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Brain Levels (brain + level)
Selected AbstractsMechanisms of change in mentalization-based treatment of BPDJOURNAL OF CLINICAL PSYCHOLOGY, Issue 4 2006Peter Fonagy There are very few less contentious issues than the role of attachment in psychotherapy. Concepts such as the therapeutic alliance speak directly to the importance of activating the attachment system, normally in relation to the therapist in individual therapy and in relation to other family members in family-based intervention, if therapeutic progress is to be made. In group therapy the attachment process may be activated by group membership. The past decade of neuroscientific research has helped us to understand some key processes that attachment entails at brain level. The article outlines this progress and links it to recent findings on the relationship between the neural systems underpinning attachment and other processes such as making of social judgments, theory of mind, and access to long-term memory. These findings allow intriguing speculations, which are currently undergoing empirical tests on the neural basis of individual differences in attachment as well as the nature of psychological disturbances associated with profound disturbances of the attachment system. In this article, we explore the crucial paradoxical brain state created by psychotherapy with powerful clinical implications for the maximization of therapeutic benefit from the talking cure. © 2006 Wiley Periodicals, Inc. J Clin Psychol 62: 411,430, 2006. [source] Up-regulation of heat shock protein HSP 20 in the hippocampus as an early response to hypoxia of the newbornJOURNAL OF NEUROCHEMISTRY, Issue 2 2006Jean-Claude David Abstract Hypoxia is an important challenge for newborn mammals. Stress generated at the brain level under low oxygenation conditions results in up-regulation of heat shock proteins (HSPs) and other stress proteins. The aim of the present work was to determine the effect of hypoxia in the newborn on some newly described small molecular weight HSPs (HSP 20 and B8) in the hippocampus, cortex and cerebellum of newborn piglets. These effects will be compared with those of other closely related proteins such as ,B crystallin, HSP 27, heme oxygenase (HO)-1, HO-2, cyclooxygenase (COX)-1 and COX-2. The piglets were submitted to hypoxia (5% O2; 95% N2) over either 1 or 4 h, with recovery periods ranging from 0 to 68 h. Western blot analysis showed that HSP 20 was rapidly induced only in the hippocampus, long before hypoxia-inducible transcription factor HIF-1,, while HSP 27 was rapidly induced in the cortex and cerebellum. Vascular epithelial growth factor was increased simultaneously in the three regions. Moreover, an increase in the expression of, respectively, HO-1 and COX-2 was observed later, but at the same time, in the three regions tested. It appears that HSP 20 can be an early marker of hypoxia in the hippocampus. The other small HSPs or stress proteins display different temporal patterns of up-regulation (HSP 27 and HO-1, COX-2) or do not show changes in their expressions (,B crystallin, HSP B8, HO-2 and COX-1). [source] Studies on neurosteroids XXIV.BIOMEDICAL CHROMATOGRAPHY, Issue 12 2008-androstane-, -diol, Determination of neuroactive androgens, androsterone, in rat brain, serum using liquid chromatography, tandem mass spectrometry Abstract The development and validation of liquid chromatography,electrospray ionization,tandem mass spectrometric (LC,ESI-MS/MS) methods that enable the quantification of neuroactive androgens, androsterone (5, -androstan-3, -ol-17-one, 3,,5, -A) and 5, -androstane-3,,17, -diol (3,,5, -Adiol), in the rat brain and serum are presented. The androgens were extracted with methanol,acetic acid, purified using solid-phase extraction cartridges, derivatized with an ESI-active reagent, isonicotinoyl azide (INA), and then subjected to LC,ESI-MS/MS. The quantifications were based on selected reaction monitoring mode using the characteristic transitions of the INA derivatives. The methods allowed the reproducible and accurate quantification of the brain and serum neuroactive androgens using a 100 mg or 100 µL sample; the intra- and inter-assay relative standard deviations were below 3.6%, and the percentage accuracy values were 97.1,103.7% for both androgens. The animal study using the methods suggests that most of 3,,5, -Adiol found in the brain is derived from the periphery, while 3,,5, -A is not only transported from the periphery into the brain, but also synthesized in the brain by the oxidation of 3,,5, -Adiol. The androgens in the rats intraperitoneally administered finasteride, a 5, -reductatse inhibitor, were also