The HortONS study. Treatment of chronic cluster headache with transcutaneous electrical nerve stimulation and occipital nerve stimulation: study protocol for a prospective, investigator-initiated, double-blinded, randomized, placebo-controlled trial.

BACKGROUND: Chronic cluster headache (CCH) is a debilitating primary headache disorder. Occipital nerve stimulation (ONS) has shown the potential to reduce attack frequency, but the occipital paresthesia evoked by conventional (tonic) stimulation challenges a blinded comparison of active stimulation and placebo. Burst ONS offers paresthesia-free stimulation, enabling a blinded, placebo-controlled study. Identification of a feasible preoperative test would help select the best candidates for implantation. This study aims to explore ONS as a preventive treatment for CCH, comparing burst stimulation to tonic stimulation and placebo, and possibly identifying a potential preoperative predictor. METHODS: An investigator-initiated, double-blinded, randomized, placebo-controlled trial is conducted, including 40 patients with CCH. Eligible patients complete a trial with the following elements: I) four weeks of baseline observation, II) 12 weeks of transcutaneous electrical nerve stimulation (TENS) of the occipital nerves, III) implantation of a full ONS system followed by 2 week grace period, IV) 12 weeks of blinded trial with 1:1 randomization to either placebo (deactivated ONS system) or burst (paresthesia-free) stimulation, and V) 12 weeks of tonic stimulation. The primary outcomes are the reduction in headache attack frequency with TENS and ONS and treatment safety. Secondary outcomes are treatment efficacy of burst versus tonic ONS, the feasibility of TENS as a predictor for ONS outcome, reduction in headache pain intensity (numeric rating scale), reduction in background headache, the patient's impression of change (PGIC), health-related quality of life (EuroQoL-5D), self-reported sleep quality, and symptoms of anxiety and depression (Hospital Anxiety and Depression Scale, HADS). Data on headache attack characteristics are registered weekly. Data on patient-reported outcomes are assessed after each trial phase. DISCUSSION: The study design allows a comparison between burst ONS and placebo in refractory CCH and enables a comparison of the efficacy of burst and tonic ONS. It will provide information about the effect of burst ONS and explore whether the addition of this stimulation paradigm may improve stimulation protocols. TENS is evaluated as a feasible preoperative screening tool for ONS outcomes by comparing the effect of attack prevention of TENS and tonic ONS. TRIAL REGISTRATION: The study is registered at Clinicaltrials.gov (trial registration number NCT05023460, registration date 07-27-2023).

An fMRI-compatible system for targeted electrical stimulation.

BACKGROUND: Neuromodulation is a rapidly expanding therapeutic option considered within neuropsychiatry, pain and rehabilitation therapy. Combining electrostimulation with feedback from fMRI can provide information about the mechanisms underlying the therapeutic effects, but so far, such studies have been hampered by the lack of technology to conduct safe and accurate experiments. Here we present a system for fMRI compatible electrical stimulation, and the first proof-of-concept neuroimaging data with deep brain stimulation (DBS) in pigs obtained with the device. NEW METHOD: The system consists of two modules, placed in the control and scanner room, connected by optical fiber. The system also connects to the MRI scanner to timely initiate the stimulation sequence at start of scan. We evaluated the system in four pigs with DBS in the subthalamic nucleus (STN) while we acquired BOLD responses in the STN and neocortex. RESULTS: We found that the system delivered robust electrical stimuli to the implanted electrode in sync with the preprogrammed fMRI sequence. All pigs displayed a DBS-STN induced neocortical BOLD response, but none in the STN. COMPARISONS WITH EXISTING METHOD: The system solves three major problems related to electric stimuli and fMRI examinations, namely preventing distortion of the fMRI signal, enabling communication that synchronize the experimental conditions, and surmounting the safety hazards caused by interference with the MRI scanner. CONCLUSIONS: The fMRI compatible electrical stimulator circumvents previous problems related to electroceuticals and fMRI. The system allows flexible modifications for fMRI designs and stimulation parameters, and can be customized to electroceutical applications beyond DBS.

[Tumor treating fields in cancer treatment in Denmark].

Tumor treating fields (TTFields) is a new non-invasive approach to cancer treatment. TTFields is low-intensity (1-5 V/m), intermediate frequency (150-200 kHz) alternating electric fields delivered locally to the tumour to selectively kill dividing cells and disrupt cancer growth. TTFields has proven safe and effective for newly diagnosed glioblastoma and is currently being tried for multiple other tumours. This review presents an introduction to TTFields, covering the main indications, the application method, the mechanism of action, the clinical results and the perspectives for implementation in Danish cancer treatment.

[Tumor treating fields in cancer treatment in Denmark].

