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PubMed2005

Monitoring emergence from coma following severe brain injury in an octogenarian using behavioural indicators, electrophysiological measures and metabolic studies: a demonstration of the potential for good recovery in older adults.

This case study describes a multi-disciplinary investigation of the emergence from coma of an 80-year old female (KE) following severe traumatic brain injury. The relationship between cognitive/behavioural ability and the integrity of cerebral function was assessed using neuropsychological measures, positron emission tomography, electroencephalography, somatosensory evoked potentials and trans-cranial magnetic stimulation. These investigations were performed as KE was beginning to emerge from coma (4 weeks) and, again, approximately 1 year following brain injury, when she was judged to have achieved her maximum level of recovery. Neuropsychological measures revealed improvement during the first year post-injury in KE's speed of information processing, memory and executive abilities. Electrophysiological and metabolic studies indicated a restoration of functional integrity that was consistent with the gradual recovery in higher brain function documented using behavioural procedures. This case study demonstrates the rehabilitation potential of pre-morbidly healthy older adults following severe traumatic brain injury.

Accidents, Traffic↗

PubMed1996

Development of fetal hippocampal grafts in intact and lesioned hippocampus.

Functional recovery observed in Parkinson's disease patients following grafting of fetal substantia nigra has encouraged the development of similar grafting therapy for other neurological disorders. Fetal hippocampal grafting paradigms are of considerable significance because of their potential to treat neurological disorders affecting primarily hippocampus, including temporal lobe epilepsy, cerebral ischemia, stroke, and head injury. Since many recent studies of hippocampal transplants were carried out with an aim of laying the foundation for future clinical applications, an overview of the development of fetal hippocampal transplants, and their capability for inducing functional recovery under different host conditions is timely. In this review, we will summarize recent developments in hippocampal transplants, especially the anatomical and/or functional integration of grafts within the host brain under specific host conditions, including a comparison of intact hippocampus with various types of hippocampal lesions or injury. Improvements in grafting techniques, methods for analysis of graft integration and graft function will be summarized, in addition to critical factors which enhance the survival and integration of grafted cells and alternative sources of donor cells currently being tested or considered for hippocampal transplantation. Viewed collectively, hippocampal grafting studies show that fetal hippocampal tissue/cells survive grafting, establish both afferent and efferent connections with the host brain, and are also capable of ameliorating certain learning and memory deficits in some models. However, the efficacy of intracerebral fetal hippocampal grafts varies considerably in different animal models, depending on several factors: the mode of donor tissue preparation, the method of grafting, the state of host hippocampus at the time of grafting, and the placement of grafts within the hippocampus. Functional improvement in many models appeared to be caused partially by re-establishment of damaged circuitry and partially by a trophic action of grafts. However, exact mechanisms of graft-mediated behavioral recovery remain to be clarified due to the lack of correlative analysis in the same animal between the degree of graft integration and behavioral recovery. Issues of mechanisms of action, degree of restoration of host circuitry and amelioration of host pathological conditions will need to be sorted out clearly prior to clinical use of fetal hippocampal transplants for susceptible neurological conditions.

Animals↗

PubMed1998

Auditory-nerve integrity after middle-fossa acoustic-tumor removal.

We sought to investigate the functional integrity of the auditory nerve in patients with postoperative hearing loss after middle cranial fossa acoustic-tumor removal in a case-series descriptive study. The study setting was a tertiary referral center, a private otologic practice. The study population comprised seven patients who underwent a middle-cranial-fossa approach for unilateral acoustic-tumor resection and sustained postoperative anacusis with an anatomically intact auditory nerve. Four were men and three women; they ranged in age from 30 to 60 years; all underwent surgery between 1990 and 1994 and agreed to return to the center to participate in the study during 1995. Diagnostic electrical promontory stimulation was used to determine the functional integrity of the auditory nerve. Our main outcome measures were the presence or absence of discrete tone perception, electrical threshold, maximum acceptable level and dynamic range, gap detection and temporal difference limen during electrical promontory stimulation. Three of the seven patients demonstrated positive responses to electrical promontory testing (e.g., discrete tone perception). All three were able to perform the gap-detection and temporal difference limen tests. None of the preoperative characteristics was related to performance on promontory stimulation testing. We conclude that the middle cranial fossa approach permits anatomic--and, in some cases, functional auditory-nerve preservation. These data suggest that auditory rehabilitation in some patients who sustain anacusis after the middle cranial fossa approach to acoustic tumors, as in neurofibromatosis 2, may be provided with cochlear implantation.

