Neurochemical Profile Research Articles

Effects of Lisdexamfetamine, a Prodrug of D-Amphetamine, on Locomotion, Spatial Cognitive Processing and Neurochemical Profiles in Rats: A Comparison With Immediate-Release Amphetamine.

D-amphetamine has been used to enhance cognitive performance over the last few decades. Due to the rapid absorption after administration, d-amphetamine shows narrow effective window and severe abuse potential. Lisdexamfetamine, a prodrug of d-amphetamine, reduces the magnitude of plasma d-amphetamine concentration and prolongs the action duration when compared with immediate-release d-amphetamine at equimolar doses. However, the differences of these two drugs, which produce distinct pharmacokinetic characteristics, in cognition improvement still unclear. In present study, we compared the effects of d-amphetamine (i.p) and lisdexamfetamine (p.o) at equimolar doses (0.2, 0.5, 1.5, 4.5, and 13.5 mg/kg of d-amphetamine base) on locomotion, spatial working memory and recognition memory in rats. Given the crucial involvement of dopamine neurotransmitter system within the medial prefrontal cortex (mPFC) in cognitive processing, microdialysis was conducted to profile the difference in neurochemical characteristics between the two drugs. In our results, d-amphetamine ranges from 0.5 to 1.5 mg/kg significantly increased locomotor activity. However, d-amphetamine ranges from 0.2 to 13.5 mg/kg failed to improve spatial working memory and recognition memory in Y-maze-based spontaneous alternation and two-trial delayed alternation tasks of rats, respectively. In contrast, lisdexamfetamine with 4.5 mg/kg significantly increased the locomotion and improved both spatial working and recognition memory. Further, microdialysis showed that lisdexamfetamine induced lower magnitude and longer duration of extracellular dopamine increase than that of d-amphetamine. These results suggest that lisdexamfetamine was more effective than d-amphetamine in improving spatial cognitive performance, which was attributed to the steady and lasting dopamine release pattern within the mPFC.

The influence of cystathionine on neurochemical quantification in brain tumor in vivo MR spectroscopy.

To evaluate the ability of the PRESS sequence (TE =97 ms, optimized for 2-hydroxyglutarate detection) to detect cystathionine in gliomas and the effect of the omission of cystathionine on the quantification of the full neurochemical profile. Twenty-three subjects with a glioma were retrospectively included based on the availability of both MEGA-PRESS and PRESS acquisitions at 3T, and the presence of the cystathionine signal in the edited MR spectrum. In eight subjects, the PRESS acquisition was performed also in normal tissue. Metabolite quantification was performed using LCModel and simulated basis sets. The LCModel analysis for the PRESS data was performed with and without cystathionine. All subjects with glioma had detectable cystathionine levels >1 mM with Cramér-Rao lower bounds (CRLB) <15%. The mean cystathionine concentrations were 3.49 ± 1.17 mM for MEGA-PRESS and 2.20 ± 0.80 mM for PRESS data. Cystathionine concentrations showed a significant correlation between the two MRS methods (r=0.58, p=.004), and it was not detectable in normal tissue. Using PRESS, 19 metabolites were quantified with CRLB <50% for more than half of the subjects. The metabolites that were significantly (p < .0028) and mostly affected by the omission of cystathionine were aspartate, betaine, citrate, γ-aminobutyric acid (GABA), and serine. Cystathionine was detectable by PRESS in all the selected gliomas, while it was not detectable in normal tissue. The omission from the spectral analysis of cystathionine led to severe biases in the quantification of other neurochemicals that may play key roles in cancer metabolism.

Language as a Window Into the Altered State of Consciousness Elicited by Psychedelic Drugs.

Psychedelics are drugs capable of eliciting profound alterations in the subjective experience of the users, sometimes with long-lasting consequences. Because of this, psychedelic research tends to focus on human subjects, given their capacity to construct detailed narratives about the contents of their consciousness experiences. In spite of its relevance, the interaction between serotonergic psychedelics and language production is comparatively understudied in the recent literature. This review is focused on two aspects of this interaction: how the acute effects of psychedelic drugs impact on speech organization regardless of its semantic content, and how to characterize the subjective effects of psychedelic drugs by analyzing the semantic content of written retrospective reports. We show that the computational characterization of language production is capable of partially predicting the therapeutic outcome of individual experiences, relate the effects elicited by psychedelics with those associated with other altered states of consciousness, draw comparisons between the psychedelic state and the symptomatology of certain psychiatric disorders, and investigate the neurochemical profile and mechanism of action of different psychedelic drugs. We conclude that researchers studying psychedelics can considerably expand the range of their potential scientific conclusions by analyzing brief interviews obtained before, during and after the acute effects. Finally, we list a series of questions and open problems that should be addressed to further consolidate this approach.

