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Elimination diet relieves ADHD, IgG blood tests are not helpful

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A study just published in the prestigious medical journal The Lancet finds a clear relationship between diet and behavior in ADHD when investigated by a supervised elimination diet but not by IgG (immunoglobulin G antibody) blood tests. The authors state:

“The effects of a restricted elimination diet in children with attention-deficit hyperactivity disorder (ADHD) have mainly been investigated in selected subgroups of patients. We aimed to investigate whether there is a connection between diet and behaviour in an unselected group of children.”

They conducted a randomised controlled trial in which children aged 4-8 years who were diagnosed with ADHD were randomly assigned to either a 5 week restricted elimination diet or instructions for a healthy diet in the first phase.

“Thereafter, the clinical responders (those with an improvement of at least 40% on the ADHD rating scale [ARS]) from the diet group proceeded with a 4-week double-blind crossover food challenge phase (second phase), in which high-IgG or low-IgG foods (classified on the basis of every child’s individual IgG blood test results) were added to the diet.”

Pediatricians and others involved were masked to group and challenge allocation. Changes in the ARS score in both phases and correlations between food-specific IgG levels related and behavior were the endpoints. What did their data show?

“Between baseline and the end of the first phase, the difference between the diet group and the control group in the mean ARS total score was 23·7 according to the masked ratings… The ARS total score increased in clinical responders after the challenge by 20·8… In the challenge phase, after challenges with either high-IgG or low-IgG foods, relapse of ADHD symptoms occurred in 19 of 30 (63%) children, independent of the IgG blood levels.“

This significant study offers three very important points here for clinicians and parents:

  1. Foods can trigger ADHD behavior.
  2. Supervised elimination diets can identify the offending foods.
  3. IgG blood tests do not identify them.

Parents and practitioners should appreciate the authors’ conclusion:

“A strictly supervised restricted elimination diet is a valuable instrument to assess whether ADHD is induced by food. The prescription of diets on the basis of IgG blood tests should be discouraged.“

Electroencephalography (brain waves), neurofeedback, and childhood disorders of learning, behavior and development

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Examination of the brain’s electrical activity (electroencephalography, EEG, ‘brain waves’) in ADHD, autistic spectrum disorder and other problems of pediatric learning, behavior and development has advanced greatly in the past decade, establishing the physiological basis for effective non-pharmacological interventions. In a review article published in the journal NeuroMolecular Medicine several years back the authors state in regard to ADHD:

“Cognitive and functional studies using electrophysiology and brain imaging frequently indicate altered processing in ADHD during performance on cognitive tasks hypothesized to measure a “core” deficit, such as response inhibition. Yet, children with ADHD appear to suffer from a more general deficit, including impairment in attentional alerting, orienting, response preparation, and control. Reward processes are also altered and, further, a strong association emerges with intraindividual variability… Task performance correlates with underactivation of, especially, frontostriatal areas of the brain, but an extended network of brain regions is also implicated. Electroencephalography studies indicate abnormalities in ADHD in relation to slow-wave activity, linked to underarousal.”

They proceed to discuss how these electrophysiological abnormalities are associated with neurotransmitter regulation in ADHD.

A fascinating study published recently in the journal Neuropharmacology investigates the correlation between brain fatty acids and EEG activity:

“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 current study used sequential linear regression to investigate the association between age, resting-state EEG and levels of long-chain polyunsaturated omega-3 and omega-6 fatty acids in red blood cells in 46 adolescent boys with ADHD symptoms.”

They observed significant correlations between docosahexaenoic acid (DHA) levels and fast frequency activity and eicosapentaenoic acid (EPA) levels and frontal theta activity. Alpha activity correlated positively with semantic memory and theta activity correlated inversely with performance on verbal memory. They conclude by summarizing:

“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.”

Impaired functional connectivity in the brain networks involved in paying attention is described in a paper published recently in the journal Biological Psychiatry:

“Current pathophysiologic models of attention-deficit/hyperactivity disorder (ADHD) suggest that impaired functional connectivity within brain attention networks may contribute to the disorder. In this electroencephalographic (EEG) study, we analyzed cross-frequency amplitude correlations to investigate differences in cue-induced functional connectivity in typically developing children and children with ADHD.”

The authors measured EEG activity in 25 children (14 with ADHD) while they performed a cross-modal attention task. They observed distinct deficits in EEG correlates of attentional control in the children with ADHD. Their conclusion:

“Our findings provide neurophysiological evidence for a specific deficit in top-down attentional control in children with ADHD that is manifested as a functional disconnection between frontal and occipital cortex.”

An interesting paper published earlier in Biological Psychiatry demonstrates that children of parents with childhood onset depression exhibit EEG deficits in selective attention:

“Individual differences in selective attention may play a role in moderating psychological vulnerabilities by shaping the ability to self-regulate emotion. Children of parents with childhood-onset depression (COD) are at increased risk for socioemotional difficulties. This study examined potential differences in selective attention as a function of parental COD.”

The authors observed that children of parents with COD were slower in their EEG response rates compared with control children. The at-risk children also showed abnormally larger slow wave amplitudes in anterior scalp sites that correlate with attention. They conclude:

“These data suggest that there are subtle deficits in selective attention among the offspring of individuals with COD, requiring that they engage more processing resources to perform effectively. This may affect their ability to adequately regulate emotion under stress.“

Another study in the same issue of Biological Psychiatry provides evidence that functional impairments in ADHD are not due to ‘developmental lag’ but to neural processing deficits that can be observed in the brain’s electrical activity. The authors state:

“We examined the development of neurophysiological markers of attention (Cue P300; contingent negative variation [CNV]) and inhibition (NoGo P300) in ADHD and control groups from childhood to adolescence for support of the developmental lag hypothesis of ADHD.”

The data they compiled led to a dismissal of the developmental lag hypothesis in favor of dysfunctional neural processing:

“These results provide strong evidence for multiple and persistent neural processing deficits in ADHD. They do not support the developmental lag hypothesis for attentional dysfunction in ADHD despite partial evidence that developmental lag contributes to inhibitory brain dysfunction during early adolescence.”

Is there good evidence for using neurofeedback (brain wave biofeedback) as an effective, physiological, non-pharmacologic intervention to promote normal function in disorders of learning, behavior and development? European scientists have made numerous contributions to this field. Consider this paper published six years ago in the German medical journal Zeitschrift für Kinder- und Jugendpsychiatrie und Psychotherapie (Journal of Child and Adolescent Psychiatry and Psychotherapy) in which the authors state:

“Neurofeedback is aiming at an improvement of ADHD core-symptoms via the voluntary modification of abnormal neurophysiologic parameters, e.g. EEG-frequency spectrum and event-related potentials…Our review presents an overview of the current research on neurofeedback for the treatment of ADHD.”

