ANXIETY

1030 years, provided new and into the biology of anxiety.

seven

Neurotransmitters and CNS Disease

probably important insights

STUDIES IN MAN

ANXIETY CLAUS BRAESTRUP St Hans Mental Hospital, Roskilde, and Research Division, A/S Ferrosan,

Soeborg,

Denmark

MOGENS NIELSEN St Hans Mental Hospital, Roskilde

To write about neurotransmitters in relation to anxiety is no simple task. It is not even easy to reach a conclusion about the subject itself. Not even on a linguistic basis is there consensus. For example, Danish has no single word for "anxiety"-not that anxiety does not flourish in Denmark, but we have to use the phrase "angst, uro, og spaending" (fear, restlessness, and tension) when speaking of the indication for anxiolytic drugs. Nor is it clear whether anxiety is a disease. In some cases we speak of "normal" anxiety, the anxiety experienced in more or less threatening situations where behaviour and mental functions are not necessarily impaired, rather the opposite. In "pathological" anxiety there seem to be no precipitating factors and behaviour and mental function are often severely impaired. This lack of precision, however, should not blur the fact that an extraordinarily large number of people in the Western world and in the East (including the People’s Republic of China) demand medical relief for anxiety. Figures for benzodiazepine sales in Denmark in one sixmonth period suggest that 8% of the population daily use a benzodiazepine to cope with anxiety, insomnia, and so on.’I The remarkably widespread use of benzodiazepines does suggest some underlying biological abnormality; on the other hand, social or cultural factors should not be underrated, and it may be significant that the prevalence of benzodiazepine use is higher for women aged 30-40 than for any other group. "... Angest er hende (Qvinden) mere tilhorende end Manden"2 (anxiety resides with woman more than man). Real insight into the biology of anxiety must await a solution to the mind-brain problem. How is a biological process, presumably electrical activity in neurons, transcribed into conscious experiences and emotions, in this context fear, apprehension, inner tension, restlessness, excitability, and hostility? All we can say now is that anxiety occurs when, in the brain, there is a certain activity pattern in certain neurons that are firing in a certain spatial and temporal pattern, and that this structurally complex activity is anxiety. Such a concept, unspecific though it is, at least justifies examination of a role for neurotransmitters. As readers of this series of articles will know, there are basically three ways of looking for a role for neurotransmitters. One approach is to search for an abnormality in CNS neurotransmitters in patients with, in this case, anxiety. Any such abnormality could then form a basis for testable hypotheses. Secondly we can develop, from psychological theory, an animal model for anxiety and investigate neurotransmitter characteristics in the brain of such animals. Finally, we can use accepted anxiolytic agents as research tools, finding out their effects on brain neurotransmitters or looking for evidence that they have other characteristic biochemical or biological interactions with the brain (e.g., their own receptors). This last approach has, over the past

schizophrenia enhanced numbers of brain dopamine receptors in the basal ganglia have been reported; reduced CSF concentrations of 5-hydroxyindoleacetic acid and lower numbers of serotonin uptake sites in blood platelets (and brain?) have been noted in depressed patients; in Parkinson’s disease the concentration of dopamine in the basal ganglia is reduced; and the levels of the inhibitory neurotransmitter y-aminobutyric acid (GABA) and its enzyme marker glutamate decarboxylase are reduced in Huntington’s chorea. Similar, measurable malfunctions of neurotransmitters have not been reported in anxiety states. A major brain dysfunction has never been demonstrated-not surprisingly, since anxiety is part ofabiologically useful reaction to danger, preparing the organism for flight or fight or, in less severe cases, enhancing cardiac output and alertness. Normal anxiety is a prerequisite for a well-functioning individual, and no abnormality should be sought. Pathological anxiety may simply represent a marginal overreaction in otherwise normal neuronal circuits, and there may not be measurable from deviations normality. Nevertheless, several physiological findings reported in anxiety states are related to neurotransmitters3-raised pulse rate, increased forearm blood flow, augmented sweat gland activity, reduced salivation, and much increased muscle activity. Such changes reflect altered autonomic activity-mainly an increase in sympathetic discharge, particularly in the (3-adrenergic system-and are probably not related to the pathology of anxiety but reflect the secondary, physiological expression of the condition. Consequently 0-adrenergic blockers can relieve symptoms of anxiety but not the underlying driving force, except in rare cases where the symptoms, in a vicious circle, worsen the anxiety. In

ANXIOUS

ANIMALS?

