Signs Of Hyperexcitability Research Articles

P 166 Case presentation – apoplex due to partial occlusion of the medial cerebral artery with sinistral hemiparesis, word-finding disorder, memory impairment and writing disorder

Anamnesis S. had helped her sister to move. She experienced dizziness and everything went black. She choked on something to drink. Then she went out on the balcony, fell due to weakness of her right leg, and she could not move the right half of the body (right arm, right leg). The right angle of his mouth hung slightly with saliva, and she slurred her speech. She was put down. Then she was unconscious for about 5 min and was hospitalised by the emergency physician with suspicion of epilepsy. Additional anamnestic data collected later: Was frequently beaten by a violent friend. After separation, day-hospital and then stationary child and adolescent psychiatric treatment for 3 months for depression and self-injury followed. HWS- and BWS-distorsion, left-convex rotation-scoliosis in the proximal BWS-region, broad-base discrete disc protrusion in the disc compartment C5/ 6 with contact to the thekal tube with initial spinal constriction, diagnosed after an accident on trampoline 9 months ago by MRT. Varicella with 3 years. Drug history: fluoxetine for about 2–3 weeks, melatonin for 2 months, Jubrele since about 1 year. Clinical findings 14 year old girl, in a somnolent state, eyes open from time to time, but can not adequately speak. Coarse motor system normal, fine motor system disturbed. Cannot write. Left forearm with fresh and old scratches. Sensorium intact. Reflexes slowed. Other clinical examination normal. With suspected apoplex because of incomplete hemiparesis an MRI was immediately performed, which showed a fresh ischemia in the region of the artery cerebri media on the left side, a disturbed perfusion in the basal ganglia and in the insular region, swelling of the frontal and frontoparietal brain region and an incomplete occlusion of the artery cerebri media, suggesting a hemorrhagic transformation and occlusion of peripheral vessels. A standard lysis therapy with Actilyse followed by secondary prophylaxis with thrombocyte aggregation inhibitors was performed. Duplex sonography showed a high-grade ACM stenosis on the left in the M1 segment. After 20 h, S. became more somnolent and showed no linguistic activities at the time. A new MRI examination showed a high-grade stenosis in the M1 segment on the left and peripherally a markedly reduced perfusion with increasing infarction. On the third day of treatment rudimentary communication returned. On the 4th day duplex sonography showed worsening of hemodynamics in the left arteria cerebri media and the EEG showed a light focus on the left temporal side, no signs of hyperexcitability. Then development of complete paresis of the right arm and progression of aphasia. The MRI proved an increase in the ischemic areas in the region supplied by the left arteria cerebri media and showed a frontoparietal substantial ischemic area as well as changes in the vascular area, which would be compatible with vasculitis. Laboratory chemistry: no elevated inflammation parameters, no coagulation disorder, no signs of an autoimmune process. Since the radiologists of the MHH Hanover considered an interventional therapy to be possible, but wanted to see the patient on the spot, the patient was transferred with helicopter to Hannover in a stable condition. Unfortunately, no additional interventional therapy was possible.

Mikronevrografi og forskning på perifer nevropatisk smerte

Microneurography is a neurophysiological technique which enables recording from single peripheral nerve fibres in persons who are awake. The method is only used in research. We discuss how microneurography has been used to map nerve-fibre functions under normal circumstances and in chronic pain conditions. The article is based on a literature search in PubMed and on the authors' own knowledge and experience of the method from their research. Microneurography has contributed to the understanding of pain under physiological conditions and in chronic pain conditions, in particular peripheral neuropathic pain. For example, signs of hyperexcitability have been found in peripheral nerve fibres in connection with neuropathies and peripheral neuropathic pain conditions, and the proportion of hyperexcitable nerve fibres has been shown to be greater in neuropathy patients with chronic pain than in neuropathy patients without pain. Findings indicate that so-called CMi nociceptors play an important role in chronic neuropathic pain. In the longer term we hope that research using microneurography will help to reveal mechanisms of direct importance for the development of targeted treatment of neuropathic pain.