They examined the outcomes of three studies that pitted neurofeedback against standard pharma stimulant treatment. What did the data show?

“Neurofeedback lead to significant improvement of attention, impulsivity and hyperactivity, without adversive side effects. Additionally, there was a  persistent amelioration of EEG parameters, while stimulants did not lead to a comparable normalization…Neurofeedback is a promising approach for the treatment of children with ADHD.”

A more recent review published in Current Psychiatry Reports documents that quantitative electroencephalography (QEEG, computerized mathematical analysis of raw EEG data) offers both diagnostic and therapeutic advantages:

“Although behavioral symptoms of inattention, impulsivity, and hyperactivity serve as a foundation for the accurate diagnosis of attention-deficit/hyperactivity disorder (ADHD), the low interrater reliability and specificity of behavioral rating scales and the absence of comprehensive screening for medical conditions that mimic ADHD have created a barrier to the effective treatment of ADHD. Recently published studies using quantitative electroencephalographic techniques have identified abnormal patterns of cortical activation through power spectral analysis, in event-related cortical potentials, and in slow cortical potentials that may serve as a basis for overcoming these barriers.”

The authors examine studies that provide evidence for the use of QEEG in differentiating ADHD from other psychiatric disorders, evaluating the response to medications, and its role in neurofeedback therapy.

More confirmation of the efficacy of neurofeedback is offered in a study published earlier this year in the European Child & Adolescent Psychiatry. The authors state:

“In a randomised controlled trial, NF [neurofeedback] training was found to be superior to a computerised attention skills training (AST)… In the present paper, treatment effects at 6-month follow-up were studied.”

They examined 94 children with ADHD, aged 8–12 years, who completed either 36 sessions of NF training or a computerised AST. Pre-training, post-training and follow-up assessment were assessed by several behaviour rating scales…with follow-up information analysed…on a per-protocol basis. What did the data show?

“Improvements in the NF group at follow-up were superior to those of the control group and comparable to the effects at the end of the training…In conclusion, behavioural improvements induced by NF training in children with ADHD were maintained at a 6-month follow-up. Though treatment effects appear to be limited, the results confirm the notion that NF is a clinically efficacious module in the treatment of children with ADHD.”

The authors of a study published last year in the Journal of Child Psychology and Psychiatry also confirmed the efficacy of neurofeedback as a treatment for ADHD in a randomised controlled clinical trial:

“…we evaluated the clinical efficacy of neurofeedback in children with ADHD in a multisite randomised controlled study using a computerised attention skills training as a control condition.”

They examined 102 children with ADHD who performed either 36 sessions of neurofeedback with one block of theta/beta training and one block of slow cortical potential (SCP) training or did a comparable amount computerised attention skills training as a control. Outcomes were evaluated by several behaviour rating scales, with ‘placebo’ scales applied to control for parental expectations. What did the data show?

“…improvements in the NF group were superior to those of the control group…Comparable effects were obtained for the two NF protocols (theta/beta training, SCP training). Parental attitude towards the treatment did not differ between NF and control group.”

The authors conclude by stating:

“Superiority of the combined NF training indicates clinical efficacy of NF in children with ADHD.“

A meta-analysis published last year in the journal Clinical EEG & Neuroscience is also reassuring:

“Since the first reports of neurofeedback treatment in Attention Deficit Hyperactivity Disorder (ADHD) in 1976, many studies have investigated the effects of neurofeedback on different symptoms of ADHD such as inattention, impulsivity and hyperactivity…In this study selected research on neurofeedback treatment for ADHD was collected and a meta-analysis was performed.”

The authors examined both prospective controlled studies and studies employing a pre- and post-design and found large effect sizes (ES) for neurofeedback on impulsivity and inattention and a medium ES for hyperactivity, leading to this conclusion:

“Due to the inclusion of some very recent and sound methodological studies in this meta-analysis…the clinical effects of neurofeedback in the treatment of ADHD can be regarded as clinically meaningful…we conclude that neurofeedback treatment for ADHD can be considered “Efficacious and Specific” (Level 5) with a large ES for inattention and impulsivity and a medium ES for hyperactivity.”

Neurofeedback training (operant conditioning) can be applied according to a wide range of protocols. Additional research is revealing the value and importance of specific protocol selection according to the case. A recent study published in the International Journal of Psychophysiology adds to this body of knowledge:

“In a randomized controlled trial, neurofeedback (NF) training was found to be superior to a computerised attention skills training concerning the reduction of ADHD symptomatology…The aims of this investigation were to assess the impact of different NF protocols (theta/beta training and training of slow cortical potentials, SCPs) on the resting EEG and the association between distinct EEG measures and behavioral improvements.”

EEG changes before and after specific NF trainings (theta/beta and SCP) or a control training were examined in 72 children with ADHD aged 8–12. Activity in the different EEG frequency bands was analyzed. What did the data show?

“In contrast to the control condition, the combined NF training was accompanied by a reduction of theta activity. Protocol-specific EEG changes…were associated with improvements in the German ADHD rating scale. Related EEG-based predictors were obtained.”

Their conclusion has significant practical importance for the neurofeedback practitioner:

“Thus, differential EEG patterns for theta/beta and SCP training provide further evidence that distinct neuronal mechanisms may contribute to similar behavioral improvements in children with ADHD.”

Interesting work with neurofeedback is also being done in China. A study published in the Chinese Journal of Contemporary Pediatrics examines the effect of neurofeedback training on the ratio slow theta (θ) and fast beta (β) brain waves:

“When the [ADHD] children fulfill cognition tasks, brain θ wave activity increases and β wave activity weakens. This study aimed to explore the efficacy of electroencephalographic (EEG) biofeedback therapy for ADHD in children by assessing the changes of the ratio of brain θ to β waves and the integrated visual and auditory continuous performance test (IVA-CPT).”

They performed EEG biofeedback therapy with 30 children with ADHD and measured the ratio of brain θ to β waves before and after therapy. IVA-CPT was used to assess the effectiveness of biofeedback therapy. What did their data show?

“After two courses of treatment, the mean ratio of brain θ to β waves in the 30 children with ADHD was significantly reduced from 12.32±4.35 (before treatment) to 6.54±1.27. IVA-CPT demonstrated that the values of six indexes measured, including integrate reaction control quotient, integrate attention quotient, auditory and visual reaction control quotients, auditory and visual attention control quotients, were significantly increased after biofeedback therapy.”

