[Epigenetics of early interactions, depression and schizophrenia]. / Epigénetique des interactions précoces, de la dépression et de la schizophrénie.

Epigenetics is the study of the variations of genetic expression that occur not because of differences in DNA structure, but because of chromatin alternations that modulate DNA transcription. The mechanisms of epigenetics are thus the link between genome and phenotype. This article will explore the best known epigenetic mechanisms, namely DNA methylation and histone modifications and how they may lead to the emergence of depression and schizophrenia. The practical interest of this research is an understanding of the role of early interactions in the development of mental illness. Hopefully this understanding will lead to therapeutic pathways aimed at neutralizing these unfavourable epigenetic influences, with the ultimate goal of prevention of mental illness.

[Medicamental treatment of schizophrenia]. / Traitement médicamenteux de la schizophrénie.

Antipsychotics play a key role in biologic therapy of schizophrenia. Following the first-generation neuroleptics, associated with many extrapyramidal side effects (severe dystonias, parkinsonian syndrome, akatisia and late dyskinesia) altering patients' compliance to the treatment, one can now find a new generation of molecules considered as atypical antipsychotics because they rarely cause neurological complications. This propriety provides a better compliance, along with a clear decrease of late dyskinesia risk but the effectiveness compared to ordinary molecules is still questioned. However, some of them can cause an increased risk of metabolic syndrome. Some molecules such as benzodiazepines and some antidepressants can also be prescribed to cure schizophrenic patients.

[An unusual hospitalization under constraint]. / Une mise en observation peu ordinaire.

The case report describes a 45-year old man presenting of the behavioral problems and an aphasia of Wernicke, hospitalized under constraint. The urinary screening in the search of psychotropic substances is positive for the cannabis and the amphetamines. The neurological localization is confirmed by cerebral CT-scan. The discussion relates on the differential diagnosis between a schizophasia and an aphasia of Wernicke, on the difficulty of a somatic diagnosis among patients agitated under the effect of a drug and to the tendency to hospitalize those too quickly under constraint, on the noxious effect of drugs on the brain.

[Psychoanalysis and neuroscience: the end of a schism ?]. / Psychanalyse et neuroscience: la fin d'un schisme ?

For some neurobiologists, present biological descriptions of the brain may integrate the theoretical frame initiated by Freud. The recent acquisitions of neurobiology prove a plasticity of the neural network anabling the inscription of the experiment. The neuroplasticity constitutes the cornerstone of the reconciliation between the psychoanalysis and neurosciences. The brain must not be considered as a rigid organ, determined and determining but well as a dynamic structure, in constant rebuilding. Contrary to the genetic determinism, the plasticity involves diversity and singularity. The variations of the feasible offered by the plasticity are seducing but to what extent towards the constraint of genetics and the epigenetic ? Both concepts, plasticity and epigenesis are well distinct. An epigenetic phenomenon associated to a maternal behaviour seems to have been proved recently in the rat. Attachment and depression require reflection in the sight of epigenesis and plasticity. The Freud concepts are not always applied to biological patterns without any clumsiness. Demonstrating psychoanalysis from neurosciences or the contrary does not seem very realistic. On the other hand there should a good reason to give rise to exchange, to make a clear distinction between psychoanalytical unconsciousness and neurological unconsciousness, and put an end to the groundless opposition between mental and cerebral.

[Biological models of schizophrenia: an update]. / Les modèles biologiques de la schizophrénie: mise à jour.

This paper is a review of the principal, currently proposed, biological models of schizophrenia. The convergence of recent neurobiological studies indicates that schizophrenia may be a neurodevelopmental and progressive disorder with multiple biochemical abnormalities involving dopamine, serotonin, glutamate and gamma-aminobutyric acidergic systems. In post-mortem tissue, structural abnormalities and alterations in synaptic connectivity have been observed in the intracortical circuitry of the prefrontal dorsal cortex. These morphological modifications could be sequelae of earlier environmental insults and genetic processes. There are probably multiple susceptibility genes, each of small effect, which act in conjunction with environmental factors: obstetric abnormalities, intra-uterine infection and abnormal nutrition. Candidate identified genes could influence neurodevelopment, synaptic plasticity and neurotransmission. If schizophrenia is clearly related to an abnormality of early brain development, the clinical expression of the illness itself is delayed typically for about two decades after birth. A similar delayed onset is also observed in the secondary psychosis associated with metachromatic leukodystrophy, a genetic disease affecting myelin. Schizophrenia is a term reserved for idiopathic cases of chronic psychosis. Strictly speaking, schizophrenia is a syndrome. There are no established laboratory tests, neuro-imaging studies, electrophysiological paradigms or neuropsychological testing batteries that can explicitly confirm this behavioural disorder to the exclusion of symptomatology: what physicians diagnose as schizophrenia today may prove to be a cluster of different illnesses, with similar and overlapping symptoms. The diagnosis criteria of the various DSM reflect the American psychiatrists' concern for establishing a consensus classification preserving a wider definition of schizophrenia or more precisely of the schizophrenic disorder. One can presume that research work established from too numerous and insufficiently specific variables doesn't permit the definition of one or several aetiologies. We hope that one day all schizophrenia will be correlated to one precise causal factor permitting the optimal targeting of interesting therapeutic approaches. The multiplicity of concepts and models reflects our questioning.