Leuprolide – A luteinizing hormone releasing hormone agonist attenuates ethanol withdrawal syndrome and ethanol-induced locomotor sensitization in mice

Ethanol inhibits the synthesis, content and release of hypothalamic luteinizing hormone releasing hormone (LHRH), and LHRH modulates the activity of several neurotransmitters that experience adaptive changes on chronic exposure to ethanol, and also implicate in ethanol dependence. Hence, it was contemplated that LHRH agonist such as leuprolide may influence the behavioral consequences of withdrawing ethanol in dependent state. In the present study, ethanol dependence was produced in mice by providing ethanol liquid diet for 10 days; and its withdrawal on day 11 led to physical signs of hyperexcitability with its peak at 6th h. Acute treatment with leuprolide (20 ng/mouse, i.c.v.), 10 min prior to peak, significantly attenuated hyperexcitability. Such effect of leuprolide was evident even in castrated mice, and castration significantly increased the hyperexcitability in ethanol withdrawal state. Chronic treatment with leuprolide (10 ng/mouse, twice daily, i.c.v.) till day 10 significantly reduced the signs of hyperexcitability in ethanol withdrawal state. In another set of experiment, ethanol (2.4 g/kg, i.p.) was administered on day 1, 4, 7, 10 and 15, which caused gradual increase in locomotor activity indicating ethanol-induced sensitization. Leuprolide (20 ng/mouse, i.c.v.), 10 min prior to the challenge dose of ethanol (2.4 g/kg, i.p.) on day 15 significantly attenuated the expression of sensitization to hyperlocomotor effect of ethanol. Similarly, administration of leuprolide (20 ng/mouse, i.c.v.), 10 min prior to ethanol on day 1, 4, 7 and 10 not only reduced the gradual increase in locomotor activity but also attenuated the sensitized locomotor response on day 15, indicated attenuation of development of sensitization. Leuprolide per se did not affect physical signs and locomotor activity in control group. In conclusion, the present study demonstrated that leuprolide treatment attenuates expression and development of ethanol dependence and sensitization in mice.

Structural and functional asymmetry in the normal and epileptic rat dentate gyrus.

The rat dentate gyrus is usually described as relatively homogeneous. Here, we present anatomic and physiological data which demonstrate that there are striking differences between the supra- and infrapyramidal blades after status epilepticus and recurrent seizures. These differences appear to be an accentuation of a subtle asymmetry present in normal rats. In both pilocarpine and kainic acid models, there was greater mossy fiber sprouting in the infrapyramidal blade. This occurred primarily in the middle third of the hippocampus. Asymmetric sprouting was evident both with Timm stain as well as antisera to brain-derived neurotrophic factor (BDNF) or neuropeptide Y (NPY). In addition, surviving NPY-immunoreactive hilar neurons were distributed preferentially in the suprapyramidal region of the hilus. Extracellular recordings from infrapyramidal sites in hippocampal slices of pilocarpine-treated rats showed larger population spikes and weaker paired-pulse inhibition in response to perforant path stimulation relative to suprapyramidal recordings. A single stimulus could evoke burst discharges in infrapyramidal granule cells but not suprapyramidal blade neurons. BDNF exposure led to spontaneous epileptiform discharges that were larger in amplitude and longer lasting in the infrapyramidal blade. Stimulation of the infrapyramidal molecular layer evoked larger responses in area CA3 than suprapyramidal stimulation. In slices from the temporal pole, in which anatomic evidence of asymmetry waned, there was little evidence of physiological asymmetry either. Of interest, some normal rats also showed signs of greater evoked responses in the infrapyramidal blade, and this could be detected with both microelectrode recording and optical imaging techniques. Although there were no signs of hyperexcitability in normal rats, the data suggest that there is some asymmetry in the normal dentate gyrus and this asymmetry is enhanced by seizures. Taken together, the results suggest that supra- and infrapyramidal blades of the dentate gyrus could have different circuit functions and that the infrapyramidal blade may play a greater role in activating the hippocampus.

