Abnormal trajectory of brain development has been suggested by previous structural magnetic resonance imaging and head circumference findings in autism spectrum disorders (ASDs); however, the neurochemical backgrounds remain unclear. To elucidate neurochemical processes underlying aberrant brain growth in ASD, we conducted a comprehensive literature search and a meta-analysis of 1H-magnetic resonance spectroscopy (1H-MRS) studies in ASD. From the 22 articles identified as satisfying the criteria, means and s.d. of measure of N-acetylaspartate (NAA), creatine, choline-containing compounds, myo-Inositol and glutamate+glutamine in frontal, temporal, parietal, amygdala-hippocampus complex, thalamus and cerebellum were extracted. Random effect model analyses showed significantly lower NAA levels in all the examined brain regions but cerebellum in ASD children compared with typically developed children (n=1295 at the maximum in frontal, P<0.05 Bonferroni-corrected), although there was no significant difference in metabolite levels in adulthood. Meta-regression analysis further revealed that the effect size of lower frontal NAA levels linearly declined with older mean age in ASD (n=844, P<0.05 Bonferroni-corrected). The significance of all frontal NAA findings was preserved after considering between-study heterogeneities (P<0.05 Bonferroni-corrected). This first meta-analysis of 1H-MRS studies in ASD demonstrated robust developmental changes in the degree of abnormality in NAA levels, especially in frontal lobes of ASD. Previously reported larger-than-normal brain size in ASD children and the coincident lower-than-normal NAA levels suggest that early transient brain expansion in ASD is mainly caused by an increase in non-neuron tissues, such as glial cell proliferation.
Asperger disorder; autistic disorder; human; neuroimaging; pervasive developmental disorder; systematic review
Recent research in autism spectrum disorder (ASD) has aroused interest in anterior cingulate cortex and in the neurometabolite glutamate. We report two studies of pregenual anterior cingulate cortex (pACC) in pediatric ASD. First, we acquired in vivo single-voxel proton magnetic resonance spectroscopy (1H MRS) in 8 children with ASD and 10 typically developing controls who were well matched for age, but with fewer males and higher IQ. In the ASD group in midline pACC, we found mean 17.7% elevation of glutamate + glutamine (Glx) (p<0.05) and 21.2% (p<0.001) decrement in creatine + phosphocreatine (Cr). We then performed a larger (26 subjects with ASD, 16 controls) follow-up study in samples now matched for age, gender, and IQ using proton magnetic resonance spectroscopic imaging (1H MRSI). Higher spatial resolution enabled bilateral pACC acquisition. Significant effects were restricted to right pACC where Glx (9.5%, p<0.05), Cr (6.7%, p<0.05), and N-acetyl-aspartate + N-acetyl-aspartyl-glutamate (10.2%, p<0.01) in the ASD sample were elevated above control. These two independent studies suggest hyperglutamatergia and other neurometabolic abnormalities in pACC in ASD, with possible right-lateralization. The hyperglutamatergic state may reflect an imbalance of excitation over inhibition in the brain as proposed in recent neurodevelopmental models of ASD.
Attentional dysfunction is among the most consistent observations of autism spectrum disorders (ASD). However, the neural nature of this deficit in ASD is still unclear. In this study, we aimed to identify the neurobehavioral correlates of attentional dysfunction in ASD. We used the Attention Network Test-Revised and functional magnetic resonance imaging to examine alerting, orienting, and executive control functions, as well as the neural substrates underlying these attentional functions in unmedicated, high-functioning adults with ASD (n = 12) and matched healthy controls (HC, n = 12). Compared with HC, individuals with ASD showed increased error rates in alerting and executive control, accompanied by lower activity in the mid-frontal gyrus and the caudate nucleus for alerting, and by the absence of significant functional activation in the anterior cingulate cortex (ACC) for executive control. In addition, greater behavioral deficiency in executive control in ASD was correlated with less functional activation of the ACC. These findings of behavioral and neural abnormalities in alerting and executive control of attention in ASD may suggest core attentional deficits, which require further investigation.
