Longitudinal study of brain function and depletion of iron stores in individual subjects

Seven men living in a controlled research unit showed decrements in iron stores due to repeated phlebotomy. For each subject, weekly measures of cognitive task performance, electroencephalographic (EEG) power and Event-Related Potentials (ERPs) were examined in relation to serum ferritin level. No reliable relationships of ferritin level to cognitive performance ability were observed. Some EEG findings appeared similar to previous observations on EEG data and iron status in cross-sectional research. For four of the seven subjects, asymmetries of EEG power in the occipital electrodes appeared related to the decline in iron status over time.     

Resting EEG theta power correlates with cognitive performance in healthy older adults

We address the degree to which resting EEG bandpower is associated with cognitive performance in 73 healthy older adults (aged 56-70). Relative theta (4-6.5 Hz) power was significantly correlated with immediate and delayed verbal recall, attention, and executive function measures. Relative delta and alpha power and peak alpha frequency did not correlate with any cognitive measures. These data indicate that high resting theta power in healthy older adults is associated with better cognitive function and may be a marker of healthy neurocognitive aging. Comparison of these with previous findings suggests that two forms of theta-frequency oscillations may exist; one indicative of healthy neurocognitive function and the other, EEG/alpha slowing linked to (future) substantial cognitive decline. Future EEG investigations of cognitive aging or decline should analyze both relative theta power and degree of EEG/alpha slowing so as not to confound these.     

Regional changes in EEG power and coherence during cognition: intensive study of two individuals

Two men underwent weekly electroencephalogram (EEG) recordings while living for several months in a controlled laboratory environment. Data collected from an eight-channel EEG during a resting period and during performance of two cognitive tasks (word fluency and mental imagery) were subjected to spectral analysis. Statistical analyses on power and coherence were conducted for each subject separately, to determine whether that individual showed a characteristic pattern of EEG activity for a given cognitive task which was stable over time. Although substantial individual differences were observed, particularly for the theta band, both subjects showed changes in the spectral information over the anterior left hemisphere during the word fluency task.     

Thyroid Function in Normals: Influences on the Electroencephalogram and Cognitive Performance

Recently it has been suggested that thyroid function may influence neuropsychological processes not only as a result of thyroid disease but also through normal neurophysiologic adaptive mechanisms. In 69 normal university students, levels of thyroid stimulating hormone (TSH), thyroxine (T4), and triiodothyronine (T3) were assayed in blood samples and related to measures of cognitive performance and to spectral measures of the EEG recorded during cognitive performance. Significant relationships were found between T3 levels and delta power in the EEG from occipital leads, with higher T3 associated with less EEG power in the left hemisphere and greater power in the right hemisphere. Higher T3 levels were associated with poorer performance on several cognitive tasks, particularly for males, although the males with higher T3 levels also showed faster correct responses on a word fluency task. These results seem to support the hypothesis that an individual's characteristic level of thyroid function is relevant to normal neuropsychological processes.     

Iron metabolism in boys involved in intensive physical training

The purpose of the present study was to compare some haematological and iron-related parameters of prepubertal boys (10-12 years old) involved in intensive physical training program in preparation for the national championship with nontrained age-matched subjects. For this purpose, iron stores, haemoglobin, ferritin and serum transferrin receptor concentrations were taken into account. The athletes' dietary intakes were similar to the respective intakes in the control group. Mean ferritin concentration was similar in investigated groups of boys at the start of the study, but significant changes between those groups occurred during the 8 months of study. Compared with the control group, the trained ones have shown significantly higher serum transferrin receptor concentration during the competition period of the training season, just when they reached maximum performance capacity. Similarly, significant difference in total body iron, estimated as the sum of the individual's red blood cells iron and iron stores, between investigated groups occurred only during the competition period. The main finding of this study is that the endurance training in boys brings about significant decrease in serum ferritin, as well as iron stores in the body. Haematological parameters and iron status of trained children revealed latent anaemia (15%) or even manifest anaemia (9%). These findings indicate high prevalence of nonanaemic iron deficiency in young athletes and bear relationship to swimming training.     

