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.

Insulin resistance impairs nigrostriatal dopamine function.

Clinical studies have indicated a link between Parkinson's disease (PD) and Type 2 Diabetes. Although preclinical studies have examined the effect of high-fat feeding on dopamine function in brain reward pathways, the effect of diet on neurotransmission in the nigrostriatal pathway, which is affected in PD and parkinsonism, is less clear. We hypothesized that a high-fat diet, which models early-stage Type 2 Diabetes, would disrupt nigrostriatal dopamine function in young adult Fischer 344 rats. Rats were fed a high fat diet (60% calories from fat) or a normal chow diet for 12 weeks. High fat-fed animals were insulin resistant compared to chow-fed controls. Potassium-evoked dopamine release and dopamine clearance were measured in the striatum using in vivo electrochemistry. Dopamine release was attenuated and dopamine clearance was diminished in the high-fat diet group compared to chow-fed rats. Magnetic resonance imaging indicated increased iron deposition in the substantia nigra of the high fat group. This finding was supported by alterations in the expression of several proteins involved in iron metabolism in the substantia nigra in this group compared to chow-fed animals. The diet-induced systemic and basal ganglia-specific changes may play a role in the observed impairment of nigrostriatal dopamine function.

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.

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.

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.

Cardiorespiratory fitness and brain atrophy in early Alzheimer disease.

OBJECTIVE: To examine the correlation of cardiorespiratory fitness with brain atrophy and cognition in early-stage Alzheimer disease (AD). BACKGROUND: In normal aging physical fitness appears to mitigate functional and structural age-related brain changes. Whether this is observed in AD is not known. METHODS: Subjects without dementia (n = 64) and subjects with early-stage AD (n = 57) had MRI and standard clinical and psychometric evaluations. Peak oxygen consumption (VO(2)(peak)), the standard measure of cardiorespiratory fitness, was assessed during a graded treadmill test. Normalized whole brain volume, a brain atrophy estimate, was determined by MRI. Pearson correlation and linear regression were used to assess fitness in relation to brain volume and cognitive performance. RESULTS: Cardiorespiratory fitness (VO(2)(peak)) was modestly reduced in subjects with AD (34.7 [5.0] mL/kg/min) vs subjects without dementia (38.1 [6.3] mL/kg/min, p = 0.002). In early AD, VO(2)(peak) was associated with whole brain volume (beta = 0.35, p = 0.02) and white matter volume (beta = 0.35, p = 0.04) after controlling for age. Controlling for additional covariates of sex, dementia severity, physical activity, and physical frailty did not attenuate the relationships. VO(2)(peak) was associated with performance on delayed memory and digit symbol in early AD but not after controlling for age. In participants with no dementia, there was no relationship between fitness and brain atrophy. Fitness in participants with no dementia was associated with better global cognitive performance (r = 0.30, p = 0.02) and performance on Trailmaking A and B, Stroop, and delayed logical memory but not after controlling for age. CONCLUSIONS: Increased cardiorespiratory fitness is associated with reduced brain atrophy in Alzheimer disease (AD). Cardiorespiratory fitness may moderate AD-related brain atrophy or a common underlying AD-related process may impact both brain atrophy and cardiorespiratory fitness.

Peripheral insulin and brain structure in early Alzheimer disease.

OBJECTIVE: Accumulating evidence suggests insulin and insulin signaling may be involved in the pathophysiology of Alzheimer disease (AD). The relationship between insulin-mediated glucoregulation and brain structure has not been assessed in individuals with AD. METHODS: Nondemented (Clinical Dementia Rating [CDR] 0, n = 31) and early stage AD (CDR 0.5 and 1, n = 31) participants aged 65 years and older had brain MRI to determine whole brain and hippocampal volume and 3-hour IV glucose tolerance tests to determine glucose and insulin area under the curve (AUC). Linear regression models were used to assess the relationship of insulin and glucose with brain volume, cognition, and dementia severity. RESULTS: In early AD, insulin and glucose AUCs were related to whole brain (insulin beta = 0.66, p < 0.001; glucose beta = 0.45, p < 0.01) and hippocampal volume (insulin beta = 0.42, p < 0.05; glucose beta = 0.46, p < 0.05). These relationships were independent of age, sex, body mass index, body fat, cardiorespiratory fitness, physical activity, cholesterol, and triglycerides. Insulin AUC, but not glucose, was associated with cognitive performance in early AD (beta = 0.40, p = 0.04). Insulin AUC was associated with dementia severity (Pearson r = -0.40, p = 0.03). Glucose and insulin were not related to brain volume or cognitive performance in nondemented individuals. CONCLUSIONS: Increased peripheral insulin is associated with reduced Alzheimer disease (AD)-related brain atrophy, cognitive dysfunction, and dementia severity, suggesting that insulin signaling may play a role in the pathophysiology of AD.

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.

Accumulation of acetyl groups following cycling: a 1H-MR spectroscopy study.

