Restoring motor control and sensory feedback in people with upper extremity amputations using arrays of 96 microelectrodes implanted in the median and ulnar nerves.

OBJECTIVE: An important goal of neuroprosthetic research is to establish bidirectional communication between the user and new prosthetic limbs that are capable of controlling >20 different movements. One strategy for achieving this goal is to interface the prosthetic limb directly with efferent and afferent fibres in the peripheral nervous system using an array of intrafascicular microelectrodes. This approach would provide access to a large number of independent neural pathways for controlling high degree-of-freedom prosthetic limbs, as well as evoking multiple-complex sensory percepts. APPROACH: Utah Slanted Electrode Arrays (USEAs, 96 recording/stimulating electrodes) were implanted for 30 days into the median (Subject 1-M, 31 years post-amputation) or ulnar (Subject 2-U, 1.5 years post-amputation) nerves of two amputees. Neural activity was recorded during intended movements of the subject's phantom fingers and a linear Kalman filter was used to decode the neural data. Microelectrode stimulation of varying amplitudes and frequencies was delivered via single or multiple electrodes to investigate the number, size and quality of sensory percepts that could be evoked. Device performance over time was assessed by measuring: electrode impedances, signal-to-noise ratios (SNRs), stimulation thresholds, number and stability of evoked percepts. MAIN RESULTS: The subjects were able to proportionally, control individual fingers of a virtual robotic hand, with 13 different movements decoded offline (r = 0.48) and two movements decoded online. Electrical stimulation across one USEA evoked >80 sensory percepts. Varying the stimulation parameters modulated percept quality. Devices remained intrafascicularly implanted for the duration of the study with no significant changes in the SNRs or percept thresholds. SIGNIFICANCE: This study demonstrated that an array of 96 microelectrodes can be implanted into the human peripheral nervous system for up to 1 month durations. Such an array could provide intuitive control of a virtual prosthetic hand with broad sensory feedback.

Behavioral and cellular consequences of high-electrode count Utah Arrays chronically implanted in rat sciatic nerve.

OBJECTIVE: Before peripheral nerve electrodes can be used for the restoration of sensory and motor functions in patients with neurological disorders, the behavioral and histological consequences of these devices must be investigated. These indices of biocompatibility can be defined in terms of desired functional outcomes; for example, a device may be considered for use as a therapeutic intervention if the implanted subject retains functional neurons post-implantation even in the presence of a foreign body response. The consequences of an indwelling device may remain localized to cellular responses at the device-tissue interface, such as fibrotic encapsulation of the device, or they may affect the animal more globally, such as impacting behavioral or sensorimotor functions. The objective of this study was to investigate the overall consequences of implantation of high-electrode count intrafascicular peripheral nerve arrays, High Density Utah Slanted Electrode Arrays (HD-USEAs; 25 electrodes mm(-2)). APPROACH: HD-USEAs were implanted in rat sciatic nerves for one and two month periods. We monitored wheel running, noxious sensory paw withdrawal reflexes, footprints, nerve morphology and macrophage presence at the tissue-device interface. In addition, we used a novel approach to contain the arrays in actively behaving animals that consisted of an organic nerve wrap. A total of 500 electrodes were implanted across all ten animals. MAIN RESULTS: The results demonstrated that chronic implantation (⩽8 weeks) of HD-USEAs into peripheral nerves can evoke behavioral deficits that recover over time. Morphology of the nerve distal to the implantation site showed variable signs of nerve fiber degeneration and regeneration. Cytology adjacent to the device-tissue interface also showed a variable response, with some electrodes having many macrophages surrounding the electrodes, while other electrodes had few or no macrophages present. This variability was also seen along the length of the electrodes. Axons remained within the proximity of the electrode tips at the distances required for theoretically effective stimulation and recording (⩽100 µm). SIGNIFICANCE: We conclude from these studies that HD-USEAs do not cause overall global effects on the animals, at least up to the two-month period investigated here. These results demonstrate for the first time that the consequences of high-electrode count intrafascicular arrays compare with other peripheral nerve electrodes currently available for clinical or investigational neuromodulation.

A new high-density (25 electrodes/mm²) penetrating microelectrode array for recording and stimulating sub-millimeter neuroanatomical structures.