measured; this treatment significantly reduced the brain 3,,5, -A and 3,,5, -Adiol levels and increased only the brain level of androstenedione, the precursor of 3,,5, -A. Copyright © 2008 John Wiley & Sons, Ltd. [source] Do psychotherapies produce neurobiological effects?ACTA NEUROPSYCHIATRICA, Issue 2 2006Veena Kumari Background:, An area of recent interest in psychiatric research is the application of neuroimaging techniques to investigate neural events associated with the development and the treatment of symptoms in a number of psychiatric disorders. Objective:, To examine whether psychological therapies modulate brain activity and, if so, to examine whether these changes similar to those found with relevant pharmacotherapy in various mental disorders. Methods:, Relevant data were identified from Pubmed and PsycInfo searches up to July 2005 using combinations of keywords including ,psychological therapy', ,behaviour therapy', ,depression', ,panic disorder', ,phobia', ,obsessive compulsive disorder', ,schizophrenia', ,psychosis', ,brain activity', ,brain metabolism', ,PET', ,SPECT' and ,fMRI'. Results:, There was ample evidence to demonstrate that psychological therapies produce changes at the neural level. The data, for example in depression, panic disorder, phobia and obsessive compulsive disorder (OCD), clearly suggested that a change in patients' symptoms and maladaptive behaviour at the mind level with psychological techniques is accompanied with functional brain changes in relevant brain circuits. In many studies, cognitive therapies and drug therapies achieved therapeutic gains through the same neural pathways although the two forms of treatment may still have different mechanisms of action. Conclusions:, Empirical research indicates a close association between the ,mind' and the ,brain' in showing that changes made at the mind level in a psychotherapeutic context produce changes at the brain level. The investigation of changes in neural activity with psychological therapies is a novel area which is likely to enhance our understanding of the mechanisms for therapeutic changes across a range of disorders. [source] The effects of selective breeding for differential rates of 50-kHz ultrasonic vocalizations on emotional behavior in ratsDEVELOPMENTAL PSYCHOBIOLOGY, Issue 1 2009Jeffrey Burgdorf Abstract Fifty-kHz ultrasonic vocalizations have previously been shown to be positively correlated with reward and appetitive social behavior in rats, and to reflect a positive affective state. In this study, rats selectively bred for high and low rates of 50-kHz vocalizations as juveniles were tested as adults in a battery of behavioral tests for social/emotional behaviors. We found that animals selectively bred for high rates of 50-kHz vocalizations exhibited more crosses into the center area of the open field apparatus, were more likely to show a preference for a dilute sucrose solution (.8%) compared to tap water, and were less aggressive than randomly bred animals. Conversely, animals bred for low rates of 50-kHz calls produced more fecal boli during both open field testing and "tickling" stimulation, and made less contact with conspecifics in a social interaction test compared to randomly bred animals. We also observed that low line rats have elevated brain levels of cholecystokinin (CCK) in the cortex, which is consistent with literature showing that CCK content in the cortex is positively correlated with rates of aversive 22-kHz USVs. Conversely, high line animals had elevated levels of met-enkephalin in several brain regions, which is consistent with the role of endogenous-opioids in the generation 50-kHz USVs and positive affect. These results suggest that animals bred for high rates of 50-kHz may show a stress resilient phenotype, whereas low line rats may show a stress prone phenotype. As such these animals could provide novel insights into the neurobiology of emotion. © 2008 Wiley Periodicals, Inc. Dev Psychobiol 51: 34,46, 2009 [source] Blood,brain barrier damage and brain penetration of antiepileptic drugs: Role of serum proteins and brain edemaEPILEPSIA, Issue 4 2009Nicola Marchi Summary Purpose:, Increased blood,brain barrier (BBB) permeability is radiologically detectable in regions affected by drug-resistant epileptogenic lesions. Brain penetration of antiepileptic drugs (AEDs) may be affected by BBB damage. We studied the effects of BBB damage on brain distribution of hydrophilic [deoxy-glucose (DOG) and sucrose] and lipophilic (phenytoin and diazepam) molecules. We tested the hypothesis that lipophilic and hydrophilic drug distribution is differentially affected by BBB damage. Methods:, In vivo BBB disruption (BBBD) was performed in