Brainstem auditory-evoked responses among children afflicted by severely hypoxic CHD.

MAIN AIM: To electrophysiologically determine the impact of moderate to severe chronic hypoxia (H) resulting from a wide array of CHD (HCHD) conditions on the integrity of brainstem function. MATERIALS AND METHODS: Applying brainstem auditory-evoked response methodology, 30 chronically afflicted HCHD patients, who already had undergone heart surgery, were compared to 28 healthy control children (1-15 yo) matched by age, gender and socioeconomic condition. Blood oxygen saturation was clinically determined and again immediately before brainstem auditory-evoked response testing. RESULTS: Among HCHD children, auditory wave latencies (I, III and V) were significantly longer (medians: I, 2.02 ms; III, 4.12 ms, and; V, 6.30 ms) compared to control (medians: I, 1.67ms; III, 3.72 ms, and; V, 5.65 ms), as well as interpeak intervals (HCHD medians: I-V, 4.25 ms, and; III-V, 2.25ms; control medians: I-V, 3.90 ms and, III-V, 1.80 ms) without significant differences in wave amplitudes between groups. A statistically significant and inverse correlation between average blood oxygen saturation of each group (control, 94%; HCHD, 78%) and their respective wave latencies and interpeak intervals was found. CONCLUSIONS: As determined by brainstem auditory-evoked responses, young HCHD patients manifestly show severely altered neuronal conductivity in the auditory pathway strongly correlated with their hypoxic condition. These observations are strongly supported by different brainstem neurological and image studies showing that alterations, either in microstructure or function, result from the condition of chronic hypoxia in CHD. The non-altered wave amplitudes are indicative of relatively well-preserved neuronal relay nuclei.

Preclinical evaluation of early multi-organ toxicity induced by liposomal doxorubicin using 67Ga-citrate.

Although liposomal doxorubicin (LPD) is widely used for cancer treatment, knowledge concerning the toxicity induced by this drug in healthy organs and tissues is limited. LPD-induced toxicity studies relative to free doxorubicin (DOX) have focused on cardiotoxicity in tumor-bearing animals. On the other hand, the results on DOX-induced cardiotoxicity depending on gender are controversial. One of the manifestations of toxicity is tissue inflammation. 67Ga-citrate has been used for decades to assess inflammation in various pathologies. In this work, the ex vivo biodistribution of 67Ga-citrate is used to evaluate induced multi-organ toxicity in healthy 10-week-old male and female CD1 mice treated for 5 weeks with LPD. Toxicity in males, determined by 67Ga-citrate, was evident only in the target organs of liposomes (spleen, liver, kidneys, and lungs); the average weight loss was 11% and mortality was 14%. In female mice, 67Ga-citrate revealed a cytotoxic effect in practically all organs, the average weight loss was 37%, and the mortality after the last dose of LPD was 66%. These results confirm the usefulness of 67Ga-citrate and the importance of stratifying by sex in the toxicological evaluation of drugs.

EEG effective connectivity during the first year of life mirrors brain synaptogenesis, myelination, and early right hemisphere predominance.

INTRODUCTION: The maturation of electroencephalogram (EEG) effective connectivity in healthy infants during the first year of life is described. METHODS: Participants: A cross-sectional sample of 125 healthy at-term infants, from 0 to 12 months of age, underwent EEG in a state of quiet sleep. PROCEDURES: The EEG primary currents at the source were described with the sLoreta method. An unmixing algorithm was applied to reduce the leakage, and the isolated effective coherence, a direct and directed measurement of information flow, was calculated. RESULTS AND DISCUSSION: Initially, the highest indices of connectivity are at the subcortical nuclei, continuing to the parietal lobe, predominantly the right hemisphere, then expanding to temporal, occipital, and finally the frontal areas, which is consistent with the myelination process. Age-related connectivity changes were mostly long-range and bilateral. Connections increased with age, mainly in the right hemisphere, while they mainly decreased in the left hemisphere. Increased connectivity from 20 to 30 Hz, mostly at the right hemisphere. These findings were consistent with right hemisphere predominance during the first three years of life. Theta and alpha connections showed the greatest changes with age. Strong connectivity was found between the parietal, temporal, and occipital regions to the frontal lobes, responsible for executive functions and consistent with behavioral development during the first year. The thalamus exchanges information bidirectionally with all cortical regions and frequency bands. CONCLUSIONS: The maturation of EEG connectivity during the first year in healthy infants is very consistent with synaptogenesis, reductions in synaptogenesis, myelination, and functional and behavioral development.

