Tag Archives: hypoxia

Intermittent hypoxia (low oxygen) of sleep apnea exacerbates insulin resistance and inflammation

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New research just published in the journal Obesity contributes to the evidence for weighty metabolic consequences of the hypoxia (reduced oxygen saturation) that occurs with sleep disordered breathing. The authors state:

“The main aim of this study is to evaluate the effects of chronic intermittent hypoxia (CIH), a hallmark of sleep apnea, on IR [insulin resistance] and NAFLD [non-alcoholic fatty liver disease] in lean mice and mice with diet-induced obesity (DIO).”

They fed the study subjects either a high fat or regular diet for 12 weeks, after which they were exposed to CIH or normal room air as a control condition for 4 weeks. Then they measured fasting blood glucose, insulin, homeostasis model assessment (HOMA) index, liver enzymes, and performed an intraperitoneal glucose tolerance test. Their data paints an interesting picture:

“In DIO mice, body weight remained stable during CIH and did not differ from control conditions…Compared to lean mice, DIO mice had higher fasting levels of blood glucose, plasma insulin, the HOMA index, and had glucose intolerance and hepatic steatosis at baseline. In lean mice, CIH slightly increased HOMA index, whereas glucose tolerance was not affected. In contrast, in DIO mice, CIH doubled HOMA index, and induced severe glucose intolerance. In DIO mice, CIH induced NAFLD, inflammation, and oxidative stress, which was not observed in lean mice.”

In other words, even though hypoxia did not further increase the body weight of the subjects with diet induced obesity, the metabolic effects including glucose intolerance, inflammation, fatty liver disease and oxidative stress were severe. I often find that the possibility of sleep disordered breathing has been overlooked in the work-up of patients with overweight or metabolic syndrome. This research adds to the compelling evidence that clinicians should bear this in mind.

“In conclusion, CIH exacerbates IR and induces steatohepatitis in DIO mice, suggesting that CIH may account for metabolic dysfunction in obesity.”

Neurotransmitters in pediatric disorders of learning, behavior and development

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Neurotransmitters, the signaling molecules of brain function, are one of the factors that must be included when evaluating and treating pediatric disorders of learning, behavior and development. A paper published in the journal Biological Psychiatry offers an overview in the context of ADHD:

“The etiology of ADHD has not been clearly identified, although evidence supports neurobiologic and genetic origins. Structural and functional imaging studies suggest that dysfunction in the fronto-subcortical pathways, as well as imbalances in the dopaminergic and noradrenergic systems, contribute to the pathophysiology of ADHD.”

Moreover, from the remedial perspective:

“Medication with dopaminergic and noradrenergic activity seems to reduce ADHD symptoms by blocking dopamine and norepinephrine reuptake. Such alterations in dopaminergic and noradrenergic function are apparently necessary for the clinical efficacy of pharmacologic treatments of ADHD.”

Another paper in the same issue discusses the neuropsychopharmacology of ADHD:

“Stimulants, a principle treatment for the disorder, act on the norepinephrine (NE) and dopamine (DA) systems; this has led to a long-standing hypothesis of catecholamine dysfunction in ADHD…Nonstimulant agents that are effective in the treatment of ADHD tend to affect the NE system, whereas those affecting only DA, or those that affect neither catecholamine, are less potent in reducing ADHD symptoms…Imaging studies suggest stimulants increases DA levels in the brain…”

The author sums up his findings by stating:

“…ADHD therapy may modify activity in the NE and DA systems to a more optimal level, thus improving responses to environmental stimuli and enhancing working memory and executive function.”

The authors of another paper in the same issue of Biological Psychiatry address the role of the catecholamine neurotransmitters dopamine and norepinephrine in prefrontal executive functions:

“The prefrontal cortex guides behaviors, thoughts, and feelings using representational knowledge, i.e., working memory. These fundamental cognitive abilities subserve the so-called executive functions: the ability to inhibit inappropriate behaviors and thoughts, regulate our attention, monitor our actions, and plan and organize for the future. Neuropsychological and imaging studies indicate that these prefrontal cortex functions are weaker in patients with attention-deficit/hyperactivity disorder and contribute substantially to attention-deficit/hyperactivity disorder symptomology.”

They describe further evidence for the importance of the catecholamine neurotransmitters in ADHD:

“Optimal levels of norepinephrine acting at postsynaptic α-2A-adrenoceptors and dopamine acting at D1 receptors are essential to prefrontal cortex function. Blockade of norepinephrine α-2-adrenoceptors in prefrontal cortex markedly impairs prefrontal cortex function and mimics most of the symptoms of attention-deficit/hyperactivity disorder, including impulsivity and locomotor hyperactivity.”

The authors conclude by stating:

“Most effective treatments for attention-deficit/hyperactivity disorder facilitate catecholamine transmission and likely have their therapeutic actions by optimizing catecholamine actions in prefrontal cortex.”

Interesting research published in the journal Sleep reveals a link between intermittent hypoxic insults (short periods of suboptimal oxygen levels) and dopamine dysregulation. The authors tested…

“…the hypothesis that intermittent hypoxic insults, occurring during this period of critical brain development, lead to persistent reductions in extracellular levels of dopamine within the striatum. We also tested the hypothesis that post-hypoxic rats exhibit increased novelty-induced behavioral activation and increased basal levels of locomotor activity, two indexes of impaired dopaminergic functioning.”

Behavior of their postnatal animals was recorded and correlated with dopamine measurements after intermittent bursts of hypoxic (oxygen-reduced) gas. They demonstrated heightened response to novelty, locomotor hyperactivity and reduced extracellular dopamine. This brings to mind an earlier post on oxygen and disorders of learning and behavior. What did the authors conclude from their data?