Iron status of children with phenylketonuria undergoing nutrition therapy assessed by transferrin receptors

Purpose: The purpose of the study was to determine the incidence of iron deficiency in children undergoing therapy for phenylketonuria using serum transferrin receptor and ferritin concentrations.Methods: A 1-year study was conducted in 37 children 2 < 13 years old with phenylketonuria (8 fed Periflex [Group I], 15 fed Phenex-2 Amino Acid-Modified Medical Food [Group II], and 14 fed Phenyl-Free [Group III]). Hemoglobin, hematocrit, serum transferrin receptor, and ferritin concentrations were assessed at baseline and 12 months and intakes of protein, iron, and vitamin C were evaluated at baseline and at 3-month intervals. Transferrin receptor and ferritin concentrations were analyzed for group differences by analysis of variance.Results: Mean protein, iron, and vitamin C intakes of all 3 groups of children were greater than Recommended Dietary Intakes for age. Only 2 of 60 3-day diet diaries of Group II children failed to contain 100% of Recommended Dietary Intakes for iron during study. The following number of children had iron status indices outside reference ranges at study end: 7 children, transferrin receptor/ferritin ratios; 4 children, transferrin receptors; 2 children, hematocrit; 1 child, ferritin. No correlation was found between iron intake and any index of iron status.Conclusions: The transferrin receptor/ferritin ratio appeared to be the most sensitive index of iron deficiency in this study. Reasons for iron deficiency with greater than recommended iron intakes by children with phenylketonuria may be multiple. Early assessment and therapy of iron deficiency may improve cognitive and behavioral outcomes of children with PKU.     

Identification of Resting and Active State EEG Features of Alzheimer’s Disease using Discrete Wavelet Transform

Alzheimer’s disease (AD) is associated with deficits in a number of cognitive processes and executive functions. Moreover, abnormalities in the electroencephalogram (EEG) power spectrum develop with the progression of AD. These features have been traditionally characterized with montage recordings and conventional spectral analysis during resting eyes-closed and resting eyes-open (EO) conditions. In this study, we introduce a single lead dry electrode EEG device which was employed on AD and control subjects during resting and activated battery of cognitive and sensory tasks such as Paced Auditory Serial Addition Test (PASAT) and auditory stimulations. EEG signals were recorded over the left prefrontal cortex (Fp1) from each subject. EEG signals were decomposed into sub-bands approximately corresponding to the major brain frequency bands using several different discrete wavelet transforms and developed statistical features for each band. Decision tree algorithms along with univariate and multivariate statistical analysis were used to identify the most predictive features across resting and active states, separately and collectively. During resting state recordings, we found that the AD patients exhibited elevated D₄ (~4–8 Hz) mean power in EO state as their most distinctive feature. During the active states, however, the majority of AD patients exhibited larger minimum D₃ (~8–12 Hz) values during auditory stimulation (18 Hz) combined with increased kurtosis of D₅ (~2–4 Hz) during PASAT with 2 s interval. When analyzed using EEG recording data across all tasks, the most predictive AD patient features were a combination of the first two feature sets. However, the dominant discriminating feature for the majority of AD patients were still the same features as the active state analysis. The results from this small sample size pilot study indicate that although EEG recordings during resting conditions are able to differentiate AD from control subjects, EEG activity recorded during active engagement in cognitive and auditory tasks provide important distinct features, some of which may be among the most predictive discriminating features.     

Genetic influences on bipolar EEG power spectra.

The EEG bipolar power spectra provide more localization than spectral measures obtained from monopolar referencing strategies, and have been shown to be useful endophenotypes of psychiatric disorders such as alcoholism. We estimated the additive genetic heritability of resting bipolar EEG power spectra in a large sample of non-twin sibling pairs. The corresponding heritabilities ranged between 0.220 and 0.647 and were highly significant at all 38 electrode pairs for theta (3-7 Hz), low-alpha (7-9 Hz), high-alpha (9-12 Hz), low-beta (12-16 Hz), middle-beta (16-20 Hz) and high-beta (20-28 Hz) frequency bands. The heritabilities were the highest in the high-alpha and low-beta bands at most electrode pairs. The heritabilities were most variable across the head in the three beta bands. Other heritability patterns were also identified within each frequency band. Our results suggest that substantial proportions of the variability in the bipolar EEG measures are explained by genetic factors.     

Do serum and red blood cell folate levels indicate iron response in hemodialysis patients?

The relationship among iron status, ferritin, and folate levels, and the possible contribution of folate measurement in the prediction of iron response in hemodialysis patients, have not been assessed. In addition to serum ferritin and transferrin saturation (TSAT), serum and red blood cell (RBC) folate levels were evaluated as indices for intravenous iron therapy responsiveness in 60 hemodialysis patients. Patients were classified as iron responders or nonresponders depending on whether they exhibited a rise in hemoglobin above 1 g/dl after administration of 1 g of iron sucrose. An inverse relation between serum ferritin concentration and RBC folate levels was found in iron responders (n=26, r=-0.62, p<0.001) but not in nonresponders (n=34, r=0.07, p=nonsignificant). Only serum and RBC folate levels could predict iron response in patients with ferritin levels above 150 microg/l (n=25), with a sensitivity of 83.3% and a specificity of 94.7%. Our findings suggest that RBC folate concentration is inversely related with ferritin levels in iron-responsive but not in non-responsive hemodialysis patients. Serum and RBC folate concentration seems to predict response to iron administration better than serum ferritin or TSAT in patients with ferritin levels above 150 microg/l; therefore, in these patients, it might be used to guide iron management.     