Alerting; anterior cingulate cortex; attentional networks; autism; executive control
Neurometabolic sequelae of children born at very low birth weight (VLBW) are not well characterized in early childhood. Proton magnetic resonance spectroscopy (1H-MRS) and developmental assessments were acquired from children age 18-22 months (16 VLBW/7 term) and 3-4 years (12 VLBW/8 term) from the anterior cingulate and left frontal periventricular white matter. Metabolites obtained included combined N-acetylaspartylglutamate and N-acetylaspartate (NAA), total choline-containing compounds (Cho), combined glutamate and glutamine (Glx), combined creatine and phosphocreatine (Cr), myo-inositol (mI), and the following ratios: NAA/Cr, Cho/Cr, Glx/Cr, mI/Cr and NAA/Cho. Significant differences were present only in white matter: at 18-22 months NAA was decreased in VLBW children (p<0.04), and at 3-4 years VLBW children showed lower Cr (p<0.01), lower NAA/Cho (p<0.005), higher Glx/Cr (p<0.02) and higher Cho/Cr (p<0.005). On developmental testing, VLBW children scored lower on language expression (p<0.05) and on the A not B test of early executive function (p<0.01) at 18-22 months, and had lower verbal intelligence quotient (IQ) (p<0.005), performance IQ (p<0.04), and several measures of early executive function including the bear-dragon test (p<0.004), gift delay (p<0.07) and summary categorization score (p<0.03) at 3-4 years. VLBW children may have neurometabolic and developmental abnormalities that persist at least through early childhood.
To examine whether patients with schizophrenia associated with idiopathic unconjugated hyperbilirubinemia (Gilbert's syndrome [GS]) have specific changes in brain metabolism.
We applied proton magnetic resonance spectroscopy (1H-MRS) to the anterior cingulate gyrus, insular cortex and thalamus of patients with schizophrenia and GS (n = 15) or without GS (n = 15), all diagnosed with schizophrenia according to the criteria of the Diagnostic and Statistical Manual of Mental Disorders, fourth edition (DSM-IV), and healthy subjects (n = 20).
In the anterior cingulate gyrus, patients with schizophrenia and GS showed significant decreases in N-acetyl aspartate/creatine–phosphocreatinine (NAA/Cr), choline/creatine–phosphocreatinine (Cho/Cr) and myoinositol/ creatine–phosphocreatinine (mI/Cr) ratios compared with healthy subjects and compared with patients with schizophrenia without GS. Patients with schizophrenia without GS also showed significant decreases in NAA/Cr, Cho/Cr and ml/Cr compared with healthy subjects. In the insular cortex, patients with schizophrenia and GS showed significant decreases in NAA/Cr, Cho/Cr and ml/Cr compared with healthy subjects and compared with patients with schizophrenia without GS. Patients with schizophrenia without GS also showed significant decreases in NAA/Cr, Cho/Cr and ml/Cr compared with healthy subjects. In the thalamus, patients with schizophrenia and GS showed significant decreases in NAA/Cr, Cho/Cr and ml/Cr compared with healthy subjects, whereas patients with schizophrenia without GS only showed a significant decrease in ml/Cr compared with healthy subjects.
Our findings suggest that brain metabolism is more severely compromised in the subtype of schizophrenia with GS.
anterior cingulate gyrus; Gilbert disease; hyperbilirubinemia; insular cortex; proton magnetic resonance spectroscopy; schizophrenia; thalamus
In vivo proton magnetic resonance spectroscopy (1H-MRS) studies of HIV-infected humans have demonstrated significant metabolic abnormalities that vary by brain region, but the causes are poorly understood. Metabolic changes in the frontal cortex, basal ganglia and white matter in 18 SIV-infected macaques were investigated using MRS during the first month of infection.
Changes in the N-acetylaspartate (NAA), choline (Cho), myo-inositol (MI), creatine (Cr) and glutamine/glutamate (Glx) resonances were quantified both in absolute terms and relative to the creatine resonance. Most abnormalities were observed at the time of peak viremia, 2 weeks post infection (wpi). At that time point, significant decreases in NAA and NAA/Cr, reflecting neuronal injury, were observed only in the frontal cortex. Cr was significantly elevated only in the white matter. Changes in Cho and Cho/Cr were similar across the brain regions, increasing at 2 wpi, and falling below baseline levels at 4 wpi. MI and MI/Cr levels were increased across all brain regions.
These data best support the hypothesis that different brain regions have variable intrinsic vulnerabilities to neuronal injury caused by the AIDS virus.
Although magnetic resonance spectroscopy has identified metabolic abnormalities in adult and childhood schizophrenia, no prior studies have investigated the relationship between neurometabolites and thought disorder. This study examined this association in language-related brain regions using proton magnetic resonance spectroscopic imaging (1H MRSI).