rats by intracarotid injection of hyperosmotic mannitol. Drugs (H3-sucrose, 3H-deoxy-glucose, 14C-phenytoin, and C14-diazepam) or unlabeled phenytoin was measured and correlated to brain water content and protein extravasation. In vitro hippocampal slices were exposed to different osmolarities; drug penetration and water content were assessed by analytic and densitometric methods, respectively. Results:, BBBD resulted in extravasation of serum protein and radiolabeled drugs, but was associated with no significant change in brain water. Large shifts in water content in brain slices in vitro caused a small effect on drug penetration. In both cases, total drug permeability increase was greater for lipophilic than hydrophilic compounds. BBBD reduced the amount of free phenytoin in the brain. Discussion:, After BBBD, drug binding to protein is the main controller of total brain drug accumulation. Osmotic BBBD increased serum protein extravasation and reduced free phenytoin brain levels. These results underlie the importance of brain environment and BBB integrity in determining drug distribution to the brain. If confirmed in drug-resistant models, these mechanisms could contribute to drug brain distribution in refractory epilepsies. [source] Monoamine variability in the chronic model of atypical absence seizuresEPILEPSIA, Issue 4 2009Eduard Bercovici Summary Purpose:, We studied the variability of the slow-spike-and-wave discharges (SSWDs) derived from AY-9944 (AY) treatment during brain development of Long-Evans hooded (LEh) rats. Methods:, Although all LEh rats received the standard dose of AY (7.5 mg/kg), we have observed an intersubject variability of the total SSWD duration at postnatal day (P) 55. Therefore, we set out to investigate the underlying brain levels of norepinephrine (NE), dopamine (DA), and serotonin (5-HT) and its metabolite (5-HIAA), as determined by high-performance liquid chromatography (HPLC) analyses from four different brain regions: thalamus (Th), frontoparietal cortex (Cx), hippocampus (Hp), and brainstem (Bs). Results:, All brains were obtained after two baseline electrocorticographic (ECoG) recordings with characteristic chronic, recurrent, bilaterally synchronous 4,6 Hz SSWD, at P 55 (336.25 ± 97.23 s/h) and P60 (494.50 ± 150.36 s) (r = 0.951, r2 = 0.904, p < 0.005, Pearson product). The thalamic NE levels and the brainstem NE, DA, and 5HT levels were all significantly correlated with baseline SSWD duration at P55 and P60 (p < 0.01, Pearson product). Conclusion:, Our data indicate that brain monoamine levels may determine the intersubject variability of SSWD duration in AY rats with chronic atypical absence seizures. [source] Possible mechanisms for the anticonvulsant activity of fructose-1,6-diphosphateEPILEPSIA, Issue 2008Janet L. Stringer Summary Fructose-1,6-diphosphate (FDP), an intracellular metabolite of glucose, has anticonvulsant activity in several models of acute seizures in laboratory animals. The anticonvulsant effect of FDP is most likely due to a direct effect since intraperitoneal and oral administration results in significant increases in brain levels. A number of mechanisms have been proposed for this action of FDP. One possibility is that peripheral administration of FDP results in changes in brain metabolism that are anticonvulsant. Glucose can be metabolized through the glycolytic or pentose phosphate pathway. There is evidence that the pentose phosphate pathway is more active in the brain than in other tissues, and that, in the presence of elevated levels of FDP, the majority of glucose is metabolized by the pentose phosphate pathway. The pentose phosphate pathway generates NADPH, which is used to reduce glutathione. The reduced form of endogenous glutathione has been shown to have anticonvulsant activity. Taken together, the data suggest a hypothesis that exogenously administered FDP gets into the brain and astrocytes where it increases the flux of glucose through the pentose phosphate pathway, generating additional NADPH for the reduction of glutathione. [source] Causal Links between Brain Cytokines and Experimental Febrile Convulsions in the RatEPILEPSIA, Issue 12 2005James G. Heida Summary:,Purpose: Despite the prevalence of febrile convulsions (FCs), their pathophysiology has remained elusive. We tested the hypothesis that components of the immune response, particularly the proinflammatory cytokine interleukin-1, (IL-1,) and its naturally occurring antagonist interleukin-1 receptor antagonist (IL-1ra) may play a role in the genesis of FC. Methods: Postnatal day 14 rats were treated with lipopolysaccharide (LPS; 200 ,g/kg, i.p.) followed by a subconvulsant dose of kainic acid (1.75 mg/kg, i.p.). Brains