Adult↗

PubMed1986

A comparison of the relative effectiveness of three transplant preservation fluids upon the integrity and function of rabbit proximal convoluted tubules perfused in vitro.

Rabbits were anaesthetized and kidneys removed directly with no flush (group NF), or alternatively kidneys were flushed (group F) with sodium phosphate buffered 140 mmol/l sucrose (PBsuc 140), Collins C2 (C2) or Euro-Collins (EC) transplant preservation solutions and stored at 4 degrees C for 0-4, 24 or 48 h. Mid-cortical proximal convoluted tubule (PCT) segments were dissected from all groups and set up for microperfusion in vitro. Observations were made of tubule morphology, fluid reabsorption rate (Jv), bath leak of the glomerular marker iothalamate and transmural potential difference (p.d.), both at 37 degrees C and at 15-20 degrees C, in order to compare the relative effectiveness of the solutions in the preservation of tubule integrity and immediate function. Tubules from kidneys flushed with EC and C2 contained luminal debris and frequently had high bath leaks of iothalamate, both indicative of poor preservation of tubule integrity. In contrast, tubules from NF kidneys and PBsuc 140-flushed kidneys were free of luminal debris with a lower incidence of high iothalamate leaks. Tubules from PBsuc 140-flushed and EC-flushed kidneys after 0-4 and 24 h storage had Jv that were similar to those of NF kidneys. Tubules from all groups of flushed kidneys after 48 h cold storage and all tubules from C2-flushed kidneys showed reduced Jv values. In all cases Jv was reduced to approximately zero when the temperature was lowered to 15-20 degrees C. Transmural p.d. was similar in all groups except for particularly low p.d. values observed in tubules from C2-flushed kidneys after 48 h storage. These observations suggest that PBsuc 140 is more effective in the preservation of tubule function during prolonged cold storage than the glucose-based Collins solutions. The marked difference in the effectiveness of C2 and EC contraindicates the inclusion of magnesium (present in C2) for preservation of kidneys, as judged by experiments on the rabbit.

Animals↗

PubMed1989

Intravenous immunoglobulin preparations: a comparative in vitro study of Fc mediated functions.

An ideal immunoglobulin (Ig) preparation intended for clinical use should be safe and efficacious. Efficacy depends on suitable levels of protective antibodies against pathogens and the functional integrity of the Ig molecule. In the present paper, the functional integrity of the Ig molecule was investigated in eight intravenous Ig preparations commercially available in our country and compared to an intramuscular preparation. The experimental approach included protein A and rheumatoid factor binding, complement activation and opsonic activity. Ultracentrifugation profiles were obtained for all Ig preparations in order to ascertain the presence of components other than the expected 7S monomeric IgG. Immune complexes were investigated with C1q solid phase and conglutinin assays. Results show that chemical treatments such as sulfonation or reduction-alkylation, and enzymatic treatment such as plasmin digestion, variably but consistently impair Fc-mediated functions. The present data emphasize the use of in vitro tests for assessing the suitability of Ig preparations for intravenous administration.

Antigen-Antibody Complex↗

PubMed2002

Effective connectivity and intersubject variability: using a multisubject network to test differences and commonalities.

