Neural Stimulation Hardware for the Selective Intrafascicular Modulation of the Vagus Nerve.

The neural stimulation of the vagus nerve is able to modulate various functions of the parasympathetic response in different organs. The stimulation of the vagus nerve is a promising approach to treating inflammatory diseases, obesity, diabetes, heart failure, and hypertension. The complexity of the vagus nerve requires highly selective stimulation, allowing the modulation of target-specific organs without side effects. Here, we address this issue by adapting a neural stimulator and developing an intraneural electrode for the particular modulation of the vagus nerve. The neurostimulator parameters such as amplitude, pulse width, and pulse shape were modulated. Single-, and multi-channel stimulation was performed at different amplitudes. For the first time, a polyimide thin-film neural electrode was designed for the specific stimulation of the vagus nerve. In vivo experiments were performed in the adult minipig to validate to elicit electrically evoked action potentials and to modulate physiological functions, validating the spatial selectivity of intraneural stimulation. Electrochemical tests of the electrode and the neurostimulator showed that the stimulation hardware was working correctly. Stimulating the porcine vagus nerve resulted in spatially selective modulation of the vagus nerve. ECAP belonging to alpha and beta fibers could be distinguished during single- and multi-channel stimulation. We have shown that the here presented system is able to activate the vagus nerve and can therefore modulate the heart rate, diastolic pressure, and systolic pressure. The here presented system may be used to restore the cardiac loop after denervation by implementing biomimetic stimulation patterns. Presented methods may be used to develop intraneural electrodes adapted for various applications.

Decoding bladder state from pudendal intraneural signals in pigs.

Neuroprosthetic devices used for the treatment of lower urinary tract dysfunction, such as incontinence or urinary retention, apply a pre-set continuous, open-loop stimulation paradigm, which can cause voiding dysfunctions due to neural adaptation. In the literature, conditional, closed-loop stimulation paradigms have been shown to increase bladder capacity and voiding efficacy compared to continuous stimulation. Current limitations to the implementation of the closed-loop stimulation paradigm include the lack of robust and real-time decoding strategies for the bladder fullness state. We recorded intraneural pudendal nerve signals in five anesthetized pigs. Three bladder-filling states, corresponding to empty, full, and micturition, were decoded using the Random Forest classifier. The decoding algorithm showed a mean balanced accuracy above 86.67% among the three classes for all five animals. Our approach could represent an important step toward the implementation of an adaptive real-time closed-loop stimulation protocol for pudendal nerve modulation, paving the way for the design of an assisted-as-needed neuroprosthesis.

Cervical Cordotomy for Intractable Pain: Do Postoperative Imaging Features Correlate with Pain Outcomes and Mirror Pain?

BACKGROUND AND PURPOSE: Percutaneous cervical cordotomy offers relief of unilateral intractable oncologic pain. We aimed to find anatomic and postoperative imaging features that may correlate with clinical outcomes, including pain relief and postoperative contralateral pain. MATERIALS AND METHODS: We prospectively followed 15 patients with cancer who underwent cervical cordotomy for intractable pain during 2018 and 2019 and underwent preoperative and up to 1-month postoperative cervical MR imaging. Lesion volume and diameter were measured on T2-weighted imaging and diffusion tensor imaging (DTI). Lesion mean diffusivity and fractional anisotropy values were extracted. Pain improvement up to 1 month after surgery was assessed by the Numeric Rating Scale and Brief Pain Inventory. RESULTS: All patients reported pain relief from 8 (7-10) to 0 (0-4) immediately after surgery (P = .001), and 5 patients (33%) developed contralateral pain. The minimal percentages of the cord lesion volume required for pain relief were 10.0% on T2-weighted imaging and 6.2% on DTI. Smaller lesions on DWI correlated with pain improvement on the Brief Pain Inventory scale (r = 0.705, P = .023). Mean diffusivity and fractional anisotropy were significantly lower in the ablated tissue than contralateral nonlesioned tissue (P = .003 and P = .001, respectively), compatible with acute-phase tissue changes after injury. Minimal postoperative mean diffusivity values correlated with an improvement of Brief Pain Inventory severity scores (r = -0.821, P = .004). The average lesion mean diffusivity was lower among patients with postoperative contralateral pain (P = .037). CONCLUSIONS: Although a minimal ablation size is required during cordotomy, larger lesions do not indicate better outcomes. DWI metrics changes represent tissue damage after ablation and may correlate with pain outcomes.