Tumor treating fields (TTFields) is a new non-invasive approach to cancer treatment. TTFields are low-intensity (1-5 V/m), intermediate frequency (150-200 kHz) alternating electric fields delivered locally to the tumour to selectively kill dividing cells and disrupt cancer growth. TTFields has proven safe and effective for newly diagnosed glioblastoma and is currently being tried for multiple other tumours. This review presents an introduction to TTFields, covering the main indications, the application method, the mechanism of action, the clinical results and the perspectives for implementation in Danish cancer treatment.

Importance of electrode position for the distribution of tumor treating fields (TTFields) in a human brain. Identification of effective layouts through systematic analysis of array positions for multiple tumor locations.

Tumor treating fields (TTFields) is a new modality used for the treatment of glioblastoma. It is based on antineoplastic low-intensity electric fields induced by two pairs of electrode arrays placed on the patient's scalp. The layout of the arrays greatly impacts the intensity (dose) of TTFields in the pathology. The present study systematically characterizes the impact of array position on the TTFields distribution calculated in a realistic human head model using finite element methods. We investigate systematic rotations of arrays around a central craniocaudal axis of the head and identify optimal layouts for a large range of (nineteen) different frontoparietal tumor positions. In addition, we present comprehensive graphical representations and animations to support the users' understanding of TTFields. For most tumors, we identified two optimal array positions. These positions varied with the translation of the tumor in the anterior-posterior direction but not in the left-right direction. The two optimal directions were oriented approximately orthogonally and when combining two pairs of orthogonal arrays, equivalent to clinical TTFields therapy, we correspondingly found a single optimum position. In most cases, an oblique layout with the fields oriented at forty-five degrees to the sagittal plane was superior to the commonly used anterior-posterior and left-right combinations of arrays. The oblique configuration may be used as an effective and viable configuration for most frontoparietal tumors. Our results may be applied to assist clinical decision-making in various challenging situations associated with TTFields. This includes situations in which circumstances, such as therapy-induced skin rash, scar tissue or shunt therapy, etc., require layouts alternative to the prescribed. More accurate distributions should, however, be based on patient-specific models. Future work is needed to assess the robustness of the presented results towards variations in conductivity.

Impact of tumor position, conductivity distribution and tissue homogeneity on the distribution of tumor treating fields in a human brain: A computer modeling study.

BACKGROUND: Tumor treating fields (TTFields) are increasingly used in the treatment of glioblastoma. TTFields inhibit cancer growth through induction of alternating electrical fields. To optimize TTFields efficacy, it is necessary to understand the factors determining the strength and distribution of TTFields. In this study, we provide simple guiding principles for clinicians to assess the distribution and the local efficacy of TTFields in various clinical scenarios. METHODS: We calculated the TTFields distribution using finite element methods applied to a realistic head model. Dielectric property estimates were taken from the literature. Twentyfour tumors were virtually introduced at locations systematically varied relative to the applied field. In addition, we investigated the impact of central tumor necrosis on the induced field. RESULTS: Local field "hot spots" occurred at the sulcal fundi and in deep tumors embedded in white matter. The field strength was not higher for tumors close to the active electrode. Left/right field directions were generally superior to anterior/posterior directions. Central necrosis focally enhanced the field near tumor boundaries perpendicular to the applied field and introduced significant field non-uniformity within the tumor. CONCLUSIONS: The TTFields distribution is largely determined by local conductivity differences. The well conducting tumor tissue creates a preferred pathway for current flow, which increases the field intensity in the tumor boundaries and surrounding regions perpendicular to the applied field. The cerebrospinal fluid plays a significant role in shaping the current pathways and funnels currents through the ventricles and sulci towards deeper regions, which thereby experience higher fields. Clinicians may apply these principles to better understand how TTFields will affect individual patients and possibly predict where local recurrence may occur. Accurate predictions should, however, be based on patient specific models. Future work is needed to assess the robustness of the presented results towards variations in conductivity.

Peripheral Neuromodulation for the Treatment of Postamputation Neuroma Pain: A Case Report.

Neuroma pain can be severe, persistent, and treatment resistant. We present a case of a 37-year-old female amputee who suffered from severe neuroma pain, which had proved resistant to pharmacologic treatment, glycerol injections, spinal cord stimulation, radiofrequency thermocoagulation, and repeated surgical removals. After treatment with peripheral nerve stimulation, using a St. Jude Medical Octrode lead implanted percutaneously under ultrasound guidance close to her painful neuroma, her ongoing pain dramatically decreased from 8 to 3 on a numeric rating scale (0-10). Peripheral neuromodulation is a promising relatively new treatment that can be used for neuroma pain.

Screening for anti-nutritional compounds in complementary foods and food aid products for infants and young children.

