Inverse association between BMI and prefrontal metabolic activity in healthy adults

Obesity has been associated with a higher risk for impaired cognitive function, which most likely reflects associated medical complications (i.e., cerebrovascular pathology). However, there is also evidence that in healthy individuals excess weight may adversely affect cognition (executive function, attention, and memory). Here, we measured regional brain glucose metabolism (using positron emission tomography (PET) and 2-deoxy-2[(18)F]fluoro-D-glucose (FDG)) to assess the relationship between BMI and brain metabolism (marker of brain function) in 21 healthy controls (BMI range 19-37 kg/m(2)) studied during baseline (no stimulation) and during cognitive stimulation (numerical calculations). Statistical parametric mapping (SPM) revealed a significant negative correlation between BMI and metabolic activity in prefrontal cortex (Brodmann areas 8, 9, 10, 11, 44) and cingulate gyrus (Brodmann area 32) but not in other regions. Moreover, baseline metabolism in these prefrontal regions was positively associated with performance on tests of memory (California Verbal Learning Test) and executive function (Stroop Interference and Symbol Digit Modality tests). In contrast, the regional brain changes during cognitive stimulation were not associated with BMI nor with neuropsychological performance. The observed association between higher BMI and lower baseline prefrontal metabolism may underlie the impaired performance reported in healthy obese individuals on some cognitive tests of executive function. On the other hand, the lack of an association between BMI and brain metabolic activation during cognitive stimulation indicates that BMI does not influence brain glucose utilization during cognitive performance. These results further highlight the urgency to institute public health interventions to prevent obesity.     

Amygdala Perfusion Is Predicted by Its Functional Connectivity with the Ventromedial Prefrontal Cortex and Negative Affect

Background

Previous studies have shown that the activity of the amygdala is elevated in people experiencing clinical and subclinical levels of anxiety and depression (negative affect). It has been proposed that a reduction in inhibitory input to the amygdala from the prefrontal cortex and resultant over-activity of the amygdala underlies this association. Prior studies have found relationships between negative affect and 1) amygdala over-activity and 2) reduced amygdala-prefrontal connectivity. However, it is not known whether elevated amygdala activity is associated with decreased amygdala-prefrontal connectivity during negative affect states.

Methods

Here we used resting-state arterial spin labeling (ASL) and blood oxygenation level dependent (BOLD) functional magnetic resonance imaging (fMRI) in combination to test this model, measuring the activity (regional cerebral blood flow, rCBF) and functional connectivity (correlated fluctuations in the BOLD signal) of one subregion of the amygdala with strong connections with the prefrontal cortex, the basolateral nucleus (BLA), and subsyndromal anxiety levels in 38 healthy subjects.

Results

BLA rCBF was strongly correlated with anxiety levels. Moreover, both BLA rCBF and anxiety were inversely correlated with the strength of the functional coupling of the BLA with the caudal ventromedial prefrontal cortex. Lastly, BLA perfusion was found to be a mediator of the relationship between BLA-prefrontal connectivity and anxiety.

Conclusions

These results show that both perfusion of the BLA and a measure of its functional coupling with the prefrontal cortex directly index anxiety levels in healthy subjects, and that low BLA-prefrontal connectivity may lead to increased BLA activity and resulting anxiety. Thus, these data provide key evidence for an often-cited circuitry model of negative affect, using a novel, multi-modal imaging approach.     