Cortical plasticity after hand prostheses use: Is the hypothesis of deafferented cortex "invasion" always true?

OBJECTIVE: To study motor cortex plasticity after a period of training with a new prototype of bidirectional hand prosthesis in three left trans-radial amputees, correlating these changes with the modification of Phantom Limb Pain (PLP) in the same period. METHODS: Each subject underwent a brain motor mapping with Transcranial Magnetic Stimulation (TMS) and PLP evaluation with questionnaires during a six-month training with a prototype of bidirectional hand prosthesis. RESULTS: The baseline motor maps showed in all three amputees a smaller area of muscles representation of the amputated side compared to the intact limb. After training, there was a partial reversal of the baseline asymmetry. The two subjects affected by PLP experienced a statistically significant reduction of pain. CONCLUSIONS: Two apparently opposite findings, the invasion of the "deafferented" cortex by neighbouring areas and the "persistence" of neural structures after amputation, could vary according to different target used for measurement. Our results do not support a correlation between PLP and motor cortical changes. SIGNIFICANCE: The selection of the target and of the task is essential for studies investigating motor brain plasticity. This study boosts against a direct and unique role of motor cortical changes on PLP genesis.

Characterization of multi-channel intraneural stimulation in transradial amputees.

Although peripheral nerve stimulation using intraneural electrodes has been shown to be an effective and reliable solution to restore sensory feedback after hand loss, there have been no reports on the characterization of multi-channel stimulation. A deeper understanding of how the simultaneous stimulation of multiple electrode channels affects the evoked sensations should help in improving the definition of encoding strategies for bidirectional prostheses. We characterized the sensations evoked by simultaneous stimulation of median and ulnar nerves (multi-channel configuration) in four transradial amputees who had been implanted with four TIMEs (Transverse Intrafascicular Multichannel Electrodes). The results were compared with the characterization of single-channel stimulation. The sensations were characterized in terms of location, extent, type, and intensity. Combining two or more single-channel configurations caused a linear combination of the sensation locations and types perceived with such single-channel stimulations. Interestingly, this was also true when two active sites from the same nerve were stimulated. When stimulating in multi-channel configuration, the charge needed from each electrode channel to evoke a sensation was significantly lower than the one needed in single-channel configuration (sensory facilitation). This result was also supported by electroencephalography (EEG) recordings during nerve stimulation. Somatosensory potentials evoked by multi-channel stimulation confirmed that sensations in the amputated hand were perceived by the subjects and that a perceptual sensory facilitation occurred. Our results should help the future development of more efficient bidirectional prostheses by providing guidelines for the development of more complex stimulation approaches to effectively restore multiple sensations at the same time.

Optimal integration of intraneural somatosensory feedback with visual information: a single-case study.

Providing somatosensory feedback to amputees is a long-standing objective in prosthesis research. Recently, implantable neural interfaces have yielded promising results in this direction. There is now considerable evidence that the nervous system integrates redundant signals optimally, weighting each signal according to its reliability. One question of interest is whether artificial sensory feedback is combined with other sensory information in a natural manner. In this single-case study, we show that an amputee with a bidirectional prosthesis integrated artificial somatosensory feedback and blurred visual information in a statistically optimal fashion when estimating the size of a hand-held object. The patient controlled the opening and closing of the prosthetic hand through surface electromyography, and received intraneural stimulation proportional to the object's size in the ulnar nerve when closing the robotic hand on the object. The intraneural stimulation elicited a vibration sensation in the phantom hand that substituted the missing haptic feedback. This result indicates that sensory substitution based on intraneural feedback can be integrated with visual feedback and make way for a promising method to investigate multimodal integration processes.

Comparison of linear frequency and amplitude modulation for intraneural sensory feedback in bidirectional hand prostheses.

