8 sec off for a total of 600 pulses per hemisphere per session. Perform this protocol of the left then right hemisphere by orienting the coil laterally, as previously described20.</li>
	<li>Adaptively titrate the rTMS stimulus intensity upwards from an initial value of 20% maximum stimulator intensity, to allow the patient to habituate to the pain and scalp discomfort associated with rTMS during the initial sessions23. Increment the stimulation intensity by 2-5% on each train of stimulation, as tolerated.
	<ol>
		<li>To assess tolerability, have the patient rate pain on a verbal analogue scale (VAS) from 0 to 10 (0 = no pain, 10 = limit of tolerability without emotional distress) after each train of stimulation is delivered.</li>
	</ol>
	</li>
	<li>Begin with a higher stimulation intensity on each session, using a level associated with moderate tolerability (VAS 5-6) from the previous session, until the patient is starting at the target intensity of 120% of resting motor threshold on each hemisphere. Maintain a verbal analogue scale of less than 9 throughout treatments during this titration process. Titration is typically completed in 2-5 days.</li>
	<li>Monitor the patient for other adverse effects during treatment. 
	Note: The most common treatment-interrupting adverse effect is a syncopal episode, arising during the first or second session of treatment in ~1% of patients. The patient may recount feeling dizzy, faint, or disoriented, and may transiently (~10 sec) lose consciousness. Regular, repeated convulsive movements or post-episode confusion lasting more than a few seconds should be absent, however. In the event of a syncopal episode, lower the headrest on the chair if possible and encourage the patient to remain still until recovered. The session may proceed if the patient is recovered and willing to go on after a few min.</li>
	<li>Monitor the patient for a generalized tonic-clonic seizure during treatment. 
	Note: These events are rare, and we have not observed a seizure in ~8,000 sessions of dmPFC-rTMS across &#62;200 individual patients to date. Regular, rhythmical, vigorous convulsive movements lasting 10-40 sec, initially around 3 Hz and becoming progressively less rapid, accompanied by unresponsiveness, are suggestive of seizure rather than syncope. However, the two may be difficult to distinguish for an untrained observer.
	<ol>
		<li>Use video monitoring during all treatments so that the episode can be reviewed by a neurologist at subsequent assessment, if necessary. In the event of such an episode, apply standard seizure first aid steps, including clearing the area of objects with the potential to cause injury, placing the patient on the ground if possible or lowering the treatment chair to the horizontal position if not, laying the patient on the left side if possible, ensuring a clear airway, and ensuring that someone remains with the patient until the seizure terminates and the person regains full alertness.</li>
		<li>Call emergency services if the seizure does not self-terminate after ~60 sec.</li>
	</ol>
	</li>
</ol>
6. Clinical Data Collection
<ol>
	<li>Collect standardized self-reported questionnaires at baseline, weekly throughout treatment and at follow-up (e.g., 2, 4, 6, 12, and 26 weeks post-treatment). Collect the following self-report data: Beck Depression Inventory (BDI-II)24, and Beck Anxiety Inventory25 on a daily basis throughout treatment.</li>
	<li>Collect depression severity scores via the clinician-rated 17-item Hamilton Rating Scale for Depression score26 (HamD17) at baseline, weekly during treatment, and at 2, 4, 6, 12 and 26 weeks post-treatment in follow-up.</li>
</ol>

Authors Ms. Dunlop and Ms. Gapriellian have no disclosures to report.

Here, MRI-guided dmPFC-rTMS was applied for treatment-resistant MDD. In general, rTMS at this site was well tolerated, with mild scalp discomfort and pain at the site of stimulation that was adequately managed using adaptive titration. In open-label trials and a chart review, both 10 Hz and theta burst stimulation resulted in significant improvements in depressive severity as measured by the HamD17 and BDI-II.
There are two critical steps worth noting in the rTMS treatment procedure...

