[Pharmacological treatments in patients with pervasive developmental disorders: A review]. / Efficacité des traitements pharmacologiques dans les troubles envahissants du développement : une revue de la littérature.

BACKGROUND: Pervasive developmental disorders (PDD) are neurodevelepmental disorders that are characterized by severe deficits in socialisation and communication, and the existence of repetitive and stereotyped interests and behaviours. It is estimated more than 60/100,000 children are suffering from PDD. Comorbid disorders are common in people with PDD, including intellectual deficiency, symptoms of attention deficit-hyperactivity, aggression and disruption, and pervasive repetitive behaviours or thoughts. These symptoms have a negative impact on the outcome and quality of life of the patients and their caregivers. The first-line management of comorbid disorders in PDD is behavioural intervention, but sometimes this is not sufficient, and the use of pharmacological treatment is needed. METHOD: We conducted a review of studies of medical treatments used in patients with PDD to establish which treatments show good evidence of efficacy in PDD. We used the Medline database and the following keywords "pervasive development disorders" or "autism spectrum disorders" or "autistic disorder" and "therapy" or "treatment". RESULTS: The treatments that showed the best efficacy on irritability in well-designed studies are second generation antipsychotics, risperidone and aripiprazole. Some studies indicate that haloperidol is efficient as well, but the very high frequency of extra-pyramidal effects limits its use. Methylphenidate has shown some efficacy on impulsivity and hyperactivity in randomised placebo-controlled studies. First data concerning atomoxetine are promising but better-designed studies are needed. Selective serotonin re-uptake inhibitors: fluvoxamine and fluoxetine have shown some efficacy in the treatment of serious and pervasive repetitive behaviours. Alpha-adrenergic treatments, clonidine and guanfacine, can help in the management of disruptive behaviours in patients with PDD. Data concerning naltrexone are contradictory, indeed many case reports of its efficacy on aggressive (mostly auto-aggressive) behaviours are reported in the literature, but well-designed studies do not find any improvement in patients treated with naltrexone compared with patients treated with placebo. First data concerning ocytocin are promising, indeed, if they were to be confirmed, that would be the first treatment efficient on the core symptoms of PDD.

Effects of bumetanide on neurobehavioral function in children and adolescents with autism spectrum disorders.

In animal models of autism spectrum disorder (ASD), the NKCC1 chloride-importer inhibitor bumetanide restores physiological (Cl-)i levels, enhances GABAergic inhibition and attenuates electrical and behavioral symptoms of ASD. In an earlier phase 2 trial; bumetanide reduced the severity of ASD in children and adolescents (3-11 years old). Here we report the results of a multicenter phase 2B study primarily to assess dose/response and safety effects of bumetanide. Efficacy outcome measures included the Childhood Autism Rating Scale (CARS), the Social Responsive Scale (SRS) and the Clinical Global Impressions (CGI) Improvement scale (CGI-I). Eighty-eight patients with ASD spanning across the entire pediatric population (2-18 years old) were subdivided in four age groups and randomized to receive bumetanide (0.5, 1.0 or 2.0 mg twice daily) or placebo for 3 months. The mean CARS value was significantly improved in the completers group (P: 0.015). Also, 23 treated children had more than a six-point improvement in the CARS compared with only one placebo-treated individual. Bumetanide significantly improved CGI (P: 0.0043) and the SRS score by more than 10 points (P: 0.02). The most frequent adverse events were hypokalemia, increased urine elimination, loss of appetite, dehydration and asthenia. Hypokalemia occurred mainly at the beginning of the treatment at 1.0 and 2.0 mg twice-daily doses and improved gradually with oral potassium supplements. The frequency and incidence of adverse event were directly correlated with the dose of bumetanide. Therefore, bumetanide improves the core symptoms of ASD and presents a favorable benefit/risk ratio particularly at 1.0 mg twice daily.

Visualization of gamma-aminobutyric acid A receptors on proopiomelanocortin-producing neurons in the rat hypothalamus.

