Importance of reward and prefrontal circuitry in hunger and satiety: Prader-Willi syndrome vs simple obesity.

BACKGROUND: The majority of research on obesity (OB) has focused primarily on clinical features (eating behavior, adiposity measures) or peripheral appetite-regulatory peptides (leptin, ghrelin). However, recent functional neuroimaging studies have demonstrated that some reward circuitry regions that are associated with appetite-regulatory hormones are also involved in the development and maintenance of OB. Prader-Willi syndrome (PWS), characterized by hyperphagia and hyperghrelinemia reflecting multi-system dysfunction in inhibitory and satiety mechanisms, serves as an extreme model of genetic OB. Simple (non-PWS) OB represents an OB-control state. OBJECTIVE: This study investigated subcortical food motivation circuitry and prefrontal inhibitory circuitry functioning in response to food stimuli before and after eating in individuals with PWS compared with OB. We hypothesized that groups would differ in limbic regions (that is, hypothalamus, amygdala) and prefrontal regions associated with cognitive control (that is, dorsolateral prefrontal cortex (DLPFC), orbitofrontal cortex (OFC) after eating. DESIGN AND PARTICIPANTS: A total of 14 individuals with PWS, 14 BMI- and age-matched individuals with OB, and 15 age-matched healthy-weight controls viewed food and non-food images while undergoing functional MRI before (pre-meal) and after (post-meal) eating. Using SPM8, group contrasts were tested for hypothesized regions: hypothalamus, nucleus accumbens (NAc), amygdala, hippocampus, OFC, medial PFC and DLPFC. RESULTS: Compared with OB and HWC, PWS demonstrated higher activity in reward/limbic regions (NAc, amygdala) and lower activity in the hypothalamus and hippocampus in response to food (vs non-food) images pre-meal. Post meal, PWS exhibited higher subcortical activation (hypothalamus, amygdala, hippocampus) compared with OB and HWC. OB showed significantly higher activity versus PWS and HWC in cortical regions (DLPFC, OFC) associated with inhibitory control. CONCLUSION: In PWS, compared with OB per se, results suggest hyperactivations in subcortical reward circuitry and hypoactivations in cortical inhibitory regions after eating, which provides evidence of neural substrates associated with variable abnormal food motivation phenotypes in PWS and simple OB.

1H-MRS at 4 tesla in minimally treated early schizophrenia.

We investigated glutamate-related neuronal dysfunction in the anterior cingulate (AC) early in schizophrenia before and after antipsychotic treatment. A total of 14 minimally treated schizophrenia patients and 10 healthy subjects were studied with single-voxel proton magnetic resonance spectroscopy ((1)H-MRS) of the AC, frontal white matter and thalamus at 4 T. Concentrations of N-acetylaspartate (NAA), glutamate (Glu), glutamine (Gln) and Gln/Glu ratios were determined and corrected for the partial tissue volume. Patients were treated with antipsychotic medication following a specific algorithm and (1)H-MRS was repeated after 1, 6 and 12 months. There were group x region interactions for baseline NAA (P=0.074) and Gln/Glu (P=0.028): schizophrenia subjects had lower NAA (P=0.045) and higher Gln/Glu (P=0.006) in the AC before treatment. In addition, AC Gln/Glu was inversely related to AC NAA in the schizophrenia (P=0.0009) but not in the control group (P=0.92). Following antipsychotic treatment, there were no further changes in NAA, Gln/Glu or any of the other metabolites in any of the regions studied. We conclude that early in the illness, schizophrenia patients already show abnormalities in glutamatergic metabolism and reductions in NAA consistent with glutamate-related excitotoxicity.

Obese children show hyperactivation to food pictures in brain networks linked to motivation, reward and cognitive control.

