Interested in the pharmacological treatment of subjects with brain lesions, we studied the effects of chronic (7 and 30 d) treatments with Ginkgo biloba extract (EGb 761, Ipsen) in two animal models of cortical hemiplegia: one induced by motor-cortex aspiration and another using a reversible inactivation of the motor cortex through chronic, localized infusion of an inhibitory neurotransmitter, y-aminobutyric acid (GABA), by means of osmotic minipumps. The elevated beam test, which evaluates coordinated walking, was used in water-deprived animals trained to drink saccharin-sweetened solutions (with or without EGb 761) and to perform to criteria before the surgical procedures. Surgery involved either sham operation, unilateral motor-cortex aspiration or unilateral, chronic infusion of GABA into the same region. From the day after surgery, the rats were administered 100 mg/kg/d of EGb 761 daily for 7 or 30 d. The extract was spontaneously taken by the rats twice daily. In all groups in which the extract was administered, a faster and more complete recovery from the motor deficits was observed, a result which was significantly different from that in rats to whom only saccharin solutions were given. No differences were detected for sensory deficits. The beneficial effects of EGb 761 were more apparent in the motor-cortex aspiration groups than in the GABA-treated rats. Histological analysis showed that EGb 761-treated rats had significantly smaller ventricular diameters than untreated animals, although immunocytochemical analysis of gliotic reaction (GFAP staining) did not show group differences. We conclude that EGb 761 has beneficial effects on recovery from cortical hemiplegia in the ralo However, EGb 761 active principle(s) and mechanism(s) of action remain to be further elucidated.

In some mammals, epileptic seizures have been induced in the cerebral cortex, hippocampus and other limbic structures after the sudden suppression of chronically infused GABA. This hyperexcitability state induced by the endogenous neurotransmitter resembles the withdrawal seizure-responses to other GABAA receptor agonists such as benzodiazepines, barbiturates and alcohol. Hyperexcitability induced by GABA withdrawal also persists in in vitro preparation. Hippocampal slices, obtained from rats with seizures induced by GABA-withdrawal showed field potential oscillations and paroxysmal activity in the Ammon's horn region 1. During GABA-withdrawal hyperexcitability the threshold of hippocampal long-term potentiation (LTP) decreased to a point in which a brief frequency stimulation that normally failed to produce long lasting changes in synaptic strength, was now able to induce LTP. Facilitation of the LTP induction was associated with a decreased GABAA-mediated inhibitory activity, because the effect of the GABAA receptor antagonist, bicuculline, was occluded during hyperexcitability and the dose-response curve for bicuculline showed a 50% efficacy reduction with a shift in the effective concentration required for half-maximal activation from 4.5–1.1 μM relative to controls. Nevertheless, the dissociation constant of the antagonist did not change significantly. Our results support the idea that changes in hippocampal plasticity under altered inhibitory neurotransmission states, like those induced by withdrawal syndromes to anxiolytic, sedative or anticonvulsant drugs may be engaged during seizures.

The sudden interruption of an intracortical instillation of exogenous gamma-aminobutyric acid (GABA) generates an epileptic focus in mammals. Seizures elicited by GABA withdrawal (GW) last for weeks. A similar withdrawal-induced hyperexcitability is also produced by several GABA(A) receptor agonists. This work reports a quantitative analysis of GW-induced hyperexcitability produced in the hippocampus in vitro. GW produced a left-ward displacement of the input/output (I/O) function, suggesting that the postsynaptic component is predominant to explain the hyperexcitability. A decrease in the inhibitory efficacy of the GABA(A) receptor agonist, muscimol, confirmed that inhibition was impaired. Binding saturation experiments demonstrated a decrease in [(3)H]-muscimol binding after GABA withdrawal showing a close correlation with the development of hyperexcitability. All these modifications coursed without changes in receptor affinity (K(D)) for muscimol or bicuculline as demonstrated by both binding studies and Schild analysis. It is concluded that, in the CA1 region of the hippocampus, it is the number of functional GABA(A) receptors, and not the affinity of the receptor, what is decreased during GW-induced hyperexcitability.