OBJECTIVE: Among the currently available neural interface devices, there has been a need for a penetrating electrode array with a high electrode-count and high electrode-density (the number of electrodes/mm(2)) that can be used for electrophysiological studies of sub-millimeter neuroanatomical structures. We have developed such a penetrating microelectrode array with both a high electrode-density (25 electrodes/mm(2)) and high electrode-count (up to 96 electrodes) for small nervous system structures, based on the existing Utah Slanted Electrode Array (USEA). Such high electrode-density arrays are expected to provide greater access to nerve fibers than the conventionally spaced USEA especially in small diameter nerves. APPROACH: One concern for such high density microelectrode arrays is that they may cause a nerve crush-type injury upon implantation. We evaluated this possibility during acute (<10 h) in vivo experiments with electrode arrays implanted into small diameter peripheral nerves of anesthetized rats (sciatic nerve) and cats (pudendal nerve). MAIN RESULTS: Successful intrafascicular implantation and viable nerve function was demonstrated via microstimulation, single-unit recordings and histological analysis. Measurements of the electrode impedances and quantified electrode dimensions demonstrated fabrication quality. The results of these experiments show that such high density neural interfaces can be implanted acutely into neural tissue without causing a complete nerve crush injury, while mediating intrafascicular access to fibers in small diameter peripheral nerves. SIGNIFICANCE: This new penetrating microelectrode array has characteristics un-matched by other neural interface devices currently available for peripheral nervous system neurophysiological research.

A case report on fixation instability in Parkinson's disease with bilateral deep brain stimulation implants.

We report on fixation instabilities in a patient diagnosed with Parkinson's disease (PD). This patient underwent deep brain stimulation (DBS) surgery bilaterally in the vicinity of the subthalamic nuclei (STN). Examination of the eye movements of this patient revealed marked fixation instability compared with a healthy age matched control. The eye movements occurring during fixation differed from other reports of fixation instabilities in that they interrupted fixation for only brief durations. These interruptive saccades (IS) had saccade-like amplitude velocity relationships. The frequency of these IS was higher in the patient with PD than in the healthy age matched control. Furthermore, the frequency of the IS in the patient reduced toward control with application of bilateral DBS in the vicinity of the STN. From our observations we conclude that fixation ability may be altered in PD and improved with DBS.

Thyroxine abuse: an unusual case of thyrotoxicosis in pregnancy.

Eating disorders and the associated behavioural problems and drug abuse are uncommon in pregnancy. When they do occur they are often unrecognized because of denial but when significant may pose a risk to both the mother and her fetus. This case illustrates a number of problems that may be encountered in women with eating disorders in pregnancy, including prolonged and recurrent metabolic disturbances and diuretic abuse. In particular it illustrates the derangements of thyroid function seen in pregnant women with eating disorders and reminds us that when a cause for thyrotoxicosis remains obscure, thyroxine abuse should be considered and explored.

Premorbid personality in patients with uni- and bipolar affective disorders and controls: assessment by the Biographical Personality Interview (BPI).

The relationship between premorbid personality and subtypes of affective disorder was investigated by means of the Biographical Personality Interview (BPI) and by a self-rating scale. Interviewer and rater (BPI) were blind to diagnosis. A total of 52 patients with unipolar depression or bipolar II disorder (D/Dm), 32 bipolar-I patients (DM) and 39 control subjects (C) were examined. Expert rating of "typus melancholicus" features (BPI) were found to be more pronounced in D/Dm than in DM and C. "Typus manicus" features were also distinguished between both clinical groups, whereas anxious-insecure features were not significantly different between the groups of patients. In contrast to the expert-rated personality variants, self-rating of personality features did not reveal any significant differences between the two clinical groups. Potential sources of the discrepancies between the questionnaire data and the interview data are discussed. It is concluded that premorbid features of "typus manicus" and "typus melancholicus" predicted, respectively, a predominant manic and a predominant depressive course of an affective disorder.

Increased sensitivity of the inositol-phospholipid system in neutrophils from patients with acute major depressive episodes.