OBJECTIVE: To investigate the neural mechanisms of food motivation in children and adolescents, and examine brain activation differences between healthy weight (HW) and obese participants. SUBJECTS: Ten HW children (ages 11-16; BMI < 85%ile) and 10 obese children (ages 10-17; BMI >95%ile) matched for age, gender and years of education. MEASUREMENTS: Functional magnetic resonance imaging (fMRI) scans were conducted twice: when participants were hungry (pre-meal) and immediately after a standardized meal (post-meal). During the fMRI scans, the participants passively viewed blocked images of food, non-food (animals) and blurred baseline control. RESULTS: Both groups of children showed brain activation to food images in the limbic and paralimbic regions (PFC/OFC). The obese group showed significantly greater activation to food pictures in the PFC (pre-meal) and OFC (post-meal) than the HW group. In addition, the obese group showed less post-meal reduction of activation (vs pre-meal) in the PFC, limbic and the reward-processing regions, including the nucleus accumbens. CONCLUSION: Limbic and paralimbic activation in high food motivation states was noted in both groups of participants. However, obese children were hyper-responsive to food stimuli as compared with HW children. In addition, unlike HW children, brain activations in response to food stimuli in obese children failed to diminish significantly after eating. This study provides initial evidence that obesity, even among children, is associated with abnormalities in neural networks involved in food motivation, and that the origins of neural circuitry dysfunction associated with obesity may begin early in life.

Genetic subtype differences in neural circuitry of food motivation in Prader-Willi syndrome.

BACKGROUND: Differences in behavioral phenotypes between the two most common subtypes of Prader-Willi syndrome (PWS) (chromosome 15q deletions and maternal uniparental disomy 15 (UPD) indicate that distinct neural networks may be affected. Though both subtypes display hyperphagia, the deletion subgroup shows reduced behavioral inhibition around food, whereas those with UPD are generally more able to maintain cognitive control over food intake impulses. OBJECTIVE: To examine the neural basis of phenotypic differences to better understand relationships between genetic subtypes and behavioral outcomes. We predicted greater food motivation circuitry activity in the deletion subtype and greater activity in higher order cognitive regions in the UPD group, especially after eating. DESIGN AND PARTICIPANTS: Nine individuals with PWS due to UPD and nine individuals with PWS due to (type 2) deletion, matched for age, gender and body mass index, underwent functional magnetic resonance imaging (fMRI) while viewing food images during two food motivation states: one before (pre-meal) and one after (post-meal) eating a standardized 500 kcal meal. RESULTS: Both PWS subgroups showed greater activity in response to food pre- and post-meal compared with the healthy-weight group. Compared with UPD, the deletion subtype showed increased food motivation network activation both pre- and post-meal, especially in the medial prefrontal cortex (mPFC) and amygdala. In contrast, the UPD group showed greater activation than the deletion subtype post-meal in the dorsolateral prefrontal cortex (DLPFC) and parahippocampal gyrus (PHG). CONCLUSION: These preliminary findings are the first functional neuroimaging findings to support divergent neural mechanisms associated with behavioral phenotypes in genetic subtypes of PWS. Results are discussed within the framework of genetic mechanisms such as haploinsufficiency and gene dosage effects and their differential influence on deletion and UPD subtypes, respectively.

The aging hippocampus: a multi-level analysis in the rat.

In the current experiment we conducted a multi-level analysis of age-related characteristics in the hippocampus of young adult (3 months), middle-aged (12 months), and old (24 months) Fisher 344xBrown Norway hybrid (FBNF1) rats. We examined the relationships between aging, hippocampus, and memory using a combination of behavioral, non-invasive magnetic resonance imaging and spectroscopy, and postmortem neuroanatomical measures in the same rats. Aging was associated with functional deficits on hippocampus-dependent memory tasks, accompanied by structural alterations observed both in vivo (magnetic resonance imaging-hippocampal volume) and postmortem (dentate gyrus neuronal density and neurogenesis). Neuronal metabolic integrity, assessed by levels of N-acetylaspartate with magnetic resonance spectroscopy, was however, preserved. Further, our results suggest that neurogenesis (doublecortin) seems to be related to both performance deficits on hippocampus-dependent tasks and hippocampal volume reduction. The observed pattern of age-related alterations closely resembles that previously reported in humans and suggests FBNF1 rats to be a useful model of normal human aging.

Use of high resolution in vivo volume selected 1H-magnetic resonance spectroscopy to investigate leukemia in humans.