MRSI was acquired bilaterally from 28 youth with childhood-onset schizophrenia and 34 healthy control subjects in inferior frontal, middle frontal, and superior temporal gyri at 1.5 T and short echo time (TR/TE=1500/30 ms). CSF-corrected “total NAA” (tNAA; N-acetyl-aspartate+N-acetyl-aspartyl-glutamate), glutamate+glutamine (Glx), creatine+phosphocreatine (Cr+PCr), choline compounds (Cho), and myo-inositol (mI) were assayed in manually drawn regions-of-interest partitioned into gray matter, white matter, and CSF and then coregistered with MRSI. Speech samples of all subjects were coded for thought disorder.
In the schizophrenia group, the severity of formal thought disorder correlated significantly with tNAA in the left inferior frontal and superior temporal gyri and with Cr+PCr in left superior temporal gyrus.
Neurometabolite concentrations in language-related brain regions are associated with thought disorder in childhood-onset schizophrenia.
Childhood-onset schizophrenia; Thought Disorder; Magnetic Resonance Spectroscopy; N-acetyl aspartate; Choline compounds
There is increasing evidence that neurodevelopmental differences in people with Fragile X syndrome (FraX) may be explained by differences in glutamatergic metabolism. Premutation carriers of FraX were originally considered to be unaffected although several recent reports demonstrate neuroanatomical, cognitive, and emotional differences from controls. However there are few studies on brain metabolism in premutation carriers of FraX.
We used proton magnetic resonance spectroscopy to compare neuronal integrity of a number of brain metabolites including N-Acetyl Aspartate, Creatine + Phosphocreatinine, Choline, myoInositol, and Glutamate containing substances (Glx) in 17 male premutation carriers of FraX and 16 male healthy control individuals.
There was no significant between-group difference in the concentration of any measured brain metabolites. However there was a differential increase in N-acetyl aspartate with aging in premutation FraX individuals compared to controls.
This is the first 1 H-MRS study to examine premutation FraX individuals. Although we demonstrated no difference in the concentration of any of the metabolites examined between the groups, this may be due to the large age ranges included in the two samples. The differential increase in NAA levels with aging may reflect an abnormal synaptic pruning process.
Fragile X; Premutation carriers; MRS; NAA
Brain metabolism, as studied by magnetic resonance spectroscopy (MRS), has been previously shown to be abnormal in Rett syndrome (RTT). However the relationship of MRS findings to age, disease severity and genotype is unknown. This study reports MRS findings in 40 RTT girls (1–14 years old) and 12 age-matched controls.
Single voxel, short echo time proton MRS of left frontal lobe white matter was performed. Levels of myo-inositol (mI), total choline (Cho), glutamate/glutamine (Glx), and N-acetyl aspartate (NAA) were expressed as ratios relative to creatine (Cr).
NAA/Cr ratios decreased and mI/Cr ratios increased with age in RTT (both p<0.03) while these ratios were stable in controls. The mean Glx/Cr ratio was 36% higher in RTT than in controls (p=0.043). The mean NAA/Cr ratio was 12.6% lower in RTT patients with seizures compared to those without seizures (p=0.017). NAA/Cr ratios also decreased with increasing clinical severity score (p=0.031). Compared to patients with T158X, R255X, and R294X mutations, and C-terminal deletions, patients with the R168X mutation tended to have the highest severity score (0.01≤p≤0.11) and the lowest NAA/Cr ratio (0.029≤p<0.14).
Decreasing NAA/Cr and increasing mI/Cr with age are suggestive of progressive axonal damage and astrocytosis in RTT respectively, while increased Glx/Cr ratio may be secondary to increasing glutamate-glutamine cycling at the synaptic level. The relationships between NAA/Cr, presence or absence of seizures, and disease severity suggest that MRS provides a non-invasive measure of cerebral involvement in RTT, with greatest impairment in patients with the R168X mutation.
The goal of this study was to investigate whether certain metabolites, specific to neurons, glial cells, and the neuronal-glial neurotransmission system, in the primary somatosensory cortex (SSC), are altered and correlated with clinical characteristics of pain in patients with chronic low back pain (LBP). Eleven LBP patients and eleven age-matched healthy controls were included. N-acetylaspartate (NAA), choline (Cho), myo-inositol (mI), and glutamine/glutamate (Glx) were measured with proton magnetic resonance spectroscopy (1H-MRS) in left and right SSC. Differences in metabolite concentrations relative to those of controls were evaluated as well as analyses of metabolite correlations within and between SSCs. Relationships between metabolite concentrations and pain characteristics were also evaluated. We found decreased NAA in the left SSC (P = 0.001) and decreased Cho (P = 0.04) along with lower correlations between all metabolites in right SSC (P = 0.007) in LBP compared to controls. In addition, we found higher and significant correlations between left and right mI (P < 0.001 in LBP vs P = 0.1 in controls) and between left mI and right Cho (P = 0.048 vs P = 0.6). Left and right NAA levels were negatively correlated with pain duration (P = 0.04 and P = 0.02 respectively) while right Glx was positively correlated with pain severity (P = 0.04). Our preliminary results demonstrated significant altered neuronal-glial interactions in SSC, with left neural alterations related to pain duration and right neuronal-glial alterations to pain severity. Thus, the 1H-MRS approach proposed here can be used to quantify relevant cerebral metabolite changes in chronic pain, and consequently increase our knowledge of the factors leading from these changes to clinical outcomes.