Default Mode Network in the Effects of Δ9-Tetrahydrocannabinol (THC) on Human Executive Function

Evidence is increasing for involvement of the endocannabinoid system in cognitive functions including attention and executive function, as well as in psychiatric disorders characterized by cognitive deficits, such as schizophrenia. Executive function appears to be associated with both modulation of active networks and inhibition of activity in the default mode network. In the present study, we examined the role of the endocannabinoid system in executive function, focusing on both the associated brain network and the default mode network. A pharmacological functional magnetic resonance imaging (fMRI) study was conducted with a placebo-controlled, cross-over design, investigating effects of the endocannabinoid agonist Δ9-tetrahydrocannabinol (THC) on executive function in 20 healthy volunteers, using a continuous performance task with identical pairs. Task performance was impaired after THC administration, reflected in both an increase in false alarms and a reduction in detected targets. This was associated with reduced deactivation in a set of brain regions linked to the default mode network, including posterior cingulate cortex and angular gyrus. Less deactivation was significantly correlated with lower performance after THC. Regions that were activated by the continuous performance task, notably bilateral prefrontal and parietal cortex, did not show effects of THC. These findings suggest an important role for the endocannabinoid system in both default mode modulation and executive function. This may be relevant for psychiatric disorders associated with executive function deficits, such as schizophrenia and ADHD.     

A case‐control study of brain structure and behavioral characteristics in 47,XXX syndrome

Trisomy X, the presence of an extra X chromosome in females (47,XXX), is a relatively common but under‐recognized chromosomal disorder associated with characteristic cognitive and behavioral features of varying severity. The objective of this study was to determine whether there were neuroanatomical differences in girls with Trisomy X that could relate to cognitive and behavioral differences characteristic of the disorder during childhood and adolescence. MRI scans were obtained on 35 girls with Trisomy X (mean age 11.4, SD 5.5) and 70 age‐ and sex‐matched healthy controls. Cognitive and behavioral testing was also performed. Trisomy X girls underwent a semi‐structured psychiatric interview. Regional brain volumes and cortical thickness were compared between the two groups. Total brain volume was significantly decreased in subjects with Trisomy X, as were all regional volumes with the exception of parietal gray matter. Differences in cortical thickness had a mixed pattern. The subjects with Trisomy X had thicker cortex in bilateral medial prefrontal cortex and right medial temporal lobe, but decreased cortical thickness in both lateral temporal lobes. The most common psychiatric disorders present in this sample of Trisomy X girls included anxiety disorders (40%), attention‐deficit disorder (17%) and depressive disorders (11%). The most strongly affected brain regions are consistent with phenotypic characteristics such as language delay, poor executive function and heightened anxiety previously described in population‐based studies of Trisomy X and also found in our sample.     

Attentional bias to food images associated with elevated weight and future weight gain: an fMRI study

Behavioral studies reveal that obese vs. lean individuals show attentional bias to food stimuli. Yet research has not investigated this relation using objective brain imaging or tested whether attentional bias to food stimuli predicts future weight gain, which are important aims given the prominence of food cues in the environment. We used functional magnetic resonance imaging (fMRI) to examine attentional bias in 35 adolescent girls ranging from lean to obese using an attention network task involving food and neutral stimuli. BMI correlated positively with speed of behavioral response to both appetizing food stimuli and unappetizing food stimuli, but not to neutral stimuli. BMI correlated positively with activation in brain regions related to attention and food reward, including the anterior insula/frontal operculum, lateral orbitofrontal cortex (OFC), ventrolateral prefrontal cortex (vlPFC), and superior parietal lobe, during initial orientation to food cues. BMI also correlated with greater activation in the anterior insula/frontal operculum during reallocation of attention to appetizing food images and with weaker activation in the medial OFC and ventral pallidum during reallocation of attention to unappetizing food images. Greater lateral OFC activation during initial orientation to appetizing food cues predicted future increases in BMI. Results indicate that overweight is related to greater attentional bias to food cues and that youth who show elevated reward circuitry responsivity during food cue exposure are at increased risk for weight gain.     