General anesthesia after neuroleptic malignant syndrome.

The neuroleptic malignant syndrome (NMS) is an uncommon and potentially lethal complication of therapy with neuroleptics characterized by pallor, hyperthermia, and extrapyramidal signs (Delay and Deniker, 1968). Malignant hyperthermia (MH) is a rare but often fatal complication of general anesthesia characterized by hyperpyrexia and muscle rigidity, but not related to neuroleptic therapy. For both syndromes, NMS and MH, a common pathophysiology has been considered (Meltzer, 1973; Itoh, 1977; Caroff, 1980). These two syndromes may also be clinically indistinguishable from "acute lethal catatonia" characterized by fever, muscular hypertonicity, and stupor, first described by Stauder in 1934. We now report a case in whom NMS appeared following neuroleptic treatment for a psychotic depressive syndrome. After remission from the NMS, the patient underwent general anesthesia nine times for electroconvulsive therapy (ECT) without ill effect. This case supports the theory of distinct pathogenic mechanisms for both NMS and MH.

Brain hypometabolism of glucose in anorexia nervosa: normalization after weight gain.

Using positron emission tomography and (18-F)-fluorodeoxyglucose, we studied cerebral glucose metabolism in 10 anorectic girls within their underweight state and after weight gain. Ten age- and sex-matched healthy volunteers were used as controls. Both groups were scanned during rest, eyes closed and with low ambient noise. In absolute values, the underweight anorectic patients, when compared to control subjects, showed a global (p = 0.002) and regional (p < or = 0.001) hypometabolism of glucose which normalized with weight gain. In relative values, no global difference could be assessed between underweight anorectic patients and controls but a trend can, nevertheless, be observed toward parietal and superior frontal cortex hypometabolism associated with a relative hypermetabolism in the caudate nuclei and in the inferior frontal cortex. After weight gain, all regions normalized for absolute and relative values, although a trend appears toward relative parietal hypometabolism and inferior frontal cortex hypermetabolism in weight gain anorectic patients. Absolute brain glucose hypometabolism might result from neuroendocrinological or morphological aspects of anorexia nervosa or might be the expression of altered neurotransmission following deficient nutritional state. As some differences exists in relative values in underweight patients and tend to persist in weight gain states, this could support a potential abnormal cerebral functioning, a different reaction to starvation within several regions of the brain or different restoration rates according to the region.

Brain hypometabolism of glucose in anorexia nervosa: a PET scan study.

Cerebral glucose metabolism was studied in 20 underweight anorectic girls and in 10 age- and sex-matched healthy volunteers using positron emission tomography with (18-F)-fluorodeoxy-glucose. Both groups were scanned during rest, with eye closed and with low ambient noise. Compared to controls, the underweight anorectic group showed a global hypometabolism (p = .002) and an absolute (p < .001) as well as relative (p < .01) hypometabolism of glucose in cortical regions, with the most significant differences found in the frontal and the parietal cortices. Within the underweight anorectic and the control groups, no correlations were found between absolute or relative rCMRGlu and BMI, anxiety scores, or Hamilton scores of depression. Different factors might explain this reduction of glucose metabolism in anorexia nervosa. It might be the consequence of neurophysiological or morphological aspects of anorexia nervosa and/or the result of some associated symptoms such as anxiety or depressed feelings. Supported by cognitive studies, we can also hypothesize a primary corticocerebral dysfunctioning in anorexia nervosa.

Frontal and parietal metabolic disturbances in unipolar depression.

The authors investigated brain glucose utilization using positron emission tomography (PET) in 12 normal volunteers and 12 unipolar unmedicated depressed patients (six endogenous; six nonendogenous) following injection of [18F]fluoro-deoxyglucose (FDG). Compared by analyses of variance, absolute and relative regional glucose metabolic rates appeared different in depressed patients and control subjects, especially in parietal and frontal lobes. In patients with unipolar depression, metabolic rates were increased in the orbital part of the frontal lobe and decreased in a frontal dorsolateral area. The metabolic supero-basal gradient calculated in the frontal cortex was significantly lower in depressed patients than in normal subjects. Decreased glucose metabolism was also observed in the parietal cortex of depressed patients. No differences in glucose metabolic rates have been detected between endogenous and nonendogenous patients. No correlation has been found between the metabolic data and the Hamilton Rating Scale.

