Developmental Vitamin D Deficiency Affects Spatial Learning in Wistar Rats.

Background: Vitamin D deficiency is a global problem. Recent evidence suggests that vitamin D is involved in brain development and function. Vitamin D deficiency has been associated with poor cognitive function in adults, but the effect of developmental vitamin D deficiency (DVDD) on cognitive function and brain development in children has not been well established.Objective: We explored the effects of DVDD on cognitive functions and brain morphology of rat pups.Methods: Wistar rat pups born to control and vitamin D-deficient dams were divided into 4 groups: control (C), deficient during gestation (dG), deficient during lactation (dL), and deficient during gestation and lactation (dGL). Spatial learning and memory were assessed by the Morris water maze test at postnatal day (PND) 24 and PND 45. Cortical thickness at the level of the hippocampus was measured at PND 63, and synapses were counted in specified areas of the hippocampus at PND 32 and PND 63.Results: Repeated-measures ANOVA revealed that at PND 24, learning (escape latency) was impaired (by 42%) in the dGL group, whereas at PND 45, both the dL and the dGL groups showed learning impairment (by 47% and 45%, respectively) compared with their respective C groups (P < 0.05). Short-term or long-term memory was largely unaffected by DVDD either at PND 24 or PND 45. Compared with the C group, all the DVDD groups had fewer synapses in the molecular layer of the hippocampus (P < 0.001). The synapse number decreased by 54% in the dGL group at PND 33 and by 70% in the dL and dGL groups at PND 63. All the DVDD groups at PND 63 showed a reduced cortical thickness (by 22%) compared with the C group (P < 0.05).Conclusion: These results suggest that a combined prenatal and postnatal DVDD for ≥6 wk in rat pups affects learning but not memory.

The ageing systemic milieu negatively regulates neurogenesis and cognitive function.

In the central nervous system, ageing results in a precipitous decline in adult neural stem/progenitor cells and neurogenesis, with concomitant impairments in cognitive functions. Interestingly, such impairments can be ameliorated through systemic perturbations such as exercise. Here, using heterochronic parabiosis we show that blood-borne factors present in the systemic milieu can inhibit or promote adult neurogenesis in an age-dependent fashion in mice. Accordingly, exposing a young mouse to an old systemic environment or to plasma from old mice decreased synaptic plasticity, and impaired contextual fear conditioning and spatial learning and memory. We identify chemokines--including CCL11 (also known as eotaxin)--the plasma levels of which correlate with reduced neurogenesis in heterochronic parabionts and aged mice, and the levels of which are increased in the plasma and cerebrospinal fluid of healthy ageing humans. Lastly, increasing peripheral CCL11 chemokine levels in vivo in young mice decreased adult neurogenesis and impaired learning and memory. Together our data indicate that the decline in neurogenesis and cognitive impairments observed during ageing can be in part attributed to changes in blood-borne factors.

Informed consent for blood tests in people with a learning disability.

AIM: This article is a report of a study of informed consent in people with a learning disability. The aims of the study were to explore the information needs of people with mild-to-moderate learning disabilities with respect to consent for blood tests and to identify ways of facilitating informed consent. BACKGROUND: The recent political agenda for social change in the UK has emphasized the right of people with a learning disability to have more autonomy and make their own decisions. As in other countries, there has also been a shift towards shared decision-making in healthcare practice. DESIGN: Qualitative study using an ethnographic approach. METHODS: An ethnographic approach was used for this qualitative study. Phase 1 involved observation of six participants with a learning disability having a routine blood test in general practice, followed by semi-structured interviews with 14 participants with a learning disability in Phase 2. Data were collected between February 2009-February 2010. FINDINGS: The data showed that consent procedures were often inadequate and provision of information to patients prior to a blood test was variable. People with a learning disability expressed clearly their information requirements when having a routine blood test; this included not wanting any information in some cases. CONCLUSIONS: Healthcare practitioners and people with a learning disability need to be familiar with current consent law in their own country to facilitate valid consent in the healthcare context. This study demonstrated the value of qualitative research in exploring the knowledge and attitudes of people with learning disability.

Maternal immune activation impairs reversal learning and increases serum tumor necrosis factor-α in offspring.