It has recently been shown that gamma-aminobutyric acid (GABA) and central-type benzodiazepine receptor agonists inhibit the expression of the POMC gene and the release of POMC-derived peptides from hypothalamic neurons. To determine whether the inhibitory effect of GABA could be accounted for by a direct action on POMC neurons, we investigated the localization of the beta 1-subunit of the GABAA-benzodiazepine-receptor complex in the arcuate nucleus. Using a monoclonal antibody raised against a synthetic fragment of the beta 1-subunit, we demonstrate the presence of GABAA receptor on POMC neurons. The proportion of POMC neurons that exhibit immunoreactivity for the beta 1-subunit of the GABAA receptor was not significantly different in the posterior portion (73.0-76.0%) and anterior portion (61.3-62.7%) of the arcuate nucleus. The data also revealed that in the arcuate nucleus, a majority of neurons that were immunostained by the antibody to the beta 1-subunit were not POMC positive. The present results support the concept that GABAA and central-type benzodiazepine receptor agonists exert a direct inhibitory action on POMC neurons. The data also indicate the existence of subsets of POMC neurons within the arcuate nucleus.

Laminar and regional distribution of galanin binding sites in cat and monkey visual cortex determined by in vitro receptor autoradiography.

The distribution of galanin (GAL) binding sites in the visual cortex of cat and monkey was determined by autoradiographic visualization of [125I]-GAL binding to tissue sections. Binding conditions were optimized and, as a result, the binding was saturable and specific. In cat visual cortex, GAL binding sites were concentrated in layers I, IVc, V, and VI. Areas 17, 18, and 19 exhibited a similar distribution pattern. In monkey primary visual cortex, the highest density of GAL binding sites was observed in layers II/III, lower IVc, and upper V. Layers IVA and VI contained moderate numbers of GAL binding sites, while layer I and the remaining parts of layer IV displayed the lowest density. In monkey secondary visual cortex, GAL binding sites were mainly concentrated in layers V-VI. Layer IV exhibited a moderate density, while the supragranular layers contained the lowest proportion of GAL binding sites. In both cat and monkey, we found little difference between regions subserving central and those subserving peripheral vision. Similarities in the distribution of GAL and acetylcholine binding sites are discussed.

Regional distribution of binding sites for neuropeptide Y in cat and monkey visual cortex determined by in vitro receptor autoradiography.

The goal of this study was to elucidate the precise regional and laminar distribution of neuropeptide Y (NPY) binding sites in feline and primate visual cortex. By means of in vitro receptor autoradiography, NPY binding sites in primate and feline visual cortex were specifically labeled with 3H-NPY. In cat area 17, the highest density of NPY-binding sites was present in lamina I and the upper half of lamina II. The density then gradually decreased towards lamina VI. Areas 18 and 19 exhibited a similar binding site-density profile. The decrease in density from superficial to deep layers was more gradual in area 18 than in areas 17 and 19. In monkey primary visual cortex (V1), layer IVc presented a high concentration of NPY binding sites, in addition to a dense zone of binding sites in layer I. Monkey secondary visual cortex (V2) displays a similar dense zone in layer I, but lacks such high density of NPY binding sites in layer IV. Therefore, the border between primary and secondary visual cortex coincides with the abrupt disappearance of this latter high density in layer IV. In cat as well as in monkey visual cortex, no significant differences were found between regions representing central vision and those representing the peripheral parts of the visual field. Comparison of our results for NPY binding sites with the distribution of alpha 1-adrenergic receptors, as recently described by Rakic et al. (J. Neurosci. 8(10):3670-3690, 1988) for primate and Parkinson et al. (Brain Res. 457:70-78, 1988) for feline visual cortex, revealed that those two patterns are very similar.

Laminar distribution of NMDA receptors in cat and monkey visual cortex visualized by [3H]-MK-801 binding.

Glutamate is the major excitatory neurotransmitter of the mammalian central nervous system. Two major classes of glutamate receptors have been reported. The actions of glutamate on its N-methyl-D-aspartate (NMDA)-type receptor may underlie developmental and adult plasticity as well as neurotoxicity. The NMDA-type of glutamate receptor in cat and monkey visual cortex was visualized by means of in vitro receptor autoradiography with the noncompetitive NMDA-receptor antagonist [3H]-MK-801. The kinetics, performed on tissue sections, revealed an apparently single, saturable site with an approximate dissociation constant (KD) of 18.5 nM in cat and 15.9 nM in monkey visual cortex. Autoradiography, performed on frontal sections of cat and monkey visual cortex, revealed a heterogeneous laminar distribution of NMDA receptors. Cat areas 17, 18, 19, and the lateral suprasylvian areas exhibited a similar NMDA-receptor distribution. In these areas, NMDA receptors were most prominent in layer II and the upper part of layer III. In monkey striate cortex, NMDA receptors were primarily concentrated in layers II, upper III, IVc, V, and VI. In monkey secondary visual cortex, [3H]-MK-801 labeling was most prominent in layers II, V, and VI; whereas in the temporal visual areas included in this study layer II displayed the heaviest receptor labeling. In neither cat nor monkey could we observe significant differences in NMDA-receptor distribution between different retinotopic subdivisions within a single visual area. Neither did we detect any periodic changes in NMDA-receptor distribution that would correspond to the compartments defined by cytochrome-oxidase in monkey V1 and V2.