Their conclusion should be appreciated by parents and clinicians alike:

“EEG biofeedback can reduce the ratio of brain θ to β waves and lead to significant decreases in inattention and hyperactivity and it is effective for treatment of ADHD in children.“

Neurofeedback is, of course, beneficial for many more conditions than ADHD. A paper published in Applied Psychophysiology and Biofeedback reviews the evidence for the effectiveness of neurofeedback for Asperger’s syndrome (AS) and autistic spectrum disorder.

“This paper summarizes data from a review of neurofeedback (NFB) training with 150 clients with Asperger’s Syndrome (AS) and 9 clients with Autistic Spectrum Disorder (ASD) seen over a 15 year period (1993–2008) in a clinical setting. The main objective was to investigate whether electroncephalographic (EEG) biofeedback, also called neurofeedback (NFB), made a significant difference in clients diagnosed with AS.”

Clients received 40–60 sessions of NFB, which was combined with training in metacognitive strategies and, for most older adolescent and adult clients, with other supportive biofeedback…Significant improvements were found on measures of attention, core symptoms, achievement, and intelligence along with a decrease in relevant EEG ratios was also observed. The authors conclude:

“The positive outcomes of decreased symptoms of Asperger’s and ADHD (including a decrease in difficulties with attention, anxiety, aprosodias, and social functioning) plus improved academic and intellectual functioning, provide preliminary support for the use of neurofeedback as a helpful component of effective intervention in people with AS.”

Advances in the science of brain electrophysiology and neurofeedback have yielded a richer repertoire of methods to individualize interventions for enhanced outcomes. Brain wave biofeedback addressing slow cortical potentials (SCP, the direct versus alternating currents in the brain generated partly by glial cells that outnumber neurons) has been vigorously investigated particularly by European researchers. A study published in the Journal of Neural Transmission…

“…compared changes in quantitative EEG (QEEG) and CNV (contingent negative variation) of children suffering from ADHD treated by SCP (slow cortical potential) neurofeedback (NF) with the effects of group therapy (GT) to separate specific from non-specific neurophysiological effects of NF.”

The authors assigned children with ADHD to either SCP neurofeedback or group therapy and correlated the effects with QEEG measurements and behavioral ratings. Children with ADHD-combined type in the NF group had improvement of selected QEEG markers that were associated with behavioral scales, with specific influences of SCP training on brain functions evident.

“To conclude, SCP neurofeedback improves only selected attentional brain functions as measurable with QEEG at rest or CNV mapping.”

Another study just published by German scientists in the journal Clinical Neurophysiology presents further evidence for neurofeedback from a randomised controlled trial:

“Children with ADHD either completed a NF training or a computerized attention skills training…At three times (pre-training, between the two training blocks and at post-training), event-related potentials (ERP) were recorded during the Attention Network Test.”

They observed an increase of the CNV specific for the slow cortical potential neurofeedback training which was associated with a larger reduction of ADHD symptomatology.

“These distinct ERP effects are closely related to a successful NF training in children with ADHD.“

A valuable study published in the journal Pediatrics offers additional evidence for the neurofeedback training of slow cortical potentials for ADHD:

“We investigated the effects of self-regulation of slow cortical potentials for children with attention-deficit/hyperactivity disorder. Slow cortical potentials are slow event-related direct-current shifts of the electroencephalogram. Slow cortical potential shifts in the electrical negative direction reflect the depolarization of large cortical cell assemblies, reducing their excitation threshold. This training aims at regulation of cortical excitation thresholds considered to be impaired in children with attention-deficit/hyperactivity disorder. Electroencephalographic data from the training and the 6-month follow-up are reported, as are changes in behavior and cognition.”

The authors gave 30 sessions of self-regulation training of slow cortical potentials to 23 children with ADHD by feeding back increasing and decreasing slow cortical potentials at central brain regions through visual and auditory stimuli. Their data painted a gratifying picture:

“Measurement before and after the trials showed that children with attention-deficit/hyperactivity disorder learn to regulate negative slow cortical potentials. After training, significant improvement in behavior, attention, and IQ score was observed…All changes proved to be stable at 6 months’ follow-up after the end of training.”

They added an intriguing hypothesis:

“It is suggested that regulation of frontocentral negative slow cortical potentials affects the cholinergic-dopaminergic balance and allows children to adapt to task requirements more flexibly.”

Another study published in Applied Psychophysiology and Biofeedback confirms that different approaches to exercising healthier brain self-regulation with neurofeedback can be successful.

“Behavioral and cognitive improvements in children with ADHD have been consistently reported after neurofeedback-treatment…This study addresses previous methodological shortcomings while comparing a neurofeedback-training of Theta-Beta frequencies and training of slow cortical potentials (SCPs). The study aimed at answering (a) whether patients were able to demonstrate learning of cortical self-regulation, (b) if treatment leads to an improvement in cognition and behavior and (c) if the two experimental groups differ in cognitive and behavioral outcome variables.”

Two groups of 19 children with ADHD ages 8-13 were assigned to either SCP or Theta/Beta training for three phases of 10 sessions each. Both groups were blind to their assignment and potentially confounding variables were assessed. What were the results?

“Both groups were able to intentionally regulate cortical activity and improved in attention and IQ. Parents and teachers reported significant behavioral and cognitive improvements. Clinical effects for both groups remained stable six months after treatment. Groups did not differ in behavioural or cognitive outcome.”

Neurofeedback practitioners hail from a variety of professional backgrounds. Good outcomes are more likely if the practitioner has multiple neurofeedback modalities to choose from according to the needs of the individual, access to objective evaluation of brain function by QEEG assessment, and the brain is supported according to its metabolic, hormonal and other needs from a functional medicine perspective.

Gluten sensitivity and childhood disorders of learning, behavior and development

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While celiac disease often goes undiagnosed, failure to recognize the non-celiac manifestations of gluten sensitivity is widespread. The neurological effects can contribute to disorders of learning, behavior and neurodevelopment even in the absence of intestinal symptoms. The authors of a study published in the Journal of Attention Disorders observe:

“Several studies report a possible association of celiac disease (CD) with psychiatric and psychological disturbances, such as ADHD.”

They examined 132 subjects affected by CD for ADHD symptoms by behavioral scale before and 6 months after a gluten-free diet was started, and found that:

“The overall score improved significantly as well as most of the ADHD-like symptomatology specific features (Bonferroni-corrected, paired-sample t tests).”

They state in their conclusion:

“The data indicate that ADHD-like symptomatology is markedly overrepresented among untreated CD patients and that a gluten-free diet may improve symptoms significantly within a short period of time. The results of this study also suggest that CD should be included in the list of diseases associated with ADHD-like symptomatology.”