The Prevalence of Metabolically Healthy Obese Subjects Defined by BMI and Dual‐Energy X‐Ray Absorptiometry

Nearly one‐third of obese (OB) people are reported to be metabolically healthy based on BMI criteria. It is unknown whether this holds true when more accurate adiposity measurements are applied such as dual‐energy X‐ray absorptiometry (DXA). We compared differences in the prevalence of cardiometabolic abnormalities among adiposity groups classified using BMI vs. DXA criteria. A total of 1,907 adult volunteers from Newfoundland and Labrador participated. BMI and body fat percentage (%BF; measured using DXA) were measured following a 12‐h fasting period. Subjects were categorized as normal weight (NW), overweight (OW), or OB based on BMI and %BF criteria. Cardiometabolic abnormalities considered included elevated triglyceride, glucose, and high‐sensitivity C‐reactive protein (hsCRP) levels, decreased high‐density lipoprotein (HDL) cholesterol levels, insulin resistance, and hypertension. Subjects were classified as metabolically healthy (0 or 1 cardiometabolic abnormality) or abnormal (≥2 cardiometabolic abnormalities). We found low agreement in the prevalence of cardiometabolic abnormalities between BMI and %BF classifications (κ = 0.373, P < 0.001). Among NW and OW subjects, the prevalence of metabolically healthy individuals was similar between BMI and %BF (77.6 vs. 75.7% and 58.8 vs. 62.5%, respectively) however, there was a pronounced difference among OB subjects (34.0 vs. 47.7%, P < 0.05). Similar trends were evident using three additional definitions to characterize metabolically healthy individuals. Our findings indicate that approximately one‐half of OB people are metabolically healthy when classified using %BF criteria which is significantly higher than previously reported using BMI. Caution should therefore be taken when making inferences about the metabolic health of an OB population depending on the method used to measure adiposity.     

Comparison of Regional Cerebral Blood Flow Responses to Hypoglycemia Using Pulsed Arterial Spin Labeling and Positron Emission Tomography

Different brain regions sense and modulate the counterregulatory responses that can occur in response to declining plasma glucose levels. The aim of this study was to determine if changes in regional cerebral blood flow (rCBF) during hypoglycemia relative to euglycemia are similar for two imaging modalities–pulsed arterial spin labeling magnetic resonance imaging (PASL-MRI) and positron emission tomography (PET). Nine healthy non-diabetic participants underwent a hyperinsulinemic euglycemic (92±3 mg/dL) – hypoglycemic (53±1 mg/dL) clamp. Counterregulatory hormone levels were collected at each of these glycemic levels and rCBF measurements within the previously described network of hypoglycemia-responsive regions (thalamus, medial prefrontal cortex and globus pallidum) were obtained using PASL-MRI and [¹⁵O] water PET. In response to hypoglycemia, rCBF was significantly increased in the thalamus, medial prefrontal cortex, and globus pallidum compared to euglycemia for both PASL-MRI and PET methodologies. Both imaging techniques found similar increases in rCBF in the thalamus, medial prefrontal cortex, and globus pallidum in response to hypoglycemia. These brain regions may be involved in the physiologic and symptom responses to hypoglycemia. Compared to PET, PASL-MRI may provide a less invasive, less expensive method for assessing changes in rCBF during hypoglycemia without radiation exposure.     

Impaired Prefrontal Hemodynamic Maturation in Autism and Unaffected Siblings

Background

Dysfunctions of the prefrontal cortex have been previously reported in individuals with autism spectrum disorders (ASD). Previous studies reported that first-degree relatives of individuals with ASD show atypical brain activity during tasks associated with social function. However, developmental changes in prefrontal dysfunction in ASD and genetic influences on the phenomena remain unclear. In the present study, we investigated the change in hemoglobin concentration in the prefrontal cortex as measured with near-infrared spectroscopy, in children and adults with ASD during the letter fluency test. Moreover, to clarify the genetic influences on developmental changes in the prefrontal dysfunction in ASD, unaffected siblings of the ASD participants were also assessed.

Methodology/Principal Findings

Study participants included 27 individuals with high-functioning ASD, age- and IQ-matched 24 healthy non-affected siblings, and 27 unrelated healthy controls aged 5 to 39 years. The relative concentration of hemoglobin ([Hb]) in the prefrontal cortex was measured during the letter fluency task. For children, neither the [oxy-Hb] change during the task nor task performances differed significantly among three groups. For adults, the [oxy-Hb] increases during the task were significantly smaller in the bilateral prefrontal cortex in ASD than those in control subjects, although task performances were similar. In the adult siblings the [oxy-Hb] change was intermediate between those in controls and ASDs.

