Oxygen is critical for brain function and iron is necessary to get it there. It’s worth re-visiting a study published six years ago in the journal Pediatrics that documents the profound effects of even intermittent hypoxia.

“A review of the evidence concerning the effect of chronic or intermittent hypoxia on cognition in childhood was performed by using both a systematic review of the literature and critical appraisal criteria of causality.”

The authors applied rigorous appraisal criteria to massive amounts of data narrowed down to 55 studies to resolve their findings:

“Adverse effects were noted at every level of arterial oxygen saturation and for exposure at every age level except for premature newborns.”

Their conclusions are emphatic:

“Adverse impacts of chronic or intermittent hypoxia on development, behavior, and academic achievement have been reported in many well-designed and controlled studies in children with CHD [congenital heart disease] and SDB [sleep-disordered breathing] as well as in a variety of experimental studies in adults…Because adverse effects have been noted at even mild levels of oxygen desaturation, future research should include precisely defined data on exposure to all levels of desaturation.”

Ferritin is the ‘storage’ form of iron in the bloodstream and one of the more reliable indicators of iron availability and utilization. Suboptimal ferritin can affect learning and behavior in two ways: by diminishing the oxygen-carrying capacity of the blood due to less hemoglobin, and by limiting the production of key neurotransmitters. The authors of a paper published in the journal Child Psychiatry & Human Development state:

“Our aim was to investigate the relation between behavioral symptoms and hematological variables which are related with iron deficiency and anemia, ferritin, hemoglobin, mean corpuscular volume (MCV), and reticulosite distribution width (RDW) in children and adolescents with pure Attention Deficit Hyperactivity Disorder (ADHD) or ADHD comorbid with other psychiatric disorders.”

The authors correlated results from the Conners Parent (CPRS) and Teacher Rating Scales (CTRS) the metrics for anemia and iron insufficiency. Their data showed that when ADHD was present with other problems (comorbidities) the association was pronounced:

“Comorbid ADHD subjects had lower mean hemoglogin and MCV. In the ADHD group in general, CPRS and CTRS Total scores were significantly negatively correlated with ferritin level. When only pure ADHD subjects were taken into account, the correlations did not reach statistical signifance. Overall, these results suggested that lower ferritin level was associated with higher behavioral problems reported by both parents and teachers. Presence of comorbid conditions might increase the effect of lower iron stores on behavioral measures.”

An interesting study published in the journal Sleep Medicine investigates the association of Restless Legs Syndrome (RLS) and iron deficiency on ADHD. The authors state:

“Increasing evidence suggests a significant comorbidity between attention-deficit/hyperactivity disorder (ADHD) and restless legs syndrome (RLS). Iron deficiency may underlie common pathophysiological mechanisms in subjects with ADHD plus RLS (ADHD+RLS). “

The data provided further evidence for the impact of iron deficiency on ADHD:

“The mean serum ferritin levels were significantly lower in children with ADHD than in the control group. There was a trend for lower ferritin levels in ADHD+RLS subjects versus ADHD. Both a positive family history of RLS and previous iron supplementation in infancy were associated with more severe ADHD scores.”

The authors offer useful advice to clinicians and parents in their conclusion:

“Children with ADHD and a positive family history of RLS appear to represent a subgroup particularly at risk for severe ADHD symptoms. Iron deficiency may contribute to the severity of symptoms. We suggest that clinicians consider assessing children with ADHD for RLS, a family history of RLS, and iron deficiency.”

Additional research published in Pediatrics documents further the adverse effect of intermittent hypoxia and snoring on childrens’ behavior. The authors’ objective:

“Sleep-disordered breathing is associated with impaired behavior and poor academic performance in children. We aimed to determine the extent of behavioral problems in snoring children, clarify the role of intermittent hypoxia, and test the reversibility of impaired behavior and poor academic performance.”

They included 1144 children in their study, correlating snoring, oxygen saturation with pulse oximetry, and impaired behavior using parental questionnaires and academic performance. The evidence was striking:

“HS [habitual snoring] was significantly associated with hyperactive and inattentive behavior , daytime tiredness , and sleepiness. These associations were independent of intermittent hypoxia. HS was also significantly associated with bad conduct, emotional symptoms , and peer problems.“

Moreover, although academic success did not make a big change when snoring ceased, hyperactive and inattentive behavior improved significantly. The authors conclude:

“We suggest that impaired behavior is a key feature of HS independent of intermittent hypoxia and improves when HS ceases.”