Evaluation of doxorubicin-induced early multi-organ toxicity in male CD1 mice by biodistribution of 18F-FDG and 67Ga-citrate. Pilot study.

The search for methods that identify early toxicity, induced by chemotherapy, is urgent. Changes in the biodistribution of radiopharmaceuticals could give information on early toxicity. Ten-week-old CD1 male mice were divided into four groups. Two groups were administered a weekly dose of 5 mg/kg of doxorubicin hydrochloride (DOX) for 5 weeks and the control groups were administered saline solution. One week after the end of treatment, the biodistribution of 18F-FDG and 67Ga-citrate were carried out, as was the quantification of plasma enzymes CK, CK-MB, LDH and AST. All enzymes were higher in the treated animals, but only significant (p < 0.05) in the case of CK-MB. 18F-FDG uptake increased in all organs of treated animals except retroperitoneal fat, being significant in spleen, brain, heart, liver, lung, kidney, and inguinal fat. 67Ga-citrate had a more complex pattern. The uptake in the DOX group was higher in spleen, lung, kidney, testes, and gonadal fat, it did not change in brain, heart, and liver, and it was lower in the rest of the organs. It only showed significant differences in lung and pancreas. A thorough discussion of the possible causes that produced the change in biodistributions of both radiopharmaceuticals is included. The pilot study showed that both radiopharmaceuticals could identify early multi-organ toxicity induced by DOX. Although 18F-FDG seems to be better, 67Ga-citrato should not be ruled out a priori. The detection of early toxicity would serve to adopt treatments that prevent its progression, thus improving patient's quality of life.

Iron therapy substantially restores qEEG maturational lag among iron-deficient anemic infants.

OBJECTIVE: To use quantitative electroencephalography (qEEG) to assess the impact of iron-deficiency anemia on central nervous system maturation in the first year of life. METHOD: Twenty-five infants (3-12 months old) presenting ferropenic anemia (IDA) and 25 healthy controls (CTL1), matched by age/gender with the former, were studied in two stages. Electroencephalogram during spontaneous sleep was recorded from all participants; the fast Fourier transform was calculated to obtain absolute power (AP) and relative power (RP) qEEG measures. In the first stage, a qEEG comparison between CTL1 and IDA was performed. Second stage consisted in comparing qEEG of the IDA infants before and after supplementation with iron (IDA-IS group), and comparing qEEG of the IDA-IS group with another control age-matched group (CTL2). Non-parametric multivariate permutation tests (NPT) were applied to assess differences between CTL1 and IDA groups, as well as IDA vs. IDA-IS, and IDA-IS vs. CTL2. RESULTS: More power in slow frequency bands and less power in fast frequency bands in 64% of IDA babies were observed. NPT evinced higher alpha AP and RP (P < 0.001), less theta AP, and less delta and theta RP in CTL1 than in IDA. After iron-restoration therapy, alpha AP and RP increased while theta AP and theta and delta RP decreased, reaching almost normal values. DISCUSSION: This work reveals CNS developmental delay through the study of qEEG (less rapid and more slow frequencies) which recovered significantly with iron supplementation. It is concluded that IDA constitutes a high risk factor for a lag of CNS maturation.

Molecular mechanisms of cognitive impairment in iron deficiency: alterations in brain-derived neurotrophic factor and insulin-like growth factor expression and function in the central nervous system.