Remember, as the authors of a paper published by GeneReviews state:

“Classic celiac disease, characterized by mild to severe gastrointestinal symptoms, is less common than nonclassic celiac disease, characterized by absence of gastrointestinal symptoms.”

The report on a study published in the journal Psychosomatics begins with the observation:

“A high prevalence of depressive symptoms, hypothetically related to serotonergic dysfunction, has been reported among adults with celiac disease. The authors used semistructured psychiatric interviews and symptom measurement scales to study mental disorders in 29 adolescents with celiac disease and 29 matched comparison subjects.

The also observe in review of the existing evidence:

“Patients with celiac disease may suffer from neurological symptoms, such as peripheral neuropathy, ataxia, intellectual deterioration, brain atrophy, and epilepsy…In addition to neurological manifestations, a significantly higher prevalence of depressive symptoms (30–69%) and depressive disorders (42%) has been reported in adult celiac disease patients, compared to medical and normal comparison subjects…Improvement in depressive disorders has been described in some celiac disease patients after they started a gluten-free diet.“

What did their findings show specifically in regard to adolescents?

“We found that celiac disease was associated with higher lifetime prevalences of major depressive disorder and disruptive behavior disorder in adolescents…at least in some of these patients major depression and disruptive behavior disorder were related to celiac disease and alleviated by treatment of celiac disease with a gluten-free diet.”

The clinical implications of the data are summarized in their conclusion:

“Celiac disease is associated with increased prevalence of depressive and disruptive behavior disorders in adolescents, particularly in the phase before diet treatment. In some cases psychiatric symptoms appear to improve after the patient starts a gluten-free diet. The possibility of undiagnosed celiac disease should be taken into account in the differential diagnosis of these disorders, since the diet treatment is essential.“

Interestingly, in light of the reports that follow, they also make this observation:

“The risk of psychological disorders is substantially higher in children with a chronic disease and, for unknown reasons, particularly in patients with inflammatory bowel disease.“

What are the mechanisms by which gluten sensitivity can contribute to neurodevelopmental disorders? A study published in the Journal of Clinical Immunology examines gut mucosal immunopathology in relation to regressive autism:

“Inflammatory intestinal pathology has been reported in children with regressive autism (affected children). Detailed analysis of intestinal biopsies in these children indicates a novel lymphocytic enterocolitis with autoimmune features…”

The authors undertook a detailed analysis of mucosal infiltrate with flow cytometry (inspected the cellular components of gut lining secretions) and intestinal biopsies, and…

“…found a prominent mucosal eosinophil [allergen-reactive white blood cell] infiltrate in affected children that was significantly lower in those on a gluten- and casein-free diet… The data provide further evidence of a pan-enteric mucosal immunopathology in children with regressive autism that is apparently distinct from other inflammatory bowel diseases.”

Antibodies to neuronal tissues, signaling molecules and key enzymes can also play a role in neurological disorders associated with gluten sensitivity. The authors of a paper published in the journal Acta Neurologica Scandinavica state:

“The high prevalence of gluten sensitivity in patients with stiff-person syndrome (SPS) lead us to investigate the relationship between gluten sensitivity and GAD-antibody-associated diseases.”

GAD is glutamic acid decarboxylase, aka glutamate decarboxylase. Most clinicians reading this are aware that GAD is a target for autoantibodies in type 1 diabetes, but may not recall that it is required to convert glutamate into GABA, our most abundant inhibitory (calming) neurotransmitter. Functional deficiencies of GABA can manifest as anxiety, restlessness, disorganized attention, inner excitability and tension with difficulty relaxing, feeling overwhelmed, worry, etc. The authors used ELISA assays for anti-GAD and for serological markers of gluten sensitivity in patients recruited from clinics based at the Royal Hallamshire hospital, Sheffield, UK. Those with gluten sensitivity were followed up after the introduction of a gluten-free diet. Their data painted a compelling picture:

“Six of seven (86%) patients with SPS were positive for anti-GAD…This compared with 9/90 (11%) patients with idiopathic sporadic ataxia…16/40 (40%) patients with gluten ataxia…and 6/10 patients with type 1 diabetes only…The titre of anti-GAD reduced following the introduction of a gluten-free diet in patients with SPS who had serological evidence of gluten sensitivity. The same was observed in patients with gluten ataxia and anti-GAD antibodies. This was also associated with clinical improvement.“

Parents of patients and the practitioners caring for them should bear their conclusion in mind:

“These findings suggest a link between gluten sensitivity and GAD antibody-associated diseases.”

Interestingly, impairment in the ability to digest gliadin (from gluten), a problem which has a genetic basis, can contribute to affective disorders. The authors of a paper published in Behavioral and Brain Functions offer evidence from an investigation of the urine of depressed patients for relevant undigested peptides:

“We find overlapping patterns of peptide peaks in severe depression, but with considerable individuality. Mass spectrometry shows that some of these peptides are probably of dietary origin, because their sequences are found only in certain dietary proteins. Opioids from casein and gliadin are typical examples.“

Their conclusion is part of the rationale for offering specific digestive enzymes (peptidases) to patients with gluten sensitivity:

“Peptide increase in urine is found when break down is deficient, and the data presented agree with reports on peptidase deficiencies in depression.”

Another mechanism by which gluten can promote autoimmune disorders with neurological, behavioral and neurodevelopmental consequences is by causing abnormal permeability (‘leakiness’) of the intestinal mucosal barrier. This causes the gut-associated immune tissue to be abnormally exposed to the intestinal contents. The authors of a paper published recently in the Annals of the New York Academy of Sciences examine the link between intestinal permeability and autoimmune disease:

“Interestingly, recent data suggest that gliadin is also involved in the pathogenesis of T1D. There is growing evidence that increased intestinal permeability plays a pathogenic role in various autoimmune diseases including CD and T1D. Therefore, we hypothesize that besides genetic and environmental factors, loss of intestinal barrier function is necessary to develop autoimmunity.”

In delineating the process by which exposure to antigen in the gut triggers a genetic susceptibility, they note:

“In all cases, increased permeability precedes disease and causes an abnormality in antigen delivery that triggers immune events, eventually leading to a multiorgan process and autoimmunity.”

Moreover…

“Alterations in the intestinal balance between beneficial and potentially harmful bacteria have also been associated with allergy, type 1 diabetes and inflammatory bowel diseases…”

These factors come to a point that disrupts the tight junctions (TJ) of the intestinal barrier by perturbing the production of zonulin, an agent involved in loss of barrier function and autoimmune disease:

“The zonulin upregulation during the acute phase of CD was confirmed by measuring zonulin concentration…Compared to healthy controls, CD subjects showed significantly higher zonulin serum concentrations during the acute phase of the disease that decreased following a gluten-free diet…Similar results were obtained from T1D subjects…Our group has generated evidence that gliadin induces increased intestinal permeability by releasing preformed zonulin…When exposed to luminal gliadin, intestinal biopsies from celiac patients in remission expressed a sustained luminal zonulin release and increase in intestinal permeability.”

