Tyrosine hydroxylase activity in sympathetic nervous system of rats with streptozocin-induced diabetes.

The activity of tyrosine hydroxylase (TOH), the rate-limiting enzyme in norepinephrine biosynthesis, was measured in selected sympathetic ganglia to develop a quantitative measure of sympathetic autonomic neuropathy in streptozocin-induced diabetic rats. Surprisingly, TOH activity was elevated twofold in diabetic prevertebral ganglia innervating the alimentary tract (i.e., superior mesenteric, celiac, and inferior mesenteric), which has terminal processes that develop neuroaxonal dystrophy in this model system. TOH activity of paravertebral ganglia (i.e., superior cervical and stellate) with nonalimentary targets was not increased in the same animals. Increased TOH activity in the prevertebral ganglia 1) developed within the 1st wk of diabetes and persisted for 10 mo, 2) did not represent a change in TOH affinity for d-1,6-methyl-5,6,7,8- tetrahydropterine cofactor, 3) was prevented by both nicotinamide pretreatment and early institution of insulin therapy, and 4) did not develop as a result of classical transsynaptic induction. Pair-feeding experiments confirmed that the most likely cause of increased TOH activity in this system was the marked hypertrophy and hyperplasia of the diabetic bowel resulting from compensatory hyperphagia. We conclude that TOH activity does not represent a suitable marker for sympathetic autonomic neuropathy in this experimental system. Rather, the increase appears to be an example of a selective increase in the synthesis of neurotransmitter enzymes, possibly in response to increased trophic support provided by the expanded target, i.e., the hypertrophic gut. The additional synthetic stress imposed on prevertebral neurons by the expansion of the innervation of the alimentary target coupled with the complex diabetic metabolic milieu may contribute to the development and selective distribution of dystrophic axonopathy to the innervation of the alimentary tract.

[Study of the mechanisms of the development of epileptic activity in neuronal networks using a simulation model]. / Badanie mechanizmów wystepowania padaczkowej aktywnosci sieci nerwowej na modelu symulacyjnym.

The occurrence of synchronous, self-sustaining seizure activity is one of the basic mechanisms underlying epileptic attacks. Using a mathematical model of neuronal network in various simulation experiments carried out in digital computer the conditions were studied of the development of pathological epileptic activity and the conditions of the parameters of this network affecting its stable function. After exceeding of a threshold value in the relation between the weights of the stimulating and inhibiting synapses an unstable epileptic response appears. In the state of the so called conditional stability the network is highly sensitive to even small changes of the parameters. These observations make possible a new look at a number of phenomena found in clinical cases and in experiments.

Auditory brain-stem (ABP) and somatosensory evoked potentials (SEP) in an animal model of a synaptic lesion: elevated plasma barbiturate levels.

Experiments were conducted to determine whether a consistent pattern of auditory nerve brain-stem evoked synaptic lesion model in cats (elevated levels of the lesion model in cats (elevated levels of the barbiturate thiopental). The ABP in response to low (10/sec) and high (80/sec) stimulus rates was recorded. In order to differentiate between the effects of the elevated drug levels on axonal propagation and on synaptic transmission, the early components of the somatosensory evoked potential (SEP) were also recorded, with particular attention to the first SEP wave, which is solely an axonal event without any intervening synapse. Calculations showed that the effect on synapses was 3.0-9.5 times greater than the effect of the drug on axonal propagation. As the level of barbiturates increased (representing a more severe synaptic lesion), the interpeak latencies of the ABP and the SEP became progressively prolonged, more so than the dependence of the first waves of both the ABP and the SEP on drug level. In general, amplitudes were not affected. At progressively elevated drug levels, higher stimulus repetition rates did not have an increasingly greater effect than lower rates on evoked response latencies and amplitudes so that this study also shows that the use of elevated stimulus rates does not hold much promise in the diagnosis of synaptic lesions.

Cellular mechanisms of epilepsy: a status report.