Conclusion/Significance

Although indirectly due to a cross-sectional design, the results of this study indicate altered age-related change of prefrontal activity during executive processing in ASD. This is a first near-infrared spectroscopy study that implies alteration in the age-related changes of prefrontal activity in ASD and genetic influences on the phenomena.     

Effect of Satiation on Brain Activity in Obese and Lean Women

Objective: To investigate the response of the brains of women to the ingestion of a meal. Research Methods and Procedures: We used measures of regional cerebral blood flow (rCBF), a marker of neuronal activity, by positron emission tomography to describe the functional anatomy of satiation, i.e., the response to a liquid meal in the context of extreme hunger (36‐hour fast) in 10 lean (BMI ≤ 25 kg/m²; 32 ± 10 years old, 61 ± 7 kg; mean ± SD) and 12 obese (BMI ≥ 35 kg/m²; 30 ± 7 years old, 110 ± 14 kg) women. Results: In lean and obese women, satiation produced significant increases in rCBF in the vicinity of the prefrontal cortex (p < 0.005). Satiation also produced significant decreases in rCBF in several regions including the thalamus, insular cortex, parahippocampal gyrus, temporal cortex, and cerebellum (in lean and obese women), and hypothalamus, cingulate, nucleus accumbens, and amygdala (in obese women only; all p < 0.005). Compared with lean women, obese women had significantly greater increases in rCBF in the ventral prefrontal cortex and had significantly greater decreases in the paralimbic areas and in areas of the frontal and temporal cortex. Discussion: This study indicates that satiation elicits differential brain responses in obese and lean women. It also lends additional support to the hypothesis that the paralimbic areas participate in a central orexigenic network modulated by the prefrontal cortex through feedback loops.     

Obesity is associated with reduced white matter integrity in otherwise healthy adults

Existing work demonstrates that obesity is independently associated with cognitive dysfunction and macrostructural brain changes; however, little is known about the association between obesity and white matter (WM) integrity. We explore this relationship in a large cohort of otherwise healthy subjects. The present study classified 103 adult participants from the Brain Resource International Database between 21 and 86 years of age without history of neurological, medical, or psychiatric illness according to BMI (normal weight, overweight, obese) and subjected them to diffusion tensor imaging (DTI). Resulting fractional anisotropy (FA) indexes for the corpus callosum and fornix were examined in relation to BMI and age in a multiple regression framework. Results indicated that increasing BMI was independently associated with lower FA in the genu, splenium, and fornix, and a BMI × age interaction emerged for FA in the splenium and body of the corpus callosum. When categorized, obese persons demonstrated lower FA than normal and overweight persons for all WM indexes, but no FA differences emerged between overweight and normal persons. Results indicate both a direct association between obesity and reduced WM tract integrity and an interaction between obesity and aging processes on certain WM tracts in otherwise healthy adults. While such findings suggest a possible role for adiposity in WM dysfunction and associated cognitive deficits, prospective studies are needed to clarify the nature of these relationships and elucidate underlying mechanisms.     

Functional imaging of working memory in obstructive sleep-disordered breathing.

Functional magnetic resonance imaging was used to map cerebral activation in 16 patients with obstructive sleep-disordered breathing (OSDB) and 16 healthy subjects, during the performance of a 2-back verbal working memory task. Six patients with OSDB were reimaged after a minimum period of 8 wk of treatment with positive airway pressure. Working memory speed in OSDB was significantly slower than in healthy subjects, and a group average map showed absence of dorsolateral prefrontal activation, regardless of nocturnal hypoxia. After treatment, resolution of subjective sleepiness contrasted with no significant change in behavioral performance, persistent lack of prefrontal activation, and partial recovery of posterior parietal activation. These findings suggest that working memory may be impaired in OSDB and that this impairment is associated with disproportionate impairment of function in the dorsolateral prefrontal cortex. Nocturnal hypoxia may not be a necessary determinant of cognitive dysfunction, and sleep fragmentation may be sufficient. There may be dissociations between respiratory vs. cortical recovery and objective vs. subjective recovery. Hypofrontality may provide a plausible biological mechanism for a clinical overlap with disorders of mood and attention.     

