Search

Rationale: Adolescent rodents differ markedly from adults in several neuro-behavioural parameters. Moreover, 'paradoxical' responses to psychostimulants have been reported at this age., Objectives: Thus, we investigated the responses of adolescent (post-natal day, PND, 34 to 43) and adult (PND >60) Sprague-Dawley male rats to the psychostimulant drug methylphenidate (MPH). We used pharmacological magnetic resonance imaging (phMRI) performed at 4.7 T under isoflurane anaesthesia. Following anatomical MRI, axial gradient echo images were collected continuously. After baseline recording (32 min), animals received MPH (0 or 4 mg/kg i.p.) and were recorded for further 32 min., Results: Region-specific changes in the blood-oxygenation level dependent (BOLD) signal were evident as a function of age. As expected, among adults MPH induced an increase of BOLD signal in nucleus accumbens (NAcc) and prefrontal cortex (PFC), with no effects in the hippocampus (Hip). Notably, among adolescents, MPH induced a marked and generalised decrease of BOLD signal, which occurred earlier in NAcc and PFC whilst being delayed in the Hip. Any bias in BOLD responses was excluded by the measurement of physiological parameters., Conclusions: The present findings highlight the utility of phMRI in animal models. The peculiar negative BOLD effect found in adolescent rats may be suggestive of a reduced cerebro-vascular feedback and/or an increased MPH-induced neuronal activation. Data are relevant for a better understanding of brain/behavioural regulation during adolescent development. Moreover, a greater understanding of the differences between adult and adolescent drug responses will aid in the development of a more appropriate age-specific treatment strategy.

Pharmacological modulation of the endocannabinoid system is a novel but poorly explored field for potential therapy. Early maternal deprivation represents an animal model for specific aspects of neuropsychiatric disorders. This study explored whether a pharmacological manipulation of the endocannabinoid system at adolescence may restore altered phenotypes resulting from early maternal deprivation. Wistar male rats, maternally deprived for 24 h on postnatal day (PND) 9, were administered the fatty-acid amide hydrolase (FAAH) inhibitor URB597 (0, 0.1 or 0.5 mg/kg/day) for six days during adolescence (PND 31-43), while tested in the intolerance-to-delay task. Deprived (DEP) adolescent rats showed a trend for higher impulsivity levels and an increased locomotor response to novelty when compared to non-deprived (NDEP) controls. The low dose of URB597 effectively decreased impulsive behaviour specifically in DEP subjects. Moreover, long-term metabolic brain changes, induced by drug treatment during adolescence, were detected in DEP animals using proton magnetic resonance spectroscopy ((1)H MRS). Significant changes were only found within the hippocampus: N-acetyl-aspartate and total creatine were up-regulated by the low dose; glutamate and glutamate plus glutamine were conversely down-regulated by the higher dose. In summary, administration of URB597 during adolescence increased self-control behaviour and produced enduring brain biochemical modifications, in a model for neuropsychiatric disorders.

Administration of methylphenidate (MPH, Ritalin) to children affected by attention deficit hyperactivity disorder (ADHD) is an elective therapy, which however raises concerns for public health, due to possible persistent neuro-behavioral alterations. We investigated potential long-term consequences at adulthood of MPH exposure during adolescence, by means of behavioral and brain MRS assessment in drug-free state. Wistar adolescent rats (30- to 44-day-old) were treated with MPH (0 or 2 mg/kg once/day for 14 days) and then left undisturbed until adulthood. Levels of impulsive behavior were assessed in the intolerance-to-delay task: Food-restricted rats were tested in operant chambers with two nose-poking holes, delivering one food pellet immediately, or five pellets after a delay whose length was increased over days. MPH-exposed animals showed a less marked shifting profile from the large/late to the small/soon reward, suggesting reduced basal levels of impulsivity, compared to controls. In vivo MRI-guided 1H MRS examinations at 4.7 T in anaesthetised animals revealed long-term biochemical changes in the dorsal striatum (STR), nucleus accumbens (NAcc), and prefrontal cortex (PFC) of MPH-exposed rats. Notably, total creatine and taurine, metabolites respectively involved in bioenergetics and synaptic efficiency, were up-regulated in the STR and conversely down-regulated in the NAcc of MPH-exposed rats. A strong correlation was evident between non-phosphorylated creatine in the STR and behavioral impulsivity. Moreover, unaltered total creatine and increased phospho-creatine/creatine ratio were detected in the PFC, suggesting improved cortical energetic performance. Because of this enduring rearrangement in the forebrain function, MPH-exposed animals may be more efficient when faced with delay of reinforcement. In summary, MPH exposure during adolescence produced enduring MRS-detectable biochemical modifications in brain reward-related circuits, which may account for increased self-control capacity of adult rats.