The cellular phenomena underlying focal epilepsy are currently understood in the context of contemporary concepts of cellular and synaptic function. Interictal discharges appear to be due to a combination of synaptic events and intrinsic currents, the exact proportion of which in any given neuron may vary according to the anatomic and functional substrate involved in the epileptic discharge and the epileptogenic agent used in a given model. The transition to seizure appears to be due to simultaneous increments in excitatory influences and decrements in inhibitory processes--both related to frequency-dependent neuronal events. A variety of specific hypotheses have been proposed to account for the increased excitability that occurs during epileptiform activity. Although each of the proposed mechanisms is likely to contribute significantly to the epileptic process, no single hypothesis provides an exclusive unifying framework within which all kinds of focal epilepsy can be understood. The spread of epileptic activity throughout the brain, the development of primary generalized epilepsy, the existence of "gating" mechanisms in specific anatomic locations, and the extrapolation of hypotheses derived from simple models of focal epilepsy to explain more complex forms of human epilepsy, all are not yet fully understood.

Spasticity.

Spasticity has been defined as velocity-dependent hyperactivity of stretch reflexes; it is therefore only one aspect of the complex syndrome produced by a lesion of the upper motoneuron. Although spasticity may be partially responsible for joint contractures, it does not produce most of the functional disability experienced by patients with upper motoneuron lesions. Paresis, fatigability, lack of dexterity, etc., account for most of these patients' complaints. The pathophysiology of spasticity is poorly understood but appears to be related to an increased excitatory state at the segmental spinal level; there is no evidence for increased sensitivity of muscle spindles in spastic patients. Several mechanisms for this increased excitability within the spinal cord have been proposed. There are different types as well as degrees of spasticity. Clinical neurophysiologic recordings of reflex activity in patients with spasticity provide the means to differentiate among the various types of spasticity, to select the therapy most likely to be effective in a particular patient, and to see the results of its employment objectively. The latter will prove whether a specific therapy is useful or not. Ablative treatment at the level of the peripheral nerve or dorsal root may be useful, particularly when spasticity is severe. Drugs such as baclofen or diazepam relieve flexor spasms but are not particularly effective against spasticity itself. Dantrolene acts to weaken muscles, but that is not often helpful. Rarely do any of these therapies increase function; there are no effective cures for paresis or related negative manifestations of chronic spasticity.

Reversibility of alcohol-related brain damage: clinical and experimental observations.

Chronic alcoholics who maintain abstinence often demonstrate remarkable improvement of neurological and mental dysfunction. This paper presents an overview of the clinical and laboratory work of our group. Reversible clinical manifestations include psychometric scores, ataxia, tremor, Parkinsonism, dyskinesia, cerebral atrophy, EEG parameters, and a CSF acidosis. Electrophysiological investigations showed that in the in vitro hippocampus of rats fed ethanol for several months there was evidence for diminished long-term potentiation, impaired neuronal inhibitory mechanisms (diminished inhibitory post-synaptic potentials and post-spike after hyperpolarisations), decreased neuronal specific membrane capacitance and increased specific membrane resistance. Golgi stains showed attenuation of hippocampal CA1 neuronal dendrites in rats fed ethanol for five months, which reverted to control size in rats permitted two months of alcohol withdrawal.

The role of interstitial potassium in the generation of low-calcium hippocampal seizures.

The explosive nature of a focal cortical seizure suggests the operation of strong positive feedback in the neuronal network. It was previously proposed that in the hippocampus this may be provided by the regenerative accumulation of potassium in the interstitium. This hypothesis was severely criticized in the past. However, it gained new impetus with the recent discovery that focal seizures can arise in mammalian hippocampal slices perfused with low calcium solutions despite the block of chemical synaptic transmission. Here, we examine the relationship of interstitial potassium concentration to the electrogenesis of these low-calcium seizures. Both the experimental data and the behavior of a simplified mathematical model describing neuronal discharge in low calcium, support the contention that interstitial potassium accumulation may play an important role in the buildup of hippocampal seizures.

Electrophysiological evidence for a presynaptic mechanism of morphine withdrawal in the neonatal rat spinal cord.

Dorsal and ventral root depolarizing responses to capsaicin (1 microM) and substance P (SP; 1 microM) were measured from the isolated, hemisected spinal cord of the neonatal rat. Capsaicin depolarized the dorsal and ventral roots. The mechanism of ventral root depolarization was presynaptic; since dorsal root depolarization preceded the ventral, and the ventral depolarization was eliminated when synaptic transmission was blocked in the absence of calcium. SP depolarized the ventral root without affecting the dorsal root. The SP-induced depolarization of the ventral root was reduced but not abolished by blocking synaptic transmission with low calcium, suggesting that SP acted postsynaptically on motoneurons and excitatory interneurons to depolarize the ventral root. Morphine (10 microM) abolished the capsaicin-induced ventral root depolarization, but only slightly suppressed the SP response (30%). The capsaicin-induced depolarization of the ventral root was enhanced greatly (238%) when morphine, which had been in the superfusion for 1 h, was removed and naloxone (1 microM) was added to the superfusion solution, whereas the SP response was not augmented during withdrawal from acute morphine. Furthermore, a putative SP antagonist ([D-Arg1, D-Pro2, D-Tryp7,9, Leu11]-SP) prevented the augmented capsaicin ventral root response during precipitated withdrawal. These data provide electrophysiological evidence for a presynaptic mechanism of acute morphine withdrawal in the neonatal rat spinal cord.

