Elevated amygdala response to faces following early deprivation.

A functional neuroimaging study examined the long-term neural correlates of early adverse rearing conditions in humans as they relate to socio-emotional development. Previously institutionalized (PI) children and a same-aged comparison group were scanned using functional magnetic resonance imaging (fMRI) while performing an Emotional Face Go/Nogo task. PI children showed heightened activity of the amygdala, a region that supports emotional learning and reactivity to emotional stimuli, and corresponding decreases in cortical regions that support perceptual and cognitive functions. Amygdala activity was associated with decreased eye-contact as measured by eye-tracking methods and during a live dyadic interaction. The association between early rearing environment and subsequent eye-contact was mediated by amygdala activity. These data support the hypothesis that early adversity alters human brain development in a way that can persist into childhood, and they offer insight into the socio-emotional disturbances in human behavior following early adversity.

Reduced Neural Satiety Responses in Women Affected by Obesity.

Overweight and obesity are major risk factors for a number of chronic diseases, including diabetes, cardiovascular diseases, and cancer. Obesity rates are on the rise worldwide with women more frequently affected than men. Hedonic responses to food seem to play a key role in obesity, but the exact mechanisms and relationships are still poorly understood. In this study, we investigate the perceived pleasantness of food rewards in relation to satiety and calories consumed during an ad libitum meal in women. Using functional magnetic resonance imaging (fMRI) and a milkshake consumption task, we studied how experienced food values are encoded in women with healthy weight, overweight or obesity. Participants rated the pleasantness and intensity of high and low caloric milkshakes in the fMRI scanner during both the fasted and fed states. We found differences in the neural responses and experienced pleasantness of high and low caloric milkshakes depending on satiety and Body Mass Index (BMI). Women with both high ad libitum consumption levels and high BMI reported greater experienced pleasantness for milkshakes. In contrast, among women with low ad libitum consumption levels, greater BMI was associated with less experienced pleasantness. At the neural level, satiety affected women with obesity to a lesser degree than women with healthy weight. Thus, having obesity was associated with altered relationships between food consumption and the hedonic responses to food rewards as well as reduced satiety effects in women.

Gamma-aminobutyric acid in peripheral tissue, with emphasis on the endocrine pancreas: presence in two species and reduction by streptozotocin.

A screen of selected periphral organs of the rat found that gamma-aminobutyric acid (GABA) is generally present outside the central nervous system, and, of those organs examined, GABA was present at the highest concentration in the pancreas (approximately 40 pmol/mg wet wt). Furthermore, this putative inhibitory neurotransmitter was found to be present at even higher levels in islets of Langerhans tissue isolated from rat pancreas (190 pmol/mg). Administration of streptozotocin, a selective beta-cell toxin, decreased pancreatic GABA levels significantly, but had no or only small effects on the GABA content of other organs. Normal teleost (catfish) Brockmann body contains about the same level of GABA as normal rat islet tissue.

Brain gamma-aminobutyric acid abnormality in tardive dyskinesia. Reduction in cerebrospinal fluid GABA levels and therapeutic response to GABA agonist treatment.

A double-blind, placebo-controlled trial of gamma-vinyl gamma-aminobutyric acid (GVG) and 4,5,6,7-tetrahydroisoxazolo-(5,4-c) pyridine-3-ol (THIP) was carried out in drug-free schizophrenic patients with tardive dyskinesia. A significant decrease in dyskinetic symptoms occurred with the administration of GVG, associated with a twofold increase in cerebrospinal fluid levels of GABA; THIP produced a more moderate, yet consistent decrease in the involuntary movements. A pathophysiologic role for gamma-aminobutyric acid (GABA)-mediated neuronal transmission in tardive dyskinesia was explored by analyzing cerebrospinal fluid GABA concentrations in drug-free schizophrenic patients with and without tardive dyskinesia. A significant reduction in cerebrospinal fluid levels of GABA was observed in the dyskinetic schizophrenics compared with the nondyskinetic controls. These data compliment a growing body of experimental evidence suggesting a critical role for GABA-ergic neurons in the pathophysiology of tardive dyskinesia.