Using in vivo proton magnetic resonance spectroscopy (1H-MRS), a new peak resonating at 2.13 ppm post-exercise has been attributed in the literature to the acetyl groups of acetylcarnitine. Since this peak is inconsistently generated by various submaximal exercise regimens, this study aimed at (a) verification of the previous chemical assignment, (b) determination of exercise conditions necessary for its induction, and (c) documentation of the recovery kinetics through 60 minutes following exercise. Ten healthy males (31 +/- 4 yr) cycled continuously for 45 minutes with intensity alternating between 50% (3 min) and 110% (2 min) of ventilatory threshold (VT). 1H-MR spectra were acquired from the vastus lateralis before and for 60 minutes following exercise. The peak at 2.13 ppm was not quantifiable at rest in any subject. However, it was present in all subjects following intense exercise (p < 0.0001), and expressed the chemical characteristics of an acetyl-containing compound. The estimated concentration, accumulation with high-intensity exercise, the presence as a single peak at 2.13 ppm, and the chemical shift were all consistent with the chemical and biophysical characteristics of acetyl groups associated with acetylcarnitine. This study provides further evidence that acetyl groups are robustly generated by intense exercise, and that the accumulation of acetyl groups in healthy subjects is dependent on the degree of exercise intensity. 1H-MRS may be used for the noninvasive study of muscle metabolism during exercise and recovery and may have special applications for studying the generation and transport of acetyl compounds, including acetylcarnitine.

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.

Magnetic resonance spectroscopy in traumatic brain injury.

Magnetic resonance spectroscopy (MRS) offers a unique non-invasive approach for assessing the metabolic status of the brain in vivo and is particularly suited to studying traumatic brain injury (TBI). In particular, MRS provides a noninvasive means for quantifying such neurochemicals as N-acetylaspartate (NAA), creatine, phosphocreatine, choline, lactate, myo-inositol, glutamine, glutamate, adenosine triphosphate (ATP), and inorganic phosphate in humans following TBI and in animal models. Many of these chemicals have been shown to be perturbed following TBI. NAA, a marker of neuronal integrity, has been shown to be reduced following TBI, reflecting diffuse axonal injury or metabolic depression, and concentrations of NAA predict cognitive outcome. Elevation of choline-containing compounds indicates membrane breakdown or inflammation or both. MRS can also detect alterations in high energy phosphates reflecting the energetic abnormalities seen after TBI. Accordingly, MRS may be useful to monitor cellular response to therapeutic interventions in TBI.

Gerstmann syndrome in systemic lupus erythematosus: neuropsychological, neuroimaging and spectroscopic findings.

Gerstmann syndrome (GS) comprises four interlaced neuropsychological symptoms including finger agnosia, right-left confusion, agraphia, and acalculia. While GS is commonly associated with focal lesions to the region of the left angular gyrus, it has also been associated with numerous diffuse etiologies including atrophy, alcoholism, carbon monoxide poisoning, lead intoxication and anaphylactic shock. Thus, a vigorous debate has emerged as to whether GS represents a syndrome arising from general brain decline or a distinct and localizing lesion. We report a right-handed patient who developed neuropsychological dysfunction secondary to systemic lupus erythematosus (SLE). Neuropsychological evaluation found the patient to exhibit symptoms consistent with the GS tetrad, as well as general cognitive decline. Magnetic resonance imaging revealed a distinct focal lesion of the left parieto-occipital white matter underlying the angular gyrus as well as diffuse atrophy. (1)H-magnetic resonance spectroscopy revealed substantial metabolic derangement in a voxel placed within the visible lesion, although substantial metabolic derangement was observed in regions remote from the focal pathology. Thus, GS in this first case in SLE would appear to comprise a focal neurological tetrad of disorders within a more general pattern of cognitive decline and metabolic derangement.

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.

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.

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.

Myths of neuropsychology: intelligence, neurometabolism, and cognitive ability.

Recently, Dodrill (1999) revised a previously described "Myth of neuropsychology" (1997) to state: "Just as below average performances on neuropsychological tests are found when intelligence is below average, to that same degree above average performances on neuropsychological tests are expected when intellectual abilities are above average." This study addresses the relationship between intellectual and neuropsychological performance in the context of Magnetic Resonance Spectroscopy (MRS) measurements of the neurometabolite N-acetylaspartate (NAA). When subjects were stratified by Full Scale IQ (Average, High Average, Superior) they differed significantly in terms of total neuropsychological performance [F(2,47) = 17.63; p <.001] and the neuronal marker NAA [F(2,47) = 3.25; p <.05]. Regression analysis across groups demonstrated that FSIQ and NAA were independently related to Total z-score [F(1,47) = 29.43; p <.0001] and accounted for over half the variance (r(2) of model =.56). The concurrent relationship of FSIQ and NAA to total neuropsychological performance suggests that the relationship between measures sensitive to intellectual ability and neuropsychological performance is real, and does not reflect arbitrary psychometric or scaling properties of the WAIS-III.

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.

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.

Neuropsychiatric systemic lupus erythematosus.

The systemic lupus erythematosus (SLE) patients with neuropsychiatric complaints requires a comprehensive and timely diagnostic approach. Despite the obvious difficulties in diagnosing neuropsychiatric SLE, the neurologic complications of SLE can be approached in a careful, logical manner with gratifying results.