Maternal immune activation (MIA) produces a variety of behavioral and brain abnormalities in rodent models of several neuropsychiatric disorders. However, it remains controversial whether MIA impairs reversal learning, a basic function of flexibility relevant to those diseases, in offspring. In the present study, we used the Morris water maze to investigate the effects of middle to late gestation stage poly(I:C) challenges on spatial learning and subsequent reversal learning performance in adolescent rats. Maternal poly(I:C) treatment induced deficits in reversal learning without affecting spatial acquisition abilities. In addition, the serum level of the proinflammatory cytokine tumor necrosis factor-α was increased in MIA rats. This study advances our understanding of how MIA affects adolescent behavior and brain function.

Prenatal Vitamin D Levels in Maternal Sera and Offspring Specific Learning Disorders.

Recent evidence has suggested potential harmful effects of vitamin D deficiency during pregnancy on offspring brain development, for example, elevated risks for neuropsychiatric disorders. Findings on general cognition and academic achievement are mixed, and no studies have examined the effect of prenatal 25-hydroxyvitamin D (25(OH)D) levels on diagnosed specific learning disorders, which was the aim of this study. We examined a nested case-control sample from the source cohort of all singleton-born children in Finland between 1996 and 1997 (n = 115,730). A total of 1607 cases with specific learning disorders (mean age at diagnosis: 9.9 years) and 1607 matched controls were identified from Finnish nationwide registers. Maternal 25(OH)D levels were analyzed from serum samples collected during the first trimester of pregnancy and stored in a national biobank. Conditional logistic regression was used to test the association between maternal 25(OH)D and offspring specific learning disorders. There were no significant associations between maternal 25(OH)D levels and specific learning disorders when vitamin D was examined as a log-transformed continuous variable (adjusted OR 0.98, 95% CI 0.82-1.18, p = 0.84) or as a categorical variable (25(OH)D < 30 nmol/L: adjusted OR 1.03, 95% CI 0.83-1.28, p = 0.77 compared to levels of >50 nmol/L), nor when it was divided into quintiles (adjusted OR for the lowest quintile 1.00, 95% CI 0.78-1.28, p = 0.99 compared to the highest quintile). This study found no association between low maternal 25(OH)D in early pregnancy and offspring specific learning disorders.

Effects of combined treatment with vitamins C and E on passive avoidance learning and memory in diabetic rats.

Learning and memory deficits occur in diabetes mellitus. Although the pathogenesis of cognitive impairment in diabetes has not been fully elucidated, factors such as metabolic impairments, vascular complications and oxidative stress are thought to play possible roles. Here we investigated the effect of chronic treatment with vitamin C (50mg/kg, p.o), vitamin E (100mg/kg, p.o) and both together on passive avoidance learning (PAL) and memory in male Wistar control and diabetic rats. Treatments were begun at the onset of hyperglycemia. Passive avoidance learning was assessed 30 days later. Retention was tested 24h after training. At the end, animals were weighed and blood samples were drawn for plasma glucose measurement. Diabetes caused impairment in acquisition and retrieval processes of PAL and memory. The combination of vitamin C and E improved learning and memory in controls and reversed learning and memory deficits in diabetic rats. Combined treatment also affected the body weight and plasma glucose level of diabetic treated animals compared to untreated diabetic animals. Hypoglycemic effects and antioxidant properties of the vitamins may be involved in the nootropic effect of such treatment. These results show that combined treatment with vitamins C and E improved PAL and memory of control rats. In addition, combined vitamins administration to rats for 30 days from onset of diabetes alleviated the negative influence of diabetes on learning and memory. Therefore, combined vitamins treatment may provide a new potential alternative for prevention of impaired cognitive functions associated with diabetes and may warrant further clinical study.

(+)-Methamphetamine-induced monoamine reductions and impaired egocentric learning in adrenalectomized rats is independent of hyperthermia.

Methamphetamine (MA) is widely abused and implicated in residual cognitive deficits. In rats, increases in plasma corticosterone and egocentric learning deficits are observed after a 1-day binge regimen of MA (10 mg/kg x 4 at 2-h intervals). The purpose of this experiment was to determine if adrenal inactivation during and following MA exposure would attenuate the egocentric learning deficits in the Cincinnati water maze (CWM). In the first experiment, the effects of adrenalectomy (ADX) or sham surgery (SHAM) on MA-induced neurotoxicity at 72 h were determined. SHAM-MA animals showed typical patterns of hyperthermia, whereas ADX-MA animals were normothermic. Both SHAM-MA- and ADX-MA-treated animals showed increased neostriatal glial fibrillary acidic protein and decreased monoamines in the neostriatum, hippocampus, and entorhinal cortex. In the second experiment, SHAM-MA- and ADX-MA-treated groups showed equivalently impaired CWM performance 2 weeks post-treatment (increased latencies, errors, and start returns) compared to SHAM-saline (SAL) and ADX-SAL groups with no effects on novel object recognition, elevated zero maze, or acoustic startle/prepulse inhibition. Post-testing, monoamine levels remained decreased in both MA-treated groups in all three brain regions, but were not as large as those observed at 72-h post-treatment. The data demonstrate that MA-induced learning deficits can be dissociated from drug-induced increases in plasma corticosterone or hyperthermia, but co-occur with dopamine and serotonin reductions.