chronic low back pain; primary somatosensory cortex; magnetic resonance spectroscopy; neuronal-glial interactions
Rapid progress in our understanding of macrostructural abnormalities in autism spectrum disorders (ASD) has occurred in recent years. However, the relationship between the integrity of neural tissue and neural function has not been previously investigated. Single-voxel proton magnetic resonance spectroscopy and functional magnetic resonance imaging of an executive functioning task was obtained in 13 high functioning adolescents and adults with ASD and 13 age-matched controls. The ASD group showed significant reductions in N-acetyl aspartate (NAA) in all brain regions combined and a specific reduction in left frontal cortex compared to controls. Regression analyses revealed a significant group interaction effect between frontal and cerebellar NAA. In addition, a significant positive semi-partial correlation between left frontal lobe NAA and frontal lobe functional activation was found in the ASD group. These findings suggest that widespread neuronal dysfunction is present in high functioning individuals with ASD. Hypothesized developmental links between frontal and cerebellar vermis neural abnormalities were supported, in that impaired neuronal functioning in the vermis was associated with impaired neuronal functioning in the frontal lobes in the ASD group. Furthermore, this study provided the first direct evidence of the relationship between abnormal functional activation in prefrontal cortex and neuronal dysfunction in ASD.
autism; FMRI; magnetic resonance spectroscopy; verbal fluency; cerebellum; frontal lobe; NAA
Childhood lead exposure adversely affects neurodevelopment. However, few studies have examined changes in human brain metabolism that may underlie known adverse cognitive and behavioral outcomes.
We examined the association between mean childhood blood lead levels and in vivo brain metabolite concentrations as adults, determined by proton magnetic resonance spectroscopy (MRS) in a birth cohort with documented low-to-moderate lead exposure.
Adult participants from the Cincinnati Lead Study [n = 159; mean age (± SD), 20.8 ± 0.9 years] completed a quantitative, short-echo proton MRS protocol evaluating seven regions to determine brain concentrations of N-acetyl aspartate (NAA), creatine and phosphocreatine (Cr), cholines (Cho), myo-inositol, and a composite of glutamate and glutamine (GLX). Correlation and multiple linear regression analyses were conducted.
Mean childhood blood lead levels were associated with regionally specific brain metabolite concentrations adjusted for age at imaging and Full-Scale intelligence quotient. Adjusted analyses estimated for a unit (micrograms per deciliter) increase in mean childhood blood lead concentrations, a decrease of NAA and Cr concentration levels in the basal ganglia, a decrease of NAA and a decrease of Cho concentration levels in the cerebellar hemisphere, a decrease of GLX concentration levels in vermis, a decrease of Cho and a decrease of GLX concentration levels in parietal white matter, and a decrease of Cho concentration levels in frontal white matter.
Gray-matter NAA reductions associated with increasing childhood blood lead levels suggest that sustained childhood lead exposure produces an irreversible pattern of neuronal dysfunction, whereas associated white-matter choline declines indicate a permanent alteration to myelin architecture.
basal ganglia; brain; cerebellum; frontal lobe; gray matter; lead exposure; magnetic resonance spectroscopy; white matter
Previous studies have shown significantly lower metabolism and functional activity in the anterior cingulate cortex (ACC) of human cocaine addicts. The present study examined whether this ACC hypoactivity is associated with altered glutamate (Glu), the primary excitatory neurotransmitter in the central nervous system (CNS), which has been recently implicated in drug addiction. Fourteen chronic cocaine addicts and 14 matched healthy volunteers were examined using 1H magnetic resonance spectroscopy at 3T. A new quantification strategy for TE-averaged point-resolved spectroscopy (PRESS) was applied to disentangle relaxation effects from J-evolution of coupled spin systems such as Glu. The concentrations of Glu as well as N-acetyl aspartate (NAA), total creatine (tCr), choline-containing compounds (tCho), and myo-inositol (Ins) were estimated from both groups. Glu/tCr was significantly lower in chronic cocaine users compared to control subjects and was significantly correlated with years of cocaine use. Glu/tCr was also positively correlated with NAA/tCr. NAA/tCr significantly decreased with age but was not significantly different between the two groups. These findings suggest a metabolic/neurotransmitter dysregulation associated with cocaine addiction and support a possible therapeutic intervention strategy aimed at normalizing the Glu transmission and function in the treatment of cocaine addiction.