Repetitive transcranial magnetic stimulation (rTMS) is a form of indirect focal cortical stimulation. rTMS employs brief, focal electromagnetic field pulses that penetrate the skull to stimulate target brain regions. rTMS is thought to engage the mechanisms of synaptic long-term potentiation and long-term depression, thereby increasing or decreasing the cortical excitability of the region stimulated1. Generally, the rTMS pulse frequency determines its effects: higher frequency stimulation tends to be excitatory, while lower frequency is inhibitory. Non-invasive stimulatory procedures are also widely used as a causal probe to induce temporary &#8216;cortical lesions&#8217;, and establish neural-behavior relationships or functional regions by temporarily disabling the function of a desired cortical region2&#8211;4.
Therapeutic rTMS involves multiple stimulation sessions, usually applied once daily over several weeks, to treat a variety of disorders, including major depressive disorder (MDD)5, eating disorders6, and obsessive-compulsive disorder7. rTMS for MDD is a potential option for medically refractory patients, and allows the clinician to noninvasively target and alter the excitability of a cortical region directly involved with depressive etiology or pathophysiology. The conventional cortical target for MDD-rTMS is the dorsolateral prefrontal cortex (DLPFC)8. However, convergent evidence from neuroimaging, lesion, and stimulation studies identifies the dorsomedial prefrontal cortex (dmPFC) as a potentially important therapeutic target for MDD9 and a variety of other psychiatric disorders characterized by deficits in self-regulation of thoughts, behaviors, and emotional states10. The dmPFC is a region of consistent activation in emotional regulation11, behavioral regulation12,13. The dmPFC is also associated with neurochemical14, structural15, and functional16 abnormalities in MDD
Described here is the procedure for 20 sessions (4 weeks) of magnetic resonance imaging (MRI) guided rTMS to the dmPFC bilaterally, as a treatment for major depressive disorder. In addition to a conventional 10 Hz protocol applied over 30 min, an intermittent theta burst stimulation protocol (TBS) is discussed, which applies 50 Hz triplet bursts at 5 Hz over a 6 min session17. Both protocols are thought to be excitatory, with the TBS protocol having the potential to achieve comparable effects using a much shorter session18. In both protocols, anatomical MRIs as well as clinical assessments are acquired prior to rTMS. Neuronavigation uses the anatomical scans to account for anatomical variability of dmPFC and optimize the location of rTMS. A relatively new 120&#176;-angled fluid-cooled rTMS coil was also used in order to stimulate deeper midline cortical structures. Finally, rTMS intensity titration was used over the first week of rTMS sessions to ensure that patients could habituate to the higher pain levels associated with dmPFC stimulation as compared to conventional DLPFC stimulation.

<table border="0" cellpadding="0" cellspacing="0">
	<tbody>
		<tr>
			<td>3T GE Signa HDx Scanner</td>
			<td>GE</td>
			<td>n/a</td>
			<td></td>
		</tr>
		<tr>
			<td>Visor 2.0 Neuronavigation System</td>
			<td>ANT Neuro</td>
			<td>n/a</td>
			<td></td>
		</tr>
		<tr>
			<td>MagPro R30 Stimulator</td>
			<td>MagVenture</td>
			<td>n/a</td>
			<td></td>
		</tr>
		<tr>
			<td>Cool-DB80 Coil</td>
			<td>MagVenture</td>
			<td>n/a</td>
			<td></td>
		</tr>
	</tbody>
</table>

mri-guided dmpfc-rtms as a treatment for treatment-resistant major depressive disorder

Here we outline the protocol for magnetic resonance imaging (MRI) guided repetitive transcranial magnetic stimulation (rTMS) to the dorsal medial prefrontal cortex (dmPFC) in patients with major depressive disorder (MDD). Technicians used a neuronavigation system to process patient MRIs to generate a 3-dimensional head model. The head model was subsequently used to identify patient-specific stimulatory targets. The dmPFC was stimulated daily for 20 sessions. Stimulation intensity was titrated to address scalp pain associated with rTMS. Weekly assessments were conducted on the patients using the Hamilton Rating Scale for Depression (HamD17) and Beck Depression Index II (BDI-II). Treatment-resistant MDD patients achieved significant improvements on both HAMD and BDI-II. Of note, angled, double-cone coil rTMS at 120% resting motor threshold allows for optimal stimulation of deeper midline prefrontal regions, which results in a possible therapeutic application for MDD. One major limitation of the rTMS field is the heterogeneity of treatment parameters across studies, including duty cycle, number of pulses per session and intensity. Further work should be done to clarify the effect of stimulation parameters on outcome. Future dmPFC-rTMS work should include sham-controlled studies to confirm its clinical efficacy in MDD.