Psychopharmacological studies in animals on the relevance of neurotransmitters in anxiety depend on the nature of the animal behaviour model that is used. Most popular are "conflict" tests. The tendency for patients with some neurotic disorders to take any action seems weak; it is as though the neurotic individual’s behaviour was excessively inhibited by anxiety. In the classical conflict tests hungry rats are trained to press a lever for food (Geller test 4-6) or thirsty rats learn to approach a water spout (modified Vogel test). Rats so trained are then punished (suppressed) with an electric shock every time they approach to eat or to drink. A conflict arises for the animal-should he accept an electric shock or remain hungry or thirsty? In such experiments, behaviour can be completely suppressed, so that the rat stops eating and drinking altogether. Benzodiazepines restore eating and drinking in such punishment inhibited animals, and it is generally believed-maybe too uncritically-that such animal models do reflect anxiety in man. All anxiolytic benzodiazepines are also potent anticonvulsants. So too are barbiturates and, to some extent, meprobamate. The pharmaceutical industry acknowledges this coincidence by applying the antipentylenetetrazol convulsion test in mice when screening new drugs for anxiolytic properties, but the underlying mechanism for the coincidence of anticonvulsant and anxiolytic properties has not been fully explored. In the "kindling" model of epilepsyconvulsions are eventually induced in animals by daily, weak subconvulsive electrical or chemical stimulation over, say, 14 days. On the 14th day a previously ineffective stimulus will induce a full-blown convulsive seizure; kindling has occurred. Neuronal pathways in the kindled brain apparently become sensitised, and the sensitisation persists for a long time. Can anxiety be regarded in a

1031 similar way as a mentally sensitised brain? Benzodiazepine receptors are increased in kindled rats. Conflict tests have been thoroughly investigated with the aim of defining a role for neurotransmitters in "anxious animals". Specific neurotransmitter agonists and antagonists have been applied systemically. Conflict behaviour was neither reduced nor enhanced by agents acting on dopamine, noradrenaline (a and (3), acetylcholine, or glycine neurotransmission. These neurotransmitters do not seem to be crucial in situations of conflict. On the other hand, studies with fearful monkeys and the partial clinical relief of anxiety achieved by the a-receptor agonist clonidine support the idea that the noradrenergic system in the brain is involved to some degree in anxiety.9 Furthermore, neuroleptic agents can relieve anxiety, especially in psychotic patients. Since neuroleptics characteristically reduce dopaminergic neurotransmission, dopamine may play a role, a secondary one probably, in anxiety.

Serotonin and Conflict Behaviour Behaviour inhibited by punishment can be restored by agents that reduce serotonin neurotransmission. For example, the serotonin receptor antagonists cyproheptadine and methysergide and the serotonin synthesis inhibitor p-chlorophenylalanine restore lever pressing in- rats in the Geller test. Serotonin antagonism thus equates with the effect of benzodiazepines. Several other animal studies support the involvement of serotonin in conflict behaviours, and an involvement of serotonin in the state of anxiety has been inferred. It is frustrating, however, that these hypotheses have not been substantiated by clinical experience. We know of no evidence relating reduced serotoninergic function to anxiolytic activity in man nor of any case where enhanced serotoninergic function (which may happen after administration of serotonin uptake inhibitors) has led to

anxiety. GABA and

Conflict Behaviour Another enigma for animal tests of anxiety is the failure of GABA agonists and antagonists to elicit clear effects on conflict behaviours. Effects of GABA were expected, because GABA seems crucially involved in the mechanism of action of benzodiazepines (see below). The failure may be more apparent than real, however. Some 30% of all synapses in the CNS use GABA for neurotransmission; many of these synapses must have other functions than relief of anxiety, so perhaps we should rather expect massive stimulation of all these synapses by, for example, the GABA agonists muscimol