were harvested at and 2 h after onset of FCs to measure brain levels of IL-1, and IL-1ra. Separate groups of animals were given intracerebroventricular (ICV) injections of IL-1,, or IL-1ra in an attempt to establish a causal relation between the IL-1,/IL-1ra system and FCs. Results: Animals with FCs showed increased IL-1, in the hypothalamus and hippocampus but not in the cortex compared with noFC animals that also received LPS and kainic acid. This increase was first detected in the hippocampus at onset of FCs. No detectable difference in IL-1ra was found in brain regions examined in either group. When animals were treated with IL-1, ICV, a dose-dependant increase was noted in the proportion of animals that experienced FCs, whereas increasing doses of IL-1ra, given to separate groups of animals, were anticonvulsant. Conclusions: Our results suggest that excessive amounts of IL-1, may influence the genesis of FCs. This may occur by overproduction of IL-1,, or by alteration in the IL-1,/IL-1ra ratio in the brain after an immune challenge. [source] Genetic loss of D-amino acid oxidase activity reverses schizophrenia-like phenotypes in miceGENES, BRAIN AND BEHAVIOR, Issue 1 2010V. Labrie Reduced function of the N -methyl- d -aspartate receptor (NMDAR) has been implicated in the pathophysiology of schizophrenia. The NMDAR contains a glycine binding site in its NR1 subunit that may be a useful target for the treatment of schizophrenia. In this study, we assessed the therapeutic potential of long-term increases in the brain levels of the endogenous NMDAR glycine site agonist D-serine, through the genetic inactivation of its catabolic enzyme D-amino acid oxidase (DAO) in mice. The effects of eliminating DAO function were investigated in mice that display schizophrenia-related behavioral deficits due to a mutation (Grin 1D481N) in the NR1 subunit that results in a reduction in NMDAR glycine affinity. Grin 1D481N mice show deficits in sociability, prolonged latent inhibition, enhanced startle reactivity and impaired spatial memory. The hypofunctional Dao 1G181R mutation elevated brain levels of D-serine, but alone it did not affect performance in the behavioral measures. Compared to animals with only the Grin 1D481N mutation, mice with both the Dao1G181R and Grin 1D481N mutations displayed an improvement in social approach and spatial memory retention, as well as a reversal of abnormally persistent latent inhibition and a partial normalization of startle responses. Thus, an increased level of D-serine resulting from decreased catalysis corrected the performance of mice with deficient NMDAR glycine site activation in behavioral tasks relevant to the negative and cognitive symptoms of schizophrenia. Diminished DAO activity and elevations in D-serine may serve as an effective therapeutic intervention for the treatment of psychiatric symptoms. [source] Seizure resistance in fat-1 transgenic mice endogenously synthesizing high levels of omega-3 polyunsaturated fatty acidsJOURNAL OF NEUROCHEMISTRY, Issue 2 2008Ameer Y. Taha Abstract n-3 polyunsaturated fatty acids (PUFA), derived from marine oils, have been shown to protect against various neurological diseases. However, very little is known about their potential anticonvulsant properties. The objective of the present study was to determine whether enrichment of brain lipids with n-3 PUFA inhibits seizures induced by pentylenetetrazol. We demonstrate that increased brain levels of n-3 PUFA in transgenic fat-1 male mice, which are capable of de novo synthesis of n-3 PUFA from n-6 PUFA, increases latency to seizure onset by 45%, relative to wildtype controls (p = 0.08). Compared with wildtype littermates, transgenic fat-1 mice have significantly (p < 0.05) higher levels of docosahexaenoic acid and total n-3 PUFA in brain total lipid extracts and phospholipids. Levels of brain docosahexaenoic acid were positively correlated to seizure latency (p < 0.05). These findings demonstrate that n-3 PUFA have anticonvulsant properties and suggest the possibility of a novel, non-drug dietary approach for the treatment of epilepsy. [source] Differential Effects of Ethanol on Serum GABAergic 3,,5,/3,,5, Neuroactive Steroids in Mice, Rats, Cynomolgus Monkeys, and HumansALCOHOLISM, Issue 3 2010Patrizia Porcu Background:, Acute ethanol administration increases plasma and brain levels of progesterone and deoxycorticosterone-derived neuroactive steroids (3,,5,)-3-hydroxypregnan-20-one (3,,5,-THP) and (3,,5,)-3,21-dihydroxypregnan-20-one (3,,5,-THDOC) in rats. However, little is known about ethanol effects on GABAergic neuroactive steroids in mice, nonhuman primates, or humans. We investigated the effects of ethanol on plasma levels