In previous work, HamD17 was used as a measure of treatment response for 10 Hz dmPFC-rTMS. Table 1 displays the pre- and post-treatment HamD17 scores in a previously published case series27. Among all subjects, pre-treatment HamD17 score was 21.66.9 that significantly decreased by 4,331% to 12.58.2 post-rTMS (t22 = 6.54, p &#60;0.0001)27. Using a remission criterion of HamD17 &#8804;7, 8 of 23 subjects remitted following treatme...

Watch this Scientific Journal Video about MRI-guided dmPFC-rTMS as a Treatment for Treatment-resistant Major Depressive Disorder at JoVE.com

MRI-guided dmPFC-rTMS as a Treatment for Treatment-resistant Major Depressive Disorder

Here we outline the procedure for MRI-guided repetitive transcranial magnetic stimulation to the dorsomedial prefrontal cortex as an experimental treatment for major depressive disorder.

Here we outline the protocol for magnetic resonance imaging (MRI) guided repetitive transcranial magnetic stimulation (rTMS) to the dorsal medial ...

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13.8K Views.  University of Toronto. Here we outline the procedure for MRI-guided repetitive transcranial magnetic stimulation to the dorsomedial prefrontal cortex as an experimental treatment for major depressive disorder.

Video: MRI-guided dmPFC-rTMS as a Treatment for Treatment-resistant Major Depressive Disorder

MRI-guided Disruption of the Blood-brain Barrier using Transcranial Focused Ultrasound in a Rat Model

Focused ultrasound (FUS) disruption of the blood-brain barrier (BBB) is an increasingly investigated technique for circumventing the BBB1-5. The BBB is a significant obstacle to pharmaceutical treatments of brain disorders as it limits the passage of molecules from the vasculature into the brain tissue to molecules less than approximately 500 Da in size6. FUS induced BBB disruption (BBBD) is temporary and reversible4 and has an advantage over chemical means of inducing BBBD by being highly localized. FUS induced BBBD provides a means for investigating the effects of a wide range of therapeutic agents on the brain, which would not otherwise be deliverable to the tissue in sufficient concentration. While a wide range of ultrasound parameters have proven successful at disrupting the BBB2,5,7, there are several critical steps in the experimental procedure to ensure successful disruption with accurate targeting. This protocol outlines how to achieve MRI-guided FUS induced BBBD in a rat model, with a focus on the critical animal preparation and microbubble handling steps of the experiment.

Microbubble-mediated focused ultrasound disruption of the blood-brain barrier (BBB) is a promising technique for non-invasive targeted drug delivery in the brain1-3. This protocol outlines the experimental procedure for MRI-guided transcranial BBB disruption in a rat model.

Focused ultrasound (FUS) disruption of the blood-brain barrier (BBB) is an increasingly investigated technique for circumventing the BBB1-5. The BBB is a ...

Osteopathic Manipulative Treatment as a Useful Adjunctive Tool for Pneumonia

Pneumonia, the inflammatory state of lung tissue primarily due to microbial infection, claimed 52,306 lives in the United States in 20071 and resulted in the hospitalization of 1.1 million patients2. With an average length of in-patient hospital stay of five days2, pneumonia and influenza comprise significant financial burden costing the United States $40.2 billion in 20053. Under the current Infectious Disease Society of America/American Thoracic Society guidelines, standard-of-care recommendations include the rapid administration of an appropriate antibiotic regiment, fluid replacement, and ventilation (if necessary). Non-standard therapies include the use of corticosteroids and statins; however, these therapies lack conclusive supporting evidence4. (Figure 1)

Osteopathic Manipulative Treatment (OMT) is a cost-effective adjunctive treatment of pneumonia that has been shown to reduce patients&#8217; length of hospital stay, duration of intravenous antibiotics, and incidence of respiratory failure or death when compared to subjects who received conventional care alone5. The use of manual manipulation techniques for pneumonia was first recorded as early as the Spanish influenza pandemic of 1918, when patients treated with standard medical care had an estimated mortality rate of 33%, compared to a 10% mortality rate in patients treated by osteopathic physicians6. When applied to the management of pneumonia, manual manipulation techniques bolster lymphatic flow, respiratory function, and immunological defense by targeting anatomical structures involved in the these systems7,8, 9, 10.