We can add to the above evidence another study published in the Archives of Pediatrics & Adolescent Medicine that also investigates the link between iron deficiency and ADHD. In addition to lower hemoglobin…

“Iron deficiency causes abnormal dopaminergic neurotransmission and may contribute to the physiopathology of attention-deficit/hyperactivity disorder (ADHD).”

Again we see serum ferritin levels correlating with the Conners’ Parent Rating Scale scores measuring severity of ADHD symptoms:

“The mean serum ferritin levels were lower in the children with ADHD…In addition, low serum ferritin levels were correlated with more severe general ADHD symptoms measured with Conners’ Parent Rating Scale…These results suggest that low iron stores contribute to ADHD and that ADHD children may benefit from iron supplementation.”

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The brain is made mostly of fat. The correct balance of fatty acids is necessary for neuronal health, nerve transmission, maintaining a normal threshold of excitability,  and the regulation of inflammation in the brain and elsewhere. A fascinating study published recently in the journal Neuropharmacology reveals the relationship between fatty acids, electrical activity (EEG), and brain function in adolescent boys with ADHD.

“Abnormal fatty acid status has been implicated in the aetiology of attention deficit hyperactivity disorder (ADHD). Delayed maturation in ADHD may result in raised frontal low frequency (theta) electroencephalographic activity (EEG) and a reduction in posterior high frequency (beta, alpha) activity.”

The authors data revealed a compelling picture when they investigated the links between the resting-state EEG and levels of omega-3 fatty acids in the red blood cells in 46 adolescent boys with ADHD symptoms (the same test that we employ):

“Docosahexaenoic acid (DHA) levels were positively associated with fast frequency activity: alpha during eyes-open and beta during eyes-closed conditions. Frontal theta activity during both eyes-open and eyes-closed conditions was…positively associated with eicosapentaenoic acid (EPA) levels. Alpha activity correlated positively with performance on fluency for categories (semantic memory). Theta activity correlated inversely with performance on delayed (25 min) verbal memory (recall + recognition/2). “

Their conclusion contains a valuable clinical ‘pearl’:

“Results support differential associations for DHA and EPA with fast and slow EEG activity respectively. Results support EEG activity as an objective biomarker of neural function associated with long-chain omega-3 fatty acids in ADHD.“

A paper published in the journal Prostaglandins, Leuokotrienes and Essential Fatty Acids adds more evidence for the role of omega-3 fatty acid status in ADHD. The authors begin by observing:

“Lower levels of long-chain polyunsaturated fatty acids, particularly omega-3 fatty acids, in blood have repeatedly been associated with a variety of behavioral disorders including attention-deficit/hyperactivity disorder (ADHD).”

When they analyzed a range of markers for key nutrients, antioxidants, oxidative stress, inflammation and fatty acids (with the appropriate controls) in relation to ADHD, their data offered a useful insight:

“The proportion of omega-3 fatty acids was found to be significantly lower in plasma phospholipids and erythrocytes in the ADHD group versus controls…”

The same journal recently presented a very interesting study on the association between fatty acid status and the brain electrical (EEG) expression of emotional activity in boys with ADHD. The authors state:

“Affective impairment is observed in children and adolescents with attention-deficit hyperactivity disorder (ADHD). Low levels of long-chain polyunsaturated fatty acids (LC-PUFA), specifically omega-3 (ω-3) fatty acids in blood measures have been linked to a range of behavioural and mood disorders including ADHD.”

The authors measured lipid fractions in the red blood cells of adolescent boys with ADHD and correlated them with an EEG indicator brain function, event-related potentials (ERP), in response to facial expressions of happiness, sadness and fearfulness. What did the data show?

“The results supported the hypothesis of a positive association between eicosapentaenoic acid (EPA) and a cognitive bias in orientation to overt expressions of happiness over both sad and fearful faces as indexed by midline frontal P300 amplitude. Additional exploratory analyses revealed a positive association between levels of docosahexaenoic acid (DHA) and the right temporal N170 amplitude in response to covert expressions of fear. The arachidonic (AA)/DHA ratio was negatively associated with the right temporal N170 amplitude also to covert expressions of fear.”

Their conclusion summarizes their additional insight into the issue of fatty acids and ADHD:

“These findings indicate that EPA and DHA may be involved in distinct aspects of affect processing in ADHD and have implications for understanding currently inconsistent findings in the literature on EFA supplementation in ADHD and depression.”