Recovery potentials following CNS lesions: a brief historical perspective in relation to modern research data on neuroplasticity.

This article begins with a brief historical account of our attempts to understand the brain by endlessly mapping out discrete structural and functional territories. These territorial or classical maps are then contrasted with the new metabolic maps, which show brain function and plasticity as it has never been conceptualized or visualized before. The new maps, along with more recent research in such areas as neuroplasticity, synaptogenesis, parallel processing, holistic brain functioning, sexual dimorphism, and individual differences, are giving our profession a solid scientific foundation on which to base many of the rehabilitation techniques used today in pediatrics, geriatrics, psychiatry, and physical disabilities.

Reflex activity and axonal conduction in the L-7 spinal cord segment following experimental compression trauma.

In cats in which the spinal cord was transected at C-1, the exposed L-7 spinal cord segment was compressed with an electromagnetically driven rod applied to the dorsal surface of the segment. With the magnitude of compression constant at 3 mm, the cord was compressed for durations of 50 msec, 0.5 sec, or 1.0 sec. Polysynaptic reflex discharges integrated in the injured segment and action potentials conducted in dorsal column axons traversing the same region were electrophysiologically measured before, during, and for 41/2 hours after trauma. Structural changes were evaluated on frozen serial sections obtained both from compressed segments and from tissue adjacent to the injury. At a compression duration of 50 msec, the amplitude of evoked reflex activity decreased abruptly, and dorsal column axonal conduction was blocked for 1 minute following compression. This early-phase response was followed by partial recovery of both functions which persisted until the end of the experiment. Prolonging compression to 0.5 sec brought about a further decrease of polysynaptic reflex activity. Axonal conduction was also decreased, but not significantly. With compression lasting 1.0 sec, no significant changes in reflex discharges and axonal conduction occurred compared with those measured at 0.5 sec. Neither function was abolished, even after the longest compression time. Prolongation of compression significantly increased both the intensity and the spread of edema, whereas changes in hemorrhage were not significant. Thus, a plateau rather than a progressive increase in severity of functional and structural posttraumatic changes was reached by increasing the duration of compression. This injury model reduces the sources of variability found in other experimental compression trauma models and permits the quantitative assessment of basic spinal cord mechanisms and correlated histopathological changes in the same preparation following trauma.

Motoneuron death and motor unit size during embryonic development of the rat.

Chronic paralysis of rat embryos during the last 4 to 6 prenatal days causes a diminution in skeletal muscle fiber numbers but inhibits motoneuron death. Consequently, as paralyzed muscles develop, an increased number of motoneurons attempts to form synapses at a reduced number of synaptic sites. Paralyzed muscle fibers receive their synapses at a single endplate, as in control muscles, but these endplates are hyperinnervated, with about twice the normal number of inputs. Counts of axons, synaptic inputs, and muscle units showed that motoneurons normally contact a maximum number of muscle fibers shortly before birth, and this number remains stable for several days postnatal until it finally is reduced to the adult number. The average motor unit size in paralyzed embryos at the time of birth was the same as in controls. We suggest that it is not necessary to postulate the existence of competition between embryonic nerve terminals in order to explain regulation of the number of muscle fibers initially contacted by a motoneuron. Motoneuron death was not immediately affected by paralysis, but paralysis "rescued" all motoneurons whose death normally would have occurred 24 hr or more after the time when paralysis was initiated, regardless of when this was. This implies that the peak period for determination to die is during embryonic day 14, when myotube formation is just beginning and no recognizable endplate structures are present in muscles. When paralyzed, motoneurons normally destined to die are capable of forming a normal number of functional nerve-muscle contacts.

Chronic ethanol-induced decreases in the response of dentate granule cells to perforant path input in the rat.