In vivo high resolution volume-selected 1H magnetic resonance spectroscopy of human tibia has been undertaken using spatial coordinates obtained from magnetic resonance images. Adult tibial marrow has a 1H spectrum rich in fatty acid resonances and is readily distinguished from the 1H spectra of surrounding leg muscle. In all four leukemic patients examined, infiltration of fat cells of tibial marrow by proliferating cells rich in mobile H2O protons was evident by magnetic resonance imaging. Selective examination of volumes of tibial marrow (1 cm3) by 1H magnetic resonance spectroscopy confirmed marked differences in the 1H spectra of marrow from these patients. Increases in the H2O peak of the 1H spectra were correlated with infiltration of blast cells and lack of control of the neoplastic disease. These studies are the first to report the use of volume selected magnetic resonance spectroscopy to selectively monitor leukemia in humans.

Frontal lobe of children with schizophrenia spectrum disorders: a proton magnetic resonance spectroscopic study.

BACKGROUND: Schizophrenia is commonly considered a neurodevelopmental disorder. Our aim was to determine whether the proton magnetic resonance spectroscopic (1H-MRS) changes seen in adults with schizophrenia are displayed in children at risk for developing schizophrenia. METHODS: Children with symptoms of schizophrenia-spectrum disorders (n = 16; mean age = 132 months) and a comparison group (n = 12; mean age 130 months) took part in a 1H-MRS study of the left frontal lobe. Areas of peaks from N-acetylaspartate (NAA), choline (Cho), and creatine (Cre) were determined and ratios of NAA/Cre and Cho/Cre calculated and compared between groups. RESULTS: The mean ratio of NAA/Cre was significantly lower in schizophrenia-spectrum subjects than the comparison group (1.67 vs. 1.92; p < .05). Medication status did not affect results in schizophrenia-spectrum subjects. CONCLUSIONS: Our findings suggest that the metabolic changes associated with adult schizophrenia are observed in children with some or all of the symptoms of schizophrenia, supporting a neurodevelopmental theory for schizophrenia.

Magnetic resonance imaging of anatomic and vascular characteristics in a canine model of human aging.

Dogs exhibit both neuroanatomical and cognitive changes as a function of age that parallel those seen in aging humans. This study describes in vivo changes in neuroanatomical and cerebrovascular characteristics of the canine brain as a function of age in a group of dogs ranging from 4 to 15 years old. Dynamic contrast-enhanced magnetic resonance imaging (MRI) was used to measure the kinetics of contrast agents in the brain. Measures of vascular volume and blood-brain barrier (BBB) permeability were derived from a pharmacokinetic analysis. Cortical atrophy and ventricular enlargement were characteristic features of the aged canine brain. Vascular volume did not vary as a function of age and BBB permeability exhibited a nonsignificant increasing trend with age. However, BBB dysfunction was detected in one middle-aged dog that in addition to having unusually large ventricles, demonstrated an early onset of diffuse senile plaques at postmortem. These findings indicate that BBB dysfunction detected by magnetic resonance imaging may be useful for predicting and potentially diagnosing early pathological conditions.

Proton magnetic resonance spectroscopy of vascular- and Alzheimer-type dementia.

OBJECTIVE: To identify biochemical differences in brain tissue between patients with dementia of the Alzheimer type and vascular dementia. DESIGN AND SUBJECTS: Proton magnetic resonance spectroscopy was used to compare 10 patients with dementia of the Alzheimer type and 8 age-matched patients with vascular dementia. RESULTS: The ratios of N-acetyl groups to creatine and N-acetyl groups to choline were lower in regions of subcortical white matter in patients with vascular dementia than in patients with dementia of the Alzheimer type (P < .02). CONCLUSION: Proton magnetic resonance spectroscopy may be useful in distinguishing between dementia of the Alzheimer type and vascular dementia.

Quantitative proton MRS predicts outcome after traumatic brain injury.