This article is about intersubject variability in the functional integration of activity in different brain regions. Previous studies of functional and effective connectivity have dealt with intersubject variability by analyzing data from different subjects separately or pretending the data came from the same subject. These approaches do not allow one to test for differences among subjects. The aim of this work was to illustrate how differences in connectivity among subjects can be addressed explicitly using structural equation modeling. This is enabled by constructing a multisubject network that comprises m regions of interest for each of the n subjects studied, resulting in a total of m x n nodes. Constructing a network of regions from different subjects may seem counterintuitive but embodies two key advantages. First, it allows one to test directly for differences among subjects by comparing models that do and do not allow a particular connectivity parameter to vary over subjects. Second, a multisubject network provides additional degrees of freedom to estimate the model's free parameters. Any neurobiological hypothesis normally addressed by single-subject or group analyses can still be tested, but with greater sensitivity. The common influence of experimental variables is modeled by connecting a virtual node, whose time course reflects stimulus onsets, to the sensory or "input" region in all subjects. Further experimental changes in task or cognitive set enter through modulation of the connections. This approach allows one to model both endogenous (or intrinsic) variance and exogenous effects induced by experimental design. We present a functional magnetic resonance imaging study that uses a multisubject network to investigate intersubject variability in functional integration in the context of single word and pseudoword reading. We tested whether the effect of word type on the reading-related coupling differed significantly among subjects. Our results showed that a number of forward and backward connections were stronger for reading pseudowords than words, and, in one case, connectivity showed significant intersubject variability. The discussion focuses on the implications of our findings and on further applications of the multisubject network analysis.

Adult↗

PubMed1995

Large-scale cortical networks and cognition.

The well-known parcellation of the mammalian cerebral cortex into a large number of functionally distinct cytoarchitectonic areas presents a problem for understanding the complex cortical integrative functions that underlie cognition. How do cortical areas having unique individual functional properties cooperate to accomplish these complex operations? Do neurons distributed throughout the cerebral cortex act together in large-scale functional assemblages? This review examines the substantial body of evidence supporting the view that complex integrative functions are carried out by large-scale networks of cortical areas. Pathway tracing studies in non-human primates have revealed widely distributed networks of interconnected cortical areas, providing an anatomical substrate for large-scale parallel processing of information in the cerebral cortex. Functional coactivation of multiple cortical areas has been demonstrated by neurophysiological studies in non-human primates and several different cognitive functions have been shown to depend on multiple distributed areas by human neuropsychological studies. Electrophysiological studies on interareal synchronization have provided evidence that active neurons in different cortical areas may become not only coactive, but also functionally interdependent. The computational advantages of synchronization between cortical areas in large-scale networks have been elucidated by studies using artificial neural network models. Recent observations of time-varying multi-areal cortical synchronization suggest that the functional topology of a large-scale cortical network is dynamically reorganized during visuomotor behavior.

Animals↗

PubMed2002

Beyond phrenology: what can neuroimaging tell us about distributed circuitry?

Unsupervised models of how the brain identifies and categorizes the causes of its sensory input can be divided into two classes: those that minimize the mutual information (i.e., redundancy) among evoked responses and those that minimize the prediction error. Although these models have the same goal, the way that goal is attained, and the functional architectures required, are fundamentally different. This review describes the differences, in the functional anatomy of sensory cortical hierarchies, implied by the two models. We then consider how neuroimaging can be used to disambiguate between them. The key distinction reduces to whether backward connections are employed by the brain to generate a prediction of sensory inputs. To ascertain whether backward influences are evident empirically requires a characterization of functional integration among brain systems. This review summarizes the approaches to measuring functional integration in terms of effective connectivity and proceeds to address the question posed by the theoretical considerations. In short, it will be shown that the conjoint manipulation of bottom-up and top-down inputs to an area can be used to test for interactions between them, in elaborating cortical responses. The conclusion, from these sorts of neuroimaging studies, points to the prevalence of top-down influences and the plausibility of generative models of sensory brain function.

Animals↗

PubMed1996

The substantia nigra as a site of synaptic integration of functionally diverse information arising from the ventral pallidum and the globus pallidus in the rat.