They summarize their findings with this important statement:

“Genetic predisposition, miscommunication between innate and adaptive immunity, exposure to environmental triggers, and loss of intestinal barrier function secondary to dysfunction of intercellular TJ all seem to be key components in the pathogenesis of autoimmune diseases. Both in CD and T1D gliadin may play a role in causing loss of intestinal barrier function and/or inducing the autoimmune response in genetically predisposed individuals…Since TJ dysfunction allows this interaction, new therapeutic strategies aimed at re-establishing the intestinal barrier function offer innovative, unexplored approaches for the treatment of these devastating diseases.”

Further confirmation of the damage gliadin does to the intestinal epithelial barrier is offered in a paper published in the Scandinavian Journal of Gastroenterology:

“We investigated whether gliadin has any immediate effect on zonulin release and signaling.”

They exposed human intestinal tissue to gliadin and evaluated zonulin release and barrier permeability by PCR (polymerase chain reaction) and immunofluorescence microscopy. They too documented similar effects:

“When exposed to luminal gliadin, intestinal biopsies from celiac patients in remission expressed a sustained luminal zonulin release and increase in intestinal permeability…”

However, they found that non-celiac patients also exhibited an increased zonulin release that, while not the magnitude of the celiac patients, caused intestinal permeability:

“…biopsies from non-celiac patients demonstrated a limited, transient zonulin release which was paralleled by an increase in intestinal permeability…”

This would be an argument in favor of everyone adopting a gluten-free diet. The authors’ conclusion is striking:

“Based on our results, we concluded that gliadin activates zonulin signaling irrespective of the genetic expression of autoimmunity, leading to increased intestinal permeability to macromolecules.”

The authors of a study published in the journal Gastroenterology add to the body of knowledge by identifying the mechanism by which gluten increases zonulin release and intestinal permeability:

“Celiac disease is an immune-mediated enteropathy triggered by gliadin, a component of the grain protein gluten. Gliadin induces an MyD88-dependent zonulin release that leads to increased intestinal permeability…We aimed to establish the molecular basis of gliadin interaction with intestinal mucosa leading to intestinal barrier impairment.“

They demonstrated that the chemokine receptor CXCR3 binds gliadin by examining CXCR3 protein and gene expression in intestinal epithelial cell lines and biopsy specimens, and gliadin-CXCR3 interaction by immunofluorescence microscopy, laser capture microscopy, real-time reverse-transcription polymerase chain reaction, and immunoprecipitation/Western blot analysis. On a positive note, the observed that…

“Gliadin binds to CXCR3 and leads to MyD88-dependent zonulin release and increased intestinal permeability…[however] Mucosal CXCR3 expression was elevated in active celiac disease but returned to baseline levels following implementation of a gluten-free diet.“

What about evidence that following a gluten-free diet helps with behavioral disorders of children and adolescents? The authors of a study published in BMC (BioMed Central) Psychiatry state:

“Coeliac disease in adolescents has been associated with an increased prevalence of depressive and disruptive behavioural disorders, particularly in the phase before diet treatment. We studied the possible effects of a gluten-free diet on psychiatric symptoms, on hormonal status (prolactin, thyroidal function) and on large neutral amino acid serum concentrations in adolescents with coeliac disease commencing a gluten-free diet.”

Moreover…

“Coeliac disease is an under-diagnosed autoimmune type of gastrointestinal disorder… Non-specific symptoms such as fatigue and dyspepsia are common, but the disease may also be clinically silent….Undetected or neglected, coeliac disease is associated with serious complications…depressive and disruptive behavioural disorders are highly common also among adolescents, particularly in the phase before diet treatment…Recently 73% of patients with untreated coeliac disease – but only 7% of patients adhering to a gluten-free diet – were reported to have cerebral blood flow abnormalities similar to those among patients with depressive disorders.“

They assessed adolescents aged 12 to 16 years with several symptom scales and followed them at intervals after starting a gluten-free diet. What did their data show?

“Adolescent coeliac disease patients with depression had significantly lower pre-diet tryptophan/ competing amino-acid (CAA) ratios and free tryptophan concentrations, and significantly higher biopsy morning prolactin levels compared to those without depression. A significant decrease in psychiatric symptoms was found at 3 months on a gluten-free diet compared to patients’ baseline condition, coinciding with significantly decreased coeliac disease activity and prolactin levels and with a significant increase in serum concentrations of CAAs.”

Parents and clinicians should consider their conclusions:

“…since diet treatment may alleviate psychiatric symptoms, and earlier diagnosis may have beneficial effects on psychological and even on neurobiological vulnerability to depression, the possibility of psychiatric complications of coeliac disease needs to be taken into account in differential diagnosis of depressive and behavioural disorders.”

A paper published in the journal Nutritional Neuroscience suggests similar indications for some children with autism spectrum disorders:

“There is increasing interest in the use of gluten- and casein-free diets for children with autism spectrum disorders (ASDs). We report results from a two-stage, 24-month, randomised, controlled trial incorporating an adaptive ‘catch-up’ design and interim analysis.”

They randomly assigned 72 Danish children to two diets and examined them for inattention and hyperactivity at baseline, 8 and 12 months. At that point there data showed that…

“…there was a significant improvement to mean diet group scores (time*treatment interaction) on sub-domains of ADOS, GARS and ADHD-IV measures. Surpassing of predefined statistical thresholds as evidence of improvement in group A at 12 months sanctioned the re-assignment of group B participants to active dietary treatment.”

The authors state in their conclusion:

“Our results suggest that dietary intervention may positively affect developmental outcome for some children diagnosed with ASD.”

What is the practical bottom line for parents and practitioners? There is mounting scientific evidence that the possibility of gluten sensitivity should not be overlooked when investigating the contributing causes to childhood disorders of learning, behavior and neurodevelopment. Given that celiac disease can be ‘silent’, and that we are particularly concerned with the non-celiac neurological manifestations of gluten sensitivity, testing for the genetic susceptibility in addition to anti-gliadin antibodies is a clinically prudent course of action.

Gastrointestinal pathology in childhood disorders of learning, behavior and development

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Can gastrointestinal pathology be a contributing factor in neurodevelopmental disorders? Consider this study published in the American Journal of Gastroenterology in which the authors begin:

“Intestinal pathology, i.e., ileocolonic lymphoid nodular hyperplasia (LNH) and mucosal inflammation, has been described in children with developmental disorders. This study describes some of the endoscopic and pathological characteristics in a group of children with developmental disorders (affected children) that are associated with behavioral regression and bowel symptoms, and compares them with pediatric controls.”