of 3,,5,- and 3,,5,-reduced GABAergic neuroactive steroids derived from progesterone, deoxycorticosterone, dehydroepiandrosterone, and testosterone using gas chromatography-mass spectrometry. Methods:, Serum levels of GABAergic neuroactive steroids and pregnenolone were measured in male rats, C57BL/6J and DBA/2J mice, cynomolgus monkeys, and humans following ethanol administration. Rats and mice were injected with ethanol (0.8 to 2.0 g/kg), cynomolgus monkeys received ethanol (1.5 g/kg) intragastrically, and healthy men consumed a beverage containing 0.8 g/kg ethanol. Steroids were measured after 60 minutes in all species and also after 120 minutes in monkeys and humans. Results:, Ethanol administration to rats increased levels of 3,,5,-THP, 3,,5,-THDOC, and pregnenolone at the doses of 1.5 g/kg (+228, +134, and +860%, respectively, p < 0.001) and 2.0 g/kg (+399, +174, and +1125%, respectively, p < 0.001), but not at the dose of 0.8 g/kg. Ethanol did not alter levels of the other neuroactive steroids. In contrast, C57BL/6J mice exhibited a 27% decrease in serum 3,,5,-THP levels (p < 0.01), while DBA/2J mice showed no significant effect of ethanol, although both mouse strains exhibited substantial increases in precursor steroids. Ethanol did not alter any of the neuroactive steroids in cynomolgus monkeys at doses comparable to those studied in rats. Finally, no effect of ethanol (0.8 g/kg) was observed in men. Conclusions:, These studies show clear species differences among rats, mice, and cynomolgus monkeys in the effects of ethanol administration on circulating neuroactive steroids. Rats are unique in their pronounced elevation of GABAergic neuroactive steroids, while this effect was not observed in mice or cynomolgus monkeys at comparable ethanol doses. [source] Dietary supplementation with melatonin reduces levels of amyloid beta-peptides in the murine cerebral cortexJOURNAL OF PINEAL RESEARCH, Issue 4 2004Debomoy K. Lahiri Abstract:, Melatonin levels decrease with aging in mice. Dietary supplementation with melatonin has recently been shown to result in a significant rise in levels of endogenous melatonin in the serum and all other tissue samples tested. Herein, the effects of dietary melatonin on brain levels of nitric oxide synthase, synaptic proteins and amyloid beta-peptides (A,) were determined in mice. Melatonin supplementation did not significantly change cerebral cortical levels of nitric oxide synthase or synaptic proteins such as synaptophysin and SNAP-25. Increased brain melatonin concentrations however, led to a significant reduction in levels of toxic cortical A, of both short and long forms which are involved in amyloid depositions and plaque formation in Alzheimer's diseases. Thus, melatonin supplementation may retard neurodegenerative changes associated with brain aging. Depletion of melatonin in the brain of aging mice may in part account for this adverse change. [source] Rapid tryptophan depletion reverses phenelzine-induced suppression of REM sleepJOURNAL OF SLEEP RESEARCH, Issue 1 2003Hans-Peter Landolt SUMMARY Treatment with the monoamine oxidase inhibitor phenelzine completely suppressed rapid eye movement (REM) sleep in five depressed patients. Hypothesizing that increased serotonergic neurotransmission eliminated REM sleep, we administered a tryptophan-free amino acid drink (TFD) known to reduce plasma tryptophan and brain levels of serotonin. The TFD reversed the REM sleep suppression, while the control drink (TFD plus tryptophan) had virtually no effect on sleep. Neither TFD nor control drink affected mood, total sleep time, sleep efficiency or the all-night electroencephalogram power spectra in non-rapid eye movement (NREM) sleep. We report the first non-disruptive, double-blind method for studying human subjects overnight with and without REM sleep. It opens up a novel strategy for investigating the functions of REM sleep, and the roles of serotonin and REM sleep in the regulation of NREM sleep and mood. [source] Prenatal protein malnourished rats show changes in sleep/wake behavior as adultsJOURNAL OF SLEEP RESEARCH, Issue 1 2000Subimal Datta SUMMARY Prenatal protein malnutrition significantly elevates brain levels of serotonin in rats, and these levels remain elevated throughout their lives. This biogenic amine is involved in the regulation of many physiological functions, including the normal sleep/wake cycle. The present study examined the effects of prenatal protein malnutrition on the sleep/wake cycle of freely moving adult rats. Six prenatally protein malnourished (6% casein) and 10 well-nourished (25% casein) male rats (90,120-day-old) were chronically implanted with a standard set of electrodes (to record