Benzodiazepines are effective and fairly selective in treating anxiety and they are very potent drugs (triazolam, for example, is active in man at doses as low as 0 - 003 mg/kg body weight). Other types of anxiolytic, such as barbiturates and meprobamate, are active at much higher doses, and it may be difficult to detect relevant biological interaction in the noise choice.

of irrelevant effects that any agent will have when doses

are

pushed too high. BENZODIAZEPINE RECEPTORS

A major advance in the understanding of the mechanism of action ofbenzodiazepines and in the understanding of anxiety was the discovery, in 1977, of benzodiazepine (BZ) receptors." Radioactively labelled diazepam binds to a protein in the neuronal plasma membrane and this membrane protein was shown to be embedded in the outer lipid membrane of the cell. Studies with the selective neurotoxic agent kainic acid and on the mutant "nervous" mouse (nrlnr) (in which the Purkinje cells in the cerebellum completely degenerate) located the binding protein to neurons in the central nervous system. BZ receptors are not found

peripherally. Before any biological entity such as a binding protein can be established as a receptor it is essential to demonstrate a relation between the putative receptor and a characteristic function of the neurotransmitter, hormone, or drug with which the receptor is presumed to interact. This is easy in some peripheral systems where, for example, the presence of a cholinergic agonist at cholinergic receptors in muscles characteristically contracts the muscle. A functional receptor interaction is less easily demonstrated for benzodiazepines because no measurable direct consequence of their action is known. An indirect approach was adopted. Different benzodiazepines offer a wide range of pharmacological potencies, and it was demonstrated that these potencies correlate well with the strength (Kj values or ED 50 values) with which the benzodiazepine binds to the binding protein in vitrolO,11 or in vivo (fig. 1). Such a correlation suggests that binding has functional relevance and indicates that the binding protein is a receptor for benzodiazepines. The I

4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridin-3-ol (THIP) to disrupt some other neuronal circuit essential to behavioural expression. However, THIP and muscimol can be applied or

directly to discrete areas of the brain, and such experiments have demonstrated that GABAergic stimulation (in the amygdaloid complex, for example) relieves suppression in conflict behaviours. GABA may well be related to anxiety states in man. PHARMACOLOGICAL STRATEGY

Mental illness is remarkably resistant to investigation by conventional biological methods; drugs are still our major research tools. Our biological understanding of the schizophrenias is based on the psychotic actions of amphetamine as antagonised by neuroleptics, and our understanding of depression is based on the depressant action of reserpine as counteracted by thymoleptics. Many of these thymoleptics inhibit uptake processes for the biogenic amines dopamine, noradrenaline, and serotonin. For a pharmacological approach to studies on anxiety, the benzodiazepine group of minor tranquillisers is the obvious

Fig. I-Correlation between pharmacological effect and benzodiazepine receptor occupancy in vivo for various benzodiazepines, zopiclone, and CL 218.872."J At ED,,, the agent inhibits the development ofclonic convulsions in 50% of mice treated subcutaneously with 150 mg/kg ofpentylenetetrazol (ordinate) or inhibits by 50% specific binding of’H-flunitrazepam (i.v.) in the brain of the living mouse. At ED.,, an agent occupies 50% of the available benzodiazepine (abscissa). CDZ=chlordiazepoxide, ZOP=zopiclone, OXAZ=oxazepam, MID= midazolam, DIAZ=diazepam, LOR=Iorazepam, FNM=flunitrazepam, CLON=clonazepam, TRZ=triazolam. (For CL 218.872 see fig. 2 legend.) receptors