Recent studies have shown that direct nerve stimulation can be used to provide sensory feedback to hand amputees. The intensity of the elicited sensations can be modulated using the amplitude or frequency of the injected stimuli. However, a comprehensive comparison of the effects of these two encoding strategies on the amputees' ability to control a prosthesis has not been performed. In this paper, we assessed the performance of two trans-radial amputees controlling a myoelectric hand prosthesis while receiving grip force sensory feedback encoded using either linear modulation of amplitude (LAM) or linear modulation of frequency (LFM) of direct nerve stimulation (namely, bidirectional prostheses). Both subjects achieved similar and significantly above-chance performance when they were asked to exploit LAM or LFM in different tasks. The feedbacks allowed them to discriminate, during manipulation through the robotic hand, objects of different compliances and shapes or different placements on the prosthesis. Similar high performances were obtained when they were asked to apply different levels of force in a random order on a dynamometer using LAM or LFM. In contrast, only the LAM strategy allowed the subjects to continuously modulate the grip pressure on the dynamometer. Furthermore, when long-lasting trains of stimulation were delivered, LFM strategy generated a very fast adaptation phenomenon in the subjects, which caused them to stop perceiving the restored sensations. Both encoding approaches were perceived as very different from the touch feelings of the healthy limb (natural). These results suggest that the choice of specific sensory feedback encodings can have an effect on user performance while grasping. In addition, our results invite the development of new approaches to provide more natural sensory feelings to the users, which could be addressed by a more biomimetic strategy in the future.

Transarterial treatment with Onyx of intracranial dural arteriovenous fistula with cortical drainage in 17 patients.

BACKGROUND AND PURPOSE: Intracranial DAVFs with cortical venous drainage have a high tendency to bleed. Complete closure of these lesions is essential to prevent clinically deleterious events. We describe our experience using Onyx in an arterial approach for treatment of DAVFs in 17 patients. MATERIALS AND METHODS: Between 2006 and 2010, we used Onyx for performing transarterial embolization in 17 patients with intracranial DAVFs and cortical venous drainage. Clinical assessment was performed before and after every treatment at discharge and at follow-up. Fourteen patients underwent follow-up MR imaging and MRA, 8 of them also underwent follow-up diagnostic angiography. RESULTS: Fifteen patients (88%) underwent 1 procedure. Complete obliteration by embolization with Onyx was achieved in 16 patients (94% acute obliteration). The mean amount of Onyx injected was 2.3 mL (range, 0.4-4.8 mL). The sole technical complication was an embolus to a branch of the MCA, which was resolved by intra-arterial tPA injection. A clinical complication of transient trochlear nerve palsy in the same patient due to mass effect of Onyx resolved spontaneously within 3 months. CONCLUSIONS: Intra-arterial embolization of cranial DAVFs with cortical venous drainage by using Onyx results in a high rate of complete obliteration (94%) with low morbidity (6%). Follow-up DSA in 8 patients revealed no evidence of reopening.

Brain arteriovenous malformation treatment using a combination of Onyx and a new detachable tip microcatheter, SONIC: short-term results.

BACKGROUND AND PURPOSE: Endovascular embolization with Onyx is one of the tools used in the treatment of intracerebral AVMs. The recent introduction of a new microcatheter with detachable tip has led us to adopt a new treatment approach by using endovascular embolization with Onyx as the main treatment for brain AVM with curative intent. The purpose of the present study is to evaluate our initial results by using this new treatment strategy with special emphasis on the safety and feasibility of the technique. MATERIALS AND METHODS: Forty-three consecutive patients were treated by embolization for brain AVM over a 14-month period, mostly by using Onyx and a microcatheter with detachable tip. Twenty-six of these patients (60%) harbored Spetzler-Martin AVMs of grades 4-5. RESULTS: Endovascular treatments were completed in 29 out of 43 patients; the median number of procedures per patient was 2 (range, 1-4). Complete obliteration by using embolization exclusively was achieved in 16 patients, resulting in a 55% cure rate in patients who concluded treatments (16/29) and 37% in the cohort (16/43). The amount of Onyx injected by using microcatheters with detachable tips was significantly larger than that injected with the nondetachable microcatheters (mean volume, 2.5 +/- 2.2 versus 1.7 +/- 1.3 mL, respectively, P < .05, t test). Seven clinical complications were observed in a total of 76 embolization sessions (9.2%). CONCLUSIONS: Endovascular embolization of brain AVM by using Onyx and SONIC results in a relatively high complete obliteration. The use of the microcatheter with detachable tip adds several advantages, mainly in that higher volumes of Onyx can be safely injected.