Drug addiction; Neurotransmitter; Relaxation; J-coupling
Kleine Levin Syndrome (KLS) is a rare disorder of periodic hypersomnia and behavioural disturbances in young individuals. It has previously been shown to be associated with disturbances of working memory (WM), which, in turn, was associated with higher activation of the thalamus with increasing WM load, demonstrated with functional magnetic resonance imaging (fMRI). In this study we aimed to further elucidate how these findings are related to the metabolism of the thalamus.
fMRI and magnetic resonance spectroscopy were applied while performing a WM task. Standard metabolites were examined: n-acetylaspartate (NAA), myo-inositol, choline, creatine and glutamate-glutamine. Fourteen KLS-patients and 15 healthy controls participated in the study. The patients with active disease were examined in asymptomatic periods.
There was a statistically significant negative correlation between thalamic fMRI-activation and thalamic NAA, i.e., high fMRI-activation corresponded to low NAA-levels. This correlation was not seen in healthy controls. Thalamic levels of NAA in patients and controls showed no significant differences between the groups. None of the other metabolites showed any co-variation with fMRI-activiation.
This study shows negative correlation between NAA-levels and fMRI-activity in the left thalamus of KLS-patients while performing a WM task. This correlation could not be found in healthy control subjects, primarily interpreted as an effect of increased effort in the patient group upon performing the task. It might indicate a disturbance in the neuronal networks responsible for WM in KLS patients, resulting in higher effort at lower WM load, compared with healthy subjects. The general relationship between NAA and BOLD-signal is also discussed in the article.
It is well established that the formation of memories for life’s experiences—episodic memory—is influenced by how we attend to those experiences, yet the neural mechanisms by which attention shapes episodic encoding are still unclear. We investigated how top-down and bottom-up attention contribute to memory encoding of visual objects in humans by manipulating both types of attention during functional magnetic resonance imaging (fMRI) of episodic memory formation. We show that dorsal parietal cortex—specifically, intraparietal sulcus (IPS)—was engaged during top-down attention and was also recruited during the successful formation of episodic memories. By contrast, bottom-up attention engaged ventral parietal cortex—specifically, temporoparietal junction (TPJ)—and was also more active during encoding failure. Functional connectivity analyses revealed further dissociations in how top-down and bottom-up attention influenced encoding: while both IPS and TPJ influenced activity in perceptual cortices thought to represent the information being encoded (fusiform/lateral occipital cortex), they each exerted opposite effects on memory encoding. Specifically, during a preparatory period preceding stimulus presentation, a stronger drive from IPS was associated with a higher likelihood that the subsequently attended stimulus would be encoded. By contrast, during stimulus processing, stronger connectivity with TPJ was associated with a lower likelihood the stimulus would be successfully encoded. These findings suggest that during encoding of visual objects into episodic memory, top-down and bottom-up attention can have opposite influences on perceptual areas that subserve visual object representation, suggesting that one manner in which attention modulates memory is by altering the perceptual processing of to-be-encoded stimuli.
Individuals diagnosed with autism spectrum disorder (ASD) exhibit lifelong abnormalities in the adaptive allocation of visual attention. The ubiquitous nature of attentional impairments in ASD has led some authors to hypothesize that atypical attentional modulation may be a factor in the development of higher-level sociocommunicative deficits.
Participants were 20 children with ASD and 20 age- and Nonverbal IQ-matched typically developing (TD) children. We used the Attention Network Test (ANT) to investigate the efficiency and independence of three discrete attentional networks: alerting, orienting, and executive control. Additionally, we sought to investigate the relationship between each attentional network and measures of sociocommunicative symptom severity in children with ASD.
Results indicate that the orienting, but not alerting or executive control, networks may be impaired in children with ASD. In contrast to TD children, correlational analyses suggest that the alerting and executive control networks may not function as independently in children with ASD. Additionally, an association was found between the alerting network and social impairment and between the executive control network and IQ in children with ASD.