OBJECTIVE: The present review examines the relationship between iron deficiency and central nervous system (CNS) development and cognitive impairment, focusing on the cellular and molecular mechanisms related to the expression and function of growth factors, particularly the insulin-like growth factors I and II (IGF-I/II) and brain-derived neurotrophic factor (BDNF), in the CNS. METHODS: Nutritional deficiencies are important determinants in human cognitive impairment. Among these, iron deficiency has the highest prevalence worldwide. Although this ailment is known to induce psychomotor deficits during development, the precise molecular and cellular mechanisms underlying these alterations have not been properly elucidated. This review summarizes the available information on the effect of iron deficiency on the expression and function of growth factors in the CNS, with an emphasis on IGF-I/II and BDNF. RESULTS AND DISCUSSION: Recent studies have shown that specific growth factors, such as IGF-I/II and BDNF, have an essential role in cognition, particularly in processes involving learning and memory, by the activation of intracellular-signaling pathways involved in cell proliferation, differentiation, and survival. It is known that nutritional deficiencies promote reductions in systemic and CNS concentrations of growth factors, and that altered expression of these molecules and their receptors in the CNS leads to psychomotor and developmental deficits. Iron deficiency may induce these deficits by decreasing the expression and function of IGF-I/II and BDNF in specific areas of the brain.

Event-related EEG oscillations to semantically unrelated words in normal and learning disabled children.

Learning disabilities (LD) are one of the most frequent problems for elementary school-aged children. In this paper, event-related EEG oscillations to semantically related and unrelated pairs of words were studied in a group of 18 children with LD not otherwise specified (LD-NOS) and in 16 children with normal academic achievement. We propose that EEG oscillations may be different in LD NOS children versus normal control children that may explain some of the deficits observed in the LD-NOS group. The EEGs were recorded using the 10/20 system. EEG segments were edited by visual inspection 1000ms before and after the stimulus, and only correct responses were considered in the analysis. Time-frequency (1-50Hz) topographic maps were obtained for the increases and decreases of power after the event with respect to the pre-stimulus average values. Significant differences between groups were observed in the behavioral responses. LD-NOS children show less number of correct responses and more omissions and false alarms than the control group. The event-induced EEG responses showed significant differences between groups. The control group showed greater power increases in the frequencies 1-6Hz than the LD-NOS group from 300 to 700ms. These differences were mainly observed in frontal regions, both to related and non-related words. This was interpreted as a deficit in attention, both to internal and external events, deficits in activation of working memory and deficits in encoding and memory retrieval in the LD-NOS children. Differences between groups were also observed in the suppression of alpha and beta rhythms in the occipital regions to related words in frequencies between 8 and 17Hz from 450 to 750ms. LD-NOS children showed shorter durations of the decreases in power than the control group. These results suggest also deficits in attention and memory retrieval. It may be concluded that LD-NOS children showed physiological differences from normal children that may explain their cognitive deficiencies.

3D statistical parametric mapping of quiet sleep EEG in the first year of life.

This paper extends previously developed 3D SPM for Electrophysiological Source Imaging (Bosch et al., 2001) for neonate EEG. It builds on a prior paper by our group that established age dependent means and standard deviations for the scalp EEG Broad Band Spectral Parameters of children in the first year of life. We now present developmental equations for the narrow band log spectral power of EEG sources, obtained from a sample of 93 normal neonates from age 1 to 10 months in quiet sleep. The main finding from these regressions is that EEG power from 0.78 to 7.5 Hz decreases with age and also for 45-50 Hz. By contrast, there is an increase with age in the frequency band of 19-32 Hz localized to parietal, temporal and occipital areas. Deviations from the norm were analyzed for normal neonates and 17 with brain damage. The diagnostic accuracy (measured by the area under the ROC curve) of EEG source SPM is 0.80, 0.69 for average reference scalp EEG SPM, and 0.48 for Laplacian EEG SPM. This superior performance of 3D SPM over scalp qEEG suggests that it might be a promising approach for the evaluation of brain damage in the first year of life.