=

1032

demonstration that BZ receptors and GABA receptors are coupled at the molecular level (see below) further substantiates the relevance of BZ receptors. The strength with which a benzodiazepine binds to the receptors does not relate in practical terms to the duration of action. Irrespective of potency, the benzodiazepines shown in fig. 1 occupy about 25% of BZ receptors at the dose at which they antagonise pentylenetetrazol. We still know hardly anything about the percentage of BZ receptors occupied in the human brain during treatment of anxiety. The BZ receptor proteins are heterogeneous. There are two classes of receptor, BZ1 and BZ2, which are either distinct proteins or two conformational states of one receptor. 12 Do these two receptors serve distinct functions? If so, selective agents could be developed and yield new and specific drugs. Preliminary evidence suggests that BZ2 receptors may be related to anxiety. 13 Receptor occupancy at BZ2 receptors rather than at BZ receptors seems to determine anti-conflict effects in rats 13 and a regional study of the distribution of BZ2 (as a percentage of total BZ receptor population) in the monkey brain revealed that BZ2 receptors mainly reside in limbic brain regions such as the amygdaloid complex, the hippocampal formation, and parts of the prefrontal cortex. These phylogenetically old brain areas have for years been related to anxiety, most recently in a comprehensive theory by Gray 14 suggesting that the subjective effects of anxiety follow from the septohippocampal pathway taking over a dominant role in physiological functions. Other parts of the limbic system seem to be involved also. BZ receptors, as measured by the total number of receptors, are not particularly abundant in the limbic system.i5 There are many receptors in cortical regions, including the cerebral cortex-a finding which stimulated hypotheses relating anticonvulsant effects of benzodiazepines to cortical inhibition. All brain structures investigated have some BZ receptors in varying numbers, the lowest being in white-matter areas such as the corpus callosum. Even the retina contains BZ receptors, though their significance is not known.

BENZODIAZEPINE RECEPTOR AND GABA

In 1967, Schmidt and co-workersl6 reported that diazepam potentiated neuronal inhibition in the cat spinal cord at the level of the first synapse into the cord. Subsequent studies indicated that GABA was the neurotransmitter mediating this so-called presynaptic inhibition-i.e., GABA acts on the presynaptic nerve terminal to inhibit release of an excitatory neurotransmitter. Electrophysiological experiments have shown that benzodiazepines enhance not only presynaptic but also postsynaptic GABAergic inhibition at various sites throughout the central nervous system 17 (see also ref. 18). This action does not involve changes in the synthesis, release, or inactivation of GABA; nor is there a direct effect of benzodiazepines as GABA agonists on the recognition site of the receptor. In 1978, Tallman and colleagues 19 observed that stimulation of GABA receptors by GABA enhanced the affinity of BZ receptors for benzodiazepines. This raised the possibility that the two receptors were close together in neuronal membranes. The BZ receptor (or at least most BZ receptors) seems to be coupled to both the GABA receptor and the chloride channel in a GABA/BZ-receptor/chloridechannel complex.19-21 Various models of this assembly of proteins have been constructed; they all express much the The GABA receptor

entity of the complex (fig. 2)

carries the

Fig. 2-Diagram of GABA receptor, benzodiazepine receptor, and chloride channel as a complex, floating in the lipid double layer 3 plasma membrane." Shown are several drugs and agents which presumably interact with the I

complex. See text for further details. CL 218.872 is a triazolopyridazine, with the structure 3-methyl-6- [4,3-b ]pyridazine; Ro 15-1788 is an imidazobenzodiazepine, ethyl-8-fluoro-5, 6-dihydro-5-methyl-6oxo-4H-imidazo [1,5-a] [1,4] benzodiazepine-3-carboxylate; CGS 8216 is a pyrazoloquinoline, 2-phenylpyrazolo(4,3-c and &bgr;CCM (methyl 0-carboline-3-carboxylate), DMCM (methyl 6,7-dimethoxy-4ethyl-P-carboline-3-carboxylate), and FG 7142 (Nêmethyl 0-carboline-3-

carboxamide) are 0-carbolines. benzodiazepin-2-one.