They performed ileocolonoscopies and biopsies on 60 children whose diagnoses included Developmental diagnoses were autism (50 patients), Asperger’s syndrome (five), disintegrative disorder (two), attention deficit hyperactivity disorder (ADHD) (one), schizophrenia (one), and dyslexia (one). The tissue specimens were reviewed by three pathologists and compared with 22 well children and 2o with ulcerative colitis. Their data for GI pathology in the affected cohort were striking:

“Ileal LNH was present in 54 of 58 (93%) affected children and in five of 35 (14.3%) controls . Colonic LNH was present in 18 of 60 (30%) affected children and in two of 37 (5.4%) controls. Histologically, reactive follicular hyperplasia was present in 46 of 52 (88.5%) ileal biopsies from affected children and in four of 14 (29%) with UC, but not in non-IBD controls. Chronic colitis was identified in 53 of 60 (88%) affected children compared with one of 22 (4.5%) controls and in 20 of 20 (100%) with UC. Scores of frequency and severity of inflammation were significantly greater in both affected children and those with UC, compared with controls.”

Considering the impact of the enteric (gut) immune and nervous systems on the brain these findings are not a surprise. “When the gut is inflamed the brain is inflamed.” The authors conclude by stating:

“A new variant of inflammatory bowel disease is present in this group of children with developmental disorders.”

A paper published last year in the Canadian Journal of Gastroenterology adds to the discussion of this topic in regard to autism. The authors state:

“There have been several reports of a link between autism and chronic gastrointestinal symptoms. Endoscopy trials have demonstrated a higher prevalence of nonspecific colitis, lymphoid hyperplasia and focally enhanced gastritis compared with controls. Postulated mechanisms include aberrant immune responses to some dietary proteins, abnormal intestinal permeability and unfavourable gut microflora.”

The authors examined two autism spectrum disorder patients with chronic intestinal symptoms and abnormal endoscopies and reviewed relevant background studies. Their findings inspired this conclusion:

“While genetic susceptibility is an important contributor in ASDs, the exact etiology of these pervasive developmental disorders remains unclear and is most likely multi-factorial…Be it an immune-mediated connection, versus a ‘brain-gut axis’ interplay such as seen in irritable bowel syndrome, the increased prevalence of GI symptoms in this group of patients cannot be denied, nor the added distress that these symptoms could have on an individual who is already communicatively challenged…a heightened awareness and lower threshold for work-up and management of GI symptoms may help improve quality of life of these patients who may be suffering in silence.”

The authors of a paper published in the Journal of Neuroimmunology consider lymphocyte subsets and inflammatory cytokines in the gut in relation to autism:

“Gastrointestinal pathology, characterized by lymphoid nodular hyperplasia and entero-colitis, has been demonstrated in a cohort of children with autistic spectrum disorder (ASD).”

They assessed inflammation in the intestines of ASD children in comparison with well controls and children with Crohn’s disease by examining inflammatory cytokines present in CD3+ lymphocytes (T helper and cytotoxic T cells):

“In both peripheral blood and mucosa, CD3+ TNFα+ and CD3+ IFNγ+ [pro-inflammatory cytokines] were increased in ASD children compared with NIC [non-inflamed controls] and reached levels similar to CD [Crohn's disease]. In contrast, peripheral and mucosal CD3+ IL-10+ [anti-inflammatory cytokine] were markedly lower in ASD children with GI symptoms compared with both NIC and CD controls. In addition, mucosal CD3+ IL-4+ [pro-inflammatory] cells were increased in ASD compared with NIC.”

Again we see a marked pattern of gastrointestinal inflammation distinguishing the ASD group. The authors conclude:

“There is a unique pattern of peripheral blood and mucosal CD3+ lymphocytes intracellular cytokines, which is consistent with significant immune dysregulation, in this ASD cohort.”

Disorders of learning, behavior and neurodevelopment in childhood and adolescence are a heterogenous group with multiple possible causes so it would be an error to expect that all children with ASD have GI pathology and a principal or accessory cause. But it would be an equal error to fail to confirm whether or not it is a contributing factor in each individual case.

Thyroid dysfunction in pediatric disorders of learning, behavior and development

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Thyroid dysfunction is not to be overlooked as a possible contributing cause to problems with learning, behavior and brain development. It can be expressed in a variety of ways, often requiring a nuanced functional analysis to detect and solve the problem. A study published in the journal Brain Research discusses an often overlooked type of thyroid dysregulation that can contribute to ADHD. The authors state:

“Attention deficit disorders are a frequent manifestation of resistance to thyroid hormone (RTH), a disorder caused by mutations in the hormone-binding domain of the human thyroid hormone receptor β gene.”

They used PET scans to measure cerebral glucose metabolism in regions of the brain involved in attention, comparing normal subjects to those with RTH. A clear-cut difference was observed:

“Compared to the control group, performance on a continuous auditory discrimination task was severely impaired in the RTH subjects, while metabolism was higher both in the right parietal cortex and the anterior cingulate gyrus. Abnormally high functional activity of the anterior cingulate during sustained attention may be associated with a decreased signal-to-noise ratio for the neural processing of task stimuli in subjects with RTH.“

In other words, resistance to thyroid hormone was associated with impaired function in the parts of the brain that are active in paying attention to and processing what we are trying to listen to. Other parts of the brain went into ‘hyperdrive’ in an attempt to compensate. Remember that this type of thyroid dysfunction, peripheral resistance to thyroid hormone, will appear normal on the usual lab tests.

A paper published in Pediatric Neurology directs our attention to the disruption of learning and behavior caused by subclinical hyperthyroidism—’subclinical’ meaning that no other overt signs of hyperthyroid are clinically apparent. The authors…

“…report three children who exhibited developmental learning disabilities (DLDs) associated with behavioral disturbances, such as attention deficit, hyperactivity, and autistic features. The thyroid function tests performed as a part of routine endocrinologic evaluation of children with DLDs revealed a hormonal profile consistent with hyperthyroidism. These children had no systemic signs of hyperthyroidism.”

Though it may not be the most sustainable long-term therapy from a functional perspective, they treated with medication to suppress thyroid hormone synthesis and reported that it…

“…resulted in good control of their hyperkinetic behavior and subsequent improvement in language function attributable to an increased attention span, thereby facilitating speech therapy.”