CSF levels of gamma-aminobutyric acid in schizophrenia. Low values in recently ill patients.

gamma-Aminobutyric acid (GABA) levels in CSF were not significantly different in 30 drug-free schizophrenic patients and in 39 normal control subjects, because the control subjects were significantly older. Schizophrenic women had significantly lower levels than age-matched normal control women (less than 30 years). The GABA levels increased with duration of illness, number of hospitalizations, and months of hospitalizations, as well as with age. They correlated nonsignificantly with psychosis levels. After short-term pimozide treatment, GABA levels in all patients were raised, albeit nonsignificantly. The date suggest that low GABA levels may be observed only in the early years of the illness, particularly in female schizophrenic patients, and that these levels increase with time and with long-term neuroleptic treatment.

Reduced plasma and CSF gamma-aminobutyric acid in affective illness: effect of lithium carbonate.

Plasma and CSF gamma-aminobutyric acid (GABA) levels were determined in patients with affective illness and normal volunteers. Plasma GABA was significantly lower in the medication-free euthymic bipolar group (n = 23, p = 0.03) compared to normal volunteers (n = 36). Lithium-treated euthymic bipolar patients (n = 26) tended to have higher plasma GABA levels (p = 0.09) than the medication-free euthymic bipolar group. Plasma GABA in nine patients, measured in the euthymic state on and off lithium, was higher during lithium treatment (p less than 0.02). In CSF, GABA was found to be significantly lower in a group of euthymic medication-free unipolar and bipolar patients (n = 9) compared to normal volunteers (n = 39, p less than 0.02). CSF GABA, on and off lithium in four bipolar patients, was significantly higher during lithium treatment (p less than 0.02). This effect of lithium, increasing CSF and plasma GABA, may be related to its mechanism of therapeutic action.

CSF GABA in normal subjects and patients with depression, schizophrenia, mania, and anorexia nervosa.

The authors examined the CSF GABA of 87 subjects: 29 normal control subjects, 11 patients with schizophrenia, 26 with depression, 6 with mania, and 15 with anorexia nervosa. Depressed patients had significantly lower CSF GABA levels than did normal subjects. This finding suggests that GABA may have a direct or indirect association with depressive affective disorders.

CSF neurochemistry in depressed, manic, and schizophrenic patients compared with that of normal controls.

A total of 114 subjects (41 depressed, 20 schizophrenic, 15 manic, and 38 normal controls) underwent lumbar puncture and their CSF was analyzed for levels of tyrosine, tryptophan, homovanillic acid (HVA), 5-hydroxyindoleacetic acid (5-HIAA), 3-methoxy-4-hydroxyphenylglycol (MHPG), choline, gamma-aminobutyric acid (GABA), and calcium. Results showed that depressed patients, particularly those over 40 years of age, had lower levels of GABA than did controls, and that their level of HVA increased with age, while controls' decreased. Schizophrenic subjects tended to have higher levels of 5-HIAA and manic subjects tended to have higher levels of HVA and MHPG. Age-associated changes were found in HVA, 5-HIAA, MHPG, GABA, and choline concentrations.

CSF neurochemistry of women with anorexia nervosa and normal women.

CSF tyrosine, tryptophan, 5-hydroxyindoleacetic acid, 3-methoxy-4-hydroxyphenylglycol (MHPG), homovanillic acid (HVA), gamma-aminobutyric acid, choline, and calcium were compared in 33 anorexic and 14 normal women. The only significant difference between groups was a lower tyrosine level in the anorexic patients; their MHPG level was nonsignificantly higher. No significant group differences in body weight or depressive subgroup were found. HVA levels were positively related to body weight, and choline was negatively correlated with anorexia severity. The role of tyrosine requires further research, but these findings do suggest that HVA and choline increase with some recovery measures and MHPG is increased with this illness.

Cerebrospinal fluid amino compounds in Parkinson's disease. Alterations due to carbidopa/levodopa.

Employing a triple-column ion-exchange/fluorometric procedure, 29 amino compounds, including amino acid neurotransmitters, were measured in lumbar cerebrospinal fluid (CSF) from two groups of patients with idiopathic Parkinson's disease de novo (n = 6) and those who were treated with carbidopa/levodopa (n = 6), and from neurologically normal controls (n = 10). Consideration was given to in vivo and in vitro factors known to influence levels of various CSF constituents. Results showed statistically significant decreases in the levels of gamma-aminobutyric acid, homocarnosine, phosphoethanolamine, and threonine, and elevation of ornithine levels, in the CSF of de novo patients with Parkinson's disease compared with controls. These changes "normalized" following treatment with carbidopa/levodopa. This study suggests that Parkinson's disease may be characterized by defects in specific amino compound metabolic pathways, resulting in central nervous system amino compound imbalances that may contribute to the pathophysiology of this disorder. Carbidopa/levodopa therapy tends to "normalize" these amino compound imbalances.