Distribution of somatostatin receptors in the cat and monkey visual cortex demonstrated by in vitro receptor autoradiography.

Somatostatin (SRIF, S14) receptors in the cat and monkey visual cortex were visualized by means of in vitro autoradiography with an iodinated agonist of SRIF, [125I-Tyr0,DTrp8]S14. The kinetics, performed on tissue sections, revealed an apparently single, saturable site (KD = 3.92 +/- 0.31 10(-10) M for the cat, and 3.82 +/- 0.28 10(-10) M for the monkey visual cortex) with pharmacological specificity for S14 and [DTrp]-substituted S14. Autoradiography, performed on frontal sections of the cat and monkey visual cortex, revealed a heterogeneous regional and laminar distribution of SRIF receptors. In cat areas 17, 18, and 19, SRIF receptors occur mainly in the supragranular layers, although small interareal and intra-areal differences are observed. The infragranular layers (V-VI) in area 19 contain a significantly higher proportion of SRIF receptors compared to both areas 17 and 18. In the antero- (AMLS) and posteromedial lateral suprasylvian area (PMLS), layers V and VI contain the highest proportion of SRIF receptors. This latter pattern is also observed in the area prostriata medially adjoining area 17 in the splenial sulcus. In the monkey visual cortex, areas 17 and 18 exhibit similar distribution patterns, SRIF receptors being primarily concentrated in layers V and VI. Neither in the cat nor the monkey visual cortex could we observe significant differences in SRIF receptor distribution between different retinotopic subdivisions within one area.

Effect of sensory deafferentation on immunoreactivity of GABAergic cells and on GABA receptors in the adult cat visual cortex.

To investigate the effects of sensory deafferentation on the cortical GABAergic circuitry in adult cats, glutamic acid decarboxylase (GAD) and gamma-aminobutyric acid (GABA) immunoreactivity and GABA receptor binding were studied in the visual cortex of normal cats and compared with cats that had received restricted binocular central lesions of the retina and had survived for 2 weeks postlesion in a normal visual environment. In the visual cortex of lesioned cats, two changes were observed in the number of GAD-immunoreactive elements in the regions affected by the retinal lesions: the number of GAD-positive puncta decreased, whereas that of GAD-immunoreactive somata increased. In contrast, no detectable changes were measured in the number of GABA-immunopositive somata or puncta. At the receptor level, we observed no differences in either the laminar distribution or the affinity of cortical GABAA and GABAB receptors labeled with [3H]-muscimol and [3H]-baclofen, respectively, in the lesioned versus normal cats. We present the hypothesis that sensory deafferentation in these adult cats (1) leads to a reduction of cortical GABAergic inhibition in the deafferented region, and (2) that this decreased inhibition may permit changes in efficiency of synapses and (3) that these changes may represent a first stage of events underlying the retinotopic reorganization preceeding the structural changes.

Immunocytochemical detection of astrocyte GABAA receptors in cat visual cortex.

A nine amino-acid peptide derived from the beta 1-subunit of the bovine GABAA receptor was used for immunization of mice and subsequent production of monoclonal antibodies (MAb). In view of the later immunocytochemical application of the MAb to sections of cat visual cortex, the MAb were characterized on similar tissue. The GABAA receptor was isolated by affinity chromatography of protein material obtained from cat cortical gray matter. The antibodies were characterized by SDS-PAGE, followed by immunoblotting and immunoadsorption. Immunocytochemical staining with the MAb revealed labeled cells throughout all layers of the cat visual cortex as well as within the white matter. The morphology of most stained cells in the white matter and of some cells in the cortical gray matter closely resembled that of astrocytes. Double immunocytochemical staining with an antiserum against glial fibrillary acidic protein (GFAP), followed by light microscopic examination, indeed confirmed that astrocytes in both white and gray matter in the cat cortex possess GABAA receptors.

