History dependence of rate covariation between neurons during persistent activity in an oculomotor integrator

Persistent firing in response to a brief stimulus is a neural correlate of short-term memory in a variety of systems. In the oculomotor neural integrator, persistent firing that encodes eye position is maintained in response to transient saccadic eye-velocity commands. To a first approximation, firing rates in the integrator vary linearly with eye position. Thus, viewed across many cells, the pattern of persistent firing in the integrator may be constrained to a unique line of stable states. Here this idea was tested by examining the relationship between firing rates of simultaneously recorded neurons. Paired recordings were obtained in awake goldfish from neurons in hindbrain area I, an essential part of the horizontal eye-position integrator. During spontaneous eye movements consisting of sequential fixations at different horizontal positions, the pair relationship between the majority of cells on the same side of the integrator was not unique: for a given rate of one cell, the rate of the paired cell assumed different values that depended systematically on the preceding saccade history. This finding suggests that the set of persistent firing states that encode eye position is not constrained to a unique line, and that models with stable states restricted to a such a line need to be modified accordingly.     

Legg-Calvé-Perthes disease in patients under 5 years of age does not always result in a good outcome. Personal experience and meta-analysis of the literature

This study attempted to analyze objectively the long-standing impression that children under 5 years of age, who have Legg-Calvé-Perthes disease, generally do well. Thirty patients, with 36 hips and onset of disease prior to their fifth birthday were reviewed at skeletal maturity. More than 50% of the hips were classified in Catterall group 3 or 4, and Herring group C. The end evaluation by the Stulberg classification showed 44.5% good, 22.2% fair and 33.3% poor results. By the Mose rating the results were respectively 27.8% good, 30.6% fair and 41.6% poor.A meta-analysis of the literature showed a very broad spectrum of results, leading to the conclusion, first, that comparison is difficult and, second, that young age is not a free ticket to a good result.     

Bioartificial liver support devices: historical perspectives

Fulminant hepatic failure (FHF) is an important cause of death worldwide. Despite significant improvements in critical care therapy there has been little impact on survival with mortality rates approaching 80%. In many patients the cause of the liver failure is reversible and if short-term hepatic support is provided, the liver may regenerate. Survivors recover full liver function and a normal life expectancy. For many years the only curative treatment for this condition has been liver transplantation, subjecting many patients to replacement of a potentially self-regenerating organ, with the lifetime danger of immunosuppression and its attendant complications, such as malignancy. Because of the shortage of livers available for transplantation, many patients die before a transplant can be performed, or are too ill for operation by the time a liver becomes available. Many patients with hepatic failure do not qualify for liver transplantation because of concomitant infection, metastatic cancer, active alcoholism or concurrent medical problems. The survival of patients excluded from liver transplantation or those with potentially reversible acute hepatitis might be improved with temporary artificial liver support. With a view to this, bioartificial liver support devices have been developed which replace the synthetic, metabolic and detoxification functions of the liver. Some such devices have been evaluated in clinical trials. During the last decade, improvements in bioengineering techniques have been used to refine the membranes and hepatocyte attachment systems used in these devices, in the hope of improving function. The present article reviews the history of liver support systems, the attendant problems encountered, and summarizes the main systems that are currently under evaluation.     

Principles and advantages of robotics in urologic surgery

Although the available minimally invasive surgical techniques (ie, laparoscopy) have clear advantages, these procedures continue to cause problems for patients. Surgical tools are limited by set axes of movement, restricting the degree of freedom available to the surgeon. In addition, depth perception is lost with the use of two-dimensional viewing systems. As surgeons view a “virtual” target on a television screen, they are hampered by decreased sensory input and a concurrent loss of dexterity. The development of robotic assistance systems in recent years could be the key to overcoming these difficulties. Using robotic systems, surgeons can experience a more natural and ergonomic surgical “feel.” Surgical assistance, dexterity and precision enhancement, systems networking, and image-guided therapy are among the benefits offered by surgical robots. In return, the surgeon gains a shorter learning curve, reduced fatigue, and the opportunity to perform complex procedures that would be difficult using conventional laparoscopy. With the development of image-guided technology, robotic systems will become useful tools for surgical training and simulation. Remote surgery is not a routine procedure, but several teams are working on this and experiencing good results. However, economic concerns are the major drawbacks of these systems; before remote surgery becomes routinely feasible, the clinical benefits must be balanced with high investment and running costs.     

Functional characterization of the D188V mutation in neuronal voltage-gated sodium channel causing generalized epilepsy with febrile seizures plus (GEFS)

Mutations in the alpha 1 subunit of the voltage-gated sodium channel (SCN1A) have been increasingly recognized as an important cause of familial epilepsy in humans. However, the functional consequences of these mutations remain largely unknown. We identified a mutation (D188V) in SCN1A segregating with generalized epilepsy with febrile seizures (GEFS) in a large kindred. Compared to wild-type sodium channels, in vitro expression of channels harboring the D188V mutation were found to be more resistant to the decline in amplitude that is normally observed over the course of high frequency pulse trains. This small change on a single aspect of channel function is compatible with an increase in membrane excitability, such as during sustained and uncontrolled neuronal discharges. These data suggest that this specific effect on sodium channel function could be a general mechanism in the pathophysiology of epilepsies caused by mutations in sodium channels in humans.     