Impairments in fear conditioning in mice lacking the nNOS gene.

The fear conditioning paradigm is used to investigate the roles of various genes, neurotransmitters, and substrates in the formation of fear learning related to contextual and auditory cues. In the brain, nitric oxide (NO) produced by neuronal nitric oxide synthase (nNOS) functions as a retrograde neuronal messenger that facilitates synaptic plasticity, including the late phase of long-term potentiation (LTP) and formation of long-term memory (LTM). Evidence has implicated NO signaling in synaptic plasticity and LTM formation following fear conditioning, yet little is known about the role of the nNOS gene in fear learning. Using knockout (KO) mice with targeted mutation of the nNOS gene and their wild-type (WT) counterparts, the role of NO signaling in fear conditioning was investigated. Plasma levels of the stress hormone corticosterone were measured to determine the relationship between physiological and behavioral response to fear conditioning. Contextual fear learning was severely impaired in male and female nNOS KO mice compared with WT counterparts; cued fear learning was slightly impaired in nNOS KO mice. Sex-dependent differences in both contextual and cued fear learning were not observed in either genotype. Deficits in contextual fear learning in nNOS KO mice were partially overcome by multiple trainings. A relationship between increase in plasma corticosterone levels following footshock administration and the magnitude of contextual, but not cued freezing was also observed. Results suggest that the nNOS gene contributes more to optimal contextual fear learning than to cued fear learning, and therefore, inhibition of the nNOS enzyme may ameliorate context-dependent fear response.

Visual paired associate learning deficits associated with elevated beta-amyloid in cognitively normal older adults.

OBJECTIVE: Previous studies have shown that paired associate learning (PAL), a type of episodic memory, is impaired in early Alzheimer's disease (AD). Such tasks require that a set of associations (e.g., pattern-location) be learned over several trials, and the objective is to reduce errors with each trial. Currently, the nature and magnitude of impairment and decline on PAL measures in cognitively normal (CN) older adults with elevated levels of beta-amyloid (Aß+) is unknown. METHOD: This study examined PAL errors in Aß+ and Aß - CN older adults, both within a single assessment and over time. Participants (210 Aß - CN, 146 Aß + CN) from the Australian Imaging, Biomarkers, and Lifestyle (AIBL) study underwent three assessments over 36-months (baseline, and 18- and 36-month follow-ups) using a computerized paired associate learning task (CPAL). Aß status was determined by positron emission tomography (PET) neuroimaging. RESULTS: No significant group differences in PAL were evident at baseline. Significant groupxtime interactions were observed, with the Aß - CN group, but not the Aß + CN group, evidencing improvement over time (Cohen's d = 0.30 [0.08, 0.51]). Despite this, no group differences were evident at 36-months. CONCLUSIONS: Results suggest that PAL dysfunction is evident over time in Aß + CNs. This indicates a lack of benefit from repeated exposure to the task over time associated with Aß+, which is not the case for Aß - CNs. Further, results suggest that assessing change in Aß+ related cognition over time, rather than at a single assessment, provides greater understanding of dysfunction in early AD. (PsycINFO Database Record (c) 2019 APA, all rights reserved).

Choline supplementation attenuates learning deficits associated with neonatal alcohol exposure in the rat: effects of varying the timing of choline administration.