Adenosine and pain relief: A clinical overview

This overview summarizes the current clinical state of knowledge in the field of adenosine-mediated pain reduction, also including a condensed experimental background of relevance for clinical implementation. Clinical investigations have been systematically performed and include experimental pain models in volunteers, as well as studies in acute perioperative pain and in chronic neuropathic pain. Adenosine has been administered as a low-dose intravenous infusion and as an intrathecal injection. Effects on pain and on signs of hyperexcitability in the nervous system have been investigated, both after administration of adenosine alone and in combination with well-known analgesic agents. The different modes of adenosine administration demonstrate reduced pain, primarily in modalities that involve mechanisms of hyperexcitability of the central nervous system, i.e., central sensitization. Because this phenomenon is an important factor in chronic pain conditions, the promising results of pain relief in patients with neuropathic pain suggest that this is especially relevant for future development and research. In addition, the potential use of adenosine in combination with other pain-modulating agents deserves further evaluation.

Correlation between function and structure in "epileptic" human hippocampal tissue maintained in vitro.

Intracellular and extracellular recordings were obtained from the CA1 region and gyrus dentatus of human hippocampi that had been surgically removed for treatment of intractable seizures. Pathologic diagnoses were obtained, and electrophysiologic results were correlated with degree of principal cell loss (sclerosis) in the regions studied. Extracellular field potentials were absent or smaller in amplitude, with abnormal characteristics, in sclerotic regions. In all regions, regardless of the degree of sclerosis, individual pyramidal or granule cells could be penetrated. These neurons showed apparently normal electrophysiologic characteristics and intact excitatory synaptic input. No signs of hyperexcitability were observed.

The effects of chronic treatment with the dihydropyridine, Bay K 8644, on hyperexcitability due to ethanol withdrawal, in vivo and in vitro.

1. The effects of chronic treatment with the dihydropyridine, Bay K 8644, were studied on the ethanol withdrawal syndrome, in vivo and in vitro. 2. Addition of racemic Bay K 8644 to the drinking mixture, throughout the chronic ethanol treatment, decreased the behavioural excitability seen during ethanol withdrawal in vivo. 3. All the signs of hyperexcitability in field potentials in the isolated hippocampal slice, caused by ethanol withdrawal, were decreased by the chronic administration of Bay K 8644. 4. These effects resembled those previously reported for chronic administration of calcium channel antagonists; racemic Bay K 8644 has both calcium channel activating and antagonist properties. 5. Measurement of brain levels of Bay K 8644 at the end of the chronic treatment showed that the compound reached micromolar concentrations during the treatment, but none could be detected in the tissues at the time of the above measurements. 6. It is possible that the results might be explained by predominance of the calcium channel antagonist properties of this compound, owing to the high central concentrations achieved during the treatment. Tolerance to the calcium channel activating properties of Bay K 8644 may also have occurred during the chronic treatment.

EVIDENCE THAT CHANGES IN HIPPOCAMPAL EXCITABILITY <italic>IN VITRO</italic> ARE CAUSED BY WITHDRAWAL FROM CHRONIC <italic>IN VIVO</italic> ETHANOL ADMINISTRATION

A complex pattern of changes in the field potentials recorded from mouse hippocampal slices, prepared after chronic ethanol treatment in vivo, has previously been demonstrated in this laboratory. In the present study, recordings from slices prepared immediately after 2 weeks of ethanol treatment, showed only an increase in paired pulse potentiation, compared with controls, whereas recordings made immediately after 16 weeks of ethanol administration showed decreases in the thresholds for single and multiple population spikes, increases in paired pulse potentiation and epileptiform activity. In hippocampal slices prepared after 24 hr withdrawal, following 16 weeks of ethanol treatment, there were no signs of hyperexcitability in the field potentials. Ratings of convulsive behaviour were increased in mice during a 12-hr period after withdrawal from 16 weeks of ethanol treatment. Corresponding behaviour ratings for the mice given ethanol for 2 weeks, or those withdrawn for 24 hr after 16 weeks ethanol treatment, were not significantly different from control values. It was concluded that epileptiform activity seen in hippocampal slices after prolonged ethanol administration may contribute to the ethanol withdrawal hyperexcitability seen in vivo.