The results provide further evidence of an impairment in the visuospatial orienting network in ASD and suggest that there may be greater interdependence of alerting and executive control networks in ASD. Furthermore, decreased ability to efficiently modulate levels of alertness was related to increased sociocommunicative deficits, suggesting that domain-general attentional function may be associated with ASD symptomatology.
Autism; reaction time; visual attention; alerting; orienting; executive control
The present study aimed to explore the neural correlates of two characteristic deficits in autism spectrum disorders (ASD); social impairment and restricted, repetitive behavior patterns. To this end, we used comparable experiences of social exclusion and rule violation to probe potentially atypical neural networks in ASD. In children and adolescents with and without ASD, we used the interactive ball-toss game (Cyberball) to elicit social exclusion and a comparable game (Cybershape) to elicit a non-exclusive rule violation. Using functional magnetic resonance imaging (fMRI), we identified group differences in brain responses to social exclusion and rule violation. Though both groups reported equal distress following exclusion, the right insula and ventral anterior cingulate cortex were hypoactive during exclusion in children with ASD. In rule violation, right insula and dorsal prefrontal cortex were hyperactive in ASD. Right insula showed a dissociation in activation; it was hypoactive to social exclusion and hyperactive to rule violation in the ASD group. Further probed, different regions of right insula were modulated in each game, highlighting differences in regional specificity for which subsequent analyses revealed differences in patterns of functional connectivity. These results demonstrate neurobiological differences in processing social exclusion and rule violation in children with ASD.
Social Exclusion; Rule Violation; Autism Spectrum Disorder; Right Insula; Functional Magnetic Resonance Imaging
A 1H magnetic resonance spectroscopic imaging (1H-MRSI) study at 3T and short TE was conducted to evaluate both the reproducibility, as measured by the inter-scan coefficient of variation (CV), and test-retest reliability, as measured by the intraclass correlation coefficient (ICC), of measurements of glutamate (Glu), combined glutamate and glutamine (Glx), myo-inositol (mI), N-acetylaspartate (NAA), creatine, and choline in 21 healthy subjects. The effect of partial volume correction on these measures and the relationship of reproducibility and reliability to data quality were also examined. A 1H-MRSI slice was prescribed above the lateral ventricles and single repeat scans were performed within 30 min to minimize physiologic variability. Inter-scan CVs based on all the voxels varied from 0.05-0.07 for NAA, creatine, and choline to 0.10-0.13 for mI, Glu, and Glx. Findings on the reproducibility of gray and white matter estimates of NAA, creatine, and choline are consistent with previous studies using longer TEs, with CVs in the range of 0.02-0.04 and ICCs in the range of 0.65-0.90. CVs for Glu, Glx, and mI are much lower than reported in previous studies at 1.5T, while white matter mI (CV=0.04, ICC=0.93) and gray matter Glx (CV=0.04, ICC=0.68) demonstrated both high reproducibility and test-retest reliability.
To characterize progression of Alzheimer's disease (AD) using proton magnetic resonance spectroscopy (1H MRS).
Eleven subjects with mild to moderate AD underwent neurocognitive testing and single-voxel 1H MRS from the precuneus and posterior cingulate region at baseline, after 24 weeks of monotherapy with a cholinesterase inhibitor, and after another 24 weeks of combination therapy with open-label memantine and a cholinesterase inhibitor. Baseline metabolites [N-acetylaspartate (NAA), myo-inositol (mI), choline (Cho), and creatine (Cr)] and their ratios in AD subjects were compared with those of an age-matched control group of 28 cognitively normal subjects.
AD subjects had significantly higher mI/Cr and lower NAA, NAA/Cr, NAA/Cho, and NAA/mI. Baseline Alzheimer's Disease Cooperative Study Activities of Daily Living (ADCS-ADL) scores significantly correlated with NAA/Cr, mI/Cr, and NAA/mI. There was an increase in mI and a decrease in NAA/mI, but no significant change in other metabolites or ratios, or neurocognitive measures, when memantine was added to a cholinesterase inhibitor.
Metabolite ratios significantly differed between AD and control subjects. Baseline metabolite ratios correlated with function (ADCS-ADL). There was an increase in mI and a decrease in NAA/mI, but no changes in other metabolites, ratios, or cognitive measures, when memantine was added to a cholinesterase inhibitor.