We can also thank the journal of Prostaglandins, Leukotrienes and Essential Fatty Acids (PLEFA) for recent scientific confirmation of something that I have personally found to be often overlooked but of critical importance in a number of cases of pediatric neurological disorders: the necessity of adequate amounts of arachidonic acid in the brain.

“Small individual studies report that people with learning disorders have lower than normal blood concentrations of docosahexaenoic acid and arachidonic acid…relatively little attention has been paid to the significance of the low arachidonic acid concentration.”

The authors correlated data on various learning disorders with arachidonic acid (AA) and docosahexaenoic acid (DHA) concentrations. Most clinicians are aware of the pro-inflammatory effect of excessive levels of arachidonic acid, but too few know how important it is that AA not be too low. Their data show that this must not be neglected:

“A meta-analysis…showed that red blood cell arachidonic acid and docosahexanoic acid concentrations were significantly lower than normal…Plasma/serum arachidonic acid and docosahexaenoic acid concentrations were also significantly lower than normal. However, in absolute amounts the arachidonic acid was as severely depressed as docosahexanoic acid within red blood cells.”

Even six years ago researchers were reporting in PLEFA on the utility of essential fatty acids in the treatment of impulsivity disorders.

“Essential fatty acids (EFAs) have been shown to benefit patients with depression, schizophrenia and dementia. More recently, their role in disorders characterised by impulsivity has attracted some attention. The psychiatric conditions of attention-deficit hyperactivity disorder and borderline personality disorder as well as the phenomena of deliberate self-harm and violence have been ameliorated by the supplementation of EFAs in a number of recent clinical trials. This paper summarises the burgeoning clinical and basic research indicating the existence of significant deficits of EFAs in impulsivity disorders and the supplementation studies of EFAs in these diverse conditions…”

As for the benefits of appropriate supplementation, a paper published a few months ago in PLEFA offers welcome evidence. The authors observe:

“Omega-3 and omega-6 long-chain polyunsaturated fatty acids (LCPUFA) are critical for infant and childhood brain development, but levels of the omega-3 fatty acids docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) are often low in the Western diet…Arachidonic acid (ARA) is also important for infant growth and development.”

They review the science on essential fatty acids as a an important intervention in childhood neurodevelopmental disorders:

“Increasing evidence from both epidemiological and intervention studies, reviewed here, indicates that DHA supplementation, during pregnancy, lactation, or childhood plays an important role in childhood neurodevelopment…Several studies have demonstrated positive associations between blood DHA levels and improvements on tests of cognitive and visual function in healthy children.”

Moreover:

“Controlled trials also have shown that supplementation with DHA and EPA may help in the management of childhood psychiatric disorders… In all studies, DHA and EPA supplementation is typically well tolerated.”

We can also appreciate an earlier study reporting a very desirable behavioral outcome from an omega-3 fatty acid emulsion:

“Post-supplementation levels of RBC membrane fatty acids were significantly higher than pretreatment levels as well as the levels in control. There was significant improvement in the symptoms of ADHD reflected by reduction in total hyperactivity scores of ADHD children derived from ADHD rating scale.”

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The brain needs a steady supply of glucose to work normally. Disorders of blood sugar regulation, whether hypoglycemia or insulin resistance (precursor to type 2 diabetes), deprives the brains cells of the fuel to produce the energy they need to function. Research just published in the journal Diabetologia examines the cognitive impairments present in adolescents when insulin resistance and overweight have progressed to type 2 diabetes.

“Central nervous system abnormalities, including cognitive and brain impairments, have been documented in adults with type 2 diabetes…Assessing adolescents with type 2 diabetes will allow the evaluation of whether diabetes per se may adversely affect brain function and structure years before clinically significant vascular disease develops.”

The authors compared two groups of overweight adolescents, one with and the other without type 2 diabetes. The depredations of insulin resistance on the brain were stunning:

“Adolescents with type 2 diabetes performed consistently worse in all cognitive domains assessed, with the difference reaching statistical significance for estimated intellectual functioning, verbal memory and psychomotor efficiency…[and] executive function, reading and spelling. MRI-based automated brain structural analyses revealed both reduced white matter volume and enlarged cerebrospinal fluid space in the whole brain and the frontal lobe in particular… In addition, assessments using diffusion tensor imaging revealed reduced white and grey matter microstructural integrity.”