Global EEG coherence as a marker for cognition in older adults at risk for dementia

Quantitative electroencephalography (EEG) provides useful information about neurophysiological health of the aging brain. Current studies investigating EEG coherence and power for specific brain areas and frequency bands have yielded inconsistent results. This study assessed EEG coherence and power indices at rest measured over the whole skull and for a wide frequency range as global EEG markers for cognition in a sample at risk for dementia. Since global markers are more reliable and less error-prone than region- and frequency-specific indices they might help to overcome previous inconsistencies. Global EEG coherence (1–30 Hz) and an EEG slowing score were assessed. The EEG slowing score was calculated by low-frequency power (1–8 Hz) divided by high-frequency power (9–30 Hz). In addition, the prognostic value of the two EEG indices for cognition and cognitive decline was assessed in a 5-year follow-up pilot study. Baseline global coherence correlated positively with cognition at baseline, but not with cognitive decline or with cognition at the 5-year follow-up. The EEG slowing ratio showed no significant association, neither with cognition at baseline or follow-up, nor with cognitive decline over a period of 5 years. The results indicate that the resting state global EEG coherence might be a useful and easy to assess electrophysiological correlate for neurocognitive health in older adults at risk for dementia. Because of the small statistical power for the follow-up analyses, the prognostic value of global coherence could not be determined in the present study. Future studies should assess its prognostic value with larger sample sizes.     

Test-retest reliability of regional electroencephalogram (EEG) and cardiovascular measures in social anxiety disorder (SAD)

Although the search for psychophysiological manifestations of social anxiety has a rich history, there appear to be no published reports examining the reliability of continuous electrocortical measures that putatively index stress vulnerability and stress reactivity in socially anxious individuals. We examined the 1-week test-retest reliability of regional electroencephalogram (EEG) alpha asymmetry and power, respiratory sinus arrhythmia (RSA), heart period, and heart period variability measures at rest and during anticipation of an impromptu speech in 26 adults diagnosed with social anxiety disorder (SAD). Across the 1-week time period, we found medium-to-large correlations for regional EEG asymmetry and large correlations for regional EEG alpha power, RSA, heart period, and heart period variability measures at rest and during speech anticipation, before and after accounting for age and medication status. These results are similar to patterns observed in nonclinical samples and appear to provide the first documented evidence of test-retest reliability of psychophysiological measures that index central nervous system activity in socially anxious individuals. These findings also provide support for the notion that resting frontal EEG asymmetry and RSA constitute relatively stable individual differences in this clinical population.     

Association between BDNF Val66Met polymorphism and trait depression is mediated via resting EEG alpha band activity

A functional polymorphism of the brain-derived neurotrophic factor, BDNF Val66Met, is associated with risk for major depression alongside impairments in memory and selective attention. This study aims to identify the mediating neural mechanisms in links between BDNF and depression using highly heritable electroencephalographic (EEG) recordings. In 305 healthy subjects, BDNF Val66Met genotypes were compared in terms of trait depression, neural function (EEG during a resting state) and cognitive performance. The mediating effects of the EEG brain imaging endophenotypes were also examined using structural equation (path) modeling. A genotype-endophenotype-phenotype path model showed that Met homozygosity predicted elevated working memory commission errors and altered EEG activity; that is elevated relative theta and delta power coupled with reduced alpha power. In turn, reduced EEG alpha activity mediated the relationship between the Met/Met genotype and trait depression. These findings demonstrate the utility of an integrative endophenotype approach. They suggest that the BDNF Met/Met homozygote has a direct impact on memory systems, but impacts trait depression via the secondary effects of neural changes.     

Task complexity modulates pilot electroencephalographic activity during real flights

Most research connecting task performance and neural activity to date has been conducted in laboratory conditions. Thus, field studies remain scarce, especially in extreme conditions such as during real flights. Here, we investigated the effects of flight procedures of varied complexity on the in‐flight EEG activity of military helicopter pilots. Flight procedural complexity modulated the EEG power spectrum: highly demanding procedures (i.e., takeoff and landing) were associated with higher EEG power in the higher frequency bands, whereas less demanding procedures (i.e., flight exercises) were associated with lower EEG power over the same frequency bands. These results suggest that EEG recordings may help to evaluate an operator's cognitive performance in challenging real‐life scenarios, and thus could aid in the prevention of catastrophic events.     