Increased cerebral functional connectivity underlying the antinociceptive effects of hypnosis

The neural mechanisms underlying the antinociceptive effects of hypnosis are not well understood. Using positron emission tomography (PET), we recently showed that the activity in the anterior cingulate cortex (midcingulate area 24a') covaries with the hypnosis-induced reduction of affective and sensory responses to noxious thermal stimulation [Faymonville et al., Anesthesiology 92 (2000) 1257-1267]. In the present study, we assessed changes in cerebral functional connectivity related to the hypnotic state, compared to simple distraction and the resting state. Nineteen highly hypnotizable right-handed volunteers were studied using H2(15)O-PET. The experimental conditions were hot noxious or warm non-noxious stimulation of the right hand during resting state, mental imagery and hypnotic state. Using a psychophysiological interaction analysis, we identified brain areas that would respond to noxious stimulations under the modulatory action of the midcingulate cortex in, and only in, the hypnotic state. Hypnosis, compared to the resting state, reduced pain perception by 50%. Pain perception during rest and mental imagery was not significantly different. Analysis of PET data showed that the hypnotic state, compared to normal alertness (i.e., rest and mental imagery), significantly enhanced the functional modulation between midcingulate cortex and a large neural network encompassing bilateral insula, pregenual anterior cingulate cortex, pre-supplementary motor area, right prefrontal cortex and striatum, thalamus and brainstem. These findings point to a critical role for the midcingulate cortex in the modulation of a large cortical and subcortical network underlying its influence on sensory, affective, cognitive and behavioral aspects of nociception, in the specific context of hypnosis.     

The pyramidal neuron in occipital,temporal and prefrontal cortex of the owl monkey (Aotus trivirgatus): regional specialization in cell structure

Recent studies have revealed marked regional variation in pyramidal cell morphology in primate cortex. In particular, pyramidal cells in human and macaque prefrontal cortex (PFC) are considerably more spinous than those in other cortical regions. PFC pyramidal cells in the New World marmoset monkey, however, are less spinous than those in man and macaques. Taken together, these data suggest that the pyramidal cell has become more branched and more spinous during the evolution of PFC in only some primate lineages. This specialization may be of fundamental importance in determining the cognitive styles of the different species. However, these data are preliminary, with only one New World and two Old World species having been studied. Moreover, the marmoset data were obtained from different cases. In the present study we investigated PFC pyramidal cells in another New World monkey, the owl monkey, to extend the basis for comparison. As in the New World marmoset monkey, prefrontal pyramidal cells in owl monkeys have relatively few spines. These species differences appear to reflect variation in the extent to which PFC circuitry has become specialized during evolution. Highly complex pyramidal cells in PFC appear not to have been a feature of a common prosimian ancestor, but have evolved with the dramatic expansion of PFC in some anthropoid lineages.     

Expression of ICAM-1, TNF-alpha, NF kappa B, and MAP kinase in tubers of the tuberous sclerosis complex

Individuals affected with tuberous sclerosis complex (TSC) develop cortical tubers characterized by disorganized cytoarchitecture and morphologically abnormal cell types, such as dysplastic neurons (DNs) and giant cells (GCs). As part of ongoing cDNA array analysis to study the molecular pathogenesis of tuber formation, we detected increased expression of intercellular adhesion molecule-1 (ICAM-1) mRNA, a cell adhesion molecule (CAM) that functions in cytokine signaling, in tubers. Western and immunohistochemical analyses revealed that ICAM-1 protein was selectively expressed in tubers, but was only minimally expressed in control cortex, adjacent nontuberal cortex, or in non-TSC focal cortical dysplasia. Increased expression of ICAM-1 was found in mice in which the Tsc1 gene was conditionally inactivated in astrocytes. Expression of molecules involved in ICAM-1 activation and cytokine signaling were increased in tubers, including tumor necrosis factor alpha (TNF-alpha), mitogen activated protein kinase (MAPK), and nuclear factor kappa B (NF-kappaB). Numerous CD68-immunoreactive macrophages were observed clustered around GCs further supporting an inflammatory response in tubers. Expression of caspase 8 and Fas support cytokine activation and detection of TUNEL reactivity suggests ongoing cell death in tubers. Specific alterations in ICAM-1, TNF-alpha, NF-kappaB1, and MAPK expression coupled with the detection of numerous CD68-immunoreactive macrophages suggests activation of proinflammatory cytokine signaling pathways in tubers that may culminate in cell death.     

Phonological short-term memory networks following recovery from Landau and Kleffner syndrome

Landau-Kleffner syndrome (LKS) is a rare acquired aphasia occurring in otherwise healthy children, together with spike-wave discharges predominating over superior temporal regions and activated by sleep. Although the outcome of language abilities is variable, a residual impairment in verbal short-term memory (STM) is frequent. This STM deficit might be related to the persistent dysfunction of those temporal lobe regions where epileptic discharges were observed during the active phase of the disorder. We tested this hypothesis by measuring brain activation during immediate serial recall of lists of 4 words, compared to single word repetition, using H(2) (15)O positron emission tomography (PET), in 3 LKS patients after recovery and in 14 healthy controls. The patients (TG, JPH, and DC) had shown abnormally increased or decreased glucose metabolism in left or right superior temporal gyrus (STG) at different stages during the active phase of their disease. At the time of this study, the patients were 6-10 years from the active phase of LKS. Results showed that Patients JPH and DC had impaired performance in the STM condition, whereas TG showed near normal performance. PET data showed that JPH and DC activated significantly less than controls left and right posterior STG. TG, having near normal STM performance, showed increased activity in the posterior part of the right STG. These data suggest that impaired verbal STM at late outcome of LKS might indeed be related to a persistent decrease of activity in those posterior superior temporal gyri that were involved in the epileptic focus during the active phase.