The sharp interruption of the intracortical instillation of exogenous γ-aminobutyric acid (GABA), generates an epileptic focus in mammals. Seizures elicited by GABA withdrawal last several days or weeks. The present work reports that GABA withdrawal-induced hyperexcitability can be produced in vitro: a sudden withdrawal of GABA (5 mM; 120 min) or benzodiazepine (60 μM flunitrazepam) from the superfusion, induced a gradual increase in the amplitude of the evoked population spike (PS) recorded on neocortical slices. PS enhancement reached 150% above the control value 2.5 h after GABA withdrawal. GABA withdrawal-induced hyperexcitability was facilitated by progesterone. PS enhancement induced by GABA withdrawal was associated with an impairment of GABA transmission occurring before epileptiform discharges were fully established. Paired pulse inhibition and evoked [3H]-GABA release appear decreased; suggesting that cortical hyperexcitability as a result of GABA withdrawal involves pre-synaptic changes. Specific muscimol binding decreased during GABA superfusion but recovered after GABA withdrawal. However, the sensitivity of the post-synaptic response to 3α-OH-5α-pregnan-20-one or allopregnanolone (alloP) was enhanced after GABA withdrawal, suggesting a functional change in the GABAA receptors. The changes described may be the cellular correlates of the withdrawal syndromes appearing after interruption of the administration of GABAA receptor agonists.

In electrophysiological terms, experimental models of durable information storage in the brain include long-term potentiation (LTP), long-term depression, and kindling. Protein synthesis correlates with these enduring processes. We propose a fourth example of long-lasting information storage in the brain, which we call the GABA-withdrawal syndrome (GWS). In rats, withdrawal of a chronic intracortical infusion of GABA, a ubiquitous inhibitory neurotransmitter, induced epileptogenesis at the infusion site. This overt GWS lasted for days. Anisomycin, a protein synthesis inhibitor, prevented the appearance of GWS in vivo. Hippocampal and neocortical slices showed a similar post-GABA hyperexcitability in vitro and an enhanced susceptibility to LTP induction. One to four months after the epileptic behavior disappeared, systemic administration of a subconvulsant dose of pentylenetetrazol produced the reappearance of paroxysmal activity. The long-lasting effects of tonic GABAA receptor stimulation may be involved in long-term information storage processes at the cortical level, whereas the cessation of GABAA receptor stimulation may be involved in chronic pathological conditions, such as epilepsy. Furthermore, we propose that GWS may represent a common key factor in the addiction to GABAergic agents (for example, barbiturates, benzodiazepines, and ethanol). GWS represents a novel form of neurono-glial plasticity. The mechanisms of this phenomenon remain to be understood.

Ethanol exerts its behavioral effects largely by interacting with receptors to brain neurotransmitters. The molecular mechanisms involving these interactions are still not well known since an ideal model for their study is currently unavailable. In addition, responses to alcohol may vary due to factors such as genetic predisposition, ethanol concentration consumed, and stimuli such as stress, socialization, etc. The chronic consumption of alcohol, similar to that of other drugs such as benzodiazepines and barbiturates, is linked to GABAergic neurotransmission. GABA is the predominant inhibitory neurotransmitter in the brain. In a context of substance abuse, these three drugs first cause a gratifying effect, later tolerance and finally, physical and psychological dependence. If consumption is interrupted abruptly, a withdrawal syndrome occurs. The Alcohol Withdrawal Syndrome (AWS) is a state of hyperexcitability characterized by anxiety, fear, muscular rigidity and tonic-clonic seizures with epileptiform-type characteristics. The epileptic seizures seen during AWS are often similar to those seen in experimental epilepsy models such as "kindling" or GABA Withdrawal Syndrome (GWS) models. A possible correlation between these models and AWS will allow for a better understanding of the cellular and molecular effects that alcohol exerts on the brain.

Attention is a term designing a highly complex cognitive process whose deficit substantially alters the individual's ability to adapt himself to his environment at the emotional, social and intelectual level. The study of the brain proccesses for selecting environmental stimuli will help to understand and define some clinical manifestations in several neuropsychiatric illnesses. Attention itself is a proceses difficult to be defined in conceptual or operational terms. However several theories have attempted to do it. Most of them agree that the individual's capacity to analyze the environmental stimuli is limited. As a result of this limitation, low relevant stimuli have to be filtered out. However, the anatomo functional brain structure (s) is difficult to locate, therefore, it is still in debate if the filter is central or peripheral. In this brief review we attempt to present the state of the relevant literature on this subject and critically analyze the electrophysiological findings in the center of the psychological models.

The present work aimed at studying the participation of the homologous contralateral zone to a unilateral somatomotor cortex lesion, once the animals had showed a significant functional recovery. We studied recovery of coordinated walking after unilateral motor cortex aspiration in rats. A callosotomy was performed 20 days after the initial lesion, without significant effects. We conclude that after this time period, the intact hemisphere plays no role in the recovery process, suggesting that at this time point recovery does not depend on the integrity of corpus callosal fibers at this rostral-caudal level.