Quantitative electroencephalography in mild cognitive impairment: longitudinal changes and possible prediction of Alzheimer's disease

The present study evaluated the clinical course of patients with mild cognitive impairment (MCI), the pattern of electroencephalography (EEG) changes following cognitive deterioration, as well as the potential of neurophysiological measures in predicting dementia. Twenty-seven subjects with MCI were followed for a mean follow up period of 21 months. Fourteen subjects (52%) progressed (P MCI) to clinically manifest Alzheimer's disease (AD), and 13 (48%) remained stable (S MCI). The two MCI subgroups did not differ in baseline EEG measures between each other and the healthy controls (n = 16), but had significantly lower theta relative power at left temporal, temporo-occipital, centro-parietal, and right temporo-occipital derivation when compared to the reference AD group (n = 15). The P MCI baseline alpha band temporo-parietal coherence, alpha relative power values at left temporal and temporo-occipital derivations, theta relative power values at frontal derivations, and the mean frequency at centro-parietal and temporo-occipital derivations overlapped with those for AD and control groups. After the follow-up, the P MCI patients had significantly higher theta relative power and lower beta relative power and mean frequency at the temporal and temporo-occipital derivations. A logistic regression model of baseline EEG values adjusted for baseline Mini-Mental Test Examination showed that the important predictors were alpha and theta relative power and mean frequency from left temporo-occipital derivation (T5-O1), which classified 85% of MCI subjects correctly.     

Variation of soluble transferrin receptor and ferritin concentrations in human serum during recovery from exercise

Serum soluble transferrin receptor (sTfR) has been proposed as a more stable index of iron status than serum ferritin in athletes. However, the variation in sTfR concentration during recovery from acute exercise is unknown. The aim of the present study was to examine the effect of prolonged moderate exercise on ferritin and sTfR concentrations, as well as on several hematologic variables up to 24 h post-exercise. Fifteen young, untrained men exercised on a cycle ergometer for 45 min at a heart rate of 150–155 beats min⁻¹ and provided blood samples before as well as immediately, 6 h, and 24 h after exercise. Ferritin and sTfR values did not change significantly with time. sTfR levels exhibited lower variation during the observation period, the median intra-individual coefficient of variation being 5.2%, as opposed to 10.9% for ferritin. In conclusion, serum ferritin concentration is not affected by prolonged moderate exercise and can be used as a reliable index of iron status, at least for athletes not involved in extreme physical activities. Serum sTfR concentration seems to be more stable and could replace ferritin as the preferred index of iron stores if problems associated with the novelty of the assay were overcome. Electronic Publication     

Loss of phase synchrony in an animal model of partial status epilepticus

Interrupting a focal, chronic infusion of GABA to the rat motor cortex initiates the progressive emergence of a sustained spiking electroencephalographic (EEG) activity, associated with myoclonic jerks of the corresponding body territory. This activity is maintained over several hours, has an average frequency of 1.5 Hz, is localized to the infusion site and never generalizes. The GABA withdrawal syndrome (GWS) has therefore features of partial status epilepticus. Changes in EEG signals associated with the GWS were studied in freely moving rats by measuring the phase synchrony between bilateral epidural records from the neocortex. Our results showed (i) epileptic activity was associated with a striking decrease in phase synchrony between all pairs of electrodes including the focus, predominantly in the 1-6 Hz frequency range. There was a mean decrease of 75.34+/-5.26% in phase synchrony levels between the period before GABA interruption and the period after epileptic activity appeared. (ii) This reduction in synchrony contrasted with an increase of power spectral density in the corresponding EEG channels over the same 1-6 Hz frequency range, (iii) neither changes in synchrony nor in nonlinear dynamics were detected before the first EEG spikes, (iv) systemic injection of ketamine, an antagonist of N-methyl-d-aspartic acid (NMDA) receptors, modified transiently both epileptic activity and the synchrony profile. (v) Spiking activity and synchrony changes were suppressed by reperfusion of GABA. Our data suggest that, during a partial status epilepticus, interactions between the epileptic focus and connected neocortical neuronal populations are dramatically decreased in low frequencies.     

Changes of EEG spectra and coherence following performance in a cognitive task in Alzheimer's disease.