Despite the harmful effects of fetal alcohol exposure, some pregnant women continue to drink alcohol. Thus, it is imperative to pursue safe, effective treatments for children with fetal alcohol spectrum disorders. Using an animal model, our laboratory has demonstrated that choline, an essential nutrient, effectively reduces the severity of some fetal alcohol effects, even when administered after the ethanol insult is complete. The present study investigated whether there is a critical developmental period when choline is most effective in attenuating ethanol's teratogenic effects. Sprague-Dawley rats were exposed to 5.25 g/kg/day ethanol during the third trimester equivalent brain growth spurt (postnatal days (PD) 4-9) via intubation. A non-intubation control group and a sham intubation control group were included. Following ethanol exposure, pups received subcutaneous injections of saline vehicle or choline chloride (100 mg/kg/day) from PD 11-20, PD 21-30, or PD 11-30. Beginning on PD 45, subjects were tested on a Morris water maze spatial learning task. Performance of both the ethanol-exposed group that did not receive choline and the ethanol-exposed group treated with choline from PD 21-30 was significantly impaired compared to controls during acquisition of the Morris water maze task. Performance of ethanol-exposed groups treated with choline from PD 11-20 or PD 11-30 was intermediate, not differing significantly from any other groups. However, during the probe trial, ethanol exposure produced significant deficits in spatial memory which were mitigated by all choline treatments, regardless of the timing of administration. These findings suggest that choline's therapeutic window may be very large, or spans across the two developmental periods examined in this study. Importantly, these findings indicate that choline supplementation may effectively reduce some alcohol-related learning impairments, even when administered in later childhood.

Developmental Thyroid Hormone Insufficiency Induces a Cortical Brain Malformation and Learning Impairments: A Cross-Fostering Study.

Thyroid hormones (THs) are essential for brain development, but few rodent models exist that link TH inefficiency to apical neurodevelopmental endpoints. We have previously described a structural anomaly, a heterotopia, in the brains of rats treated in utero with propylthiouracil (PTU). However, how the timing of an exposure relates to this birth defect is unknown. This study seeks to understand how various temporal treatments of the mother relates to TH insufficiency and adverse neurodevelopment of the offspring. Pregnant rats were exposed to PTU (0 or 3 ppm) through the drinking water from gestational day 6 until postnatal day (PN) 14. On PN2 a subset of pups was cross-fostered to a dam of the opposite treatment, to create 4 conditions: pups exposed to PTU prenatally, postnatally, during both periods, or not at all (control). Both PTU and TH concentrations were characterized in the mother and offspring over time, to capture the dynamics of a developmental xenobiotic exposure. Brains of offspring were examined for heterotopia presence and severity, and adult littermates were assessed for memory impairments. Heterotopia were observed under conditions of prenatal exposure, and its severity increased in animals in the most prolonged exposure group. This malformation was also permanent, but not sex biased. In contrast, behavioral impairments were limited to males, and only in animals exposed to PTU during both the gestational and postnatal periods. This suggests a distinct TH-dependent etiology for both phenotypes, and illustrates how timing of hypothyroxinemia can induce abnormal brain structure and function.

Plasma homovanillic acid correlates inversely with history of learning problems in healthy volunteer and personality disordered subjects.

Central dopaminergic activity is critical to the functioning of both motor and cognitive systems. Based on the therapeutic action of dopaminergic agents in treating attention deficit hyperactivity disorder (ADHD), ADHD symptoms may be related to a reduction in central dopaminergic activity. We tested the hypothesis that dopaminergic activity, as reflected by plasma homovanillic acid (pHVA), may be related to dimensional aspects of ADHD in adults. Subjects were 30 healthy volunteer and 39 personality disordered subjects, in whom morning basal pHVA concentration and a dimensional measure of childhood ADHD symptoms (Wender Utah Rating Scale: WURS) were obtained. A significant inverse correlation was found between WURS Total score and pHVA concentration in the total sample. Among WURS factor scores, a significant inverse relationship was noted between pHVA and history of "childhood learning problems". Consistent with the dopaminergic dysfunction hypothesis of ADHD and of cognitive function, pHVA concentrations were correlated with childhood history of ADHD symptoms in general and with history of "learning problems" in non-ADHD psychiatric patients and controls. Replication is needed in treated and untreated ADHD samples to confirm these initial results.

Effects of hormone replacement therapy and aging on cognition: evidence for executive dysfunction.

The present study was designed to explore whether the frontal lobe hypothesis of cognitive aging may be extended to describe the cognitive effects associated with estrogen use in postmenopausal women. Postmenopausal estrogen-only users, estrogen + progesterone users, and non-users (60-80 years old), as well as young, regularly cycling women (18-30 years old) completed an item and source memory task. Since source memory is thought to rely more on executive processes than item memory, we hypothesized that aging and estrogen effects would be greater for source memory than for item memory. Neuropsychological tests explored whether the effects of aging and estrogen use were revealed on other tests of frontal lobe function. Results from the experimental task revealed greater aging and estrogen effects for source memory than for item memory, and neuropsychological results revealed aging and estrogen effects on a subset of tests of executive function. Women on estrogen + progesterone therapy did not outperform non-users, suggesting that the addition of progesterone to hormone therapy may mitigate the benefits induced by estrogen use alone. Overall, findings support the hypothesis that estrogen use may temper age-related cognitive decline by helping to maintain functions subserved by the frontal lobes.