OBJECTIVE: To determine whether proton MRS (1H-MRS) neurochemical measurements predict neuropsychological outcome of patients with traumatic brain injury (TBI). BACKGROUND: Although clinical indices and conventional imaging techniques provide critical information for TBI patient triage and acute care, none accurately predicts individual patient outcome. METHODS: The authors studied 14 patients with TBI soon after injury (45+/-21 days postinjury) and again at 6 months (172+/-43 days) and 14 age-, sex-, and education-matched control subjects. N-acetylaspartate (NAA), creatine, and choline were measured in normal-appearing occipitoparietal white and gray matter using quantitative 1H-MRS. Outcome was assessed with the Glasgow Outcome Scale (GOS) and a battery of neuropsychological tests. A composite measure of neuropsychological function was calculated from individual test z-scores probing the major functional domains commonly impaired after head trauma. RESULTS: Early NAA concentrations in gray matter predicted overall neuropsychological performance (r = 0.74, p = 0.01) and GOS (F = 11.93, p = 0.007). Other metabolite measures were not related to behavioral function at outcome. CONCLUSION: 1H-MRS provides a rapid, noninvasive tool to assess the extent of diffuse injury after head trauma, a component of injury that may be the most critical factor in evaluating resultant neuropsychological dysfunction. 1H-MRS can be added to conventional MR examinations with minimal additional time, and may prove useful in assessing injury severity, guiding patient care, and predicting patient outcome.

MR spectroscopy study of dichloroacetate treatment after ischemic stroke.

In a double-blind, placebo-controlled study, we used 1H MR spectroscopy to assess the effect of a single infusion of sodium dichloroacetate on lesion lactate 1 to 5 days after ischemic stroke. Apparent trends toward a reduction in lactate/N-acetyl compound ratios were seen at the higher drug doses employed, and in patients treated in the first 2 days following infarction. Use of spectroscopic measures as endpoints is feasible in acute stroke clinical trials.

Biochemical markers of intelligence: a proton MR spectroscopy study of normal human brain.

Proton magnetic resonance spectroscopy (1H-MRS) offers a unique non-invasive approach to measurement of N-acetylaspartate (NAA) and choline (Cho), putative markers of neuronal and glial integrity. Previous studies revealed that these neurochemicals predict cognitive impairment in diseased subjects, although little is known about their relationship to cognitive functioning in healthy people. We measured the concentrations of NAA and Cho in the left occipitoparietal white matter of 26 healthy adults and compared them with intellectual performance assessed by the Wechsler Adult Intelligence Scale-3. We found that NAA (b = 0.6, p < 0.01) and Cho (b = -0.42, p < 0.01) were independently associated with the Full-Scale Intelligence Quotient. Together, these metabolites accounted for a large proportion of the variance in intelligence (r2 = 0.45). Possible mechanisms underlying these correlations, such as mitochondrial function and myelin turnover, are discussed. 1H-MRS is a sensitive new tool to assess the neuronal underpinnings of cognitive function non-invasively.

Metabolic and cognitive response to human traumatic brain injury: a quantitative proton magnetic resonance study.

Proton magnetic resonance spectroscopy (1H-MRS) offers a unique insight into brain cellular metabolism following traumatic brain injury (TBI). The aim of the present study was to assess change in neurometabolite markers of brain injury during the recovery period following TBI. We studied 19 TBI patients at 1.5, 3, and 6 months postinjury and 28 controls. We used 1H-MRS to quantify N-acetylaspartate (NAA), creatine (Cre), choline (Cho), and myoinositol (mIns) in occipitoparietal gray matter (GM) and white matter (WM) remote from the primary injury focus. Neuropsychological testing quantified cognitive impairment and recovery. At 1.5 months, we found cognitive impairment (mean z score = -1.36 vs. 0.18,p < 0.01), lower NAA (GM: 12.42 mM vs. 13.03, p = 0.01; WM: 11.75 vs. 12.81, p < 0.01), and elevated Cho (GM: 1.51 vs. 1.25, p < 0.01; WM: 1.98 vs. 1.79, p < 0.01) in TBI patients compared with controls. GM NAA at 1.5 months predicted cognitive function at outcome (6 months postinjury; r = 0.63, p = 0.04). GM NAA continued to fall by 0.46 mM between 1.5 and 3 months (p = 0.02) indicating continuing neuronal loss, metabolic dysfunction, or both. Between 3 and 6 months, WM NAA increased by 0.55 mM (p = 0.06) suggesting metabolic recovery. Patients with poorer outcomes had elevated mean GM Cho at 3 months postinjury, suggesting active inflammation, as compared to patients with better outcomes (p = 0.002). 1H-MRS offers a noninvasive approach to assessing neuronal injury and inflammation following TBI, and may provide unique data for patient management and assessment of therapeutic efficacy.

Biochemical markers of cognition: a proton MR spectroscopy study of normal human brain.