Magnetic resonance spectroscopy; Alzheimer's disease; Activities of daily living; Image biomarker; Memantine; Cholinesterase inhibitors
Superior performance on the Embedded Figures Task (EFT) has been attributed to weak central coherence in perceptual processing in Autism Spectrum Disorders (ASD). The present study used functional magnetic resonance imaging to examine the neural basis of EFT performance in 7-12 year old ASD children and age and IQ matched controls. ASD children activated only a subset of the distributed network of regions activated in controls. In frontal cortex, control children activated left dorsolateral, medial and dorsal premotor regions whereas ASD children only activated the dorsal premotor region. In parietal and occipital cortices, activation was bilateral in control children but unilateral (left superior parietal and right occipital) in ASD children. Further, extensive bilateral ventral temporal activation was observed in control, but not ASD children. ASD children performed the EFT at the same level as controls but with reduced cortical involvement, suggesting that disembedded visual processing is accomplished parsimoniously by ASD relative to typically developing brains.
The temporoparietal junction (TPJ) is a key node in the brain's ventral attention network (VAN) that is involved in spatial awareness and detection of salient sensory stimuli, including pain. The anatomical basis of this network's right-lateralized organization is poorly understood. Here we used diffusion-weighted MRI and probabilistic tractography to compare the strength of white matter connections emanating from the right versus left TPJ to target regions in both hemispheres. Symmetry of structural connectivity was evaluated for connections between TPJ and target regions that are key cortical nodes in the right VAN (insula and inferior frontal gyrus) as well as target regions that are involved in salience and/or pain (putamen, cingulate cortex, thalamus). We found a rightward asymmetry in connectivity strength between the TPJ and insula in healthy human subjects who were scanned with two different sets of diffusion-weighted MRI acquisition parameters. This rightward asymmetry in TPJ-insula connectivity was stronger in females than in males. There was also a leftward asymmetry in connectivity strength between the TPJ and inferior frontal gyrus, consistent with previously described lateralization of language pathways. The rightward lateralization of the pathway between the TPJ and insula supports previous findings on the roles of these regions in stimulus-driven attention, sensory awareness, interoception and pain. The findings also have implications for our understanding of acute and chronic pains and stroke-induced spatial hemineglect.
Autism spectrum disorders (ASD) are associated with severe impairments in social functioning. Because faces provide nonverbal cues that support social interactions, many studies of ASD have examined neural structures that process faces, including the amygdala, ventromedial prefrontal cortex and superior and middle temporal gyri. However, increases or decreases in activation are often contingent on the cognitive task. Specifically, the cognitive domain of attention influences group differences in brain activation. We investigated brain function abnormalities in participants with ASD using a task that monitored attention bias to emotional faces.
Twenty-four participants (12 with ASD, 12 controls) completed a functional magnetic resonance imaging study while performing an attention cuing task with emotional (happy, sad, angry) and neutral faces.
In response to emotional faces, those in the ASD group showed greater right amygdala activation than those in the control group. A preliminary psychophysiological connectivity analysis showed that ASD participants had stronger positive right amygdala and ventromedial prefrontal cortex coupling and weaker positive right amygdala and temporal lobe coupling than controls. There were no group differences in the behavioural measure of attention bias to the emotional faces.
The small sample size may have affected our ability to detect additional group differences.
When attention bias to emotional faces was equivalent between ASD and control groups, ASD was associated with greater amygdala activation. Preliminary analyses showed that ASD participants had stronger connectivity between the amygdala ventromedial prefrontal cortex (a network implicated in emotional modulation) and weaker connectivity between the amygdala and temporal lobe (a pathway involved in the identification of facial expressions, although areas of group differences were generally in a more anterior region of the temporal lobe than what is typically reported for emotional face processing). These alterations in connectivity are consistent with emotion and face processing disturbances in ASD.