Case study: psychiatric misdiagnosis of non-24-hours sleep-wake schedule disorder resolved by melatonin.

This case study describes a 14-year-old male suffering from significant academic and personal difficulties, who has been diagnosed with depression, schizotypal personality disorder, and learning disabilities. Because of excessive sleepiness, assessment for a potential sleep disorder was performed. An overnight polysomnographic study revealed no primary sleep disorders. Wrist actigraphy revealed a non-24-hour sleep-wake pattern. Delay in temperature rhythm and dissociation with melatonin rhythms were also noted. Treatment with oral melatonin restored normal sleep-wake schedule. In a follow-up psychiatric evaluation, none of the above diagnoses were present. Greater awareness of sleep disorders may prevent psychiatric misdiagnosis of treatable sleep-wake schedule disorders.

Allopregnanolone inhibits learning in the Morris water maze.

The progesterone metabolite allopregnanolone (3alpha-OH-5alpha-pregnane-20-one) inhibits neural functions, enhancing the GABA induced GABA(A) receptor activation. This effect is benzodiazepine like and benzodiazepines are known to impair memory. Acute effects of allopregnanolone on the hippocampus dependent spatial learning in the Morris water maze have not been studied. Adult male Wistar rats where injected (i.v.) with allopregnanolone (2 mg/kg), or vehicle, daily for 11 days. At 8 or 20 min after each injection, studies of place navigation were performed in the Morris water maze. Allopregnanolone concentrations in plasma and in nine different brain areas where analyzed by radioimmunoassay. The latency to find the platform was increased 8 min after the allopregnanolone injection, while normal learning was seen after 20 min. Swim speed did not differ between groups. A higher number of rats were swimming close to the pool wall (thigmotaxis) in the 8 min allopregnanolone group compared to the other groups. Allopregnanolone concentrations in the brain tissue at 8 min were 1.5 to 2.5 times higher then at 20 min after the allopregnanolone injections. After vehicle injections the brain concentrations of allopregnanolone were at control levels. Plasma concentrations of allopregnanolone followed the same pattern as in the brain, with the exception of an increase 8 min after vehicle injections. The natural progesterone metabolite allopregnanolone can inhibit learning in the Morris water maze, an effect not caused by motor impairment. The learning impairment might be due to a combination of changed swimming behavior and difficulties in navigation.

Administration of D,L-fenfluramine to rats produces learning deficits in the Cincinnati water maze but not the Morris water maze: relationship to adrenal cortical output.

Fenfluramine (FEN) is an amphetamine derivative with anorectic properties similar to amphetamine, but without the stimulatory or abuse potential. Administration of FEN produces an immediate release of serotonin as well as inhibits reuptake; ultimately FEN produces a decrease in serotonin stores in the central nervous system. We have previously shown that the administration of FEN to rats results in increased adrenal cortical hormones under resting conditions, without simultaneous elevations in adrenocorticotropin hormone (ACTH). We hypothesized that the adrenal output would be altered following stress and that the altered adrenal output would affect learning and memory, since the adrenal hormones influence learning and memory capability. In this series of experiments, we administered D,L-FEN (15 mg/kg) four times every 2 h on a single day to rats and investigated the effect on hormonal output following forced swim and the effect on sequential learning in the Cincinnati water maze and spatial learning in the Morris maze beginning 3 days after FEN administration. Animals that received FEN had increased corticosterone and aldosterone titers following forced swim relative to control animals, although no differences in ACTH or testosterone were noted. Animals exposed to FEN had lasting deficits in the Cincinnati water maze but not in the Morris water maze, regardless of testing order. These deficits in the Cincinnati water maze appear to be mediated by the elevation in adrenal output since adrenalectomy abolished the effect of FEN. Corticosterone levels were shown to be elevated during the behavioral testing period in animals exposed to FEN.

Efficacy and tolerability of levetiracetam in patients with therapy-resistant epilepsy and learning disabilities.