The susceptibility to develop cortically induced focal and generalized seizures was examined in Genetic Absence Epilepsy Rats from Strasbourg (GAERS), an inbred strain of Wistar rats with absence epilepsy. A GABA-withdrawal syndrome induced after suppression of a 2-h intracortical GABA infusion was used as a model of focal epileptogenesis: localized cortical discharges appear at the infusion site within 1 h. GAERS were more prone to develop a GABA-withdrawal syndrome than non-epileptic inbred controls and non-selected Wistar rats. After a transient suppression of absence seizures following GABA infusion in GAERS, generalized spike-and-wave discharges and focal spikes were recorded simultaneously in the cortex. GAERS also showed a higher incidence of systemic pentylenetetrazol-induced convulsions at the dose of 25 mg/kg. Higher doses had similar convulsant effects in all groups. In conclusion, the results confirm a genetic susceptibility in GAERS and/or resistance in inbred non-epileptic rats to focal and generalized seizures involving the cortex. Rats with absence epilepsy appear to be more prone to seizures elicited by cortical GABA deficiency.

Steroids which are produced by the brain are called neurosteroids, and they are able to modulate neurotransmissions: GABAergic; glutamatergic; glycinergic, and cholinergic (nicotine receptor). These effects are of short latency and duration, and do not implicate the cellular genome. The interaction of these neurosteroids with membrane receptors contribute to the regulation of neuronal excitability, and their study has allowed a better understanding of cognitive, hormonal, and epileptic phenomena as well as the development of new drugs with anxiolytic, antidepressive, anesthetic and anti-epileptic effects.

We have previously shown beneficial effects of a Ginkgo biloba extract (EGb761-IPSEN) in accelerating functional recovery from hemiplegia induced by unilateral motor cortex ablation. Here, we report the behavioral and histological effects of various dose regimes of EGb761. In young rats (3 months), 10 mg/kg/day for 7 days produced an improvement in motor performance, relative to untreated controls, on the last day of treatment. Applying a priming (P)-maintenance (M) dose regime (P-7 = 7 days, M-21 = 21 days), a P-7 of 50 (all doses expressed in mg/kg/day) and a M-21 of 10 promoted recovery from the second day after surgery. However, in aged rats (26-28 months old) this treatment ameliorated motor performance only after the 10th day of treatment. A P-7 of 100 or 200 and a M-21 of 50 or 100 produced an acceleration of behavioral recovery in aged animals. Improvement was evident by the fifth day of treatment and was maintained after the treatment regimen. These two groups also demonstrated reduced glial fibrillary acid protein (GFAP) immunostaining and ex vacuo hydrocephalus. Thus, the confirmed efficacy of EGb in hemiplegic rats can be enhanced by an appropriate posology.

Changes in the strength of the synaptic connections is critical to many aspects of the nervous system physiology, included learning, memory (24, 34, 40), and some neuropathologies. A model that displays a long term modification of synaptic responses, therefore, presents us with an opportunity to analyze the plastic and adaptive mechanism of the nervous system to various influences, such as the effect of certain psychiatric drugs or to pathological conditions. Long-term potentiation (LTP) is a useful model for the study of neural plasticity. it is generally agreed that LTP, defined as a long-lasting enhancement of synaptic transmission, has two phases: induction and maintenance. Several studies have suggested that the main mechanisms involved in the induction of LTP include the participation (mainly in CA1 and dentate area of the hippocampus) of both NMDA and non-NMDA types of glutamate receptors, of calcium, etc. The dynamics of these mechanisms may explain, at least in part, the main properties of LTP, viz., synapse specificity, cooperativity and associativity. With respect to the maintenance phase, some scientists believe that it is exclusively presynaptic, while others believe that only postsynaptic mechanisms are involved, Recent experimental evidence suggests, however, that both presynaptic and postsynaptic components are involved. Several investigations have shown that both induction and maintenance of LTP can be altered by various factors: by the administration of glutamatergic and GABAergic agonists or antagonists, by the anatomical site of stimulation as well as the parameters of stimulation, among others. Of particular relevance to medical practice, it has been the demonstration that several drugs used in the psychiatric pharmacotherapy can modify LTP. LTP is also known to be changed in experimental models of epilepsy, and some cellular mechanisms important in LTP are altered while others are preserved in the brains of patients whit neurodegenerative diseases, such as Alzheimer disease. Since LTP is very important in the understanding of plastic mechanisms in the nervous system, this review provides several lines of evidence about the pre and postsynaptic mechanisms involved in the induction and maintenance of this interesting phenomenon.