Although only a subset of children with learning and behavioral disorders will be found to found to have subclinical hyperthyroidism, it is a possibility that should be borne in mind and ‘crossed off the list’. The authors state:

“Although routine screening of all children with DLDs for thyroid dysfunction may not be cost-effective, selective screening of children with familial attention-deficit hyperactivity disorder and those with attention-deficit and hyperactivity in association with DLDs and pervasive developmental disorders appears to be justified.”

Another study published in the journal Psychoneuroendocrinology draws our attention to functional disturbances in thyroid hormone regulation from a different perspective. The authors state:

“Thyroid abnormalities have been associated with attention deficit/hyperactivity disorder (ADHD) and with other childhood psychiatric disorders. The goal of this study was to determine the relationships between thyroid hormone concentrations, neurocognitive functioning, and psychiatric diagnosis in children.”

They examined 338 children referred to a clinic for learning and behavior problems, measuring their thyroid stimulating hormone (TSH) levels and free thyroxine index (FT4I) and correlating them with diagnostic and descriptive information. Not surprisingly, the data showed that it was the more subtle functional abnormalities rather than gross pathologic ones that discriminated different types of ADHD:

“Thyroid abnormalities were uncommon in children referred for ADHD. After excluding children with thyroid disease, there was a greater proportion with low concentrations of normal FT4I for ADHD–Predominantly Inattentive type, but not for ADHD–Combined Type. High concentrations of normal FT4I were associated with mood lability, preoccupations, and lower ratings of attention problems. Thyroxine concentrations within the normal range were differentially associated with ADHD–Combined Type compared to ADHD–Predominantly Inattentive, mood disorders, and pervasive developmental disorders.”

The authors sum up their findings for this group of children with subtle disturbances in thyroxine regulation:

“Thyroxine concentrations were associated with mood symptoms and unusual behaviors, and were less strongly related to attentional functioning. Thyroxine concentrations were not related to hyperactivity.”

We can gain additional insight into the issue of thyroid hormone resistance and ADHD from a case report published in the journal Deutsche Medizinische Wochenschrift (German Medical Weekly). The authors state:

“Two siblings with goiter and attention deficit-hyperactivity disorder were presented. Earlier laboratory tests showed increased serum levels of thyroid hormones in association with non-suppressed serum levels of thyrotropin (TSH) in both children.”

Review for lay readers: as in the first paper cited, elevation of thyroid hormones in hyperthyroidism is accompanied by low levels of TSH (thyroid stimulating hormone ‘aka’ thyrotropin, which is  produced in the pituitary; it stimulates thyroid hormone production in the thyroid gland on a feedback loop). Resistance to thyroid hormone by its receptors in the rest of the body can cause TSH to be high even when thyroid hormones are elevated. Peripheral resistance can also cause a low thyroid state with labs that look normal. The doctors in this case did what was necessary to rule out hyperthyroid disease:

“Because hyperthyroidism caused by inappropriate secretion of thyrotropin was suspected, a cerebral MRI was performed. A pituitary adenoma was excluded in both children. Before antithyroid drug treatment was initiated, both patients were referred to our hospital. Careful medical history, clinical examination of the patients and careful interpretation of the laboratory results finally led to the diagnosis resistance to thyroid hormone (RTH).”

This spared the children inappropriate aggressive thyrostatic treatment (thyroid suppression or destruction). Moreover, there are functional therapies for RTH. I certainly concur with the authors’ conclusion:

“Careful medical history, correct interpretation of laboratory results, comprehensive clinical examination and molecular genetic analysis are important in the diagnosis of RTH.”

A paper recently published in the Journal of Affective Disorders sheds more light on how profound thyroid dysregulation evidenced by an increase TSH can be. The authors begin by observing:

“The relationship of bipolar disorder (BD) and altered thyroid function is increasingly recognized. Recently, a behavioral phenotype of co-occurring deviance on the Anxious/Depressed (A/D), Attention Problems (AP), and Aggressive Behavior (AB) syndrome scales has been identified as the Child Behavior Checklist Dysregulation Profile (CBCL-DP), which itself has been linked to BD. This study tested for differences in thyroid function within a sample of psychiatric children and adolescents with and without the CBCL-DP.”

They correlated the CBCL-DP scores according to each behavioral phenotype with serum levels of TSH, fT3 (free T3) and fT4 (free T4). What did their data show?

“In participants showing the CBCL-DP, basal serum TSH was elevated compared to controls. More CBCL-DP subjects than controls showed subclinical hypothyroidism. No differences were observed for serum fT3 and fT4 levels.“

Here again we see the manifestation of resistance to thyroid hormone, this time with elevated TSH and normal fT3 and fT4. It is likely, in our experience, that the chronic microinflammation resulting in peripheral resistance to thyroid hormone (RTH) is due to autoimmune/allergic phenomena that are simultaneously activating microglial cells (immune cells in the brain) to produce neuroinflammation. In this case the brain gets a ‘double whammy’—RTH and brain inflammation.

Bringing the matter even more up to date, an excellent and important paper recently published in the journal Clinical Endocrinology clearly articulates why it is mandatory for clinicians to be alert to functional changes in thyroid hormone measurements that are usually within the ‘normal’ laboratory reference range.The authors stated their initial objective:

“Thyroid hormone concentrations outside the normal range affect brain development, but their specific influence on behaviour and mental abilities within normal values is unknown. The objective of this study was to investigate whether thyroid hormone concentrations are related to neurodevelopment and ADHD (attention deficit and hyperactivity disorder) symptoms in healthy preschoolers.”

They assessed mental and motor development with McCarthy’s scales for neuropsychological outcomes and ADHD-DSM-IV for ADHD symptoms, correlating them with thyroid hormones TSH, free T4 and T3. What did the data show?

“Children with TSH concentrations in the upper quartile of the normal range performed lower on McCarthy’s scales and were at higher risk for attention deficit and hyperactivity/impulsivity symptoms. In the Menorca cohort, a decrease of 5·8 and 6·9 points was observed in memory and quantitative skills, respectively. In contrast, high T4 concentrations were associated with decreased risk of having 1–5 attention deficit symptoms…No associations were observed with T3.”