The objective of this review video-article is three-fold: a) summarize the findings of randomized controlled studies on the efficacy of OMT in adult patients with diagnosed pneumonia, b) demonstrate established protocols utilized by osteopathic physicians treating pneumonia, c) elucidate the physiological mechanisms behind manual manipulation of the respiratory and lymphatic systems. Specifically, we will discuss and demonstrate four routine techniques that address autonomics, lymph drainage, and rib cage mobility: 1) Rib Raising, 2) Thoracic Pump, 3) Doming of the Thoracic Diaphragm, and 4) Muscle Energy for Rib 1.5,11

Pneumonia is one of the top ten leading causes of death in the U.S. Osteopathic manipulative techniques (OMT) may be utilized as an adjunctive therapy in the treatment of pneumonia to enhance biomechanical and immune function; and ultimately, to reduce hospital stay, duration of antibiotics, incidence of respiratory failure, and mortality. In this video-article, we will review randomized controlled studies on the use of OMT in pneumonia patients, as well as demonstrate specific hands-on techniques that are routinely practiced by osteopathic physicians when treating pulmonary infections.

Pneumonia, the inflammatory state of lung tissue primarily due to microbial infection, claimed 52,306 lives in the United States in 20071 and resulted in ...

Isolated Hepatic Perfusion as a Treatment for Liver Metastases of Uveal Melanoma

Isolated hepatic perfusion (IHP) is a procedure where the liver is surgically isolated and perfused with a high concentration of the chemotherapeutic agent melphalan. Briefly, the procedure starts with the setup of a percutaneous veno-venous bypass from the femoral vein to the external jugular vein. Via a laparotomy, catheters are then inserted into the proper hepatic artery and the caval vein. The portal vein and the caval vein, both supra- and infrahepatically, are then clamped. The arterial and venous catheters are connected to a heart lung machine and the liver is perfused with melphalan (1 mg/kg body weight) for 60 min. This way it is possible to locally perfuse the liver with a high dose of a chemotherapeutic agent, without leakage to the systemic circulation.
In previous studies including patients with isolated liver metastases of uveal melanoma, an overall response rate of 33-100% and a median survival between 9 and 13 months, have been reported. The aim of this protocol is to give a clear description of how to perform the procedure and to discuss IHP as a treatment option for liver metastases of uveal melanoma.

Here, we present a protocol how to perform an isolated liver perfusion (IHP) with melphalan and we also discuss IHP as a treatment option for liver metastases of uveal melanoma.

Isolated hepatic perfusion (IHP) is a procedure where the liver is surgically isolated and perfused with a high concentration of the chemotherapeutic ...

Evaluation of the Efficacy of the H. pylori Protein HP-NAP as a Therapeutic Tool for Treatment of Bladder Cancer in an Orthotopic Murine Model

Bladder cancer is one of the most common malignancies of the urogenital tract. Intravesical injection of Bacillus Calmette-Gu&#233;rin (BCG) is the gold standard treatment for the high-grade non-muscle invasive bladder cancer (NMIBC). However, since the treatment-related side effects are relevant, newer biological response modifiers with a better benefit/side effects ratio are needed.
The tumour microenvironment can influence both tumour development and therapy efficacy. In order to obtain a good model, it is desirable to implant tumour cells in the organ from which the cancer originates.
In this protocol, we describe a method for establishing a tumour in the bladder cavity of female mice and subsequent delivery of therapeutic agents; the latter are exemplified by our use of Helicobacter pylori neutrophil activating protein (HP-NAP). A preliminary chemical burn of the mucosa, followed by the injection of mouse urothelial carcinoma cell line MB49 via urethral catheterization, enables the cells to attach to the bladder mucosa. After a period, required to allow an initial proliferation of the cells, mice are treated with HP-NAP, administrated again via catheterization. The anti-tumour activity of HP-NAP is evaluated comparing the tumour volume, the extent of necrosis and the degree of vascularization between vehicle- and HP-NAP-treated animals.

Evaluation of the Efficacy of the H. pylori Protein HP-NAP as a Therapeutic Tool for Treatment of Bladder Cancer in an Orthotopic Murine Model

Here the method to establish a syngeneic mouse model of orthotopic bladder tumour to evaluate the anti-tumour efficacy of the bacterial protein HP-NAP is described.

Bladder cancer is one of the most common malignancies of the urogenital tract. Intravesical injection of Bacillus Calmette-Gu&#233;rin (BCG) is the gold ...