The present paper reviews some of the most important findings concerning the disconnection syndrome. It describes the commisurotomized patients' performance on linguistic, sensory, emotion, attentional, memory, and reaction time tasks; exponds several physiological mechanisms underlying behavioral deficits on such patients and proposes some processes by which patients behave normally on daily tasks. The role of the corpus callosum as an interhemispheric integration structure is analyzed as well as some epistemological issues raised toy the Disconnection Syndrome.

The acute effects of two GABA B receptor antagonists (phaclofen and CGP-35348) were studied in two types of epileptogenic activity: that produced by intracortical injections of baclofen and that appearing after withdrawal of chronic intracerebral GABA infusion (the GABA-withdrawal syndrome, GWS). Intracortical baclofen induced two types of electrographic paroxysmal discharges: one consisting of single spike-and-wave (pattern 1) and another of poly spike-and-wave patterns (pattern II). Both patterns showed similar latencies and temporal evolution of spike frequency discharges. Phaclofen, applied directly into the baclofen-induced epileptogenic focus, suppressed pattern 11 but was ineffective in modifying both pattern I and the GWS. CGP-35348, administered systemically, inhibited both patterns I and II. Intracortical microinjection of baclofen or phaclofen in rats showing a GWS had no effect, nor the systemically given CGP 35348. These results indicate a differential participation of GABAB receptors in GABA-related epileptic syndromes of cortical origin.

Abstract There is a general belief in developmental neuropsychology that patients who have had brain damage in early life often escape the severe behavioral deficits that accompany similar types of injury at maturity. Many neuropsychologists believe that recuperation from the effects of cortical injury is more complete when damage occurs during infancy than during adulthood. Hans-Lucas Teuber, an eminent neuropsychologist, expressed this notion more directly when he wrote: “If I’m going to have brain damage, I’d best have it early rather than late in life.”1 There are a number of documented examples in the clinical literature of children who, because they had uncontrollable seizures, have had surgical removals of the entire left hemisphere of the brain before seven years of age. But many of these children have gone on to develop quite normal cognitive and language skills, and were rated average in school performance and activities of everyday life.

Abstract The art and science of neurology is based on the physician’s ability to name and diagnose the diseases of the nervous system. These specialists can now employ a highly sophisticated battery of both classic and new technologies that can be used to identify the problem (the CAT and PET scans, the EEG, among others, which were discussed in Chapter 2). Despite all this elegant and expensive machinery, the neurologist must still be able to recognize the sometimes very dramatic and sometimes quite subtle changes in sensory, motor, and behavioral functions that can be caused by disease or injury to the brain. Once a diagnosis has been reached, what then? With all the high-tech machinery available, there are still no “miraculous” cures or treatments for brain injuries or diseases. In fact, the options for effective medical treatment of brain injury and degenerative disorders, such as Parkinson’s or Alzheimer’s disease, are very limited. That may be one reason why neurologists are often guarded or downright pessimistic in their prognoses.

Abstract For many science writers and scientists, the human brain is the last uncharted frontier. Science fiction stories tell of futuristic devices that can read a person’s thoughts as they are taking place. In fact, in the movie Foxfire, Clint Eastwood steals a Russian fighter plane whose computer flight systems are controlled directly by the pilot’s thoughts. Are there such windows on the mind that can tell us how the brain’s activity enables us to speak, think, or drive a car? Some scientists believe that modem diagnostic machines can do just that.

Abstract If someone were to ask you what organ in the body controls blood circulation, you would immediately say, “The heart does that.” In the same way, most of us have pretty fixed ideas about what structure in the body controls behavior-the brain. Indeed, we certainly take it for granted that the brain is the “organ of the mind,” and we know, for example, that when people have brain damage, their behavior is often affected. So, there is apparently good reason to believe strongly that the brain is the seat of behavior. How we think about the brain and what it does will certainly have an impact on the kinds of medicine we would apply to the treatment of head injury and brain damage. Thus, to treat mental illness, we must have a working concept of what mental illness is and how it is caused. For example, it wouldn’t make much sense to give drugs to change the specific chemistry of nerve cells if we believed that hallucinations were really due to evil spirits invading the body. How we treat disease is very much influenced by what we believe about causality and what we take to be “good” scientific data. But what is good at one time may be considered laughable or even dangerous at another period in history. It wasn’t all that long ago that patients had holes drilled in their heads to relieve headache or to release evil spirits thought to have been causing their problems.