INTRODUCTION: The purpose was to evaluate the effects of levetiracetam (LEV) in routine therapy in learning disabled patients with therapy-resistant epilepsy. METHODS: In an open observational add-on study design, 46 patients (residents of the Bethel Epilepsy Centre) with severe therapy-resistant epilepsy and different degrees of learning disabilities, who were treated with LEV between its introduction in Autumn 2000 and February 2002, were evaluated retrospectively. Information on monthly seizure frequencies, seizure severity and psychiatric status was extracted from the current patient case records. A 3 months baseline and a 3 months LEV treatment period (after 3 months of titration) were compared. Responders were defined as having a 50% reduction in seizure frequency and being evaluated as good or very good in an ad hoc global clinical efficacy scale. When only one criterion was positive, a careful individual decision was made based on the impact on the patients' daily activities. RESULTS: The responder rate was 41.3% (34.8 for 50% seizure reduction). It was higher in focal and multifocal epilepsy as compared to symptomatic generalised epilepsy/Lennox Gastaut Syndrome (P<0.05). Antiepileptic response occurred in doses between 500 and 4000 mg/day. Changes in seizure severity were rare. Nine patients experienced positive psychotropic effects (mostly improved vigilance and mood); six of these patients had antiepileptic effects as well. Twelve patients had adverse effects, mostly mild; in three cases, however, more severe effects led to discontinuation. CONCLUSIONS: LEV is an effective and generally well-tolerated drug for this patient group, especially in focal and multifocal epilepsy.

Academic achievement and psychological adjustment in short children. The National Cooperative Growth Study.

Limited information is available on the educational and behavioral functioning of short children. Through 27 participating medical centers, we administered a battery of psychologic tests to 166 children referred for growth hormone (GH) treatment (5 to 16 years) who were below the third percentile for height (mean height = -2.7 SD). The sample consisted of 86 children with isolated growth-hormone deficiency (GHD) and 80 children with idiopathic short stature (ISS). Despite average intelligence, absence of significant family dysfunction, and advantaged social background, a large number of children had academic underachievement. Both groups showed significant discrepancy (p < .01) between IQ and achievement scores in reading (6%), spelling (10%), and arithmetic (13%) and a higher-than-expected rate of behavior problems (GHD, 12%, p < .0001; ISS, 10%, p < .0001). Behavior problems included elevated rates of internalizing behavior (e.g., anxiety, somatic complaints) and externalizing behavior (e.g., impulsive, distractable, attention-seeking). Social competence was reduced in school-related activities for GHD patients (6%, p < .03). The high frequency of underachievement, behavior problems, and reduced social competency in these children suggests that short stature itself may predispose them to some of their difficulties. Alternately, parents of short, underachieving children may be more likely to seek help. In addition, some problems may be caused by factors related to specific diagnoses.

The health effects of aluminium--a review.

This review covers the occurrence of aluminium in soil, air, water and food. In addition, aluminium levels in body tissues and its movement within the body have been considered. The adverse effects of aluminium that have been reported in recent years include Alzheimer's disease, dementia and hyperactivity and learning disorders in children.

Evaluation of toxic metals and essential elements in children with learning disabilities from a rural area of southern Brazil.

Children's exposure to metals can result in adverse effects such as cognitive function impairments. This study aimed to evaluate some toxic metals and levels of essential trace elements in blood, hair, and drinking water in children from a rural area of Southern Brazil. Cognitive ability and δ-aminolevulinate dehydratase (ALA-D) activity were evaluated. Oxidative stress was evaluated as a main mechanism of metal toxicity, through the quantification of malondialdehyde (MDA) levels. This study included 20 children from a rural area and 20 children from an urban area. Our findings demonstrated increase in blood lead (Pb) levels (BLLs). Also, increased levels of nickel (Ni) in blood and increase of aluminum (Al) levels in hair and drinking water in rural children were found. Deficiency in selenium (Se) levels was observed in rural children as well. Rural children with visual-motor immaturity presented Pb levels in hair significantly increased in relation to rural children without visual-motor immaturity (p < 0.05). Negative correlations between BLLs and ALA-D activity and positive correlations between BLLs and ALA-RE activity were observed. MDA was significantly higher in rural compared to urban children (p < 0.05). Our findings suggest that rural children were co-exposed to toxic metals, especially Al, Pb and Ni. Moreover, a slight deficiency of Se was observed. Low performance on cognitive ability tests and ALA-D inhibition can be related to metal exposure in rural children. Oxidative stress was suggested as a main toxicological mechanism involved in metal exposure.