Abnormal medial prefrontal cortex connectivity and defective fear extinction in the presymptomatic G93A SOD1 mouse model of ALS

Amyotrophic lateral sclerosis (ALS) is a fatal progressive neuropathy associated with the degeneration of spinal and brainstem motor neurons. Although ALS is essentially considered as a lower motor neuron disease, prefrontal cortex atrophy underlying executive function deficits have been extensively reported in ALS patients. Here, we examine whether prefrontal cortex neuronal abnormalities and related cognitive impairments are present in presymptomatic G93A Cu/Zn superoxide dismutase mice, a mouse model for familial ALS. Structural characteristics of prelimbic/infralimbic (PL/IL) medial prefrontal cortex (mPFC) neurons were studied in 3-month-old G93A and wild-type mice with the Golgi–Cox method, while mPFC-related cognitive operations were assessed using the conditioned fear extinction paradigm. Sholl analysis performed on the dendritic material showed a reduction in dendrite length and branch nodes on basal dendrites of PL/IL neurons in G93A mice. Spine density was also decreased on basal dendrite segments of branch order five. Consistent with the altered morphology of PL/IL cortical regions, G93A mice showed impaired extinction of conditioned fear. Our findings indicate that abnormal prefrontal cortex connectivity and function are appreciable before the onset of motor disturbances in this model.     

Cortical activation and lamina terminalis functional connectivity during thirst and drinking in humans

The pattern of regional brain activation in humans during thirst associated with dehydration, increased blood osmolality, and decreased blood volume is not known. Furthermore, there is little information available about associations between activation in osmoreceptive brain regions such as the organum vasculosum of the lamina terminalis and the brain regions implicated in thirst and its satiation in humans. With the objective of investigating the neuroanatomical correlates of dehydration and activation in the ventral lamina terminalis, this study involved exercise-induced sweating in 15 people and measures of regional cerebral blood flow (rCBF) using a functional magnetic resonance imaging technique called pulsed arterial spin labeling. Regional brain activations during dehydration, thirst, and postdrinking were consistent with the network previously identified during systemic hypertonic infusions, thus providing further evidence that the network is involved in monitoring body fluid and the experience of thirst. rCBF measurements in the ventral lamina terminalis were correlated with whole brain rCBF measures to identify regions that correlated with the osmoreceptive region. Regions implicated in the experience of thirst were identified including cingulate cortex, prefrontal cortex, striatum, parahippocampus, and cerebellum. Furthermore, the correlation of rCBF between the ventral lamina terminalis and the cingulate cortex and insula was different for the states of thirst and recent drinking, suggesting that functional connectivity of the ventral lamina terminalis is a dynamic process influenced by hydration status and ingestive behavior.     

Systemic Neurochemical Alterations in Schizophrenic Brain: Glutamate Metabolism in Focus

We have used a systemic approach to establish a relationship between enzyme measures of glial glutamate and energy metabolism (glutamine synthetase and glutamine synthetase-like protein, glutamate dehydrogenase isoenzymes, brain isoform creatine phosphokinase) and two major glial proteins (glial fibrillary acidic protein and myelin basic protein) in autopsied brain samples taken from patients with schizophrenia (SCH) and mentally healthy subjects (23 and 22 cases, respectively). These biochemical parameters were measured in tissue extracts in three brain areas (prefrontal cortex, caudate nucleus, and cerebellum). Significant differences in the level of at least one of the glutamate metabolizing enzymes were observed between two studied groups in all studied brain areas. Different patterns of correlative links between the biochemical parameters were found in healthy and schizophrenic brains. These findings give a new perspective to our understanding of the impaired regulation of enzyme levels in the brain in SCH.     