Ro 53663 is

1,3-dihydro-5-methyl-2H-1,4-

recognition site for GABA, which recognises the positive and negative charge within a certain distance in the GABA molecule. When GABA occupies GABA receptors-for example, after release from a nerve terminal-there is a conformational shift in the GABA receptor which in turn increases the probability that chloride channels will open (the channel can be visualised as a hole in the membrane which is either open or closed). The cell membrane is normally impermeable to chloride ions. When chloride channels are open, chloride ions float freely downstream, normally from the outside into the cell. The cell attains a more negative electric potential inside and is more difficult to excite: inhibition has occurred. Remarkably little happens to chloride channels or to GABA receptors when benzodiazepines occupy BZ receptors-i.e., benzodiazepines by themselves do not open chloride channels or inhibit neurons. However, when GABA is added to a neuron on top of a benzodiazepine it produces a greater chloride flux through the neuronal membrane than before the benzodiazepine was added. On the basis of electrical fluctuation analyses, Study and Barker22 have proposed that this is accomplished, not by the chloride channel staying open for longer than normal (about 25 ms) nor by an enhanced conductance of each channel (conductance relates to the number of ions passing per second), but by an increase in the frequency of channel opening. Thus GABA has greater success in opening chloride channels when diazepam is present on the BZ receptor. Tolerance to benzodiazepines may occur if the GABA/BZ receptors decouple. Barbiturates exert some of their effects through the complex in a different way. Barbiturates inhibit binding of 3H-dihydropicrotoxinin to brain membranes, to sites which probably relate to the chloride channel. 20 This suggests that barbiturates may interact directly with the chloride channel. Barbiturates, notably the hypnotic type, increase the time that each chloride channel is open (from 25 ms to 90 ms) and enhance GABA mediated inhibition in this way.22 Some of the toxic effects of barbiturates might be explained by a direct effect on chloride channels. Benzodiazepines are much less toxic-even when they fully occupy the BZ receptor, all they do is change the tuning of the GABA chloride channel system. The GABA receptor chloride channel coupling is still intact and functional. There exist a great variety of agents with effects on the GABA/BZ receptor complex (fig. 2). The receptor

1033

antagonists Ro 15-1788 and CGS 8216 and the convulsive ligands such as DMCM and(3-CCM will be discussed below. CL 218.872 and zopiclone act on the BZ receptor, and their pharmacological and clinical profile is very similar to that of the benzodiazepines. Agents acting on the GABA receptor produce either convulsions (antagonists) or anticonvulsant effects (agonists). Some sedative agents, barbiturates, and some phosphodiesterase inhibitors (etazolate, tracazolate) enhance chloride channel function while convulsant agents such as picrotoxinin and Ro 5-3663 reduce chloride channel function. A target within the complex for phenytoin, ethanol, and valproate has been proposed but not identified. ENDOGENOUS LIGANDS

One of the most intriguing questions about BZ receptors concerns the nature of the presumed endogenous ligand. An endogenous ligand would be a substance present in the brain which interacts with BZ receptors. Such a ligand might serve a neurotransmitter or a neuromodulator role; we do not yet know which. Endorphins, endogenous morphinelike agents, were discovered subsequent to the identification of opiate receptors. It is not generally agreed whether endogenous ligands must exist for well-defined receptors. We think not. There is no theoretical reason why BZ receptors should not remain classified as drug receptors (as opposed to neurotransmitter and hormone receptors) for which no endogenous ligand exists. The pharmacological effects of benzodiazepine appear to involve a modulatory action on GABAergic neurotransmission, and if this modulation has physiological function, which is likely, this function can be accomplished by other means than by the existence ofaligand for the benzodiazepine recognition site. In the search for endogenous BZ receptor ligands, several agents have been extracted from biological sources and characterised by virtue of their interaction with the receptor. The most potent agent is -carboline-3-carboxylic acid ethyl ester (3-CCE) which was obtained in small amounts from human urine.23 f3-CCE as such, however, is not found in the brains of animals and it has not been possible to identify, in the brain, other derivatives of this 13-carboline which act on benzodiazepine receptors. Hypoxanthine, inosine, and nicotinamide24°25 on the other hand are definitely present in the brain but they have only very weak affinity for the receptors. They are some 100 000 times less active than (3-CCE and are apparently too weak for serious consideration as endogenous ligands for BZ receptors. Two other candidate endogenous ligands, nepenthin26 and diazepam binding inhibitor, 27 have lately been proposed but their relevance remains to be clarified. NEW TYPES OF BENZODIAZEPINE RECEPTOR LIGAND