Substance P, enkephalins, somatostatin, cholecystokinin, oxytocin, and vasopressin in human spinal cord.

Several neuropeptides were immunohistologically studied in normal human spinal cords. Substance P, methionine-enkephalin, leucine-enkephalin, and cholecystokinin positive fibers were found in all cytoarchitectonic layers, with a specific distribution pattern for each peptide. Somatostatin, oxytocin, and vasopressin immunoreactivities were restricted to particular spinal layers. Perikarya and proximal dendrites were visualized and classified by comparison with previous Golgi analyses. Substance P was contained in "radiate cells" of layer III, methionine-enkephalin in marginal neurons as well as in layer II "stellate cells," and somatostatin in layer II "islet cells." Several results differed from those reported in other species. Chemical neuroanatomy may provide new insights into the neuronal organization of the human spinal cord.

Substance P neurons in the human hippocampus: an immunohistochemical analysis in the infant and adult.

An analysis of the distribution of substance P immunoreactive nerve cell bodies and fibres is given for infant and adult human hippocampus by using the peroxidase-antiperoxidase technique of Sternberger. The description covers the substance P distribution in the area dentata, the Ammon's horn, the subicular complex and the entorhinal cortex. Each region shows a specific pattern in its substance P immunoreactivity. In general, the hippocampal neurons occur in three major classes of interneurons: large (20-35 microns) horizontal bipolar or multipolar neurons in the alveus, in the deep part of the subicular complex, the entorhinal cortex, and in the white matter of the angular bundle; small (10-20 microns) and large (20-35 microns) vertically oriented bipolar or multipolar neurons in the stratum oriens, in the stratum pyramidale of the Ammon's horn, and in the deep part of the subicular complex and the entorhinal cortex; large (20-35 microns) multipolar neurons in the hilus. Substance P immunoreactive fibres are particularly abundant around pyramidal cells of the CA2 and CA3 subfields of the Ammon's horn and around granule cells of the area dentata. They are also detected in the fimbria and angular bundle. Comparative study of the infant and adult hippocampus reveals no variation in the area dentata and Ammon's horn except that substance P immunoreactive fibres are more abundant in the molecular layer of the area dentata in adults. In contrast, a far more extensive number of substance P immunoreactive cell bodies are detected in the deep layers of the subicular complex and the entorhinal cortex, as well as in the white matter of the angular bundle in infants aged between three and 12 months old. This rich substance P immunoreactive network raises questions concerning its function within the human hippocampus.

Club endings containing substance P-like immunoreactivity in human retinal vessels: Whole mount preparation.

Substance P-like immunoreactivity was studied by fluorescence immunohistochemistry in human retinal vessels of the whole mount preparation. Substance P immunoreactive nerve fibers were seen to run along the arteries and some veins. Club terminals are in contact with the vessel wall. Substance P may act as a vasoregulator in the human retina.

Changes in neurohypophysial cholecystokinin content during oestrous cycle in the rat.

Cholecystokinin content in the neurointermediate lobe of the rat pituitary was measured by radioimmunoassay during the different stages of the oestrous cycle. Higher levels were observed in pro-oestrus and oestrus than in metoestrus and dioestrus rats. This difference is similar to the variation observed in the same circumstance concerning oxytocin in the neurohypophysis and neurosecretory activity in magnocellular neurons. These results are discussed in relation to the coexistence of oxytocin and cholecystokinin in neurons of the hypothalamoneurohypophysial system.

Proenkephalin A associated peptides in the autonomic nervous system of the human infant gastrointestinal tract.

The digestive tract of neonates and infants were examined by immunohistochemistry using specific antisera raised against proenkephalin A related peptides. Proenkephalin A, methionine-enkephalin and leucine-enkephalin are observed in nerve fibres in the smooth muscles in the myenteric and submucosal plexuses or in neuronal cell bodies of the myenteric plexus. In these structures synenkephalin has general distribution as methionine-enkephalin but not the same as leucine-enkephalin. Co-localization of synenkephalin and methionine-enkephalin is found in several neurones. These results suggest that proenkephalin A is the precursor-protein in some enkephalinergic neurones of the human gut. A gradient in the density of immunoreactivity is observed and is maximal in the distal small bowel. This gradient contrasts with observations made in rodents where major enkephalin immunoreactivity is observed in the proximal digestive tract. These findings give evidence that proenkephalin A-derived peptides could have effects in the motility of the human gut.

Neurotensin containing neurones in the human hippocampus of the adult and during development.