Autism spectrum disorders (ASD) are characterized by inflexible and repetitive behaviour. Response monitoring involves evaluating the consequences of behaviour and making adjustments to optimize outcomes. Deficiencies in this function, and abnormalities in the anterior cingulate cortex (ACC) on which it relies, have been reported as contributing factors to autistic disorders. We investigated whether ACC structure and function during response monitoring were associated with repetitive behaviour in ASD. We compared ACC activation to correct and erroneous antisaccades using rapid presentation event-related functional MRI in 14 control and ten ASD participants. Because response monitoring is the product of coordinated activity in ACC networks, we also examined the microstructural integrity of the white matter (WM) underlying this brain region using diffusion tensor imaging (DTI) measures of fractional anisotropy (FA) in 12 control and 12 adult ASD participants. ACC activation and FA were examined in relation to Autism Diagnostic Interview-Revised ratings of restricted and repetitive behaviour. Relative to controls, ASD participants: (i) made more antisaccade errors and responded more quickly on correct trials; (ii) showed reduced discrimination between error and correct responses in rostral ACC (rACC), which was primarily due to (iii) abnormally increased activation on correct trials and (iv) showed reduced FA in WM underlying ACC. Finally, in ASD (v) increased activation on correct trials and reduced FA in rACC WM were related to higher ratings of repetitive behaviour. These findings demonstrate functional and structural abnormalities of the ACC in ASD that may contribute to repetitive behaviour. rACC activity following errors is thought to reflect affective appraisal of the error. Thus, the hyperactive rACC response to correct trials can be interpreted as a misleading affective signal that something is awry, which may trigger repetitive attempts at correction. Another possible consequence of reduced affective discrimination between error and correct responses is that it might interfere with the reinforcement of responses that optimize outcomes. Furthermore, dysconnection of the ACC, as suggested by reduced FA, to regions involved in behavioural control might impair on-line modulations of response speed to optimize performance (i.e. speed-accuracy trade-off) and increase error likelihood. These findings suggest that in ASD, structural and functional abnormalities of the ACC compromise response monitoring and thereby contribute to behaviour that is rigid and repetitive rather than flexible and responsive to contingencies. Illuminating the mechanisms and clinical significance of abnormal response monitoring in ASD represents a fruitful avenue for further research.
autism; anterior cingulate cortex; response monitoring; functional MRI; diffusion tensor imaging
We investigated the effects of disease progression on brain regional neurochemistry in a mutant mouse model of familial amyotrophic lateral sclerosis (FALS; the G93A model) using in vivo and in vitro magnetic resonance spectroscopy (MRS). There were numerous changes in the brain spectra that were brain region dependent. At early time points starting around 80 days of age there were increases in brain glutamate. At later time points there were more extensive changes including decreased NAA, decreased glutamate and increased glutamine, taurine and myo-inositol. The effects of the disease were most severe in spinal cord followed by medulla and then sensorimotor cortex. There were no changes noted in cerebellum as a control region. The effects of creatine supplementation in the diet (2%) were measured in wild-type and FALS animals in medulla, cerebellum and cortex. The increase in brain creatine was largest in cerebellum (25%) followed by medulla (11%) and then cortex (4%) reflecting the ordering of creatine kinase activity. There was a protective effect of creatine on NAA loss in the medulla at late stages. Creatine supplementation had a positive effect on weight retention leading to a 13% increase in weight between 120-130 days. MRS shows promise in monitoring multiple facets of neuroprotective strategies in ALS and ALS models.
Amyotrophic lateral sclerosis; glutamate; motor neuron disease; amino acids; N-acetyl aspartate
In MR spectroscopy, we evaluated cerebral metabolic changes in patients 2–4 years after clipping or endovascular therapy of intracranial aneurysms.
A prospective study was conducted in 36 patients after SAH, treated surgically (n=23) or by endovascular embolisation (n=13). Control group consisted of 20 healthy volunteers.
The clinical evaluation was based on the Glasgow Coma Scale, Hunt and Hess grade, and Glasgow Outcome Scale. MR spectroscopy was performed with 1.5T system with PRESS sequence, at echo time of 35 ms, in frontal lobes unchanged in MR examination. Ratios of N-acetylaspartate (NAA), choline (Cho), myo-inositol (mI) and glutamine/glutamate complex (Glx) to creatine were assessed.
Only a slight, statistically insignificant reduction of NAA/Cr and an insignificant increase of mI/Cr were noted; other metabolite ratios were close to the ones in the control group. Similar results were obtained in patients after surgical clipping and after endovascular therapy. Only in patients with aneurysms of anterior communicating artery complex (AcoA), the NAA/Cr ratio showed a significant reduction as compared to that of non-AcoA patients and of the control group. No significant changes of metabolite ratios were found in patients with internal carotid artery (ICA) and middle cerebral artery (MCA) aneurysms, with regard to aneurysm lateralisation.
Surgical clipping and endovascular embolisation of ICA, MCA and posterior circulatory aneurysms do not induce changes in metabolite concentration in frontal lobes assessed in MR spectroscopy. In patients with AcoA aneurysms, 2–4 years after obliteration, there were found persistent metabolic changes in unchanged brain tissue of the frontal lobes, corresponding to neuronal damage (dysfunction).
MR spectroscopy; intracranial aneurysms; clipping; embolisation