time it

thought that only pharmacologically a few benzodiazepine-like agents benzodiazepines interacted with high affinity with BZ receptors. However, the potent BZ receptor ligand J3-CCE lacks the characteristic For active

some

was

and

of effects the anticonflict Similar findings were reported for Ro 15-178830 and CGS 8216.31 On the other hand, these agents could reverse or prevent benzodiazepines from eliciting their usual sedative, anticonvulsant, and anticonflict effects in animals and, to a certain extent, in man.32,33 They represent BZ receptor antagonists. The clinical value of the BZ receptor antagonist is not yet clear. The antagonists might be useful in patients sedated by benzodiazepine overdoses, after minor surgery where

anticonvulsant

and

benzodiazepines.28,29

used for amnestic analgesia, to effect of antischistosomal or to detect benzodiazepine tolerance (and benzodiazepines, abstinence misuse) by precipitating symptoms. The receptor will be useful as antidotes for not probably antagonists massive benzodiazepine overdoses: the competitive nature of the interaction would demand a very high dose of antagonist, with toxicity from non-BZ-receptor related effects. We prefer to call &bgr;-CCE, Ro 15-1788, and CGS 8216 BZ receptor antagonists rather than benzodiazepine antagonists because these agents also antagonise a third group of newly discovered BZ receptor ligands, the convulsive ligands. Two &bgr;-carbolines, DMCM and &bgr;-CCM, produce convulsions in mice and rats by a direct effect on BZ receptors. It was a great surprise to realise that one single type of receptor, the BZ receptor, was the target for two classes of agent, convulsive ligands and benzodiazepines, with exactly opposite effects. (This will be discussed, in the context of epilepsy, by Dr L. Spero.) The BZ receptor antagonists inhibit effects of both classes of ligand simply by occupying the receptor and obstructing access by other ligands. These highly specialised ways of interacting with the BZ receptor are probably not related to the concept ofBZ/BZ2 receptor heterogeneity but rather to the nature of the coupling of benzodiazepine and GABA receptors. The current hypothesis is that benzodiazepine-like agents will enhance GABAneurotransmission while "convulsive" ligands, having negative efficacy, will reduce GABA

benzodiazepines counteract

the

were

sedative

neurotransmission.34 ANXIOGENIC BENZODIAZEPINE RECEPTOR INTERACTION

BZ receptor ligands with negative efficacy were described as "convulsive" because convulsions was the obvious and direct pharmacological characteristic. Will these agents also cause anxiety in man? For ethical reasons experiments of this kind are unacceptable, but experiments with the agent FG 7142 have thrown some light on the question. FG 7142 is a BZ receptor ligand of the j3-carboline type which was selected for human investigation because it was a receptor antagonist with very weak stimulant properties in rats. We expected beneficial effects on vigilance. FG 7142 does not produce convulsions in animals. When FG 7142 was given orally to four healthy volunteers35 in doses which probably lead to occupation of BZ receptors in the CNS, severe recurrent attacks of anxiety were reported, beginning as the plasma concentration of FG 7142 rose and lasting only about 5 min. The German speaking volunteers used phrases such as "Vernichtungsgefiihl", "starke innere Spanning", "Unrühe" which can be translated as "severe anxiety". The symptoms were accompanied by a compulsive urge to move, increased systolic blood pressure and pulse rate, and increased plasma growth hormone and cortisol levels. No preconvulsive signs were seen on EEGs. One highly drug experienced volunteer felt unable to proceed with the experiment and demanded a benzodiazepine antidote. Within 2 min of intravenous administration of 1 mg of lormetazepam he felt completely relieved and relaxed. Anxiety in relation to BZ receptors has not been described for agents other than FG 7142. It is well known, however, that drugs may produce anxiety, in convulsive therapy of psychiatric patients, pentylenetetrazol produces severe anxiety just before the induction of convulsions (see also ref. 36). Lysergide (LSD) and amphetamine produce anxiety in some individuals, but this anxiety is probably secondary to hallucinations and delusions. CONCLUSION

Anxiety probably involves many brain neurotransmittersnotably, GABA, serotonin, noradrenaline, and dopamine. Pathological defects have not been identified. The benzodiazepine group of anxiolytics exert their effects via a

1034

GABA/BZ-receptor/chloride-channel complex; this complex can also mediate anxiety. Endogenous ligands for BZ

18. Costa 19.

not been identified. We thank Dr 1. Munkvad and Dr 0. Rafaelsen for stimulating discussions.