Evidence from in vitro and in vivo studies suggests that the therapeutic and prophylactic effects of lithium in recurrent affective disorders are due to an attenuation of the inositol-phospholipid (IPL) second messenger system. An increased sensitivity of this signal transduction system might therefore constitute a risk factor for affective illness. The extent of the agonist-induced release of intracellular Ca2+ (Ca2+ response) can be used as an indicator of the sensitivity of the IPL system. Using this paradigm, we have measured the agonist-induced Ca2+ response in neutrophils of 17 unmedicated patients who were experiencing an acute major depressive episode. The neutrophils were stimulated by the chemotactic peptide formylmethionylleucylphenylalanine, which activates the IPL system in the cells. The sensitivity of the IPL system in these patients was significantly greater (dose-response curve shifted to the left) compared with its sensitivity in healthy age- and sex-matched control subjects. The results indicate that acute episodes of major depression are associated with an increased sensitivity of the IPL system.

Cholinergic REM induction test: muscarinic supersensitivity underlies polysomnographic findings in both depression and schizophrenia.

Disinhibition of rapid eye movement (REM) sleep (e.g. shortening of REM latency, heightened REM density) is frequently encountered in patients with a major depressive disorder (MDD). Administration of cholinomimetics prior to or during sleep leads to a more pronounced advance of REM sleep in depressed patients compared to healthy controls and patients with other psychiatric disorders. The present study tested whether the cholinergic REM induction test (CRIT) with 1.5 mg RS 86 (an orally acting muscarinic agonist) differentiates patients with MDD (n = 40) from those with schizophrenia (n = 43) and healthy controls (n = 36). The most pronounced shortening of REM latency after cholinergic stimulation occurred in patients with MDD. However, a significant number of patients with schizophrenia also displayed short REM latencies (REM latency < 25 minutes) under placebo conditions and after cholinergic stimulation. REM density measures more clearly differentiated patients with MDD from those with schizophrenia. It is concluded that a subgroup of patients suffering from schizophrenia displays signs of a muscarinic receptor supersensitivity.

Increased sensitivity to agonist stimulation of the Ca2+ response in neutrophils of manic-depressive patients: effect of lithium therapy.

The agonist-stimulated increase of intracellular free-Ca2+ concentration, an indicator of the sensitivity of the inositol phospholipid second-messenger generating system, was measured in neutrophils from patients with manic-depressive disorder, and controls. Dose-response curves of the calcium response were determined by measuring the fluorescence of neutrophils loaded with fura-2 and stimulated with various concentrations of the chemotactic tripeptide formylmethionylleucylphenylalanine. EC50 values were obtained for 14 medication-free patients (5 acutely depressive, and 9 symptom free remitted patients with a history of manic-depression or recurrent major depression), 9 lithium-treated, euthymic manic-depressive patients and 10 drug-free healthy controls. The EC50 values of the untreated patients were significantly lower than in the controls. Lithium-treated patients had EC50 values significantly higher than controls. These results suggest that manic-depressive disorder is associated with an increased sensitivity of the inositol phospholipid second-messenger generating system, which is counteracted by lithium treatment.

Hypothalamic-pituitary-adrenal axis function in elderly endurance athletes.

To explore the effects of repeated episodes of hypercortisolemia on hypothalamic-pituitary-adrenal axis regulation, we studied plasma ACTH and cortisol (CORT) responses to 100 micrograms human CRH (hCRH) in 10 dexamethasone (1.5 mg)-pretreated elderly endurance athletes who had abstained from physical activity for at least 48 h before testing and 13 sedentary age-matched controls. Basal CORT and ACTH levels were indistinguishable between runners and sedentary controls, whereas CORT responses to hCRH were significantly increased in endurance athletes, and ACTH responses tended to be higher in this group. Comparing the dexamethasone/hCRH test results of the runners with those of an age-matched sample of previously studied depressed patients (n = 9), similar hormone responses to CRH challenge were noted. The mechanisms underlying these alterations may either be a stepwise decrease in corticotropic sensitivity to the negative feedback signal leading to a switch to positive glucocorticoid feedback, an enhanced cosecretion of ACTH secretagogues such as vasopressin, or a combination of both. In conclusion, hypothalamic-pituitary-adrenal axis physiology seems to be determined by previous stressful events associated with hypercortisolemia, regardless of its etiology.

N-Trifluoroacetyl-ethanolamine: a proposed urinary metabolite of halothane: validation and measurement in children.