Electroencephalographic measures combined with cognitive tasks are widely used for the assessment of cognitive and pathophysiological changes in Alzheimer's disease (AD). Instead of the analysis of EEG data obtained during the performance of the task, in this study data recorded in the immediate after-task period were analyzed. It was expected that this period would correspond to the electrophysiological consequences of the cognitive effort. Data of 14 patients with AD (MMS score: 16-24) were compared to that of 10 healthy control subjects. Reverse counting of a fix duration was used as a cognitive task. Changes of relative frequency spectra, and those of inter-and intrahemispheric coherence were analyzed. Relative theta power was significantly higher in AD patients compared to the controls both before and after the task. The performance of the task resulted in an increase of the relative alpha2 band in the AD group, whereas it slightly decreased in the control group. The most prominent coherence differences between AD and controls were found in the alpha1 band, especially for long-range coherence values. Coherence in this frequency band increased in the control group following the task, not seen in the AD group. We conclude that EEG parameters calculated from epochs following the completion of a cognitive task clearly differentiates patients with AD from normal controls. The electrophysiological changes found in AD may correspond to the decrease of functional connectivity of cortical areas and to the malfunctioning of the networks engaged in the cognitive task investigated.     

Dynamic changes in quantitative electroencephalogram during continuous performance test in children with attention-deficit/hyperactivity disorder

To establish whether dynamic EEG changes in children with attention-deficit/hyperactivity disorder (ADHD) differ from those observed in controls, the authors investigated the effect of the continuous performance test (CPT) on delta, theta, alpha and beta frequency bands. High-resolution electroencephalography (EEG) was recorded during eyes-open resting and CPT performance in 16 right-handed children meeting the DSM-IV criteria for ADHD and 16 age-matched controls. Significant CPT vs. eyes-open differences in EEG activities was observed in children with ADHD. In particular, switching to CPT induced an alpha power increase in children with ADHD and an alpha power decrease in controls. This may reflect a primary deficit associated with cortical hypoarousal in ADHD. These EEG results agree with behavioral findings leading the authors to suggest that dynamic changes in neural network activities are impaired in children with ADHD.     

Modulation of gamma-band spectral power by cognitive task complexity

This study evaluated the utility of electroencephalographic (EEG) measures as indices of regional cerebral activation during performance of visuo-semantic analysis tasks in neurologically intact adult volunteers. EEG was recorded from 28 scalp locations as participants performed three visual discrimination tasks designed to tap into increasingly more complex operations regularly involved in the recognition of living animate objects. In addition, data from a control task involving the same stimuli, but requiring no cognitive decision or response, was included. EEG records were quantified using power spectrum measures in five frequency bands (delta, theta, alpha, beta, and gamma). Results showed a significant linear increase in absolute power in the gamma band with increasing task complexity over left hemisphere frontal and occipital regions, and over right temporoparietal regions.     

The HLA linked iron loading gene in an Afrikaner population.

The serum ferritin concentration was used as a screening test to identify the presence of iron overload in 599 Afrikaans subjects (300 males and 299 females) living in the South Western Cape, South Africa. Seventeen of the males with concentrations greater than 400 micrograms/l were reevaluated three and five years later. Serum ferritin concentrations were measured again and further diagnostic procedures were carried out. These included an assessment of alcohol intake and measurements of serum gamma glutamyltransferase, the percentage saturation of transferrin, and HLA-A,-B,-C, and -DR loci typing on the subjects as well as their families. Liver biopsies were performed on some affected subjects. Of the original 16 index subjects, four were diagnosed as homozygous for the HLA linked iron loading gene which is responsible for the clinical disease idiopathic haemochromatosis. Six appeared to be heterozygotes, three were heterozygotes who were also abusing alcohol, and two did not fit into any of the diagnostic groups. The calculated gene frequency was 0.082, with an expected heterozygote frequency of 0.148. The fact that no females were identified in the study suggested that the diagnostic criteria for homozygosity (serum ferritin greater than 400 micrograms/l and % saturation greater than 60%) were set too high. The data were therefore recalculated for the 300 males; when this was done the gene frequency was 0.115 and the heterozygote frequency 0.024. Two subjects were diagnosed as homozygotes in the study of family members and 37 as heterozygotes (33 definite and four probable). Both the homozygotes and nine of the heterozygotes showed mild to moderate disturbances of iron metabolism. There was considerable overlap between the phenotype expression in these nine heterozygotes and the homozygotes, probably as a result of setting the threshold for the serum ferritin concentrations at the relatively high value of 400 microgram/ml. By doing this a small subset of heterozygotes with biochemical abnormalities was identified. The results of the present pilot study suggest a high frequency of the HLA linked iron loading gene in the Afrikaner population of South Western Cape.