Cerebellar morphometric and spectroscopic biomarkers for Machado-Joseph Disease

Machado-Joseph disease (MJD) or Spinocerebellar ataxia type 3 (SCA3) is the most common form of dominant SCA worldwide. Magnetic Resonance Imaging (MRI) and Proton Magnetic Resonance Spectroscopy (1H-MRS) provide promising non-invasive diagnostic and follow-up tools, also serving to evaluate therapies efficacy. However, pre-clinical studies showing relationship between MRI-MRS based biomarkers and functional performance are missing, which hampers an efficient clinical translation of therapeutics. This study assessed motor behaviour, neurochemical profiles, and morphometry of the cerebellum of MJD transgenic mice and patients aiming at establishing magnetic-resonance-based biomarkers. 1H-MRS and structural MRI measurements of MJD transgenic mice were performed with a 9.4 Tesla scanner, correlated with motor performance on rotarod and compared with data collected from human patients. We found decreased cerebellar white and grey matter and enlargement of the fourth ventricle in both MJD mice and human patients as compared to controls. N-acetylaspartate (NAA), NAA + N-acetylaspartylglutamate (NAA + NAAG), Glutamate, and Taurine, were significantly decreased in MJD mouse cerebellum regardless of age, whereas myo-Inositol (Ins) was increased at early time-points. Lower neurochemical ratios levels (NAA/Ins and NAA/total Choline), previously correlated with worse clinical status in SCAs, were also observed in MJD mice cerebella. NAA, NAA + NAAG, Glutamate, and Taurine were also positively correlated with MJD mice motor performance. Importantly, these 1H-MRS results were largely analogous to those found for MJD in human studies and in our pilot data in human patients. We have established a magnetic resonance-based biomarker approach to monitor novel therapies in preclinical studies and human clinical trials.

Perception is associated with the brain's metabolic response to sensory stimulation.

Processing of incoming sensory stimulation triggers an increase of cerebral perfusion and blood oxygenation (neurovascular response) as well as an alteration of the metabolic neurochemical profile (neurometabolic response). Here, we show in human primary visual cortex (V1) that perceived and unperceived isoluminant chromatic flickering stimuli designed to have similar neurovascular responses as measured by blood oxygenation level-dependent functional magnetic resonance imaging (BOLD-fMRI) have markedly different neurometabolic responses as measured by proton functional magnetic resonance spectroscopy (1H-fMRS). In particular, a significant regional buildup of lactate, an index of aerobic glycolysis, and glutamate, an index of malate-aspartate shuttle, occurred in V1 only when the flickering was perceived, without any relation with other behavioral or physiological variables. Whereas the BOLD-fMRI signal in V1, a proxy for input to V1, was insensitive to flickering perception by design, the BOLD-fMRI signal in secondary visual areas was larger during perceived than unperceived flickering, indicating increased output from V1. These results demonstrate that the upregulation of energy metabolism induced by visual stimulation depends on the type of information processing taking place in V1, and that 1H-fMRS provides unique information about local input/output balance that is not measured by BOLD-fMRI.

MAFLD progression contributes to altered thalamus metabolism and brain structure

Metabolic associated fatty liver disease (MAFLD), commonly known as non-alcoholic fatty liver disease, represents a continuum of events characterized by excessive hepatic fat accumulation which can progress to nonalcoholic steatohepatitis (NASH), fibrosis, cirrhosis, and in some severe cases hepatocellular carcinoma. MAFLD might be considered as a multisystem disease that affects not only the liver but involves wider implications, relating to several organs and systems, the brain included. The present study aims to investigate changes associated with MAFLD-induced alteration of thalamic metabolism in vivo. DIAMOND (Diet-induced animal model of non-alcoholic fatty liver disease) mice were fed a chow diet and tap water (NC NW) or fat Western Diet (WD SW) for up to 28 weeks. At the baseline and weeks 4, 8, 20, 28 the thalamic neurochemical profile and total cerebral brain volume were evaluated longitudinally in both diet groups using 1H-MRS. To confirm the disease progression, at each time point, a subgroup of animals was sacrificed, the livers excised and placed in formalin. Liver histology was assessed and reviewed by an expert liver pathologist. MAFLD development significantly increases the thalamic levels of total N-acetylaspartate, total creatine, total choline, and taurine. Furthermore, in the WD SW group a reduction in total cerebral brain volume has been observed (p < 0.05 vs NC NW). Our results suggest that thalamic energy metabolism is affected by MAFLD progression. This metabolic imbalance, that is quantifiable by 1H-MRS in vivo, might cause structural damage to brain cells and dysfunctions of neurotransmitter release.