It has been postulated that trifluoroacetyl chloride, a halothane metabolite, can bind covalently with the phosphatidylethanolamine component of the hepatic cell membrane and cause cell necrosis. Breakdown of the necrotic hepatocyte would release N-trifluoroacetyl-ethanolamine (TFAE) into the serum with subsequent urinary excretion. An original High Performance Liquid Chromatography (HPLC) method for the measurement of TFAE is described. In six children 1% halothane was administered for one hour and the halothane uptake measured. Urinary excretion of TFAE was measured for up to eight days and found to be 0.09 +/- 0.07% or less of the absorbed halothane. In children TFAE is not a major urinary metabolite of halothane.

Biliary excretion of the halothane metabolite trifluoroacetic acid in infants.

In humans the biliary excretion of trifluoroacetic acid, the major halothane metabolite, has not been studied. We investigated the biliary excretion of trifluoroacetic acid in two infants aged five months and two months following halothane anaesthesia for the operation of choledocholithotomy. Bile, urine and faeces were collected continuously for five days after operation and trifluoroacetic acid excretion measured. Estimates of halothane uptake, daily bile flow and the proportion of daily bile flow collected via the T-tube drainage catheter were subject to percentage errors possibly as large as 50%. Of the total trifluoroacetic acid produced from halothane metabolism, it was estimated that 17% in the five-month-old infant and 20% in the two-month infant was excreted in bile. In the five-month-old infant where approximately 80% of the bile produced entered the duodenum in the normal way, no faecal trifluoroacetic acid was detected suggesting an enterohepatic circulation for this metabolite.

Halothane in children with chronic liver disease.

Exacerbation of pre-existing liver disease after halothane anaesthesia has been reported in adult patients. A prospective study was performed in 38 children with biopsy-proven liver disease to assess the effect of surgery and halothane anaesthesia on liver function. Plasma liver enzyme levels were measured immediately preoperatively and again four to eight days after surgery and halothane anaesthesia. Minor elevations of both AST and ALT occurred in four patients but this was not associated with a clinical deterioration in the patients' postoperative recovery. In the children studied pre-existing liver disease did not predispose to a deterioration of liver function following surgery and halothane anaesthesia.

A urinary cysteine-halothane metabolite: validation and measurement in children.

An attempt was made in children to identify a urinary halothane-cysteine conjugate which had been described previously in adult patients following administration of halothane. If this conjugate was found it would indicate that a reductive metabolite of halothane binds covalently with the sulphydryl-containing amino acid, cysteine, a reaction which could lead to hepatic injury. The potential halothane-cysteine conjugate, N-acetyl-S-(2-bromo-2-chloro-1,1-difluoroethyl)-L-cysteine (acetyl BCFEC), was prepared and the identity of the compound established using hydrogen-1 and carbon-13 NMR spectroscopy and methane chemical ionization mass spectrometry. A measurement technique for acetyl BCFEC was developed using HPLC with u.v. detection at 200 nm. In six children after halothane anaesthesia, one child being studied twice, urine was collected for up to 1 week and analysed for acetyl BCFEC. Little or no acetyl BCFEC was detected in any of the 43 urine samples tested, indicating that in children it is not a significant urinary metabolite of halothane.

Halothane metabolism in children.

Halothane (1% v/v inspired) was administered for 60 min to six children of mean age 74 months (range 14-119 months). Uptake of halothane was measured from the difference in the concentration in inspired and expired gas and varied from 176 to 310 mg kg-1, depending on minute ventilation. After administration of halothane ceased, its elimination in expired gas was measured in four patients until the conclusion of anaesthesia; 32-37% of the absorbed halothane was expired 90 min after halothane administration ceased. Urinary excretion of trifluoroacetic acid, fluoride and bromide was measured for up to 1 week. Of the absorbed halothane, 11.4% (range 6.3-18.2%) was excreted in urine as trifluoroacetic acid and 0.37% (range 0.10-0.64%) as inorganic fluoride. The urinary half-life of trifluoracetic acid was 41.8 h (range 10.4-59.1 h). The quantitative and qualitative metabolism of halothane via the reductive and oxidative pathways in children are comparable to values found in adults. No differences in the metabolism of halothane by children were found which would explain the different incidence of halothane-associated hepatitis compared with adults.