In the current study we explored the relationship between neurometabolites measured by proton magnetic resonance spectroscopy (1H-MRS) and cognitive ability assessed with a battery of neuropsychological tests. Forty-five participants were recruited from the local college community, and examined utilizing neuropsychological testing and 1H-MRS. Our central finding was that N-acetylaspartate (NAA) was associated with overall neuropsychological performance (F(1,42) = 23.16, p < 0.0001], r2 = 0.35. We found an even stronger association between timed neuropsychological measures and NAA (F(1,42) = 31.15, p < 0.0001], r = 0.43. These results reveal the specific relationship of NAA to neuropsychological functioning in normal human brain. The current observations in healthy individuals are consistent with the hypothesis that variability in NAA levels and neuropsychological performance may be related to mitochondrial function.

Neuropsychophysiological study of children at risk for schizophrenia: a preliminary report.

OBJECTIVE: This initial report, from an ongoing study, examines whether children who have symptoms of schizophrenia spectrum disorder display neuropsychological or neuroanatomic abnormalities similar to those seen in adults with schizophrenia. METHOD: Experimental subjects were 12 children between 8 and 12 years of age who displayed symptoms of early-onset schizophrenia or schizotypal personality disorder, as assessed through the Schedule for Affective Disorders and Schizophrenia for School-Age Children. The experimental subjects were compared with 13 controls on neuropsychological test performance, magnetic resonance imaging measurements, and proton magnetic resonance spectroscopy results. RESULTS: Findings from the first phase of this project reveal significant overall group differences for several morphometric magnetic resonance imaging measurements and all neuropsychological measures. Differences between the groups were found for amygdala volume, mesial temporal volume, callosal area, and anatomic asymmetry. Magnetic resonance spectroscopy data showed a trend toward group differences. CONCLUSIONS: These findings support a neurodevelopmental model of schizophrenia which postulates that environmentally or genetically programmed events in utero disrupt the establishment of fundamental aspects of brain structure and function.

Neurometabolism of active neuropsychiatric lupus determined with proton MR spectroscopy.

PURPOSE: To determine the neurometabolism of patients with active neuropsychiatric systemic lupus erythematosus (NPSLE) by using proton MR spectroscopy. METHODS: Thirty-six patients with SLE and eight control subjects were studied with proton MR spectroscopy to measure brain metabolites. Peaks from N-acetylaspartate (NAA), creatine (Cr), choline (Cho), and at 1.3 parts per million (ppm) lipid, macromolecules, and lactate were measured. Patients were classified as having major NPSLE (seizures, psychosis, major cognitive dysfunction, delirium, stroke, or coma) (n = 15) or minor NPSLE (headache, minor affective disorder, or minor cognitive disorder) (n = 21). Patients with major NPSLE were severely ill and hospitalized. RESULTS: SLE patients had lower NAA and increased metabolites at 1.3 ppm than did control subjects (NAA/Cr(SLE) = 1.90 +/- 0.35, NAA/Cr(Control) = 2.16 +/- 0.26; 1.3 ppm/Cr(SLE) = 0.49 +/- 0.41, 1.3 ppm/Cr(Control) = 0.27 +/- 0.05). NAA/Cr in patients with current or prior major NPSLE was lower than in patients without major NPSLE. Increased peaks at 1.3 ppm were present in all SLE subgroups, but particularly in patients with major NPSLE. These resonances were not evident at an echo time of 136, indicating that these signals were not lactate. CONCLUSION: Major NPSLE, past or present, is associated with decreased levels of NAA. Elevated peaks around 1.3 ppm do not represent lactate even in severely ill patients, indicating that global ischemia is not characteristic of NPSLE. Neurochemical markers determined by MR spectroscopy may be useful for determining activity and degree of brain injury in NPSLE.

Proton MR spectroscopic findings correspond to neuropsychological function in traumatic brain injury.