20.

No reprints of individual articles in this series are available.

21.

receptors have

E, Guidotti A, Mao CC, Suria A. New concepts on the mechanism of action of

benzodiazepines. Life Sci 1975; 17: 167-86. Tallman JF, Paul SM, Skolnick P, Gallager DW. Receptors for the age of anxiety: Pharmacology of the benzodiazepines. Science 1980; 207: 274-81. Olsen RW. Drug interactions at the GABA receptor-ionophore complex, Annu Rev Pharmacol 1982; 22: 245-77.

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Rehabilitation RESEARCH ASPECTS OF REHABILITATION AFTER ACUTE BRAIN DAMAGE IN ADULTS* In 1979, the Royal Commission on the N.H.S. included a forceful appendix castigating doctors for being too concerned with acute episodes of illness and not concerned enough with the management of prolonged and permanent disability.’I Concern was expressed that little had changed since reports from the Health Departments of England and Wales2 and Scotland. Rehabilitation is a labour-intensive activity, however, and before recommending an increase in the scale and pattern of provision, it is important to determine the most effective rehabilitation for improving outcome in various types of patient. Adults recovering from an episode of acute brain damage make up a sizeable proportion of patients requiring rehabilitation. Funded by a special project grant from the Medical Research Council, the group was established in 1977 to review current research, identify areas. of relative neglect, and make recommendations. *Report of a coordinating group. Its members were: C. Aitken, Edinburgh (rehabilitation); A. Baddeley, Cambridge (psychologist); M. R. Bond, Glasgow (psychiatrist); J. C. Brocklehurst, Manchester (geriatrician); D. N. Brooks, Secretary, Glasgow (psychologist); R. L. Hewer, Bristol (neurologist); B. Jennett, Chairman, Glasgow (neurosurgeon); P. London, Birmingham (accident surgeon); T. Meade, London (epidemiologist); F. Newcombe, Oxford (psychologist); D. A. Shaw, Newcastle upon Tyne (neurologist); M. Smith, Department of Health and Social Security observer; and D. R. James, Medical Research Council observer.

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Braestrup C, Nielsen M, Olsen CE. Urinary and brain &bgr;-carboline-3-carboxylates as potent inhibitors of brain benzodiazepine receptors. Proc Natl Acad Sci (USA) 1980;

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It

decided to concentrate on patients with persisting disability after stroke or head injury (the commonest causes of acute brain damage in adults) taking into account the striking differences between both groups of patients. These include the age groups affected and the pathological lesion, which is focal in stroke and widespread in head injury. Consequently, the main sequel of stroke is the focal physical deficit, while, after head injury, the most consistent feature is behavioural, personality, and cognitive disability. Many of the older stroke victims also have degenerative conditions which affect both the brain and other systems; the capacity of the brain to adapt is thereby reduced, and there is also the threat of further episodes of organ failure, limiting the prognosis for life. Survivors after head injury, on the other hand, may face 30-40 years of disabled life, although younger brains have a considerable potential for learning new skills. Given advice, young brain-damaged patients may succeed in reorganising their lives effectively. In spite of these differences, however, we considered it useful to assess together the problems posed for rehabilitation by both groups of patients. The group visited several centres in England and Scotland where there was particular interest in rehabilitation after either stroke or head injury. was

Head Injury: 1. Departments of Neurosurgery and Psychological Medicine, University of Glasgow. 2. Wolfson Rehabilitation Unit, Atkinson Morley’s Hospital, London. 3. Joint Services Rehabilitation Unit, R.A.F. Chessington. 4. Kemsley Unit, St. Andrew’s Hospital, Northampton. Stroke: 1. Avon Stroke Unit, Frenchay Hospital, Bristol. 2. Departments of Community Medicine and of Rheumatology and Rehabilitation, Northwick Park Hospital, Middlesex.