Partial colocalization of the GABAA receptor with parvalbumin and calbindin D-28K in neurons of the visual cortex and the dorsal lateral geniculate nucleus of the cat.

Monoclonal antibodies to a synthetic peptide fragment of the beta 1-subunit of the bovine central GABAA/benzodiazepine receptor were used to investigate immunocytochemically the distribution of this receptor in the visual system of the cat. Labeled neurons were observed in all layers of the visual cortex and the dorsal lateral geniculate nucleus. About half of the total cortical or geniculate neuronal population was found to be positive. To further identify immunocytochemically these GABAA receptor expressing cells, double stainings were undertaken with, on one hand, the monoclonal antibodies directed against the receptor complex, and on the other hand polyclonal antisera directed against cat muscle parvalbumin or chicken calbindin D-28K. A high degree of colocalization between either of the two calcium binding proteins and the GABAA receptor was found in the upper layers (I, II and III) of the visual cortex and in the A and C laminae of the dorsal lateral geniculate nucleus; all calbindin D-28K-positive cells were immunoreactive for the GABAA receptor. The parvalbumin-positive cells, scattered throughout all layers of the dorsal lateral geniculate nucleus and the visual cortex, except cortical layer I, were also all positive for the GABAA receptor. However, a large proportion of all GABAA receptor bearing cells were negative for one of the calcium binding proteins.

Diazepam decreases performance in a long-term memory task using visual shapes.

We designed a memory task involving visual recognition sensitive enough to demonstrate the long-term amnesic effect of diazepam. Following memorization of a list of abstract visual stimuli (Fourier), subjects were evaluated on recognition performance immediately following acquisition and after a 3-day drug clearance interval. Administration of 15 mg diazepam 1 h before acquisition imposed a significant (10-24%) deficit only in delayed recognition. In contrast, a drug-free acquisition followed by a diazepam-challenged delayed recognition did not influence recognition. Moreover, 1 h after administration, diazepam did not significantly impair detection or visual discriminative performances. Given the persistence of an important deficit in recognition memory in the absence of any drug, this paradigm promises to be useful for studying regional cerebral blood flow during long-term memory performance.

Visualisation of loss of 5-HT2A receptors with age in healthy volunteers using [18F]altanserin and positron emission tomographic imaging.

We used [18F]altanserin and positron emission tomography (PET) to image serotonin 5-HT2A receptors in humans. The highest [18F]altanserin uptake is found in the cerebral cortex, with specific-to-nonspecific binding ratios varying from 0.53 to 1.91 in humans between 24 and 48 years of age. In all neocortical regions studied, [18F]altanserin uptake correlates negatively with age. No correlations were found between age and uptake in the cerebellum, the regional cerebral blood flow, or the time course of metabolization of [18F]altanserin. The reduction in cerebral 5-HT2A receptor binding thus directly reflects the loss of specific 5-HT2A receptors with age.

Variability of energy metabolism and nuclear T3-receptors within the skeletal muscle tissue of pigs different with respect to the halothane gene.