Voluntary behaviour in mammals requires the integration of information from different parts of the cerebral cortex, notably the limbic, associative and sensorimotor areas, in a neural network that eventually controls the muscles. One region of the brain that has been proposed to subserve such a function are the basal ganglia which receive inputs from all cortical areas. Although information from different cortical areas passes through the basal ganglia as a series of separate parallel pathways there are several sites where integration of the diverse information could occur. In this study we the identify a neural network at the synaptic level that may underlie a powerful mechanism for the integration, within the basal ganglia, of the diverse types of information arising from the cortex. By double anterograde tracing and immunocytochemistry at both the light and electron microscopic levels, we show that individual neurons in the substantia nigra pars reticulata and dopaminergic neurons in the pars compacta each receive multiple GABAergic synaptic inputs both from neurons in the ventral pallidum (which receive input from limbic areas via the nucleus accumbens) and from neurons in the globus pallidus (which receive input from associative and sensorimotor cortices via the neostriatum). Thus, information subserving functions such as emotion, motivation, cognition and movement converges onto basal ganglia output neurons, leading eventually to the muscles, and also on to the dopaminergic neurons which themselves subserve an integrative role by modulating the flow of information from the cortex through the basal ganglia at the level of the neostriatum and nucleus accumbens.

Animals↗

PubMedDate not supplied

Perspectives of leprosy patients on MDT services after integration of NLEP functions into primary health care.

Sixty-five leprosy patients residing in rural Digapahandi block of Ganjam district were studied during July-August 2001 in order to ascertain their perspectives regarding different MDT services after NLEP functions were integrated into primary health care (PHC) in Orissa after September 1999. They included 43.08% multibacillary (MB) cases and 61.92% paucibacillary (PB) cases. Assessment was done by personal interviews of adult patients and the parents of child cases after verification of their treatment cards at the sub-centre. Patient's knowledge regarding the availability of MDT services under PHC services and utilization of these services were highlighted. Influence of different socio-demographic factors was also studied. Basing on the study results, recommendations were made for sustained NLEP functions through PHC in order to improve the utilization of MDT services, which will help in the elimination of leprosy.

Adult↗

PubMed1997

Functional activation of cerebral blood flow after cardiac arrest in rat.

After a period of global cerebral ischemia, CO2 reactivity and the hemodynamic-metabolic activation to functional stimulation are transiently suppressed. This raises the question of whether the impaired functional coupling reflects disturbances of functional integrity of the brain or an impaired cerebrovascular reactivity. We, therefore, compared the recovery of CO2 reactivity with that of somatosensory evoked potentials, functional flow activation and neurologic deficits in a rodent model of cardiac arrest-induced cerebral ischemia, followed by up to 7 days of reperfusion. Cardiac arrest of 10 minutes' duration was produced in 24 animals by electrical fibrillation of the heart. Five animals were sham-operated controls. Resuscitation was performed by external cardiac massage, using standard resuscitation procedures. Functional activation was carried out under chloralose anesthesia by electrical stimulation of forepaws. CO2 reactivity was tested by ventilation of animals with 6% CO2. During functional and hypercapnic stimulation CBF was measured in the somatosensory cortex using laser-Doppler flowmetry, and at the end of the experiment by 14C-iodoantipyrine autoradiography. Neurologic deficits were scored by evaluating consciousness and various sensory and motor functions. In control animals 6% CO2 increased CBF measured by laser-Doppler flowmetry by 28.8% +/- 8.7%. Forepaw stimulation generated somatosensory evoked potentials with an amplitude of 750 +/- 217 microV and increased CBF measured by laser-Doppler flowmetry by 86.0% +/- 18.1%. After return of spontaneous circulation, CO2 reactivity was transiently reduced to about 30% of control at 1 hour of reperfusion (P < 0.05) but returned to near control at 5 hours. Somatosensory evoked potential amplitudes were reduced to 15% of control at 45 minutes of reperfusion and returned to only 50% to 60% at 3 and 7 days after return of spontaneous circulation (P < 0.05). Functional activation of blood flow was completely suppressed during the first hour after return of spontaneous circulation but also recovered to 50% to 60% of control at 3 days after return of spontaneous circulation (P < 0.05). Linear regression analysis revealed a significant correlation between recovery of functional activation of blood flow and both recovery of the amplitude of somatosensory evoked potentials (P = 0.03) and the neurologic deficit score (P = 0.02), but not between neurologic deficit score and recovery of CO2 reactivity or somatosensory evoked potential amplitudes. These data demonstrate that the suppression of functional activation of blood flow after 10 minutes cardiac arrest is not related to impairment of coupling mechanisms but reflects ongoing disturbances of the functional integrity of the brain. Assessment of functional flow coupling is a reliable way to study postischemic recovery of the brain.