Effects of blood flow to the prefrontal cortex on high-intensity exercise combined with high-decibel music

We studied the effects of high-intensity exercise (70-75% of VO₂ max) combined with high-decibel music (100 dB) on cognitive function (measured by the Stroop test) and related blood flow changes to the prefrontal cortex (measured by Oxy-hemoglobin (Hb), Deoxy-Hb, tissue oxygen index (TOI), and normalized tissue hemoglobin index (nTHI)). The subjects of the study were 28 healthy female university students in their early 20s. Subjects were categorized into control group (CG), music group (MG), exercise group (Ex), and music and exercise group (MnEx). A crossover design was implemented so that all subjects participated in all test groups. We found no significant difference in reaction time between CG and MG for the neutral and incongruent tasks of Stroop test. However, there were significant improvements in the neutral and incongruent tasks for both the Ex (p < 0.01) and MnEx (p < 0.01) groups. Oxy-Hb measurements in the prefrontal cortex of the brain supported the Stroop test data. We found no difference between Ex and MnEx in the TOI; however, there was a significant decrease (p < 0.05) in MnEx compared to Ex. In addition, Ex resulted in a significant increase (p < 0.05) in nTHI as compared to CG. These results indicate that high decibel music could negatively affect prefrontal cortex activation of the brain during exercise.     

Altered Resting-State Functional Connectivity of the Frontal-Striatal Reward System in Social Anxiety Disorder

We investigated differences in the intrinsic functional brain organization (functional connectivity) of the human reward system between healthy control participants and patients with social anxiety disorder. Functional connectivity was measured in the resting-state via functional magnetic resonance imaging (fMRI). 53 patients with social anxiety disorder and 33 healthy control participants underwent a 6-minute resting-state fMRI scan. Functional connectivity of the reward system was analyzed by calculating whole-brain temporal correlations with a bilateral nucleus accumbens seed and a ventromedial prefrontal cortex seed. Patients with social anxiety disorder, relative to the control group, had (1) decreased functional connectivity between the nucleus accumbens seed and other regions associated with reward, including ventromedial prefrontal cortex; (2) decreased functional connectivity between the ventromedial prefrontal cortex seed and lateral prefrontal regions, including the anterior and dorsolateral prefrontal cortices; and (3) increased functional connectivity between both the nucleus accumbens seed and the ventromedial prefrontal cortex seed with more posterior brain regions, including anterior cingulate cortex. Social anxiety disorder appears to be associated with widespread differences in the functional connectivity of the reward system, including markedly decreased functional connectivity between reward regions and between reward regions and lateral prefrontal cortices, and markedly increased functional connectivity between reward regions and posterior brain regions.     

The regional cerebral blood flow pattern of the normal human brain and its factor structure

The regional cerebral blood flow (rCBF) pattern of the normal human brain was drawn, and its structure was studied. Relative rCBF estimates for 66 regions of interest (cerebral anatomical-functional areas) were obtained using positron emission tomography in 158 healthy subjects aged 18–49 years. The rCBF rate variation range was 89–121% of the rCBF rate averaged over all regions of interest, taken as 100%. The rCBF rates were the highest (>115%) in the paracentral lobule, precuneus, insular cortex, primary visual cortex, and Broca’s area and the lowest (<95%) in the mediobasal regions of the temporal gyri and caudate nuclei. Analysis of the factor structure of the resultant pattern made it possible to classify cerebral anatomical-functional areas according to a predominant effect of one of the following factors on the interdependence between rCBF rates: (1) cytoarchitectonic characteristics; (2) the functional state of the cortex during quiet wakefulness; or (3) the brain vascular region to which the area belongs. The obtained pattern should be taken into account in both mapping of the functions of a normal brain and clinical diagnosis.     