Energy metabolism of skeletal muscle tissue of pigs growing from approximately 12 to 18 kg (12 homozygous halothane negative, HH; 16 heterozygotes, Hh; 17 homozygous halothane susceptible, hh) was measured in vivo using 31P nuclear magnetic resonance (NMR) spectroscopy. Data for intracellular pH, phosphocreatine (PCr), phosphomonoesters (PME), and ATP were analyzed by canonical discriminant analysis, an artificial neural network approach, and analysis of variance. Within the hh pigs, two subpopulations could be distinguished before the application of halothane treatment. Some of the hh pigs had a high PME concentration in the biceps femoris muscle (hh(pme+)), whereas others had a low concentration (hh(pme-)) (2.18 +/- .12 for hh(pme+) vs 1.68 +/- .12 mM for hh(pme-), P < .004). The hh(pme+) pigs were statistically different from HH pigs for pH (P < .03), PME (P < .004), and PCr (P < .008) before halothane treatment. The hh(pme-) pigs were not different from the Hh and HH pigs with respect to PME when measured before halothane treatment (P > .05). However, intracellular pH (P < .03) and PCr (P < .008) of the hh(pme-) pigs were different from those of HH pigs (7.15 vs 7.19 for pH and 38.7 vs 35.1 for PCr, respectively). When combining intracellular pH, PME, and PCr within a canonical discriminant analysis, all were measured before halothane treatment, Hh pigs were found to be different from HH pigs (Mahalanobis distance different from zero, P < .02). In a second experiment, growth rate, depth of longissimus muscle, and maximal binding capacity of nuclear T3-receptors of skeletal muscle tissue were different (P < .05, P < .002, and P < .02, respectively) among pigs selected from the same genetic lines. Of the variability in depth of the longissimus muscle, 22% was explained by variability in maximal binding capacity of nuclear T3-receptors. These results, if confirmed with a large number of pigs, might open new possibilities for selection procedures for leanness because, with respect to halothane susceptibility, a shift between genotypic and phenotypic variability was observed.

Scopolamine-induced impairment of delayed recognition of abstract visual shapes.

Since the limbic system, whose involvement in cognitive processes is well documented, constitutes a major central cholinergic area, the effect of cholinergic drugs on cognitive tasks has been studied extensively. In the present study, we used a long-term visual recognition task to evaluate the persistence of the scopolamine-induced anterograde amnesia beyond drug clearance intervals. Following memorization of a list of abstract shapes, subjects were evaluated on recognition performance immediately after encoding, and after a 3-day interval. Administration of scopolamine (0.4-0.8 mg) 70 min prior to encoding induced a significant (8-16%) deficit in delayed recognition performance. In contrast, a scopolamine challenge on delayed recognition following a drug-free encoding did not influence memory performance. In contrast, even at peak levels, scopolamine did not alter immediate recognition, detection or visual discriminative performances. Hence, the presence of scopolamine during the encoding of the shapes induced a significant long-term memory deficit that persisted after scopolamine clearance. Therefore, this paradigm is useful for imaging regional brain activation during impaired recognition without the confounding direct effects of scopolamine on cerebral blood flow or metabolism, two physiological variables underlying the indirect measurement of brain activation.

Human brain activity related to speed discrimination tasks.

The regional cerebral blood-flow (rCBF) pattern of the human brain was measured using positron emission tomography (PET) while subjects viewed, detected, judged the speed of a moving random dot pattern (RDP) or compared speeds of successive RDPs. In all four conditions, retinal input was identical. Two additional conditions, continuous presentation of a moving and a stationary RDP, were included to identify human MT/V5 (hMT/V5). Both speed discrimination tasks involved the right cuneus and right lingual gyrus and to a lesser degree the left lingual gyrus and a more anterior lingual region in the right hemisphere. There was, however, little or no differential activity over hMT/V5 during either speed discrimination. Direct comparison of the two speed discrimination tasks revealed higher activity in the right middle fusiform gyrus, a result reminiscent of that obtained in earlier studies using orientation and direction as the attribute to be discriminated. These results confirm that processing in the human visual cortex is task dependent and underscore the role of the middle fusiform gyrus in temporal comparison of simple attributes.

Regional brain activity during shape recognition impaired by a scopolamine challenge to encoding.

In the present positron emission tomography (PET) study, we examine the effect of a scopolamine-induced challenge to encoding upon the pattern of regional cerebral blood flow during recognition of a list of abstract visual shapes 3 days after encoding of these shapes. This study was conducted to test hypotheses concerning the fusiform and thalamic contributions to object recognition arising from a previous imaging study of impaired recognition. In that study, we demonstrated that activity in the fusiform cortex and the thalamus during shape recognition was modulated by memory challenges. These memory challenges included, on one hand, impaired storage as a consequence of diazepam administration during encoding, and, on the other hand, impaired retrieval caused by a perceptual challenge. Activation in the fusiform cortex decreased during impaired recognition, irrespective of the type of challenge. In contrast, thalamic activation increased only when the recognition deficit resulted from impaired memory storage. Based on these results, we hypothesized that fusiform activation during recognition reflects the matching of an incoming stimulus with a stored one, whereas thalamic activation reflects retrieval attempts. These hypotheses would receive considerable support if scopolamine, which also impairs memory storage, induced similar modulations of fusiform and thalamic activation. In the present study, we observed that a scopolamine challenge to encoding does indeed modulate the activity in the very same regions that were previously modulated by a diazepam challenge. Hence, a similar memory deficit, although primarily effected through different neurochemical pathways, was paralleled by a similar modulation of activity in the same set of nodes in the shape recognition network. In the fusiform cortex, scopolamine decreased recognition-related activity, as did the sensory challenge of retrieval. Furthermore, covariate analysis demonstrated that the level of fusiform activity linearly correlates with behavioural performance. In the thalamus, activation increased following impaired encoding. This is in accordance with the idea that enhanced thalamic activity reflects increased effort expended in retrieval. In addition, in the intraparietal sulcus, differential activation also increased following impaired memory storage, possibly reflecting enhanced visuospatial attention in an effort to compensate for impaired performance.