Neural pathways between sacrocaudal afferents and lumbar pattern generators in neonatal rats.

Projections of sacrocaudal afferents (SCA) onto lumbar pattern generators were studied in isolated spinal cords of neonatal rats. A locomotor-like pattern could be produced by SCA stimulation in the majority of the preparations. The SCA-induced lumbar rhythm was abolished after blocking synaptic transmission in the sacrococcygeal (SC) cord by bathing its segments in a low-calcium, high-magnesium artificial cerebrospinal fluid and restored when the synaptic block was alleviated by local application of calcium onto specific SC segments prior to SCA stimulation. Thus the SCA evoked lumbar rhythm involves synaptic activation of relay neurons in the SC cord. Functional activation of these relays depends on non-N-methyl-D-aspartate (NMDA) receptors because the lumbar rhythm was abolished when the non-NMDA receptor antagonist CNQX was added to the SC cord. By contrast, pharmacological block of the rhythmicity in the SC cord by specific antagonists of NMDA receptors and alpha1 and alpha2 adrenoceptors did not impair the SCA-induced lumbar rhythm. Midsagittal splitting experiments of parts of the SC and lumbar cord revealed that crossed and uncrossed ascending/propriospinal pathways are coactivated by SCA stimulation. We suggest that these pathways ascend onto the thoracolumbar cord through the lateral, ventrolateral, and ventral funiculi, because a complete block of the lumbar rhythm could only be obtained with a bilateral interruption of all of these funiculi. The relevance of our findings to the neural control of the rhythmogenic networks in the spinal cord is discussed.

Histological and 1H magnetic resonance spectroscopic imaging analysis of quinolinic acid-induced damage to the rat striatum.

NAA has been described as a neuron-specific compound. NAA levels as determined by magnetic resonance spectroscopic imaging (MRSI) have been used to determine degree of neuronal loss in several neurological diseases, but there has been limited work to document the accuracy and reliability of this technique. This study addresses this question quantitatively with histological analysis of cell viability and tissue shrinkage in quinolinic acid (QA)-induced damage of the rat striatum compared with 1H MRSI measurement of N-acetyl aspartate (NAA) as a noninvasive measure of neuronal loss. Both 1H MRSI and histology detect damage to the lesioned striatum; however, there are differences in the degree of damage as assessed by the two methods. Although partial-volume effects and tissue shrinkage may decrease the sensitivity of MR to such damage, the sparing of axons by QA may be another important factor in the differences in assessment. These results indicate that further studies of NAA metabolism and its distribution within neurons are warranted.

Immunological disorders of increased severity in children with AIDS associated with hepatitis B and C infections.

Two groups of children were set up: children infected with HIV and hepatitis viruses and children infected with HIV, but not with hepatitis viruses, too. The immunological aspects investigated referred to the Ig serum value, the absolute number of T CD4 lymphocytes and the T CD4/T CD8 ratio. The subjects of the first group (in whom hepatitis markers were present) displayed increased IgA and IgM values at a higher rate than those of the second group (54.87% against 32%, 83.3% against 53%), as well as a lowering below 300/ml of the number of T CD4 lymphocytes (50% against 29.4%). On the other hand, increased IgG levels and values below 0.8 of the T CD4/T CD8 ratio were found at similar rates in the two groups of children (77.4% against 80% and 70.5% against 70% respectively). By means of the data obtained, the authors try to point out one of the ways by which hepatitis viruses, considered as a potential cofactor in the AIDS development, contribute to the course of this disease, namely by intensifying the immunological disorders.

Mathematical model for the AIDS epidemics evolution in Romania.