“These data, in conjunction with our previous observations, support our hypothesis that intermittent hypoxic insults occurring during a period of critical brain development lead to sequestration of dopamine presynaptically within nigrostriatal axons. We postulate that neonatally occurring hypoxic insults are one potential pathogenic mechanism underlying disorders of minimal brain dysfunction, such as attention-deficit/hyperactivity disorder, characterized by executive dysfunction and hyper responsiveness to novel stimuli, which is responsive to agents promoting enhanced extracellular levels of synaptic dopamine.”

More nuanced evidence for the importance of neurotransmitters in ADHD is presented in a paper published in the journal Progress in Brain Research that highlights dopamine-serotonin interactions.

“Poor control of attention-related and motor processes, often associated with behavioural or cognitive impulsivity, are typical features of children and adults with attention-deficit hyperactivity disorder (ADHD). Until recently clinicians have observed little need to improve on or add to the catecholaminergic model for explaining the features of ADHD. Recent genetic and neuroimaging studies however provide evidence for separate contributions of altered dopamine (DA) and serotonin (5-HT) function in this disorder.”

Their findings are an excellent example of the importance of considering each child as an individual and avoiding the regrettable tendency to ‘rubber-stamp’ a diagnosis and associated treatment—in this case stimulants or re-uptake inhibitors:

“While the monoamine metabolite levels excreted in ADHD are often correlated, this may well flow from a starting point where 5-HT activity is anomalously higher or lower than the generally lower than normal levels for DA. It appears that perhaps both situations may arise reflecting different diagnostic subgroups of ADHD, and where impulsive characteristics of the subjects reflect externalizing behaviour or cognitive impulsivity…Interactions mediated by macroglia are also likely. However, it remains difficult to ascribe specific mechanisms to their effects (in potentially different subgroups of patients)…”

Moreover, there are individual differences in the receptors for dopamine that come into play with ADHD. In a study published in Archives of General Psychiatry the authors examine polymorphisms in dopamine receptors.

“Attention-deficit/hyperactivity disorder (ADHD) is one of the most heritable neuropsychiatric disorders, and a polymorphism within the dopamine D4 receptor (DRD4) gene has been frequently implicated in its pathogenesis.”

They investigated polymorphisms (gene variants) for both the dopamine D1 receptor (DRD1) gene and the dopamine transporter (DAT1) gene in 105 children with ADHD in comparison with 103 healthy controls, and used cerebral cortical thickness and the presence of DSM-IV–defined ADHD as metrics. The data painted an interesting picture:

“Possession of the DRD4 7-repeat allele was associated with a thinner right orbitofrontal/inferior prefrontal and posterior parietal cortex. This overlapped with regions that were generally thinner in subjects with ADHD compared with controls…By contrast, there were no significant effects of the DRD1 or DAT1 polymorphisms on clinical outcome or cortical development.”

The authors sum up the significance of their findings:

“The DRD4 7-repeat allele, which is widely associated with a diagnosis of ADHD, and in our cohort with better clinical outcome, is associated with cortical thinning in regions important in attentional control. This regional thinning is most apparent in childhood and largely resolves during adolescence.”

In other words, there are genetic differences in the dopamine receptor and transport systems that can manifest as brain thinning and problems with attention.

The practical message is that children (and adults) with disorders of learning and behavior should be evaluated as individuals for problems with neurotransmitter production, transport and receptor populations. The functional approach prefers physiological interventions to supply depleted or insufficient resources for intrinsic neurotransmitter production and receptor maintenance, strategies to protect receptors and transporters from inflammatory damage due to autoimmune microglial activation, and related physiological treatment methods.

Effects of suboptimal oxygen and iron on learning and behavior

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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.”

Oxidative therapies can make infections worse

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Journal of Molecular MedicineThis area of scientific investigation is less well known to both the lay and professional reader, but it has profound practical importance. It concerns how our bodies handle oxygen in health and disease and adapt to low oxygen states. One issue of the Journal of Molecular Medicine is entirely devoted to hypoxia (low oxygen) and human disease. It contains papers encompassing a range of conditions including cardiovascular, gastrointestinal, kidney and lung diseases, cancer and more. The focus here is on one paper that extensively reviews the regulation of oxygen in immunity and the response to infection. This is particularly important because there seem to be many clinicians who assume that increasing oxygen saturation in the locale of an infection helps to get rid of it (through oxidative damage to the pathogen and healthier surrounding tissues). Due to the research over the past several years on the powerful and important role of hypoxia inducible factor (HIF) we can understand that this is incorrect. “The hypoxia-inducible transcription factor (HIF-1α) is a major regulator of energy homeostasis and cellular adaptation to low oxygen stress.” It exerts powerful control over the white blood cells that respond to infection: “HIF-1α has been discovered to function as a global regulator of macrophage and neutrophil inflammatory and innate immune functions.” They refer to HIF-1α as “a master regulator of innate immunity.” This is a fascinating review with references to many other studies if you care to read it, but the main point I want to bring to your attention is this: “A paradoxical result of these findings is that, due to HIF-1α activation, macrophages actually phagocytose and kill bacteria better under hypoxic conditions than they do under normoxic conditions.” This means white blood cells kill bacteria more effectively in a low oxygen environment than they do when oxygen in that location is normal. They go on to explain its role in viral and parasitic infections and the progression of viral infections to cancer. They go on to conclude: “The proof-of-principle experiments described suggest further exploration of HIF-1α augmentation to boost innate defense function. This may be of interest as a therapeutic strategy in infectious disease conditions complicated by antibiotic resistance or compromised host immunity.” Certainly this is a complex system and much more could be said, but the practical message is this: think each case through very carefully before advising or receiving oxidative therapies for infection.