Percutaneous Hepatic Perfusion (PHP) with Melphalan as a Treatment for Unresectable Metastases Confined to the Liver

Unresectable liver metastases of colorectal cancer can be treated with systemic chemotherapy, aiming to limit the disease, extend survival or turn unresectable metastases into resectable ones. Some patients however, suffer from side effects or progression under systemic treatment. For patients with metastasized uveal melanoma there are no standard systemic therapy options. For patients without extrahepatic disease, isolated liver perfusion (IHP) may enable local disease control with limited systemic side effects. Previously, this was performed during open surgery with satisfying results, but morbidity and mortality related to the open procedure, prohibited a widespread application. Therefore, percutaneous hepatic perfusion (PHP) with simultaneous chemofiltration was developed. Besides decreasing morbidity and mortality, this procedure can be repeated, hopefully leading to a higher response rate and improved survival (by local control of disease). During PHP, catheters are placed in the proper hepatic artery, to infuse the chemotherapeutic agent, and in the inferior caval vein to aspirate the chemosaturated blood returning through the hepatic veins. The caval vein catheter is a double balloon catheter that prohibits leakage into the systemic circulation. The blood returning from the hepatic veins is aspirated through the catheter fenestrations and then perfused through an extra-corporeal filtration system. After filtration, the blood is returned to the patient by a third catheter in the right internal jugular vein. During PHP a high dose of melphalan is infused into the liver, which is toxic and would lead to life threatening complications when administered systemically. Because of the significant hemodynamic instability resulting from the combination of caval vein occlusion and chemofiltration, hemodynamic monitoring and hemodynamic support is of paramount importance during this complex procedure.

Percutaneous Hepatic Perfusion PHP with Melphalan as a Treatment for Unresectable Metastases Confined to the Liver

In this manuscript, we describe percutaneous isolated hepatic perfusion with simultaneous chemofiltration as treatment for unresectable liver metastases. This procedure is performed under general anaesthesia in the angiosuite by an experienced team, consisting of an interventional radiologist, a clinical perfusionist and anaesthesiologist.

Unresectable liver metastases of colorectal cancer can be treated with systemic chemotherapy, aiming to limit the disease, extend survival or turn ...

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 ...

MRI-guided Focused Ultrasound Thalamotomy for Patients with Medically-refractory Essential Tremor

Essential tremor (ET) is the most common type of tremor in adults. While ET does not result in decreased life expectancy, the disabilities associated with ET can have a significant impact on quality of life, mood, functional activities, and socialization. Patients suffering from ET not sufficiently treated with first line medications may be eligible for alternative strategies such as deep brain stimulation, radiofrequency ablation, and MRI guided focused ultrasound (MRgFUS). High-intensity MRgFUS is an emerging modality to treat ET, its attraction for patients being that it is noninvasive and associated with short recovery time, as patients are home the day after treatment. While MRgFUS centers are still limited, it will become important for clinicians to consider MRgFUS as a treatment alternative, particularly in the case of a patient for whom open surgery is contraindicated. This article outlines the steps of patient selection, equipment setup, sonication, and post-treatment follow-up, as well as critical steps to be aware of when performing a MRgFUS procedure.

High-intensity MRI guided focused ultrasound is an emerging noninvasive technique to precisely ablate brain tissue. It has been shown to be safe and effective in treating medically-refractory essential tremor. This article describes the protocol for thalamotomy from patient selection to equipment setup to post-treatment follow-up.

Essential tremor (ET) is the most common type of tremor in adults. While ET does not result in decreased life expectancy, the disabilities associated with ...

Vagus Nerve Stimulation As an Adjunctive Neurostimulation Tool in Treatment-resistant Depression

Vagus nerve stimulation (VNS) is an approved neurostimulation therapy. The purpose of the method is to treat patients with therapy-resistant depression (TRD). VNS exhibits antidepressive and stabilizing effects. This method is particularly useful as a long-term treatment, in which up to two-thirds of patients respond. The vagus nerve stimulator is positioned on the left vagus nerve during a surgical procedure and is activated telemetrically by a wand connected to a handheld computerized device. The treating physician can perform various adjustments of the vagus nerve stimulator during in-office visits (e.g., by modifying stimulation intensity or stimulation frequency) to achieve maximum therapeutic effects with low side effects. Set-up of the device usually takes several months. Typical side effects include wound infection, temporary salivation, coughing, paralysis of the vocal cords, bradycardia, or even asystole. The patient can stop the VNS by placing a magnet over the generator. The current protocol describes delivery of the specific stimulation tool and methods for adjusting the tuning parameters to achieve the best remission rates in patients with TRD.