Concentrations of gamma-aminobutyric acid and adenosine in the CSF in progressive myoclonus epilepsy without Lafora's bodies.

Progressive myoclonus epilepsy without Lafora's bodies (PME) is a rare inherited disease found predominantly in Finland, where the incidence is one case per 20,000 to 30,000 children. This fatal disease is characterized by normal early development, progressive stimulus-sensitive myoclonus, ataxia, dysarthria, occasional grand mal seizures, and loss of cerebellar Purkinje cells. Concentrations of gamma-aminobutyric acid in the CSF averaged 89 +/- 10 pmole/mL (mean +/- SE) in eight patients with PME, compared with 135 +/- 18 pmole/mL in ten control patients. The concentrations of adenosine (16 pmole/mL v 17 pmole/mL), inosine (560 pmole/mL v 570 pmole/mL) and hypoxanthine (6.2 nmole/mL v 6.1 nmole/mL) were the same in patients with PME and in controls.

Huntington's disease. Cerebrospinal fluid GABA levels in at-risk individuals.

Gamma-aminobutyric acid (GABA) was measured by the ion-exchange fluorometric method in CSF from 22 individuals at risk for Huntington's disease (HD), six individuals with HD, and five neurologically normal controls. The mean (+/- SD) GABA level in the specimens from patients with HD was 142 +/- 27 pmoles/ml, whereas that of the normal control specimens was 297 +/- 87 pmoles/ml. The mean GABA level of the specimens from the individuals at risk for HD was 209 +/- 79 pmoles/ml; however, nine of these were in the normal range with a mean value of 281 +/- 72 pmoles/ml, while the other 13 were below the normal range with a mean value of 159 +/- 27 pmoles/ml. The data indicate that low GABA levels in CSF are evident prior to the onset of symptoms of HD but a predictive value can only be determined by continued observation of the clinical course of these at-risk individuals.

Clinical implications of enzyme-mediated alterations of gamma-aminobutyric acid content in human CSF.

Pooled samples of lumbar CSF from nine patients with neurologic disorders were aliquoted and subjected to the differential influence of temperature for four hours. The determination of the gamma-amino-butyric acid (GABA) levels in CSF by ion-exchange-fluorometric analysis before and after incubation showed a progressive increase in GABA content of CSF as a function of temperature, reaching a maximum at 50 degrees C. However, no increases in GABA level were noted in CSF incubated at 80 degrees C or 100 degrees C. These in vitro increases in the GABA content of untreated CSF appear to be entirely secondary to enzyme action, subject to individual and temperature variability, and necessitate standardization of clinical CSF protocols.

Cerebrospinal fluid as a reflector of central cholinergic and amino acid neurotransmitter activity in cerebellar ataxia.

Cerebrospinal fluid (CSF) amino acid neurotransmitters, related compounds, and their precursors, choline levels, and acetylcholinesterase activity were measured in the CSF of patients with cerebellar ataxia during a randomized, double-blind, crossover, placebo-controlled clinical trial of physostigmine salicylate. The CSF gamma-aminobutyric acid, methionine, and choline levels, adjusted for age, were significantly lower in patients with cerebellar ataxia compared with controls. Physostigmine selectively reduced the level of CSF isoleucine and elevated the levels of phosphoethanolamine. No change occurred in CSF acetylcholinesterase activity and in the levels of plasma amino compounds in patients with cerebellar ataxia when compared with controls. Median ataxia scores did not statistically differ between placebo and physostigmine nor did functional improvement occur in any of the patients.

Levels of gamma-aminobutyric acid in cerebrospinal fluid in various neurologic disorders.