Sex-Dependent Social and Repetitive Behavior and Neurochemical Profile in Mouse Model of Autism Spectrum Disorder.

Autism spectrum disorder (ASD) is a neurodevelopmental condition characterized by deficits in social interaction, impaired communication, and repetitive behaviors. ASD presents a 3:1 ratio of diagnosed boys and girls, raising the question regarding sexual dimorphic mechanisms underlying ASD symptoms, and their molecular basis. Here, we performed in vivo proton magnetic resonance spectroscopy in juvenile male and female Tsc2+/− mice (an established genetic animal model of ASD). Moreover, behavior and ultrasonic vocalizations during social and repetitive tasks were analyzed. We found significant sexual dimorphisms in the levels of metabolites in the hippocampus and prefrontal cortex. Further, we observed that female mutant animals had a differential social behavior and presented an increase in repetitive behavior. Importantly, while mutant females displayed a more simplified communication during social tasks, mutant males exhibited a similar less complex vocal repertoire but during repetitive tasks. These results hint toward sex-dependent alterations in molecular and metabolic pathways, which can lead to the sexual dimorphic behaviors and communication observed in social and repetitive environments.

Behavioral and neurochemical profile of MK-801 adult zebrafish model: Forebrain β2-adrenoceptors contribute to social withdrawal and anxiety-like behavior

Deficits in social communication and interaction are core clinical symptoms characterizing multiple neuropsychiatric conditions, including autism spectrum disorder (ASD) and schizophrenia. Interestingly, elevated anxiety levels are a common comorbid psychopathology characterizing individuals with aberrant social behavior. Despite recent progress, the underlying neurobiological mechanisms that link anxiety with social withdrawal remain poorly understood. The present study developed a zebrafish pharmacological model displaying social withdrawal behavior, following a 3-h exposure to 4 μΜ (+)-MK-801, a non–competitive N-methyl-d-aspartate (NMDA) receptor antagonist, for 7 days. Interestingly, MK-801-treated zebrafish displayed elevated anxiety levels along with higher frequency of stereotypical behaviors, rendering this zebrafish model appropriate to unravel a possible link of catecholaminergic and ASD–like phenotypes. MK-801-treated zebrafish showed increased telencephalic protein expression of metabotropic glutamate 5 receptor (mGluR5), dopamine transporter (DAT) and β2–adrenergic receptors (β2-ARs), supporting the presence of excitation/inhibition imbalance along with altered dopaminergic and noradrenergic activity. Interestingly, β2-ARs expression, was differentially regulated across the Social Decision-Making (SDM) network nodes, exhibiting increased levels in ventral telencephalic area (Vv), a key-area integrating reward and social circuits but decreased expression in dorso-medial telencephalic area (Dm) and anterior tuberal nucleus (ATN). Moreover, the co-localization of β2-ARs with elements of GABAergic and glutamatergic systems, as well as with GAP-43, a protein indicating increased brain plasticity potential, support the key-role of β2-ARs in the MK-801 zebrafish social dysfunctions. Our results highlight the importance of the catecholaminergic neurotransmission in the manifestation of ASD–like behavior, representing a site of potential interventions for amelioration of ASD-like symptoms.

Behavioural and neurochemical effects after repeated administration of N‐ethylpentylone (ephylone) in mice