Marked age-related changes are noted in the neurotensin distribution of the human hippocampus. Different neuronal structures containing neurotensin are detected by immunohistochemistry during postnatal brain growth from birth to 4 years but no later. They are the neurotensin-immunoreactive pyramidal cells of the subiculum and presubiculum. Their axonal fibres are seen in the alveus and the fimbria. There are also the neurotensin-immunoreactive granular cells of the hilus. The varicosities of the mossy fibres are detected among the pyramidal cells of the CA3 and CA2 subfields of the Ammon's horn. After 4 years of age, only the varicosities are shown by immunohistochemistry, thus there is probably an important decrease in the neurotensin concentration in the cell bodies of the granular cells and also in the pyramidal neurons of the subiculum and presubiculum.

High concentration of somatostatin-14 neurones in the infant human hippocampus.

The distribution of somatostatin-14 immunoreactivity (SRIF-14-IR) was studied in the hippocampal formation of the human infant. The most prominent accumulation of SRIF-14-IR cell bodies and processes occurred in the CA1 subfield of the stratum oriens in the Ammon's horn, in the hilus of the area dentata, in the deeper layers of the subicular complex and in the entorhinal cortex. SRIF-14-IR neurones are also detected in the angular bundle though they are rare in the alveus and absent in the fimbria.

Transient neurotensin in the cat inferior olive during development.

By immunohistochemistry, a large number of neurotensin immunoreactive nerve terminals are found in the kitten inferior olive of the medulla oblongata. They are present in the dorsal lamella of the principal olive, in the ventrolateral outgrowth and in the medial part of the caudal dorsal accessory olive. They are absent in the medial accessory olive. They disappear in the adult cat. Neurotensin immunoreactivity is absent in the developing rat inferior olive. This localization in the cat suggests a neuronal origin in the mesencephalon, mainly in the red nucleus. These results confirm our recent report on a transient large neurotensinergic innervation of the human developing principal olive.

Cholecystokinin distribution in the human striatum and related subcortical structures.

The distribution of cholecystokinin immunoreactive nerve cell bodies and processes is reported in the human striatum and adjacent structures such as the claustrum, the pallidum, the bed nucleus of the stria terminalis and the substantia innominata. Cholecystokinin-positive terminals are present in the striatum where they are arranged in a patchy pattern. Cholecystokinin-positive somata are observed in the claustrum and in the bed nucleus of the stria terminalis but not in the striatum, the pallidum or the substantia innominata. Dense networks of cholecystokinin-positive woolly fibres are present in the bed nucleus of the stria terminalis and the substantia innominata. These results suggested that cholecystokinin is involved in the compartmental organization of the human striatum. This compartmentalization has functional and pathological implications. Involvement of the cholecystokinin system in some basal ganglia diseases is therefore expected. Presence of neuronal cholecystokinin in the accumbens nucleus, bed nucleus of the stria terminalis and substantia innominata also suggests that this peptide may interact at different levels in the human limbic system.

Decrease of vasoactive intestinal peptide, methionine-enkephalin, substance P and increase of neuropeptide Y immunoreactive nerve fibres in aganglionic colon of Hirschsprung's disease.

Ganglionic and aganglionic full-thickness samples, at 4 levels of the colon of 26 infants with Hirschsprung's disease, were studied by immunohistochemistry. In the distal part of the aganglionic bowel, we observe a decrease of substance P and vasoactive intestinal peptide, an absence of methionine-enkephalin and an increase in neuropeptide Y nerve fibres. When detected, substance P and vasointestinal peptide are mainly present in abnormal bundle nerve fibres. In the middle part of the aganglionic bowel, a slight increase in the number of normal nerve fibres containing substance P, methionine-enkephalin and vasoactive intestinal peptide is observed. Some vasoactive intestinal peptide abnormal bundle nerve fibres are detected. They are less numerous than in the distal part. In the proximal ganglionic bowel, the number of vasoactive intestinal peptide, substance P and methionine-enkephalin normal nerve fibres is increased compared to the middle aganglionic segment but is slightly lower than in the normal colon. Again vasoactive intestinal peptide abnormal bundle nerve fibres are present at that level and are also detected in more proximal ganglionic bowel up to the hepatic flexure of the colon. Thus, abnormal distribution of neuropeptides is also found in more proximal ganglionic bowel and not only in the aganglionic segment of bowel usually specific of Hirschsprung's disease.

Co-existence of cholecystokinin- or gastrin-like peptides with other peptides in the hypophysis and the hypothalamus.

The presence of cholecystokinin and gastrin has been reported in the hypothalamohypophyseal system. These peptides present a peculiar distribution in the hypothalamic nuclei, the median eminence, and the neurohypophysis. CCK and gastrin have close relationships with other peptides like oxytocin, CRF, vasopressin, and the enkephalins; these relationships vary in different projecting areas and in different types of hypothalamic neurons. The functional role of G-CCK in neurosecretion seems to be linked to the role of these closely associated peptides and certainly deserves further investigation.