Clinical and electrophysiological effect of right and left repetitive transcranial magnetic stimulation in patients with major depressive disorder / Efecto clínico y electrofisiológico de la estimulación magnética transcraneal repetitiva derecha e izquierda en pacientes con transtorno depresivo mayor

Major Depressive Disorder (MDD) is a common psychiatric disorder that represents one of the main public health problems worldwide. It has been projected that for 2020 it will be the second cause of disability-adjusted life years just below ischemic heart disease. Quantitative electroencephalogram provides the opportunity to study cortical oscillatory activity across the different frequency bands. It constitutes an accessible tool to explore the clinical and neurophysiologic correlates underlying psychiatric disorders as well as the effect of diverse therapeutic options and the performance through cognitive tasks. Repetitive transcranial magnetic stimulation is a technique that allows the stimulation of the cerebral cortex noninvasively, relatively painlessly and with fairly few side effects. The vast majority of rTMS studies target left dorsolateral prefrontal cortex (DLPFC) based on imaging studies showing that left prefrontal cortex dysfunction is pathophysiologically linked to depression. However, there is some evidence implicating right PFC in the pathophysiology of depression. Comparison of antidepressant efficacy of diverse stimulation frequencies is relevant since a main concern around rTMS is its potential to induce seizures; hence we consider that frequency of stimulation is an important aspect to be studied. For this study we aimed to elucidate the clinical efficacy of rTMS comparing two groups of depressed patients stimulated over DLPFC, one over the left (at 5 Hz) and other over the right (at 1 Hz). We also meant to know if there were clinical and electroencephalographic differential long-term after-effects between those groups of treatment. We included twenty right-handed patients with a DSM-IVR diagnosis of MDD. They were assigned into two groups of treatment. Group 1 received 5Hz rTMS over the left DLPFC. Group 2 received 1Hz rTMS over the right DLPFC. We obtained two EEG measurements in order to analyze Z score of broad-band spectral parameters and cross-spectral. No statistical differences among groups were found in response to treatment after weekly comparisons of clinimetric scores and significant differences between baseline and final assessment by HDRS, MADRS, BDI and HARS. The major rTMS effect on EEG was observed in the group that received 1 Hz over the right DLPFC and no significant effects were observed for the group that received 5 Hz over the left DLPFC. Our results propose that administration of 15 sessions on either left (5 Hz) or right (1 Hz) rTMS over DLPFC is sufficient to reach response to treatment, assessed by HDRS, MADRS, BDI and HARS in subjects with MDD. Moreover, in both cases rTMS was able to induce an equivalent antidepressant effect. The major effect of rTMS on EEG was observed in the right 1 Hz rTMS group where changes were elicited mainly over frontal, central and temporal regions on alpha and particularly beta frequency bands. In a lesser extent for left 5 Hz rTMS group the main effect was observed on anterior regions for beta and particularly alpha frequency bands. We believe it is pertinent to continue exploring the therapeutic potential of lower stimulation frequencies, for what further research including larger samples is still necessary to confirm these trends.