N-ethyl-pentylone (NEP), also known as 'ephylone' and N-ethylnorpentylone, has been identified as one of the most recent novel psychostimulants to emerge into the illicit drug market and it has been associated with some intoxications and even fatalities. However, little is known about the consequences of its repeated consumption as well as the role of the monoaminergic system in such consequences. Thus, the aim of our study was to investigate the neurochemical profile and the behavioural effects after both acute and repeated NEP exposure. Male OF1mice were acutely (1, 3, 10mg/kg, i.p.) or repeatedly (1, 3, 10mg/kg, i.p., 5days, twice/day) exposed to NEP, and anxiety-like behaviour, aggressiveness, social interaction, depressive-like symptoms, body temperature, changes in monoaminergic enzymes and neurotransmitters levels as well as ΔFosB in striatum and prefrontal cortex (PFC) from post-mortem tissue were analysed short after drug-exposure or during drug-withdrawal. Acute administration of NEP induced anxiolytic effects but also an aggressive behaviour and social exploration deficits in mice, which persist during NEP-withdrawal. Moreover, NEP induced hyperthermia as well as depressive-like symptoms after repeated administrations that may be related to the decrease in serotonin and noradrenaline levels observed in striatum and PFC. Finally, the long-term increase in ΔFosB levels in striatum after NEP chronic exposure points to a high risk of dependence. Altogether indicates that NEP consumption induces different neurological and neuropsychiatric disorders accompanied by changes in the monoaminergic system, posing a threat to public health.

Dose-Dependent Neuroprotective Effects of Bovine Lactoferrin Following Neonatal Hypoxia-Ischemia in the Immature Rat Brain.

Injuries to the developing brain due to hypoxia–ischemia (HI) are common causes of neurological disabilities in preterm babies. HI, with oxygen deprivation to the brain or reduced cerebral blood perfusion due to birth asphyxia, often leads to severe brain damage and sequelae. Injury mechanisms include glutamate excitotoxicity, oxidative stress, blood–brain barrier dysfunction, and exacerbated inflammation. Nutritional intervention is emerging as a therapeutic alternative to prevent and rescue brain from HI injury. Lactoferrin (Lf) is an iron-binding protein present in saliva, tears, and breast milk, which has been shown to have antioxidant, anti-inflammatory and anti-apoptotic properties when administered to mothers as a dietary supplement during pregnancy and/or lactation in preclinical studies of developmental brain injuries. However, despite Lf’s promising neuroprotective effects, there is no established dose. Here, we tested three different doses of dietary maternal Lf supplementation using the postnatal day 3 HI model and evaluated the acute neurochemical damage profile using 1H Magnetic Resonance Spectroscopy (MRS) and long-term microstructure alterations using advanced diffusion imaging (DTI/NODDI) allied to protein expression and histological analysis. Pregnant Wistar rats were fed either control diet or bovine Lf supplemented chow at 0.1, 1, or 10 g/kg/body weight concentration from the last day of pregnancy (embryonic day 21–E21) to weaning. At postnatal day 3 (P3), pups from both sexes had their right common carotid artery permanently occluded and were exposed to 6% oxygen for 30 min. Sham rats had the incision but neither surgery nor hypoxia episode. At P4, MRS was performed on a 9.4 T scanner to obtain the neurochemical profile in the cortex. At P4 and P25, histological analysis and protein expression were assessed in the cortex and hippocampus. Brain volumes and ex vivo microstructural analysis using DTI/NODDI parameters were performed at P25. Acute metabolic disturbance induced in cortical tissue by HIP3 was reversed with all three doses of Lf. However, data obtained from MRS show that Lf neuroprotective effects were modulated by the dose. Through western blotting analysis, we observed that HI pups supplemented with Lf at 0.1 and 1 g/kg were able to counteract glutamatergic excitotoxicity and prevent metabolic failure. When 10 g/kg was administered, we observed reduced brain volumes, increased astrogliosis, and hypomyelination, pointing to detrimental effects of high Lf dose. In conclusion, Lf supplementation attenuates, in a dose-dependent manner, the acute and long-term cerebral injury caused by HI. Lf reached its optimal effects at a dose of 1 g/kg, which pinpoints the need to better understand effects of Lf, the pathways involved and possible harmful effects. These new data reinforce our knowledge regarding neuroprotection in developmental brain injury using Lf through lactation and provide new insights into lactoferrin’s neuroprotection capacities and limitation for immature brains.

A pilot spectroscopy study of adversity in adolescents.