Positron-emission tomography imaging of long-term shape recognition challenges.

Long-term visual memory performance was impaired by two types of challenges: a diazepam challenge on acquisition and a sensory challenge on recognition. Using positron-emission tomography regional cerebral blood flow imaging, we studied the effect of these challenges on regional brain activation during the delayed recognition of abstract visual shapes as compared with a baseline fixation task. Both challenges induced a significant decrease in differential activation in the left fusiform gyrus, suggesting that this region is involved in the automatic or volitional comparison of incoming and stored stimuli. In contrast, thalamic differential activation increased in response to memory challenges. This increase might reflect enhanced retrieval attempts as a compensatory mechanism for restoring recognition performance.

Human brain regions involved in direction discrimination.

To obtain further evidence for the functional specialization and task-dependent processing in the human visual system, we used positron emission tomography to compare regional cerebral blood flow in two direction discrimination tasks and four control tasks. The stimulus configuration, which was identical in all tasks, included the motion of a random dot pattern, dimming of a fixation point, and a tone burst. The discrimination tasks comprised the identification of motion direction and successive direction discrimination. The control tasks were motion detection, dimming detection, tone detection, and passive viewing. There was little difference in the activation patterns evoked by the three detection tasks except for decreased activity in the parietal cortex during the detection of a tone. Thus attention to a nonvisual stimulus modulated different visual cortical regions nonuniformly. Comparison of successive discrimination with motion detection yielded significant activation in the right fusiform gyrus, right lingual gyrus, right frontal operculum, left inferior frontal gyrus, and right thalamus. The fusiform and opercular activation sites persisted even after subtracting direction identification from successive discrimination, indicating their involvement in temporal comparison. Functional magnetic resonance imaging (fMRI) experiments confirmed the weak nature of the activation of human MT/V5 by successive direction discrimination but also indicated the involvement of an inferior satellite of human MT/V5. The fMRI experiments moreover confirmed the involvement of human V3A, lingual, and parietal regions in successive discrimination. Our results provide further evidence for the functional specialization of the human visual system because the cortical regions involved in direction discrimination partially differ from those involved in orientation discrimination. They also support the principle of task-dependent visual processing and indicate that the right fusiform gyrus participates in temporal comparison, irrespective of the stimulus attribute.

Regions in the human brain activated by simultaneous orientation discrimination: a study with positron emission tomography.

In order to compare regional cerebral activity involved in simultaneous as opposed to successive orientation discrimination, we used positron emission tomography to measure regional cerebral blood flow, in two threefold sets of conditions, in a large number of subjects. The first such triad involved simultaneous orientation discrimination, orientation identification and detection, with all tasks using the same pair of gratings. The second triad consisted of successive orientation discrimination with its corresponding identification and detection tasks. Comparisons between tasks within each triad isolate attention to orientation and, respectively, spatial or temporal comparison. The subtraction of detection from simultaneous discrimination revealed activation of right fusiform, right lingual, left precentral, left cingulate and left temporal cortex, in addition to right insula, cerebellum and left thalamus. Only the fusiform, insular and precentral activations remained when the corresponding identification was subtracted from simultaneous discrimination. In contrast, most of the non-visual activation sites remained when simultaneous discrimination was compared with successive discrimination, which also revealed a left lingual activation. These experiments provide further evidence for task-dependent processing in the human visual system and suggest that the right fusiform cortex is involved in spatial as much as temporal comparisons.