The neurotoxic effects of chronic ethanol consumption were investigated in the rat hippocampus by electrophysiological analyses of synaptic function of entorhinal afferents to stratum moleculare of the dentate gyrus. Rats were maintained on ethanol- or sucrose-containing liquid diets for a period of 20 weeks and were withdrawn from the special diets for a period of 8 weeks prior to acute electrophysiological studies. Synaptic response strength (Input/Output (I/O) functions) and synaptic potentiation (paired-pulse, frequency and long-term) were evaluated in each rat. Chronic ethanol treatment failed to influence the response strength or potentiation of basic synaptic responses (EPSP). Rather, the ethanol effects were confined to the population spike (PS). Chronic ethanol treatment produced reductions in PS responses 1) in the asymptotic portions of the I/O curves, 2) in paired-pulse potentiation, 3) in response to 1 and 5 Hz low-frequency stimulation and 4) during the development of long-term potentiation. Expressing PS amplitude as a function of EPSP amplitude emphasized the independence of these actions from those of the synaptic potentials. Definitive evidence concerning the cellular alterations underlying these effects of chronic ethanol treatment are presently lacking. However, available evidence supports the hypothesis that the ethanol-induced decreases in PS responses result from a reduction in the "excitability" of granule cells in the dentate gyrus.

Evoked potentials in the clinical neurosciences.

The use of evoked potentials for the evaluation of disorders of the nervous system has become a most valuable aid to the neurosurgeon and neurologist, often providing information of critical value without recourse to invasive techniques. In order to employ these techniques, it is helpful to understand the principles of evoked potential electrogenesis and the methodology used for analysis of evoked potential clinical data. This article is aimed at providing the clinical neurosurgeon with this type of information and with a review of current clinical applications in this rapidly developing field.

CNS myelin and synapses in a spontaneous mouse ovarian teratoma showing neural differentiation. An immunohistochemical and electron microscopic study.

A morphologic (light-, electron microscopic, and immunohistochemical) study of a spontaneous ovarian teratoma, originating in the LT strain of mice and showing predominantly neural differentiation, has revealed an unusually large number of mature myelinated axons and synapses within areas of well-differentiated neuroepithelium. Most of the myelin was determined to be of CNS origin by its staining characteristics with the LFB-PAS stain, the absence of reticulin fibers by light microscopy and of basal laminae by electron microscopy in relation to the myelin sheaths, the presence of associated cells identified morphologically as oligodendrocytes, and by the strongly positive immunohistologic reaction obtained for myelin basic protein. Most synapses likewise appeared to be of the CNS type. This murine ovarian teratoma may therefore be a useful tool for the study of neoplastic myelinogenesis and synaptogenesis.

A stereological analysis of the neuronal and synaptic content of the frontal and cerebellar cortex of weanling rats undernourished from birth.

The frontal cortex and granular layer of the cerebellum have been examined in 30-day-old rats undernourished from birth. Quantitative stereological procedures at the light microscopical level have been used to estimate the volume proportion and numerical densities of neuronal nuclei. Similar methods at the electron microscopical level were employed to calculate the numerical densities of synapses. Hence, synapse-to-neuron ratios have been calculated in these brain regions. In the frontal cortex, the undernourished group of rats showed a 37% deficit (P less than 0.05) in the synapse-to-neuron ratio. This was due to a combination of an increase in the numberical density of neurons and a decrease in the numerical density of synapses, although, individually, neither of these reached statistical significance at the 5% level. In the granular layer of the cerebellum there was a 31% (P less than 0.01) deficit in the synapse-to-neuron ratio. This was a function of the reduced numerical density of synapses, with no difference in the numerical density of granule cells between groups. For the frontal cortex, the volume proportion of neuronal nuclei was significantly greater in the undernourished group of rats. There were no significant differences between control and undernourished rats in the volume of the 'forebrain' occupied by cortex. The mean diameters of neuronal nuclei and synaptic discs did not differ in any given region between treatment groups. These observations are discussed in context with the previously published results on synapses and neurons in undernourished animals.

Neuromuscular synapse testing in two cases of suicidal organophosphorous pesticide poisoning.

Electromyographic neuromuscular testing was performed for two patients with a very low blood cholinesterase activity due to suicidal poisoning with organophosphorous pesticides. Electromyographic results did not differ significantly from those obtained in healthy nonexposed adults. Neuromuscular synapse functioning was normal, as was determined by electromyography. Neurological signs and symptoms are described in detail.