Background:Childhood adversity is a global health problem affecting 25–50% of children worldwide. Few prior studies have examined the underlying neurochemistry of adversity in adolescents. This cross-sectional study examined spectroscopic markers of trauma in a cohort of adolescents with major depressive disorder (MDD) and healthy controls. We hypothesized that historical adversity would have a negative relationship with spectroscopic measures of glutamate metabolites in anterior cingulate cortex.Methods:Adolescent participants (aged 13–21) underwent a semi-structured diagnostic interview and clinical assessment, which included the self-report Childhood Trauma Questionnaire (CTQ), a 28-item assessment of childhood adversity. Proton magnetic resonance spectroscopy (1H-MRS) scans at 3 Tesla of an anterior cingulate cortex (ACC) voxel (8 cm3) encompassing both hemispheres were collected using a 2-dimensional J-averaged sequence to assess N-acetylaspartate (NAA), Glx (glutamate+glutamine) and [NAA]/[Glx] concentrations. Generalized linear models assessed the relationships between CTQ scores and metabolite levels in ACC.Results:Thirty-nine participants (17 healthy controls, 22 depressed participants) underwent 1H-MRS and completed the CTQ measures. There were decrements in [NAA]/[Glx] ratio in the ACC of participants with childhood adversity while no significant relationship between CTQ total score and any of the ACC metabolites was found in the combined sample. Exploratory results revealed a positive association between Glx levels and CTQ scores in depressed participants. Conversely the [NAA]/[Glx] ratio had a negative association with total CTQ scores in the depressed participants. Emotional Abuse Scale showed a significant negative relationship with [NAA]/[Glx] ratio in the combined sample when adjusted for depression severity.Conclusions:Our findings suggest that childhood adversity may impact brain neurochemical profiles. Further longitudinal studies should examine neurochemical correlates of childhood adversity throughout development and in populations with other psychiatric disorders.

13.1 DISTINCT NEURAL UNDERPINNINGS FOR AUTISM SPECTRUM DISORDER AND ADHD

Individuals with autism spectrum disorder (ASD) suffer from significantly higher rates of psychiatric comorbidities compared to typically developing populations. Novel neuroimaging modalities may offer a unique way to clarify the neural underpinnings associated with ASD and other common coexisting disorders. The purpose of this talk is to examine the neurochemical and neural connectivity profile in youth with ASD with and without associated psychopathology using the advanced neuroimaging techniques of proton magnetic resonance spectroscopic (1HMRS) and diffusion tensor imaging (DTI). Our presentation will focus on 2 neuroimaging studies: 1) an 1HMRS imaging study to examine brain neurotransmitter glutamate activity in the pregenual anterior cingulate cortex (pACC) in youth with ASD (N = 37) with and without emotional dysregulation (ED); and 2) a DTI study to examine the neural structural connectivity profile of ADHD in youth with and without ASD (N: ASD = 15, ADHD = 16). The results of the 1HMRS study show that pACC glutamate activity was significantly higher in youth with ASD vs age- and sex-matched healthy controls (95.5 ±14.6 vs 76.6 ±17.7; p < 0.001, MD: –18.8 ± 33.9; ED: –1.21 [–1.84 to –0.57]). The pACC glutamate activity was additionally significantly higher in the presence of ED (p = 0.005). The pACC glutamate activity positively correlated with the severity of ASD (p = 0.002; r = 0.5) and ED (p = 0.05; r = 0.6). Results of the DTI study revealed that the dorsal brain aberrant neural connectivity profile observed with ADHD was also observed with ADHD in youth with ASD. Abnormally high brain glutamate activity was observed as a common neural underpinning between ASD and ED. Furthermore, the neural pathway abnormality associated with ADHD is distinctly expressed in youth with ASD who have ADHD. These results suggest that novel neuroimaging modalities may be able to help elucidate the neural underpinnings of ASD and other commonly co-occurring psychopathologies.

Distribution and neurochemical characteristic of the cardiac nerve structures in the heart of chinchilla (Chinchilla laniger Molina).

The heart innervation is made up of plexo-ganglionic formation containing sympathetic, parasympathetic, and sensory components. We examined the distribution and neurochemical coding of the ganglia and nerve fibers in the chinchilla's heart. The heart sections of 10 male and 10 female adult chinchillas were processed in accordance with the thiocholine method for acetylcholine esterase (AChE), and the SPG method for detecting the presence of adrenergic fibers was applied. The routine technique of immunohistochemical (IHC) staining with primary antibodies directed against ChAT, VAChT, DbH, TH, CART, NPY, VIP, GAL and SOM was used. The secondary antibodies were conjugated with Alexa Fluor 488 and Alexa Fluor 555 fluorophores. The epicardium contained ganglia and nerve fibers, the myocardium had a few ganglion neurocytes and nerve fibers, and the endocardium contained only nerve fibers. In the epicardium, AChE-positive fibers were more prevalent than SPG-positive fibers. All the ganglion cells were immunopositive for ChAT and VAChT. Some cells also had a positive reaction to DbH and TH. Fibers containing cholinergic and adrenergic markers were numerous, while many of them were ChAT/DbH- and VAChT/TH-positive. CART/NPY and CART/VIP, as well as CART and GAL, were observed to be colocalized in ganglion neurocytes, as well as in individual cells. The nerve fibers were found to contain all the neurotransmitters we tested for, as well as the following co-occurrences: ChAT/DbH, VAChT/TH, CART/NPY, CART/VIP, CART/GAL, and CART/SOM. Our analysis of the neurochemical profile of the nerve structures in chinchilla's heart showed that, despite interspecies differences, the general pattern of the distribution of autonomic nervous system structures is similar to that of other mammals' species, including humans.