Cerebral glucose uptake in lindane-treated rats

The pesticide and ectoparasiticide lindane, γ-isomer of hexachlorocyclohexane, is a powerful CNS-stimulant inducing convulsions and other signs of hyperexcitability in mammals. The present work was carried out to investigate the effect of lindane on brain regional glucose uptake at convulsant and non-convulsant doses. Local glucose uptake was measured in male Wistar rats using a modification of the 2-deoxyglucose (2-DG) method. Animals received i.p. [ 3H]2-DG and the amount of label in different brain structures of control and lindane-treated animals was assayed by a liquid scintillation counting of 18 dissected regions. Lindane at single convulsant dose (150 mg/kg, p.o.) increased 2-DG uptake in olfactory tubercules, hypothalamus, hippocampus, parafloculi and hypophysis. The uptake was decreased in parietal cortex, thalamus and pons-medulla. The pattern of 2-DG uptake after a single non-convulsant dose of 30 mg/kg p.o. was not so modified. After 1 week of treatment with 10 mg/kg per day p.o., increased 2-DG uptake was observed in superior colliculi while it was decreased in parietal cortex. The increase of 2-DG uptake in limbic regions observed at the convulsive dose agrees with the experimental association between poisoning signs induced by lindane and damage in the limbic system.

DIFFERENTIAL EFFECTS OF THE BENZODIAZEPINE ANTAGONISTRO 15-1788 AFTER “GENERAL ANAESTHETIC” DOSES OF BENZODIAZEPINES IN MICE

The effects of the benzodiazepine antagonist Ro 15-1788 20 mg kg-1 after "general anaesthetic" doses of several benzodiazepines were studied in mice, in order to determine if the effects of the latter were attributable to an action at benzodiazepine receptors. Male CDI mice were used and the end-points for anaesthesia were loss of the righting reflex and loss of the foot pinch reflex. The effects of midazolam, and to a lesser extent those of chlordiazepoxide and of diazepam on these reflexes, were antagonized partially by Ro 15-1788. When the antagonist was given after high doses of flurazepam, convulsions were produced. Calculation of the likely membrane concentrations of the benzodiazepines showed that these fitted the lipid solubility correlation for general anaesthesia. Ro 15-1788 did not decrease the lethal effects of the benzodiazepines. With flurazepam, chlordiazepoxide and diazepam it caused signs of hyperexcitability, which in the case of flurazepam led to the death of the animals.

Lipid composition of the synaptosome and erythrocyte membranes during chronic ethanol-treatment and withdrawal in the rat

Male Sprague-Dawley rats were intoxicated by inhalation of ethanol vapor for 21 days. This allowed high tolerance to the hypnotic effect of ethanol and withdrawal syndrome to be developed. The chronic intoxication brought about modifications of the synaptosome and erythrocyte membrane lipid composition which were not due to the reduction in food intake that parallels intoxication. The fatty acid composition of the phospholipids was modified but the level of cholesterol and the level of phospholipid remained unchanged. The modifications concerned the levels of linoleic (18:2) and arachidonic (20:4) acids which decreased in the synaptosomes. In the red blood cell membranes, ethanol affected the levels of the octadecenoic acids (18:1) which rose, and linoleic acid (18:2) which fell. These disturbances were present when the withdrawal syndrome was at its highest and also 3 days after withdrawal when the signs of hyperexcitability were no longer visible in the animal. Modifications in the brain membrane lipid composition parallel the behavioral tolerance to ethanol; however the present results show that the apparent readaptation of the central nervous system to withdrawal of alcohol occurs earlier than the return to normal of the membrane lipid modifications.

Effect of phencyclidine on inhibition in the hippocampal slice.

The effects of phencyclidine (PCP) on synaptic transmission were studied in the hippocampal slice. Population spikes evoked by orthodromic or antidromic stimulation were recorded from CAl pyramidal cells. Bath applied PCP (10(-4) M) reduced moderately both the orthodromic and antidromic population spikes. Lower concentrations, 5 X 10(-6) to 5 X 10(-5) M of PCP, which did not depress the population spikes, reduced inhibition of the orthodromically evoked spike in a dose dependent reversible manner. Diazepam (10(-6) to 10(-5) M) restored the inhibition despite the continued presence of PCP. It is suggested that PCP-induced seizures and other signs of hyperexcitability could be a result of reduced inhibition.