cortical electroencephalogram, neck muscle electromyogram, electrooculogram, and hippocampal theta wave) to objectively measure states of sleep and wakefulness. Six-hour polygraphic recordings were made between 10.00 and 16.00 h; a time when the rats normally sleep. Prenatally malnourished rats spent 20% more time in slow wave sleep (SWS) compared to the well-nourished rats. The total percentage of time spent in rapid eye movement (REM) sleep was 61% less in prenatally malnourished rats compared to well-nourished control rats. These findings demonstrate the adverse consequences of prenatal protein malnutrition on the quality and quantity of adult sleep in rats. These sleep changes are potentially detrimental to normal social behavior and cognitive functions. Prenatally malnourished rats are an excellent animal model to study the role of endogenous serotonin in the regulation of the normal sleep/wake cycle. [source] Return of the cycad hypothesis , does the amyotrophic lateral sclerosis/parkinsonism dementia complex (ALS/PDC) of Guam have new implications for global health?NEUROPATHOLOGY & APPLIED NEUROBIOLOGY, Issue 4 2005P. G. Ince Recently published work provides evidence in support of the cycad hypothesis for Lytico,Bodig, the Guamanian amyotrophic lateral sclerosis/parkinsonism dementia complex (ALS/PDC), based on a new understanding of Chamorro food practices, a cyanobacterial origin of ,-methylaminoalanine (BMAA) in cycad tissue, and a possible mechanism of biomagnification of this neurotoxic amino acid in the food chain. BMAA is one of two cycad chemicals with known neurotoxic properties (the other is cycasin, a proven developmental neurotoxin) among the many substances that exist in these highly poisonous plants, the seeds of which are used by Chamorros for food and medicine. The traditional diet includes the fruit bat, a species that feeds on cycad seed components and reportedly bioaccumulates BMAA. Plant and animal proteins provide a previously unrecognized reservoir for the slow release of this toxin. BMAA is reported in the brain tissue of Guam patients and early data suggest that some Northern American patients dying of Alzheimer's disease (AD) have detectable brain levels of BMAA. The possible role of cyanobacterial toxicity in sporadic neurodegenerative disease is therefore worthy of consideration. Recent neuropathology studies of ALS/PDC confirm understanding of this disorder as a ,tangle' disease, based on variable anatomical burden, and showing biochemical characteristics of ,AD-like' combined 3R and 4R tau species. This model mirrors the emerging view that other neurodegenerative disease spectra comprise clusters of related syndromes, owing to common molecular pathology, with variable anatomical distribution in the nervous system giving rise to different clinical phenotypes. Evidence for ,ubiquitin-only' inclusions in ALS/PDC is weak. Similarly, although there is evidence for ,-synucleinopathy in ALS/PDC, the parkinsonian component of the disease is not caused by Lewy body disease. The spectrum of sporadic AD includes involvement of the substantia nigra and a high prevalence of ,incidental',-synucleinopathy in sporadic AD is reported. Therefore the pathogenesis of Lytico,Bodig appears still to have most pertinence to the ongoing investigation of the pathogenesis of AD and other tauopathies. [source] Structural brain abnormalities in adolescents with autism spectrum disorder and patients with attention deficit/hyperactivity disorderTHE JOURNAL OF CHILD PSYCHOLOGY AND PSYCHIATRY AND ALLIED DISCIPLINES, Issue 12 2007Sarah Brieber Background:, Although autism spectrum disorder (ASD) and attention deficit/hyperactivity disorder (ADHD) are two distinct neurodevelopmental diseases, they share behavioural, neuropsychological and neurobiological characteristics. For the identification of endophenotypes across diagnostic categories, further investigations of phenotypic overlap between ADHD and autism at the behavioural, neurocognitive, and brain levels are needed. Methods:, We examined regional grey matter differences and similarities in children and adolescents with ASD and ADHD in comparison to healthy controls using structural magnetic resonance imaging (MRI) and voxel-based morphometry. Results:, With regard to clinical criteria, the clinical groups did not differ with respect to ADHD symptoms; however, only patients with ASD showed deficits in social communication and interaction, according to parental rating. Structural abnormalities across both clinical groups compared to controls became evident as grey matter reductions in the left medial temporal lobe and as higher grey matter volumes in the left inferior parietal cortex. In