Multimodal Imaging and Visual Evoked Potentials Reveal Key Structural and Functional Features That Distinguish Symptomatic From Presymptomatic Huntington's Disease Brain.

Huntington's disease (HD) is a progressive neurodegenerative disorder characterized by motor, cognitive, and psychiatric abnormalities. Currently, matched analyses of structural and functional differences in the brain from the same study cohort and, specifically, in HD patients from an ethnically diverse Indian population are lacking. Such findings aid in identifying noninvasive and sensitive imaging biomarkers. The aim of the study was to understand the structural and functional differences between HD and control brain, and presymptomatic and symptomatic HD brain in the Indian population. Seventeen HD (11 symptomatic HD [S-HD] and six presymptomatic HD [P-HD], with comparable CAG repeats), and 12 healthy controls were examined. Macrostructural (volume), microstructural (diffusivity), and functional (neurochemical levels and glucose metabolism) imaging of the brain was done along with the determination of visual latencies. HD brain showed increased intercaudate distance; significant subcortical volumetric loss; reduced fractional anisotropy; increased mean, axial, and radial diffusivity; lower levels of total N-acetyl aspartate; elevated total choline levels; and reduced glucose metabolism compared with control brain. Interestingly, compared with P-HD, S-HD patients demonstrated a strong inverse correlation between age at onset and CAG repeat length, and prolonged P100 latency. In addition, caudate and putamen in S-HD brain showed significant volumetric loss and increased diffusivity compared with P-HD brain. HD brain showed distinct macrostructural, microstructural, and functional differences compared with control brain in the Indian population. Interestingly, patients with S-HD had a significant volumetric loss, increased diffusivity, altered neurochemical profile, and delayed P100 latency compared with P-HD patients. Examining these alterations clinically could aid in monitoring the progression of HD.

PRATEEK: Integration of Multimodal Neuroimaging Data to Facilitate Advanced Brain Research

Background: In vivo neuroimaging modalities such as magnetic resonance imaging (MRI), functional MRI (fMRI), magnetoencephalography (MEG), magnetic resonance spectroscopy (MRS), and quantitative susceptibility mapping (QSM) are useful techniques to understand brain anatomical structure, functional activity, source localization, neurochemical profiles, and tissue susceptibility respectively. Integrating unique and distinct information from these neuroimaging modalities will further help to enhance the understanding of complex neurological diseases. Objective: To develop a processing scheme for multimodal data integration in a seamless manner on healthy young population, thus establishing a generalized framework for various clinical conditions (e.g., Alzheimer’s disease). Methods: A multimodal data integration scheme has been developed to integrate the outcomes from multiple neuroimaging data (fMRI, MEG, MRS, and QSM) spatially. Furthermore, the entire scheme has been incorporated into a user-friendly toolbox- “PRATEEK”. Results: The proposed methodology and toolbox has been tested for viability among fourteen healthy young participants. The data-integration scheme was tested for bilateral occipital cortices as the regions of interest and can also be extended to other anatomical regions. Overlap percentage from each combination of two modalities (fMRI-MRS, MEG-MRS, fMRI-QSM, and fMRI-MEG) has been computed and also been qualitatively assessed for combinations of the three (MEG-MRS-QSM) and four (fMRI-MEG-MRS-QSM) modalities. Conclusion: This user-friendly toolbox minimizes the need of an expertise in handling different neuroimaging tools for processing and analyzing multimodal data. The proposed scheme will be beneficial for clinical studies where geometric information plays a crucial role for advance brain research.

Relaxation-corrected macromolecular model enables determination of 1 H longitudinal T1 -relaxation times and concentrations of human brain metabolites at 9.4T.