Vagus nerve stimulation (VNS) has been shown to be effective as an adjunct treatment for treatment-resistant depression (TRD). VNS leads to antidepressive and antisuicidal effects and quality of life improvements. This protocol offers a step-by-step guide to managing and adjusting a vagus nerve stimulator for efficient treatment of TRD.

Vagus nerve stimulation (VNS) is an approved neurostimulation therapy. The purpose of the method is to treat patients with therapy-resistant depression ...

Involving Individuals with Developmental Language Disorder and Their Parents/Carers in Research Priority Setting

A protocol for involving individuals presenting with developmental language disorder (DLD) (iDLD) and their parents/carers (iDLDPC) in a research priority setting exercise is presented.
iDLD have difficulties with communication skills, such as understanding language, word-finding and discourse. Such difficulties mean existing research priority setting protocols are difficult for iDLD to access, since they require sophisticated communication skills. Thus, a novel protocol for involving iDLD in these exercises is warranted. The same protocol is recommended for use with iDLDPC, to ensure accessibility.
The protocol is presented in 4 steps. Step 1 describes a program of activities delivered by trained, specialist DLD speech and language therapists (SLTs) that prepares iDLD/iDLDPC for involvement. Step 2 outlines an approach to elicit iDLD/iDLDPC&#8217;s opinions on research priorities. Steps 3 and 4 describe methods to analyze and integrate this data at multiple stages of the research priority setting process.
9 trained specialist DLD SLTs delivered steps 1 and 2. 17 iDLDs and 25 iDLDPCs consented to involvement. Opinions from all participants were elicited, and this data was used to influence the process and output of the exercise.
An advantage of this protocol is its accommodation of the heterogeneity in support needs of iDLD/iDLDPC, through a menu of options, whilst also providing a structured framework. Due to the novelty of the protocol, the methods for data integration were developed by the research group. These are potential limitations of the protocol, and may bring the reliability and validity under scrutiny, which are yet to be tested.
This protocol enables meaningful involvement of iDLD/iDLDPC in&#160;research priority setting and could be utilized for people with other kinds of speech, language or communication needs. Further research should evaluate the effectiveness of the protocol and whether it can be adapted for involvement of such populations in other research studies.

A protocol to enable individuals with developmental language disorder (DLD) and their parents/carers to meaningfully participate in a research priority setting exercise is established. The protocol includes a defined program of activities for data collection, and methods to incorporate this data into the broader research priority setting process.

A protocol for involving individuals presenting with developmental language disorder (DLD) (iDLD) and their parents/carers (iDLDPC) in a research priority ...

The Miniature Pig: A Large Animal Model for Cochlear Implant Research

Cochlear implants (CI) are the most effective method to treat people with severe-to-profound sensorineural hearing loss. Although CIs are used worldwide, no standard model exists for investigating the electrophysiology and histopathology in patients or animal models with a CI or for evaluating new models of electrode arrays. A large animal model with cochlea characteristics similar to those of humans may provide a research and evaluation platform for advanced and modified arrays before their use in humans. 
To this end, we established standard CI methods with Bama mini-pigs, whose inner ear anatomy is highly similar to that of humans. Arrays designed for human use were implanted into the mini pig cochlea through a round window membrane, and a surgical approach followed that was similar to that used for human CI recipients. Array insertion was followed by evoked compound action potential (ECAP) measurements to evaluate the function of the auditory nerve. This study describes the preparation of the animal, surgical steps, array insertion, and intraoperative electrophysiological measurements. 
The results indicated that the same CI used for humans could be easily implanted in mini-pigs via a standardized surgical approach and yielded similar electrophysiological outcomes as measured in human CI recipients. Mini-pigs could be a valuable animal model to provide initial evidence of the safety and potential performance of novel electrode arrays and surgical approaches before applying them to human beings.

Miniature pigs (mini-pigs) are an ideal large animal model for research into cochlear implants. Cochlear implantation surgery in mini-pigs can be utilized to provide initial evidence of the safety and potential performance of novel electrode arrays and surgical approaches in a living system similar to human beings.

Cochlear implants (CI) are the most effective method to treat people with severe-to-profound sensorineural hearing loss. Although CIs are used worldwide, ...