Protons J-coupled to 13C were selectively detected in the mouse head by in vivo 1H NMR imaging based on Twin Spin Echo DOuble Resonance (T-SEDOR) excitation. This pulse sequence combines a good chemical specificity with high sensitivity, requires no solvent pre-saturation and is well adapted to the imaging modality. 1H T-SEDOR maps of the mouse head allowed detection of areas of preferential accumulation of 13C-enriched compounds, upon repeated injections of uniformly 13C-labelled glucose, which induced hyperglycemia. The results demonstrated the feasibility, both in time scale and metabolite concentration, of applying T-SEDOR MRI for in vivo mapping brain areas characterized by enhanced rates of glucose uptake and/or accumulation of its metabolites.

By utilizing achievements and results of two previous concerted research projects on magnetic resonance imaging and spectroscopy (MRS), the EU BIOMED 1 Concerted Action on "Cancer and brain disease characterization and therapy assessment by quantitative MRS" was specifically aimed at: 1) developing at a multicentre level harmonized methodologies and protocols for quantitative and reproducible MRS measurements, as a basis for validating these procedures in well controlled clinical and experimental conditions; and 2) providing multicentre critical reviews on the present understanding of the significance of MRS parameters as possible new markers of diagnosis, prognosis and response to therapy. The programme comprised the following main areas of collaborative research and multicentre evaluation: a) development of methods and protocols for quality assessment, calibration and absolute metabolite quantification in in vivo localized, volume-selective MRS; b) design and validation of a new method for assessing localization performance in spectroscopic imaging (MRSI); c) interlaboratory comparison of different methods of signal processing and data analysis, for improving signal quantification in vivo and in vitro MRS spectra; d) quality assessment of high resolution MRS analyses of biological fluids; e) protocol for assembling a pilot data base of MR spectra of tumour extracts for pattern recognition analysis; f) multicentre review on evaluation of the significance of MRS parameters in monitoring lipid metabolism and function in cancer; and g) multicentre review on evaluation of drug pharmacokinetics and metabolism using MRS. The main results and conclusions of four multi-centre trials on items (a), (b) and (c), which involved 24 teams, are reported in the accompanying papers of this series.

We have performed a multicentre trial to assess the performance of three techniques for absolute quantification of cerebral metabolites using in vivo proton nuclear magnetic resonance (NMR). The techniques included were 1) an internal water standard method, 2) an external standard method based on phantom replacement, and 3) a more sophisticated method incorporating elements of both the internal and external standard approaches, together with compartmental analysis of brain water. Only the internal water standard technique could be readily implemented at all participating sites and gave acceptable precision and interlaboratory reproducibility. This method was insensitive to many of the experimental factors affecting the performance of the alternative techniques, including effects related to loading, standing waves and B1 inhomogeneities; and practical issues of phantom positioning, user expertise and examination duration. However, the internal water standard method assumes a value for the concentration of NMR-visible water within the spectroscopic volume of interest. In general, it is necessary to modify this assumed concentration on the basis of the grey matter, white matter and cerebrospinal fluid (CSF) content of the volume, and the NMR-visible water content of the grey and white matter fractions. Combining data from 11 sites, the concentrations of the principal NMR-visible metabolites in the brains of healthy subjects (age range 20-35 years) determined using the internal water standard method were (mean+/-SD): [NAA]=10.0+/-3.4 mM (n=53), [tCho]=1.9+/-1.0 mM (n=51), [Cr + PCr]=6.5+/-3.7 mM (n=51). Evidence of system instability and other sources of error at some participating sites reinforces the need for rigorous quality assurance in quantitative spectroscopy.

Background and Purpose: Transmissible spongiform encephalopathy (TSE) diseases are fatal, progressive neurodegenerative disorders affecting both humans and animals. Clinical signs typically appear after years and even decades of silent disease progression. This study was aimed at investigating whether altered brain MRI patterns may precede clinical signs in a TSE rodent model. Methods: In vivo T2-weighted (T2W) MRI examinations (4.7 T) were performed on Golden Syrian hamsters (GSH) intracerebrally, orally, or intraperitoneally (i.p.) infected with the 263K scrapie strain. Histopathological analyses were performed on i.p. infected GSH at the end of one-day or longitudinal MRI sessions. Results: T2W-MRI hyperintensity was detected in the thalamic nuclei of GSH with clinical signs, irrespective of the infection route. Hyperintensity in the thalamus was also observed in pre-clinical animals, between 106 and 121 days post-infection (dpi), while normal T2W intensity was detected in four animals examined between 72 and 96 dpi. Pathological prion protein deposition (but no astrogliosis and only occasionally, weak spongiosis) was detected between 106 and 121 dpi. Conclusions: The altered T2W-MRI pattern detected in the thalamus of asymptomatic i.p. infected GSH provides a useful basis for evaluating the effectiveness of possible therapeutic approaches at early stages of TSE disease. [ABSTRACT FROM AUTHOR]