BACKGROUND AND PURPOSE: Traumatic brain injury (TBI) causes substantial irreversible damage to neurons. Our aim was to investigate whether proton MR spectroscopic measures of diffuse cellular integrity were related to neuropsychological dysfunction after TBI. METHODS: Twelve patients with TBI (mean, 53 +/- 23 days postinjury) and 14 control subjects were included in the study using paired MR spectroscopy and neuropsychological assessment. N-acetylaspartate (NAA), creatine, and choline were measured in normal-appearing occipitoparietal white and occipital gray matter using short-echo quantitative spectroscopy. A composite measure of neuropsychological function was calculated from z-scored individual tests probing the major functional domains commonly impaired after head trauma. RESULTS: Patients with TBI displayed reduced NAA in white matter and elevated choline in gray matter, suggestive of neuronal injury and inflammation, respectively. NAA and creatine in white and gray matter were significantly associated with composite neuropsychological function and many individual neuropsychological tests. Gray matter choline, although abnormal, was not related to neuropsychological function. CONCLUSION: The concordance between neurometabolic levels and behavioral function supports the hypothesis that diffuse axonal injury is an important contributor to brain dysfunction after TBI.

Developmental instability and working memory ability in children: a magnetic resonance spectroscopy investigation.

This study of children (ages 7 through 12) wishes to determine (a) whether variation in frontal lobe brain chemistry, determined from proton magnetic resonance spectroscopy (1H-MRS), is related to performance on a working memory task in children, and (b) whether developmental instability (DI; the imprecise expression of the genetic plan for development due to several known genetic and environmental effects) underlies phenotypic variation in brain chemistry. 1H-MRS assessed neurometabolites in a right frontal white matter voxel. The Visual Two-Back test assessed working memory. A composite measure of DI was created from measures of minor physical anomalies, fluctuating asymmetry of body characteristics, and fluctuating asymmetry of dermatoglyphic features. Greater DI strongly predicted lower concentrations of creatine-phosphocreatine (Cre) and choline-containing compounds, whereas Cre and N-acetyl-aspartate positively correlated with working memory skills. Working memory skills thus seem related to frontal lobe energy metabolism, which in turn is related to DI.

Effects of chronic haloperidol and clozapine treatments on frontal and caudate neurochemistry in schizophrenia.

N-Acetyl-aspartate (NAA), a marker of neuronal integrity, has been found to be reduced in frontal regions in schizophrenia. However, the impact of antipsychotic drug type on NAA has not been carefully evaluated. We studied outpatients with schizophrenia/schizoaffective disorders chronically treated with haloperidol or clozapine and normal controls with single-voxel 1H-MRS of the caudate nuclei and the left frontal lobe. Concentrations of NAA, choline containing compounds (Cho) and creatine plus phosphocreatine (Cre) were determined and corrected for the proportion of cerebrospinal fluid (CSF) in each voxel. The haloperidol-treated group had significantly lower CSF-uncorrected and CSF-corrected left frontal NAA than the normal controls, with the clozapine group having intermediate concentrations. The haloperidol-treated group had significantly lower CSF-uncorrected caudate NAA than the normal controls, but the three groups did not differ after correcting for CSF fraction. Performance times in the Grooved Pegboard, a measure of motor dexterity and proxy for parkinsonism, were correlated with CSF-uncorrected and CSF-corrected left frontal NAA. Demographic and illness-related variables were not related to NAA. Exposure to haloperidol-like drugs may in part account for the frontal NAA reductions previously reported in schizophrenia. Adjustment for proportion of voxel CSF should be considered in 1H-MRS studies.

Brain abnormalities in schizophrenia-spectrum children: implications for a neurodevelopmental perspective.

Children with symptoms of schizophrenia-spectrum disorder (N = 20) were compared to controls (N = 20) matched for age and socioeconomic status. Structural brain abnormalities were assessed with magnetic resonance imaging and functional brain abnormalities with neuropsychological tests. Children with schizophrenia-spectrum disorder had smaller amygdala and temporal cortex volumes, along with reduced callosal areas and an unusual pattern of neuroanatomic asymmetries. No differences were noted in overall brain volume, ventricular volume, hippocampal volume, or frontal area. Schizophrenia-spectrum children were also characterized by deficits in all neuropsychological functions examined. Some types of verbal memory and frontal lobe skills were especially deficient. These results support the hypothesis that children with schizophrenia-spectrum disorder have significant brain abnormalities, similar in some ways to those seen in adult schizophrenics. In conjunction with recent primate studies, the current results draw attention to the role of the amygdala as one relevant factor in the pathogenesis of schizophrenia.