El trastorno depresivo mayor es una entidad psiquiátrica que representa uno de los principales problemas de salud pública a nivel mundial. Se ha proyectado que para el año 2020 será la segunda causa de discapacidad únicamente por debajo de la cardiopatía isquémica. La utilización del electroencefalograma cuantitativo ofrece la oportunidad de estudiar la actividad oscilatoria cortical a través de las diferentes bandas de frecuencias. Éste constituye una herramienta para explorar las características clínicas y neurofisiológicas que subyacen a los trastornos psiquiátricos, así como un instrumento para evaluar el efecto de diversas opciones terapéuticas y el desempeño de los sujetos durante la realización de tareas cognitivas. La estimulación magnética transcraneal repetitiva (EMTr) es una técnica que permite la estimulación de la corteza cerebral de manera no invasiva, relativamente sin dolor y con pocos efectos secundarios. Con base en los estudios de neuroimagen que vinculan la fisiopatología de la depresión con disfunción en la corteza prefrontal dorsolateral (CPFDL), la mayoría de las investigaciones se han enfocado en estimular dicha corteza en el hemisferio izquierdo. No obstante, existen pruebas que implican a la corteza prefrontal derecha con la fisiopatología de la depresión. La relevancia de comparar la eficacia antidepresiva de diversas frecuencias radica en el hecho de que un tema de interés particular alrededor de la EMTr es su potencial para inducir convulsiones, por ello consideramos que la exploración de las diversas frecuencias de estimulación con efecto terapéutico constituye un aspecto importante de estudio. Para este trabajo nos propusimos determinar la eficacia antidepresiva de la EMTr comparando dos grupos de pacientes que fueron estimulados en la CPFDL derecha a 1 Hz o en la izquierda a 5 Hz. También buscamos dilucidar si existen diferencias clínicas y electroencefalográficas a largo plazo entre grupos de tratamiento. Para este estudio se incluyeron 20 pacientes con diagnóstico de trastorno depresivo mayor de acuerdo con los criterios del DSM-I V. Los sujetos fueron asignados aleatoriamente a uno de dos grupos de tratamiento. Un grupo recibió EMTr sobre la CPFDL izquierda a 5Hz; el otro recibió estimulación a 1 Hz sobre la corteza contralateral. Se obtuvieron dos registros electroencefalográficos, uno basal y otro final, con el fin de comparar las medidas espectrales de banda ancha y estrecha, pretratamiento y postratamiento. Se realizaron evaluaciones clinimétricas con las escalas de Hamilton para Depresión y Ansiedad, la escala de Depresión de Montgomery-Asberg y el Inventario de Beck. No encontramos diferencias significativas al comparar la respuesta a la EMTr entre ambos grupos. Los pacientes de ambos grupos presentaron respuesta a tratamiento (disminución de ≥50% de la sintomatología depresiva) medida por clinimetría. El efecto más importante de la EMTr sobre el EEG se observó en el grupo de estimulación derecha a 1 Hz donde encontramos disminución postratamiento en los valores Z de banda estrecha alfa y beta, principalmente en regiones fronto-centro-temporales. Aunque en menor proporción, en el grupo de estimulación izquierda a 5 Hz encontramos incrementos significativos post EMTr, predominantemente en las bandas beta y alfa sobre todo en regiones anteriores. No se encontraron resultados significativos en el análisis de banda ancha. Nuestros resultados sugieren que la administración de 15 sesiones de EMTr ya sea sobre la CPFDL derecha (1 Hz) o izquierda (5 Hz) es capaz de lograr respuesta antidepresiva. Nuestros hallazgos electrofisiológicos sugieren que uno de los efectos a largo plazo de la EMTr es la reorganización de los circuitos neuronales implicados en la depresión.

Working memory impairment and recovery in iron deficient children.

OBJECTIVE: Iron is an important oligoelement participating in multiple metabolic processes, including the synthesis of catecholamines, and its deficiency (ID) throughout development is particularly insidious on brain maturation and the emergence of cognitive functions during school age. A working memory (WM) study in 8-10-year-old ID children is presented. It is hypothesized that an impairment in WM exists in ID school-age children and a substantial restoration of this mental ability should occur after iron supplementation. METHODS: Event-related potentials (ERPs) were recorded during the completion of a Sternberg-type task in control, ID and ID-iron supplemented children. RESULTS: ID children showed less correct answers and diminished ERP amplitude in frontal, central, parietal and temporal regions compared to control children. After iron supplementation and normalizing bodily iron stores, behavioral and ERP differences disappeared between ID and control children. CONCLUSIONS: Considering that WM is fundamentally related to attention ability, the results presented here confirm and reinforce previous observations: ID severely diminishes attention [Otero GA, Pliego-Rivero FB, Contreras G, Ricardo J, Fernandez T. Iron supplementation brings up a lacking P300 in iron deficient children. Clin Neurophysiol 2004;115:2259-66] and WM while iron supplementation substantially restores the cognitive capabilities tested. SIGNIFICANCE: This is one of very few reports using ERP showing a diminished WM capability in ID school-age children.