The authors conclusion places both clinicians and parents on the alert:

“These abnormalities are not likely to result from education or socioeconomic bias and may result from a combination of subtle vascular changes, glucose and lipid metabolism abnormalities and subtle differences in adiposity in the absence of clinically significant vascular disease.”

On the hypoglycemic pole of glucose regulation we can appreciate earlier fascinating research published Pediatric Research documenting an impaired neurotransmitter response to falling blood sugar in children with ADD (the catecholamines epinephrine and norepinephrine attenuate the drop in blood sugar).

“Eating simple sugars has been suggested as having adverse behavioral and cognitive effects in children with attention deficit disorder (ADD)…metabolic, hormonal, and cognitive responses to a standard oral glucose load (1.75 g/kg) were compared in 17 children with ADD and 11 control children.”

Their data showed a significant difference between ADD and control children:

“The late glucose fall stimulated a rise in plasma epinephrine that was nearly 50% lower in ADD than in control children. Plasma norepinephrine levels were also lower in ADD than in control children…”

The authors’ conclusion indicates the need for conscientious blood sugar management through dietary and other measures:

“These data suggest that children with ADD have a general impairment of sympathetic activation involving adrenomedullary as well as well as central catecholamine regulation [of blood sugar].”

Similar phenomena are presented in a paper published in the Journal of the American Academy of Child & Adolescent Psychiatry describing abnormalities of brain metabolism in girls with ADHD:

“This study assesses the effect of attention-deficit hyperactivity disorder (ADHD) and gender on cerebral glucose metabolism (CMRglu), using positron emission tomography and 18F-fluorodeoxyglucose.”

An interesting gender difference emerged from the data:

“However, the global CMRglu in ADHD girls was 15.0% lower than in normal girls, while global CMRglu in ADHD boys was not different than in normal boys. Furthermore, global CMRglu in ADHD girls was 19.6% lower than in ADHD boys and was not different between normal girls and normal boys.”

Gender differences that must be respected are pronounced here and throughout medicine and biology:

“The greater brain metabolism abnormalities in females than males strongly stress that more attention be given to the study of girls with ADHD.”

Addressing the dysfunctions in blood sugar dysregulation associated with disorders of learning and behavior requires understanding that deleterious eating conducts can manifest as a form of self-medication. A paper recently published in Current Psychiatry Reports brings attention to this:

“In the past decade, we have become increasingly aware of strong associations between overweight/obesity and symptoms of attention-deficit/hyperactivity disorder (ADHD) in children, adolescents, and adults.”

The need to satisfy imperious physiological urges on a cellular level when an individuals genetic needs are not being met can overwhelm all advice and intention to acquire more wholesome and sustainable habits:

“It is also proposed—based on the compelling evidence that foods high in fat, sugar, and salt are as addictive as some drugs of abuse—that excessive food consumption could be a form of self-medication. This view conforms with the well-established evidence that drug use and abuse are substantially higher among those with ADHD than among the general population.”

True remediation demands a functional medicine approach to resolve the underlying cellular and metabolic needs that are not being met so they can be supported in a physiological and sustainable manner to restore normal function.

A paper published in the Journal of Nutrition, Health & Aging brings us back to the fundamental importance of glucose regulation for the brain.

“The regulation of glycaemia (thanks to the ingestion of food with a low glycaemic index ensuring a low insulin level) improves the quality and duration of intellectual performance, if only because at rest the brain consumes more than 50% of dietary carbohydrates, approximately 80% of which are used only for energy purpose. In infants, adults and aged, as well as in diabetes, poorer glycaemic control is associated with lower performances, for instance on tests of memory. At all ages, and more specifically in aged people, some cognitive functions appear sensitive to short term variations in glucose availability.“

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The journal Prostaglandins, Leukotrienes and Essential Fatty Acids published an important paper earlier this year that clarifies why there have been conflicting results in earlier studies on the use of omega-3 fatty acids in the treatment of ADHD. The authors demonstrated that EPA (eicosapentanoic acid) and DHA (docosahexanoic acid) were each associated with a different type of response in different areas of the brain. This is a good example of the importance of the functional medicine approach that investigates the details of underlying causes and customizes treatment for the individual. The authors state “These findings indicate that EPA and DHA may be involved in distinct aspects of affect processing in ADHD and have implications for understanding currently inconsistent findings in the literature on EFA supplementation in ADHD and depression.” Lapis Light patients already know about the importance of objectively measuring essential fatty acids with the proper blood test for neurodevelopmental and neurodegenerative disorders.

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