Ultrahigh field MRS has improved characterization of the neurochemical profile. To compare results obtained at 9.4T to those from lower field strengths, it is of interest to quantify the concentrations of metabolites measured. Thus, measuring T1 -relaxation times is necessary to correct for T1 -weighting that occurs in acquisitions for single-voxel spectroscopy and spectroscopic imaging. A macromolecule (MM) simulation model was developed to fit MM contributions to the short TE inversion series used to measure T1 -relaxation times. An inversion series with seven time points was acquired with metabolite-cycled STEAM to estimate T1 -relaxation times of metabolites. A short TE was employed in this study to retain signals from metabolites with short T2 -relaxation times and J-couplings. The underlying macromolecule spectrum was corrected by developing a sequence-specific, relaxation-corrected simulated MM model. Quantification of metabolite peaks was performed using internal water referencing and relaxation corrections. T1 -relaxation times for metabolites range from approximately 750 to approximately 2000 ms and approximately 1000 to approximately 2400 ms in gray matter (GM)- and white matter (WM)- rich voxels, respectively. Quantification of metabolites was compared between GM and WM voxels, as well as between results that used a simulated MM spectrum against those that used an experimentally acquired MM spectrum. Metabolite concentrations are reported in mmol/kg quantities. T1 -relaxation times are reported for nonsinglet resonances for the first time at 9.4T by use of a MM simulation model to account for contributions from the MM spectrum. In addition to T1 -relaxation times, quantification results of metabolites from GM- and WM-rich voxels are reported.

UPLC-MS/MS-based profiling of 31 neurochemicals in the mouse brain after treatment with the antidepressant nefazodone

Depression, typically understood as a mental disorder, is characterized by monoamine neurotransmitter deficiencies in the central nervous system (CNS). A majority of antidepressants have been developed to increase endogenous levels of monoamine neurotransmitters, such as dopamine (DA), norepinephrine (NE), and serotonin (5-HT) in brain tissue. Increasingly, the critical effects of a variety of neurotransmitters, including those of the dopaminergic, serotonergic, kynurenergic, cholinergic, histaminergic, and GABAergic systems, as well as several amino acids, have been spotlighted as neuromodulators over the years in various behavioral and emotional responses. In the present study, we developed a simple method for simultaneous analysis of 31 neurochemicals in mouse whole brain tissue using liquid chromatography tandem mass spectrometry (LC-MS/MS). Our neurochemical profiles were classified into seven categories according to metabolic pathways composed of neurotransmitters and their precursors or metabolites. The analytical method was validated by intra- and inter-day precision, accuracy, sensitivity, and selectivity, and finally applied for neurochemical profiling in the mouse brain following nefazodone treatment. In this study, the modulation of 5-HT and DA by nefazodone was confirmed in the mouse brain, as previously reported. Interestingly, nefazodone-induced broad-spectrum neurochemical changes could suggest that nefazodone has novel anti-depressive and anti-cholinesterase potency via increasing endogenous levels of betaine and acetylcholine in the mouse brain. This neurochemical profiling approach may represent a meaningful tool for better understanding brain neurochemistry and neurotoxicity in discovery and development of CNS drugs.

Dendritic spine remodeling and plasticity under general anesthesia.

Ever since its first use in surgery, general anesthesia has been regarded as a medical miracle enabling countless life-saving diagnostic and therapeutic interventions without pain sensation and traumatic memories. Despite several decades of research, there is a lack of understanding of how general anesthetics induce a reversible coma-like state. Emerging evidence suggests that even brief exposure to general anesthesia may have a lasting impact on mature and especially developing brains. Commonly used anesthetics have been shown to destabilize dendritic spines and induce an enhanced plasticity state, with effects on cognition, motor functions, mood, and social behavior. Herein, we review the effects of the most widely used general anesthetics on dendritic spine dynamics and discuss functional and molecular correlates with action mechanisms. We consider the impact of neurodevelopment, anatomical location of neurons, and their neurochemical profile on neuroplasticity induction, and review the putative signaling pathways. It emerges that in addition to possible adverse effects, the stimulation of synaptic remodeling with the formation of new connections by general anesthetics may present tremendous opportunities for translational research and neurorehabilitation.