addition, autism-specific brain abnormalities were found as increased grey matter volume in the right supramarginal gyrus. Conclusions:, While the shared structural deviations in the medial temporal lobe might be attributed to an unspecific delay in brain development and might be associated with memory deficits, the structural abnormalities in the inferior parietal lobe may correspond to attentional deficits observed in both ASD and ADHD. By contrast, the autism-specific grey matter abnormalities near the right temporo-parietal junction may be associated with impaired ,theory of mind' abilities. These findings shed some light on both similarities and differences in the neurocognitive profiles of ADHD and ASD patients. [source] Annotation: Deconstructing the attention deficit in fragile X syndrome: a developmental neuropsychological approachTHE JOURNAL OF CHILD PSYCHOLOGY AND PSYCHIATRY AND ALLIED DISCIPLINES, Issue 6 2004K.M. Cornish Background:, Fragile X syndrome is one of the world's leading hereditary causes of developmental delay in males. The past decade has witnessed an explosion of research that has begun to unravel the condition at its various levels: from the genetic and brain levels to the cognitive level, and then to the environmental and behavioural levels. Our aim in this review is to attempt to integrate some of the extensive body of knowledge to move the research a step closer to understanding how the dynamics of atypical development can influence the specific cognitive and behavioural end-states frequently observed in children and adolescents with fragile X syndrome. Methods:, We conducted a review of the current neuropsychological and neuropsychiatric approaches that have attempted to delineate the pattern of ,spared' and ,impaired' functions associated with the phenotype. Results:, The profile of findings suggests that fragile X syndrome should not be viewed merely as a catalogue of spared and impaired cognitive functions or modules. Instead, there appears to be a process of almost gradual modularisation whereby cognitive mechanisms become domain specific as a function of development itself (Karmiloff-Smith, 1992). The results of a decade of intense research point towards an early weakness in one or more components of executive control rather than single, static higher-level deficits (e.g., spatial cognition, speech processing). This weakness affects both the development of more complex functions and current performance. Conclusions:, The prevailing tendency to interpret developmental disorders in terms of fixed damage to distinct modular functions needs to be reconsidered. We offer this review as an example of an alternative approach, attempting to identify an initial deficit and its consequences for the course of development. Through better definition of the cognitive and behavioural phenotype, in combination with current progress in brain imaging techniques and molecular studies, the next decade should continue to hold exciting promise for fragile X syndrome and other neurodevelopmental disorders. [source] Levodopa: Faster and better word learning in normal humansANNALS OF NEUROLOGY, Issue 1 2004Stefan Knecht MD Dopamine is a potent modulator of learning and has been implicated in the encoding of stimulus salience. Repetition, however, as required for the acquisition and reacquisition of sensorimotor or cognitive skills (e.g., in aphasia therapy), decreases salience. We here tested whether increasing brain levels of dopamine during repetitive training improves learning success. Forty healthy humans took 100mg of the dopamine precursor levodopa or placebo daily for 5 days in a randomized double-blind and parallel-group design. Ninety minutes later on each day, subjects were trained on an artificial vocabulary using a high-frequency repetitive approach. Levodopa significantly enhanced the speed, overall success, and long-term retention of novel word learning in a dose-dependent manner. These findings indicate new ways to potentiate learning in a variety of domains if conventional training alone fails. [source] Evaluation of pharmacokinetics, brain levels and protein binding of centpropazine in ratsBIOPHARMACEUTICS AND DRUG DISPOSITION, Issue 2 2004Venkatesh Atul Bhattaram Abstract The pharmacokinetics of centpropazine (CNPZ), an antidepressant, was studied in rats. CNPZ was administered to groups of rats (n=3 to 5) via oral (40 mg/kg), intravenous (5 mg/kg), intraperitoneal (5 mg/kg) and intraduodenal (4 and 8 mg/kg) routes. The AUCs of CNPZ were estimated and the bioavailabilities were calculated. CNPZ was characterized by a short elimination half-life (39.5 min), a high clearance (118 ml/min/kg) and a relatively large volume of