Delayed CNS maturation in iron-deficient anaemic infants.

Direct evidence of CNS developmental alterations in iron-deficient anaemic (IDA) infants was obtained. Twenty 3-15-month-old IDA and 20 non-IDA infants (age and gender matched), healthy in every other respect, were studied. Complete blood and iron kinetics tests determined an IDA status. Psychomotor development was assessed through the test of Rogers and co-workers [Rogers SJ, Donovan CM, D'Eugenio D, Brown SL, Whiteside E, Moersch MS, Schafer DS. (eds) Developmental Programming for Infants and Young Children, Vol 2. University of Michigan Press, 1981] and under the 10-20 International System qEEG was performed (sleep/stage II). A Pearson's correlation test was applied between haematological, psychomotor and broad band EEG variables, and through ANOVA psychomotor and AP means were compared. IDA infants showed lower scores in cognition, fine motor and social/emotional areas, higher delta/theta and lower alpha power. Most correlations between haematological/psychological variables were positive. Delta/theta correlations were negative with self-care/gross and motor items while alpha/beta AP showed positive correlations with psychomotor and haematological variables. A clear association was found between EEG alterations and a low haematological/iron profile leading to a delayed psychomotor development.

Changes in EEG current sources induced by neurofeedback in learning disabled children. An exploratory study.

The objective of this work was to explore Neurofeedback (NFB) effects on EEG current sources in Learning Disabled (LD) children, and to corroborate its beneficial consequences on behavioral and cognitive performance. NFB was given in twenty 30-min sessions to 11 LD children to reduce their abnormally high theta/alpha ratios (Experimental Group). Another five LD children with the same characteristics received a placebo treatment (Control Group). In the Control Group no changes in behavior or EEG current source were observed. In the Experimental Group, immediately after treatment children showed behavioral and cognitive improvements, but current source analysis showed few modifications; however, 2 months after treatment many changes occurred: a decrease in current of frequencies within the theta band, mainly in left frontal and cingulate regions, and enhancement in current of frequencies within the alpha band, principally in the right temporal lobe and right frontal regions, and of frequencies within the beta band, mainly in left temporal, right frontal and cingulate cortex regions. In conclusion, NFB is a possibly efficacious treatment for LD children with an abnormally high theta/alpha ratio in any lead. The changes observed in EEG current sources may reflect the neurophysiological bases of the improvement that children experienced in their behavioral and cognitive activities.

Iron supplementation brings up a lacking P300 in iron deficient children.

OBJECTIVE: A decrease in iron concentration is accompanied by alterations in catecholaminergic and GABAergic neurotransmission systems, important in learning, memory and attention. It was hypothesized that iron deficient children would present attention deficits. A visual-event related potentials (ERPs) study is presented using an oddball paradigm in order to determine the P300 in ID children. METHODS: After medical examination, blood was obtained from 201 children for a complete hematological study. Two groups were selected, iron deficient (ID) (serum iron <60 microg/dl) and control (C) (serum iron >60 microg/dl). In both groups ERPs were recorded while executing a continuous performance task (oddball paradigm). Afterwards iron levels were restored in ID children by iron supplementation (ID-IS group) and all tests reapplied. RESULTS: ID children almost lacked a P300 in central and parietal regions. After iron supplementation, P300 clearly became evident although its Pz amplitude remained smaller compared to C children. CONCLUSIONS: A clear and strong correlation was found between ID and attention alterations in children. Iron supplementation nearly brings the P300 to normal levels although it is not known if the P300 difference in Pz is due to other nutritional/environmental deficits or to developmental psychomotor impairments in ID children. SIGNIFICANCE: It has been long known that iron deficient children have cognitive impairments but there is an insufficient number of electrophysiological works allowing to identify the source of this problem. In this work an attention deficit is demonstrated in ID children through a severely reduced P300, which recovers substantially after iron supplementation.