Use of Intranasal Insulin as Neuroprotection From Hyperglycemia in Rat Model of Extremely Preterm Infants

Background: Hyperglycemia is common in extremely preterm infants (EPI) and is a risk factor for increased mortality and morbidity, including abnormal neurodevelopment. Hippocampus-mediated cognitive deficits are common in this population. In a rat model of insulinopenic hyperglycemia, abnormal neurochemistry in the hippocampus was found, with lactate, glutamate (Glu):glutamine (Gln) ratio lower and Phosphorylated Creatinine (PCr):Creatinine (Cr) higher. Intranasal insulin has been shown to improve cognitive function in animal models of Alzheimer’s disease and type 2 diabetes mellitus, as well as in adult human studies of Alzheimer’s disease. No study has previous investigated the use of intranasal insulin on preventing the long-term effects of hyperglycemia in the EPI population. Objective: To determine whether administration of intranasal insulin during early postnatal days would negate the effects of hyperglycemia on the developing hippocampus in neonatal rat model of streptozotocin (STZ)-induced hyperglycemia. Design/Methods: STZ (80mg/kg IP) was injected on postnatal day (P) 2, and littermates in the control group were injected with an equivalent volume of citrate buffer. STZ pups were randomized to intranasal insulin, 3U twice daily from P3-P6 (STZ + INS) or left untreated (STZ). Neurochemical profile (consisting of 20 metabolites, PCr:Cr and Glu:Gln ratios) of the hippocampus was evaluated using ultra-high-field (9.4 T) magnetic resonance spectroscopy (MRS) on P7 (acute effects) and P56 (long-term effects) compared with the control group (CON)(N=6/group). Results: Mean glucose values from P3-P6 were higher in STZ groups (STZ = 279.0 +/- 132.2 mg/dL, STZ+INS = 274.4 +/- 89.5 mg/dL, CONT = 128.4 +/- 15.1 mg/dL). The neurochemical profile was different at both P7 and P56. On P7, compared with the control, the taurine (Tau) was higher in the STZ groups (p = 0.007. At P56, PCr:Cr was higher in the STZ group compared to CONT and STZ+INS groups (p = 0.04). No difference noted between the STZ+INS and CONT groups. No other metabolites were altered. Conclusion: Neonatal hyperglycemia alters the acute and long-term neurochemical profile in the hippocampus of developing rats. The increase in PCr:Cr ratio in the STZ group indicates lower demand for ATP and PCr, secondary to decreased neuronal activity, which has been demonstrated in previous studies. PCr:Cr ratio of the STZ+INS group was no different than control, indicating that intranasal insulin reverses the negative effect on neuronal activity caused by neonatal hyperglycemia.

Association Between Anterior Cingulate Cortex Neurochemical Profile and Clinical Remission After Electroconvulsive Treatment in Major Depressive Disorder: A Longitudinal 1H Magnetic Resonance Spectroscopy Study.

The aim of the study was to assess anterior cingulate cortex (ACC) neurochemical profile of patients with unipolar major depressive disorder (MDD) before and after electroconvulsive therapy (ECT) by using 1H magnetic resonance spectroscopy (1H-MRS). Using 1H-MRS, the metabolite levels of choline, glutamate + glutamine (Glx), myo-inositol, N-acetylaspartate, and total creatine were measured in ACC before and after 4-week ECT. The Montgomery-Åsberg Depression Rating Scale (MADRS) was implemented by blind raters to evaluate the efficacy of the treatment. Electroconvulsive therapy-remitter (ER) and nonremitter groups were compared using the 1-way repeated measures analysis of variance. Thirty patients with unipolar MDD (aged 41.3 ± 10.0 years, 66.7% female) were included in the study. The ER group (n = 16, 53.3%) and NR group did not differ regarding baseline Global Assessment of Functioning and MADRS scores. At the end of 4-week ECT treatment, results did not suggest any significant difference for metabolite levels in ACC. When compared with the NR group, the ER group had higher baseline levels of Glx (8.8 ± 1.8 vs 6.3 ± 2.0, P = 0.005) and total creatine (5.3 ± 0.6 vs 4.7 ± 0.5, P = 0.010). In addition, elevated baseline Glx (r = -0.68, P = 0.002) was associated with lower MADRS scores at the end treatment. Finally, the change in Glx levels was correlated with change in MADRS scores after ECT (r = 0.47, P = 0.049). Modest sample size and 1H-MRS at 1.5 Tesla are limitations of the study. Results suggested that Glx levels could be a predictor of remission. Studies with larger samples should explore neurochemical correlates of ECT in unipolar MDD.