distribution (1945 ml/kg) after intravenous administration. After oral administration CNPZ exhibited a very low oral bioavailability (,0.2%). The total first pass effect (Egit+liver) was calculated as 98.7%. The bioavailability of CNPZ was similar when administered by intraduodenal and oral routes. CNPZ readily penetrated into the brain and reached Cmax by 30 min post oral dosing. About 92.0%±0.8% of the drug was bound to serum proteins. Low oral bioavailability of CNPZ following oral administration is likely due to its metabolism by intestinal mucosa and liver. Copyright © 2004 John Wiley & Sons, Ltd. [source] Modulation of synaptic plasticity by stress and antidepressantsBIPOLAR DISORDERS, Issue 3 2002Maurizio Popoli Recent preclinical and clinical studies have shown that mechanisms underlying neuronal plasticity and survival are involved in both the outcome of stressful experiences and the action of antidepressants. Whereas most antidepressants predominantly affect the brain levels of monoamine neurotransmitters, it is increasingly appreciated that they also modulate neurotransmission at synapses using the neurotransmitter glutamate (the most abundant in the brain). In the hippocampus, a main area of the limbic system involved in cognitive functions as well as attention and affect, specific molecules enriched at glutamatergic synapses mediate major changes in synaptic plasticity induced by stress paradigms or antidepressant treatments. We analyze here the modifications induced by stress or antidepressants in the strength of synaptic transmission in hippocampus, and the molecular modifications induced by antidepressants in two main mediators of synaptic plasticity: the N -methyl- D -aspartate (NMDA) receptor complex for glutamate and the Ca2+/calmodulin-dependent protein kinase II (CaM kinase II). Both stress and antidepressants induce alterations in long-term potentiation of hippocampal glutamatergic synapses, which may be partly accounted for by the influence of environmental or drug-induced stimulation of monoaminergic pathways projecting to the hippocampus. In the course of antidepressant treatments significant changes have been described in both the NMDA receptor and CaM kinase II, which may account for the physiological changes observed. A central role in these synaptic changes is exerted by brain-derived neurotrophic factor (BDNF), which modulates both synaptic plasticity and its molecular mediators, as well as inducing morphological synaptic changes. The role of these molecular effectors in synaptic plasticity is discussed in relation to the action of antidepressants and the search for new molecular targets of drug action in the therapy of mood disorders. [source] The endocannabinoid system in brain reward processesBRITISH JOURNAL OF PHARMACOLOGY, Issue 2 2008M Solinas Food, drugs and brain stimulation can serve as strong rewarding stimuli and are all believed to activate common brain circuits that evolved in mammals to favour fitness and survival. For decades, endogenous dopaminergic and opioid systems have been considered the most important systems in mediating brain reward processes. Recent evidence suggests that the endogenous cannabinoid (endocannabinoid) system also has an important role in signalling of rewarding events. First, CB1 receptors are found in brain areas involved in reward processes, such as the dopaminergic mesolimbic system. Second, activation of CB1 receptors by plant-derived, synthetic or endogenous CB1 receptor agonists stimulates dopaminergic neurotransmission, produces rewarding effects and increases rewarding effects of abused drugs and food. Third, pharmacological or genetic blockade of CB1 receptors prevents activation of dopaminergic neurotransmission by several addictive drugs and reduces rewarding effects of food and these drugs. Fourth, brain levels of the endocannabinoids anandamide and 2-arachidonoylglycerol are altered by activation of reward processes. However, the intrinsic activity of the endocannabinoid system does not appear to play a facilitatory role in brain stimulation reward and some evidence suggests it may even oppose it. The influence of the endocannabinoid system on brain reward processes may depend on the degree of activation of the different brain areas involved and might represent a mechanism for fine-tuning dopaminergic activity. Although involvement of the various components of the endocannabinoid system may differ depending on the type of rewarding event investigated, this system appears to play a major role in modulating reward processes. British Journal of Pharmacology (2008) 154, 369,383; doi:10.1038/bjp.2008.130; published online 14 April 2008 [source] | |||||||||||||||||||||||||||||||