Adipocyte triglyceride turnover and lipolysis in lean and overweight subjects

Human obesity is associated with decreased triglyceride turnover and impaired lipolysis in adipocytes. We determined whether such defects also occur in subjects with only moderate increase in fat mass. Human abdominal subcutaneous adipose tissue was investigated in healthy, nonobese subjects [body mass index (BMI) > 17 kg/m² and BMI < 30 kg/m²]. Triglyceride age, reflecting lipid turnover, was examined in 41 subjects by assessing the incorporation of atmospheric ¹⁴C into adipose lipids. Adipocyte lipolysis was examined as the ability of lipolytic agents to stimulate glycerol release in 333 subjects. Adipocyte triglyceride age was markedly increased in overweight (BMI ≥ 25 kg/m²) compared with lean subjects (P = 0.017) with triglyceride T_1/2 of 14 and 9 months, respectively (P = 0.04). Triglyceride age correlated positively with BMI (P = 0.002) but not with adipocyte volume (P = 0.2). Noradrenaline-, isoprenaline- or dibutyryl cyclic AMP-induced lipolysis was inversely correlated with triglyceride age (P < 0.01) and BMI (P < 0.0001) independently of basal lipolysis, gender, and nicotine use. Current, but not the highest or lowest BMI in adult life, correlated significantly (inversely) with lipolysis. In conclusion, adipocyte triglyceride turnover and lipolytic activity are decreased in overweight subjects and reflect the current BMI status. These changes may confer an increased risk for early development and/or maintenance of excess body fat.     

Differential effects of normal aging on sources of standard N1, target N1 and target P300 auditory event-related brain potentials revealed by low resolution electromagnetic tomography (LORETA)

The P300 event-related potential (ERP) is considered to be closely related to cognitive processes. In normal aging, P300 scalp latencies increase, parietal P300 scalp amplitudes decrease and the scalp potential field shifts to a relatively more frontal distribution. Based on ERPs recorded in 172 normal healthy subjects aged between 20 and 88 years in an auditory oddball paradigm, the effects of age on the electrical activity in the brain corresponding to N1 and P300 components were estimated by means of low resolution electromagnetic tomography (LORETA). This distributed approach directly computes a unique 3-dimensional electrical source distribution by assuming that neighbouring neurons are simultaneously and synchronously active. N1 LORETA generators, located predominantly in both auditory cortices and also symmetrically in prefrontal areas, increased with advancing age for standards but remained stable for targets. P300 LORETA generators, located symmetrically in the prefrontal cortex, in the parieto-occipital junction and in the inferior parietal cortex (supramarginal gyrus) and medially in the superior parietal cortex, were differentially affected by age. While age did not affect parieto-occipital sources, superior parietal and right prefrontal sources decreased pronouncedly. Thus, in normal aging, P300 current density decreased in regions were a fronto-parietal network for sustained attention was localized.     

Decreased Chloride Channel Expression in the Dorsolateral Prefrontal Cortex in Schizophrenia

Alterations in GABAergic neurotransmission are implicated in several psychiatric illnesses, including schizophrenia. The Na-K-Cl and K-Cl cotransporters regulate intracellular chloride levels. Abnormalities in cotransporter expression levels could shift the chloride electrochemical gradient and impair GABAergic transmission. In this study, we performed Western blot analysis to investigate whether the Na-K-Cl and K-Cl cotransporter protein is abnormally expressed in the dorsal lateral prefrontal cortex and the anterior cingulate cortex in patients with schizophrenia versus a control group. We found decreased K-Cl cotransporter protein expression in the dorsal lateral prefrontal cortex, but not the anterior cingulate cortex, in subjects with schizophrenia, supporting the hypothesis of region level abnormal GABAergic function in the pathophysiology of schizophrenia. Subjects with schizophrenia off antipsychotic medication at the time of death had decreased K-Cl cotransporter protein expression compared to both normal controls and subjects with schizophrenia on antipsychotics. Our results provide evidence for KCC2 protein abnormalities in schizophrenia and suggest that antipsychotic medications might reverse deficits of this protein in the illness.