Animals↗

PubMed1997

The reorganization of motor units in motor neuron disease.

We studied 78 patients with motor neuron disease (MND) using concentric needle electromyography. Analysis on weak and maximal effort was performed using our own, fully automated, computer method, EMG-LAB. In addition to the conventional parameters of single motor unit action potentials (MUAPs) and interference pattern, new criteria were applied: the range of the acting motor units and the functional recruitment order. A total of 375 muscles of MND patients and 120 control muscles were investigated. The electromyographic data were analyzed separately in five groups of muscles, classified A, B, C, D, and E according to their clinical condition. Those results allowed us to discern six neurophysiological stages (N(0,1,2,3,4,5)) from the early to the most advanced phase. It has been confirmed that reinnervation in MND is adequate to compensate for the loss of over 50% of motor neurons but it is only a transitory phase in the morbid course. At stages N(O-5), the electrophysiological data reflect structural and functional integrity of the functioning motor units. Evaluation of not only single MUAPs but also of the full range of acting motor units and their recruitment order allowed a deeper look into the underlying pathophysiological mechanisms.

Action Potentials↗

PubMed1994

Interacting brain stem components of opiate-activated, descending, pain-inhibitory systems.

This is a review of research aimed at elucidating how various opiate analgesia substrates in rat brain stem interact with one another to bring about opiate analgesia. The three substrates studied are the midbrain periaqueductal grey (PAG), the bulbar nucleus raphe magnus (RM), and the bulbar nucleus reticularis paragigantocellularis (PGC). The methods used in the reviewed studies are unique in that behavioral and neuronal responses are assessed in consequence of nanoinjecting opiates (met-enkephalin) into subset pairs of these structures. Responses to single and conjoint injections are compared. Effects on neuronal and behavioral responses in consequence of disruption of these structures with tetracaine block are also discussed. It is seen that PGC cannot serve as an opiate analgesia substrate if the functional integrity PAG is impaired. However PAG does not depend on PGC's functional integrity.

Animals↗

PubMed1987

Sensitivity of yeast cells to reactive oxygen species generated in the extracellular space.

Even when cytoplasmic scavenging activities are plentiful, yeast cells (S. cerevisiae) remain particularly sensitive towards reactive oxygen species generated in the extracellular space (either by the xanthine/xanthine oxidase reaction or by the redox cycling of menadione). A sharp reduction of the extent of cellular alterations when SOD and/or catalase were supplemented in the incubation buffer, points to a contribution of both O-.2 and H2O2 in the toxic process. Although oxygen metabolites as well as t-butylhydroperoxide (tBH), a highly toxic organic peroxide, may be directly responsible for cellular damage, their toxicity is largely reduced in the presence of Desferal. A role of metal ions in potentiating the toxicity points to the involvement of OH. radicals, actually produced in the medium. With tBH, metal cations would be rather active in promoting peroxidative chain reactions. In the case of an extracellular oxidative attack, it may be foreseen that the plasma membrane will form a preferential target. An increased permeability of the plasma membrane towards ionized molecules and uncharged polycarboxylic acids is indeed observed after an oxidative treatment. The loss of selective permeability is, as a rule, correlated with a drop in viability. Early alterations, disrupting the functional organization of the plasma membrane have been sought. The permease involved in the active transport of purine(s) has appeared to be an appropriate marker for checking its functional integrity. This transport function appears to be very sensitive to damage induced by O-.2 generators, particularly under conditions in which the resulting lethality is still kept low and in which the energization of active transport processes remains unimpaired.

Carboxylic Acids↗

PubMed1988

Endocrine evaluation in the assessment of male reproductive hazards.