Levels of gamma-aminobutyric acid (GABA) in CSF were measured by the ion exchange-fluorometric method in 136 patients who underwent evaluation for neurologic disorders. In 19 patients with no organic neurologic or mental disorders who acted as normal controls, the mean (+/-SD) GABA level in CSF was 239 +/- 76 picomoles/mL. Patients with acute hypoxic encephalopathy showed a mean GABA level in CSF higher than that of the controls, a difference that was statistically significant. In all the other disorders studied, the mean GABA level in CSF was either equal to or lower than that found in the controls. Statistically significant reductions of the GABA level in CSF were seen in patients with Huntington's disease, dementias, cerebellar cortical atrophy, multiple sclerosis, epilepsy, and Parkinson's disease.

Central nervous system gamma-aminobutyric acid activity in man. Relationship to age and sex as reflected in CSF.

Central nervous system gamma-aminobutyric acid (GABA) activity was demonstrated to be an age- and sex-dependent phenomenon through the study of GABA concentration in lumbar CSF obtained from 87 drug-free normal individuals. Evaluation of the data from homogeneous subgroups of this population disclosed that both the propensity of lumbar CSF GABA levels to decrease with age and the magnitude of the rostrocaudal GABA concentration gradient are more pronounced in females, suggesting possible neuroendocrine involvement. Thus, age and sex are important variables that normally influence central GABAergic activity. Patient populations included in clinical investigations must be age- and sex-matched to avoid invalid conclusions biased by these physiologic variations in CSF GABA concentrations.

THIP treatment of Huntington's disease.

We evaluated the therapeutic efficacy of gamma aminobutyric acid (GABA) system stimulation in four patients with classical Huntington's disease and one with the hypokinetic-rigid form. Orally administered THIP (4,5,6,7-tetrahydroisoxazolo-[5,4,-c] pyridin-3-ol), a novel GABA receptor agonist, failed to improve motor or cognitive function during a 2-week trial. At maximum levels, THIP mimicked another putative GABA agonist, muscimol, in causing unsteadiness of gait, diminished attention to sensory stimuli, and somnolence. These effects suggest that central GABA systems participate in the regulation of some human and behavioral functions. CSF content of homovanillic acid, a major metabolite of dopamine, increased during high-dose THIP therapy, suggesting that augmentation of dopaminergic function may have contributed to the drug's lack of efficacy.

Low cerebrospinal fluid gamma-aminobutyric acid content in seizure patients.

Gamma-Aminobutyric acid (GABA) has been implicated in the neurochemistry of epilepsy. Lumbar cerebrospinal fluid (CSF) GABA concentrations determined using an ion-exchange fluorometric assay reflect brain GABA content. The mean lumbar CSF GABA concentration among 21 medicated patients with intractable seizures was significantly lower (p less than 0.001) than that of 20 unmedicated normal volunteers. Patients with generalized tonic-clonic (grand mal) and complex partial (psychomotor) seizures had significantly lower (p less than 0.05) CSF GABA concentrations than those with simple partial (focal sensory/motor) seizures. Although lumbar CSF GABA levels in our seizure patients did not significantly correlate with serum concentrations of phenytoin, phenobarbital, or primidone, additional study of medication-free epileptic patients may be required to evaluate the possibility of anticonvulsant-drug-induced CSF GABA alterations.

Lack of effect of carbamazepine on gamma-aminobutyric acid in cerebrospinal fluid.

Carbamazepine was administered to nine patients with manic-depressive illness at doses ranging from 600 to 1600 mg per day, achieving blood levels between 6 and 11 microgram per milliliter. Compared to medication-free values, GABA levels in the cerebrospinal fluid (CSF) were not significantly altered by an average of 30 days' treatment with carbamazepine. These preliminary data do not support a major effect of carbamazepine on brain GABA as reflected in CSF as a mechanism for its anticonvulsant or psychotropic effects.

Effect of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) on levels of glutathione in the extrapyramidal system of the mouse.

Treatment of mice with the proximate neurotoxin MPTP depletes striatal dopamine levels. Depletion of striatal dopamine and metabolites in MPTP-treated mice is accompanied by depletion of glutathione (GSH) in the substantia nigra (SN). Striatal GSH and nigral amino acid levels were not significantly affected by MPTP. Results suggest that GSH depletion in SN may represent an index of regional vulnerability to metabolic oxidative stress and also of selective susceptibility to the toxic effects of MPTP.