The individuals are distributed in 9 risk groups (adults and children), in which an HIV transmission way is predominant. Taking into account a simplified graph of the HIV infection evolution, kinetic equations for the number of individuals from each risk group--situated in various stages of HIV infection--are written. The approximative solutions of these equations give us: the characteristic exponents of the temporal evolutions of the main and secondary local epidemics; the ratios Ci/Bi and Di/Bi of asymptomatically contaminated and dead (as consequence of AIDS) versus symptomatically contaminated; the onset of local epidemics in various risk groups; the relative amplitude of the secondary local epidemics versus the main local ones.

Mathematical model for the AIDS epidemic's evolution in Romania.

The individuals are distributed in 9 risk groups (adults and children), in which an HIV transmission way is predominant. Taking into account a simplified graph of the HIV infection evolution, kinetic equations for the number of individuals from each risk group--situated in various stages of HIV infection--are written. The approximative solutions of these equations give us: the characteristic exponents of the temporal evolutions of the main and secondary local epidemics; the ratios Ci/Bi and Di/Bi of asymptomatically contaminated and dead (as consequence of AIDS)--versus symptomatically contaminated; the onset of local epidemics in various risk groups; the relative amplitude of the secondary local epidemics versus the main local ones.

[Ultrasound cystometry with reference to urinary bladder form and bladder filling]. / Sonographische Zystometrie unter Berücksichtigung der Harnblasenform und der Harnblasenfüllung.

In 103 patients we performed sonographic determination of the volume (V) of the urinary bladder, being the product of the transversal (q), ventrodorsal (t) and craniocaudal (h) diameters, and compared this with the excreted volumes of urine. Depending on the shape and filling of the bladder we found different correlations from which it was possible to calculate three correction factors (F) for the formula V = (q x t x h) x F:F = 1.25 for volumes less than 150 ml; F = 0.9 for spherically sagittal section and volumes greater than 150 ml. The factor 0.5 given in most textbooks on sonography will in the majority of cases result in underestimating the urinary bladder volumes. Accurate sonocystometry taking the shape and filling into consideration is imperative for performing follow-up and treatment monitoring in neurogenic disturbances of voiding of the bladder or occlusive disturbances of flow in the region of the urethra.

Serum creatinine in patients with spinal cord injury.

In a group of 18 male patients with spinal cord injury, we found serum creatinine to be within normal limits or only minimally elevated despite significant reduction in creatinine clearance. In 8 control subjects with serum creatinine between 1.0 and 1.5 mg/dL (88.4 and 132.6 mumol/L), the measured creatinine clearance was 66.4 +/- 28.2 mL/min. In contrast, in the 5 patients with spinal cord injury whose serum creatinine was in the same range, the measured creatinine clearance was only 31.0 +/- 19 mL/min. Urinary creatinine excretion was lower in patients with spinal cord injury than in the 18 male controls (653 mg/24 hr vs. 1505 mg/24 hr). The decreased urinary creatinine could not be explained by differences in age, sex, or body weight. We calculated the relationship of creatinine clearance (Ccr) and serum creatinine (Scr) in patients with spinal cord injury to be given by the equation Ccr (mL/min) = 45/Scr (mg/dL), r = 0.73. We recommend timed urine collections for creatinine to estimate creatinine clearance accurately for clinical evaluation of patients with spinal cord injury.

Experimental studies on the cardiological effects of ipriflavone on the isolated rabbit heart and in rat and dog.

7-Isopropoxy-isoflavone (Ipriflavone) treatment of rabbits for 8 days at daily oral doses of 30 mg/kg significantly decreases the oxygen consumption of their isolated hearts. In anoxia this effect is more pronounced. 10-day oral treatment of rabbits with 10 or 20 mg/kg/day of ipriflavone led to a significant decrease of the lactic acid content in the myocardium, especially, in the ischaemic region. A 6-day oral pre-treatment of rats with 30 mg/kg/day of ipriflavone significantly decreases the coronary ligation-induced damage of the mitochondria and myofibrils. Electron microscope autoradiography shows that ipriflavone significantly counteracts the coronary ligation induced calcium accumulation in the mitochondria. Ipriflavone seems to influence the mitochondrial energetics in a positive manner. It has an oxygen sparing effect.