Male reproductive function requires the integrated functioning of the hypothalamus, pituitary, and testis. The disturbance of endocrine function at any of these levels may result in hypogonadism and infertility. The clinical and laboratory evaluation of these disorders is reviewed here.

Endocrine Glands↗

PubMed2002

An artificial peptide with corticotropin-releasing factor receptor-2 (CRF-R2) selective properties: the role of primary structure in the induction of signal transduction pathways.

Considerable plasticity can occur within the amino acid sequence of amphiphilic peptide hormones. This is particularly evident within the corticotropin-releasing factor (CRF) family of peptides where, despite less than 15% sequence similarity among the four paralogous lineages, all are capable of acting as high affinity ligands to members of the CRF receptor family. This suggests that these peptides could undergo many mutational changes and remain as high affinity ligands to their receptors as long as the functional motifs do not change radically. Because paralogous peptide lineages are a product of genome duplications, additional genes encoding peptide-like sequences, which through mutation have lost their functional integrity, may exist. Function to these sequences may be restored if the appropriate motifs are reinserted into the primary structure. We screened rat genomic DNA with highly degenerate polymerase chain reaction (PCR) primers targeted to hybridize with the termini of CRF-related sequences. One set of sauvagine-based primers hybridized with a 120-bp sequence. The theoretical peptide sequence (SV4) showed similarity to the CRF family of peptides at the primary structure level. The encoded sequence was prepared by solid-phase synthesis and its activity assayed against mouse R1 and human R1/R2 receptors. SV4 did not bind to either mouse or human variants of the R1 receptor, but did bind to the R2 receptor with an affinity comparable to human CRF. SV4 exhibited a similar efficacy of cellular activation as CRF in trials quantifying the acidification rate of human R2alpha-transfected Chinese hamster ovary (CHO) cells, but not R1-transfected cells. SV4 utilizes adenylate cyclase as the principal secondary messenger of R2 signal transduction but, unlike urocortin or sauvagine, does not activate guanylate cyclase-, calcium- or mitogen-activated protein (MAP) kinase-mediated pathways. These data suggest that this artificial peptide may be useful to understand the cyclic adenosine monophosphate (cAMP)-dependent component of the CRF-R2 signal transduction cascade, and that additional sequences in the genome may be used to engineer bioactive peptides.

Amino Acid Sequence↗

PubMed2003

Becoming a new neuron in the adult olfactory bulb.

New neurons are continually recruited throughout adulthood in certain regions of the adult mammalian brain. How these cells mature and integrate into preexisting functional circuits remains unknown. Here we describe the physiological properties of newborn olfactory bulb interneurons at five different stages of their maturation in adult mice. Patch-clamp recordings were obtained from tangentially and radially migrating young neurons and from neurons in three subsequent maturation stages. Tangentially migrating neurons expressed extrasynaptic GABA(A) receptors and then AMPA receptors, before NMDA receptors appeared in radially migrating neurons. Spontaneous synaptic activity emerged soon after migration was complete, and spiking activity was the last characteristic to be acquired. This delayed excitability is unique to cells born in the adult and may protect circuits from uncontrolled neurotransmitter release and neural network disruption. Our results show that newly born cells recruited into the olfactory bulb become neurons, and a unique sequence of events leads to their functional integration.

Animals↗

PubMed2000

The 'Wheel of Misfortune': a taxonomic approach to human factors in accident investigation and analysis in aviation and other complex systems.

The analysis and reporting of the human factors aspects of accidents in aviation and other complex systems continues to present difficulties for investigators and analysts alike. Reason's 'latent conditions' model has had a major impact on the way accidents are conceptualized but it has proven difficult to apply as a practical tool. Recent attempts to overcome these difficulties are discussed and an alternative conceptualization is proposed. This conceptualization is based on a blend of several well-supported theoretical models in cognitive engineering and can be used to formulate a parsimonious analysis system for the investigation and reporting of the human factors aspects of accidents. Two well-known examples of transportation disasters are briefly described and related to the proposed conceptual framework. The proposed framework serves three important functions in accident investigation and analysis: a heuristic function, an investigative function, and an integrative function.

Accidents, Aviation↗