A range of compounds with negative nutritional impact - 'anti-nutrients' - are found in most plant foods. The contents of anti-nutrients in processed foods depend on the ingredients and processing. Anti-nutrients in complementary foods for children can have a negative impact on nutritional status. The aim of this study was to screen complementary foods from developing countries for the anti-nutritional compounds, phytate, polyphenols, inhibitors of trypsin and chymotrypsin, and lectins. Commercial products based on whole grain cereals were included as a 'worst-case' scenario for anti-nutrient exposure in Europe. Contents of minerals (iron, zinc and calcium), in which absorption or utilisation is affected by anti-nutrients, were analysed. Thirty-six products representing foods used in food aid programmes, local blended foods, fortified instant porridges and 'baby foods' were analysed. The content of minerals indicated that the fortification of a number of products did not meet the declared levels of iron, zinc and calcium. The phytate content ranged from 68 to 1536 mg/100 g, confirming a persistent problem of high levels of phytate in processed cereal- and legume-based products. The phytate : Fe molar ratio exceeded the recommended level of <1.0 in 32 of the 36 products. The total polyphenols varied from 1.3 to 9.3 mg gentisic acid equivalents g(-1) . Screening low-molecular weight soluble polyphenols may be more relevant in complementary foods than total polyphenolic compounds. Trypsin and chymotrypsin inhibitors and lectins were found in residual amounts in most products, indicating efficient degradation by heat processing. However, young infants and malnourished children may have reduced pancreatic function, and upper limits for residual trypsin inhibitors are needed.

The anatomy of the Göttingen minipig hypothalamus.

The microscopic organization of the Göttingen minipig (sus scrofa) hypothalamus was studied using Nissl stain, acetylcholinesterase histochemistry, and immunohistochemical staining for calretinin, tyrosin hydroxylase, oxytocin, vasopressin, and orexin A. Mediolaterally the minipig hypothalamus can be divided into three cytoarchitectonic distinct longitudinal zones. The periventricular longitudinal zone comprises the supraoptic, paraventricular, median preoptic, anteroventral periventricular, suprachiasmatic and arcuate nuclei. The medial longitudinal zone includes the prominent medial preoptic, ventromedial, dorsomedial and medial mammillary nuclei. Together with the anterior hypothalamic area, they can be further divided into distinct subregions. The dorsal and posterior hypothalamic areas and the retromammillary and lateral mammillary nuclei are cyto- and chemoarchitectonically distinct but cannot be further divided into subregions. The cell sparse, fiber rich lateral longitudinal zone comprises the lateral preoptic and lateral hypothalamic area as well as the perifornical, lateral tuberal and tuberomammillary nuclei. The findings presented here indicate that the cyto- and chemoarchitecture of the Göttingen minipig hypothalamus is comparable to that of rat, landrace pig, monkey, and human and that the Göttingen minipig may be well suited for future, non-primate, large mammal, hypothalamic research.

Determination of shikimate in crude plant extracts by micellar electrokinetic capillary chromatography.

A method based on micellar electrokinetic capillary chromatography (MECC) has been developed for the determination of shikimate in water and crude plant extracts. The analytes are separated in a cholate-taurine buffer by MECC at pH 7.3 and measured by direct UV detection at 206 nm. Shikimate showed linearity up to 12.5 mM, with a squared correlation coefficient (r(2)) of 0.9997. The method has concentration limit of detection (cLOD) and concentration limit of quantification (cLOQ) at 24.4 and 67.8 microM, respectively, corresponding to detection in the femtomol range. The number of theoretical plates (N) was estimated to 245,000 for the optimized system using a capillary with an effective length of 560 mm. The method was tested on plant samples by measuring the shikimate content in leaves of rapeseed plants grown in hydroponic solutions containing the herbicide glyphosate, a well-known inhibitor of the shikimate pathway. In crude extracts of these plants, shikimate was found to accumulate in the leaves, confirming earlier reports of shikimate as a potential biomarker for glyphosate treatment. The method now developed was also able to detect shikimate-3-phosphate, but this compound was not accumulated in glyphosate inhibited plants as found for shikimate.

Electrostimulation: a future treatment option for patients with neurogenic urodynamic disorders?

This paper provides an overview of electrical stimulation of the nervous system as a treatment option for urodynamic dysfunction and of some of the recent results in this field. The set-up used in our studies for improved bladder filling in spinal cord injured patients by conditional stimulation of the dorsal penile/clitoral nerve is a highly efficient way to limit neurogenic detrusor overactivity and increase bladder capacity. Ongoing studies suggest that recording of bladder nerve activity is stable over time and may be a technique for chronic monitoring of bladder activity. Bladder emptying exploiting an anodal blocking technique permits bladder emptying without simultaneous urethral-perineal contraction, thus enabling a physiological voiding pattern in one continuous sequence. In patients with supraspinal lesions, deep brain electrical stimulation is established only as treatment for a subgroup of patients suffering from Parkinson's disease. Yet, with improved electrode designs and increased clinical experience and experimental results, probably other groups of patients may be candidates for deep brain stimulation. In our study in pigs there was a trend towards increased bladder capacity and compliance in response to stimulation, which is encouraging as several neurological diseases are accompanied by overactive bladder with reduced capacity.