Bottom line: when there are symptoms of learning, behavioral or developmental disorders, the astute parent or clinician must ask “Is there any indication that thyroid function needs to be investigated in this case?” If so, it must be borne in mind that there are types of thyroid dysfunction that occur in the presence of ‘normal’ values for TSH, T3 and T4. The authors emphasize this in their conclusion:

“Despite being within the normal range, high TSH concentrations are associated with a lower cognitive function and high TSH and low free T4 with ADHD symptoms in healthy preschoolers. Statistically significant differences were observed in the highest quartiles of TSH, suggesting a need for re-evaluation of the upper limit of the normal TSH range.“

HPA hormone dysregulation in pediatric disorders of learning, behavior and neurodevelopment

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There is a large body of evidence that compels us not to overlook hormonal dysregulation in ADHD and other disorders of learning, behavior and brain development. A paper published not long ago in the journal European Neuropsychopharmacology addresses the broad topic of neurosteroids. The authors state in regard to the steroid hormones active in the nervous system:

“Neurosteroids play a significant role in neurodevelopment and are involved in a wide variety of psychopathological processes…there is increasing evidence for their critical role from the early stages of brain development until adolescence.“

They proceed to review the involvement of neurosteroids in neurodevelopment and mental disorders in children and adolescents, noting in particular:

“Adequate physiological levels protect the developing neural system from insult and contribute to the regulation of brain organization and function. Neurosteroids may be involved in the pathophysiology and pharmacotherapy of a variety of disorders in children and adolescents, including schizophrenia, depression, eating disorders, aggressive behavior and attention deficit.”

A paper published in the journal Neuropediatrics examines the association of hypothalamo-pituitary-adrenal (HPA) axis dysfunction and intelligence performance:

“The aim of the present study was to examine the effects of hypothalamo-pituitary-adrenal (HPA) axis reactivity on intelligence test performance in subjects with attention-deficit/hyperactivity disorder (ADHD). We investigated the extent to which an increase or decrease in cortisol after stress was associated with the intelligence test performance in 68 clinic-referred children with ADHD.”

They administered a battery of tests for both assessment and stressor applications, plus…

“A saliva sample was collected from each subject before and after psychological testing in order to measure the level of cortisol in the saliva.”

Salivary cortisol is the most reliable and necessarily non-invasive way to measure functional cortisol levels as we know here from extensive clinical experience. Their data painted a striking picture:

“Decreases in the level of cortisol after the test were correlated with poor intelligence performance and the decrease of cortisol in respect to baseline significantly affected the verbal, performance and total IQ in subjects who showed blunted responses to stress.”

A fine study published recently in the Chinese Journal of Contemporary Pediatrics further investigates…

“…the function of the hypothalamus-pituitary-adrenal (HPA) axis in children with attention deficit hyperactivity disorder (ADHD).”

128 boys with ADHD at ages of 6 to 14 years were diagnosed and grouped according to the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV): ADHD-predominantly inattention type, ADHD-predominantly hyperactive impulsive type and ADHD-combined type. 30 healthy boys served as the control group. They tested cortisol and assessed intelligence level with Raven′s standard progressive matrices. What did the data show?

“The mean plasma cortisol level in the ADHD group was significantly lower than that in the control group. The three ADHD subgroups showed significantly decreased plasma cortisol level compared with the control group. The plasma level of cortisol was the lowest in the ADHD-HI group, followed by the ADHD-I group and the ADHD-C group.”

Their conclusion should be borne in mind by both clinicians and parents:

“In the non-stress state, the HPA axis may be dysfunctional in children with ADHD, which may be attributed to the under reactivity of the HPA axis. Lower plasma cortisol…may closely be related to attention deficit, hyperactivity and impulsive behaviors.“

More valuable research was published in the Yonsei Medical Journal (Korea) in which the authors state:

“Children with attention-deficit/hyperactivity disorder (ADHD) often perform poorly during cognitive tests. We sought to evaluate cortisol as potential moderator of performance in mentally challenging tasks in children with ADHD.”

They measured salivary cortisol in 90 children with ADHD before and after administration of a continuous performance test (CPT). Their data adds evidence that cortisol dysregulation in association with poorer performance can be either abnormally high or low:

“Children whose cortisol level increased after testing displayed a significantly longer response time and increased response time variability scores as compared to children who did not display increase of cortisol after the CPT test.”

Since activation of α1 adrenergic receptor mediates both cortisol level increase and attention impairment, they also conclude that in association with cortisol:

“The result of the current study suggests that stress-induced high norepinephrine (NE) release may accompany poorer attention performance in patients with ADHD.”

The authors of a paper published in European Child & Adolescent Psychiatry offer additional evidence that children with ADHD must be evaluated as individuals for varying patterns of cortisol dysregulation:

“The aim of this study was to investigate whether a different pattern of HPA axis activity is found between the inattentive (I) and combined (C) subtypes of ADHD, in comparison with healthy control children.”

They studied the effects of stress by comparing cortisol responses to a psychosocial stressor (a public speaking task). Their data revealed interesting differences:

“Children with ADHD-I showed an elevated cortisol response to the psychosocial stressor, in contrast to children with ADHD-C who showed a blunted cortisol response to the psychosocial stressor…hyperactivity symptoms were clearly related to a lower cortisol reactivity to stress. The results indicate that a low-cortisol responsivity to stress may be a neurobiological marker for children with ADHD-C, but not for those with ADHD-I.”

The authors of a paper published in the Journal of Attention Disorders draw our attention to the link between sensory hyperarousal and HPA axis dysregulation with their investigation of salivary cortisol levels:

“To determine if sensory overresponsivity (SOR) is a moderating condition impacting the activity of the Hypothalamic Pituitary Adrenal (HPA) Axis in children with ADHD.”

Children with ADHD and known SOR were compared with those with ADHD but without SOR and normal children, all of whom participated in a Sensory Challenge Protocol. Salivary cortisol was used as a measure of HPA activity with two prechallenge and seven postchallenge samples taken. Interestingly, their data showed…

“…a borderline significant difference found between the ADHDt [without SOR] and ADHDs [with SOR] group and a significant difference between ADHDt and the typical [normal] group.”

In other words, salivary cortisol measurements distinguished both ADHD groups from the normal group.

Clarification of the different patterns of HPA axis dysregulation in ADHD was reported in the Journal of Abnormal Child Psychology:

“Disruptions to hypothalamic-pituitary-adrenal (HPA) axis function have been associated with varying forms of psychopathology in children. Studies suggesting children with ADHD have blunted HPA function have been complicated by the prevalence of comorbid diagnoses and heterogeneity of ADHD. The goals of this research were to assess the relations between waking and stress–response salivary cortisol levels and comorbid disruptive behavior (DBD) and anxiety (AnxD) disorders and problems in boys with ADHD, and to examine whether cortisol levels varied across ADHD subtypes.”

The authors examined salivary cortisol on waking and in reaction to venipuncture (to determine stress-response levels), psychiatric symptoms and behavioral problems in 170 elementary school-age boys. The data left no doubt that there are dysfunctional subtypes of ADHD, emphasizing the importance of evaluating each child as an individual:

“Boys’ comorbid AnxD and anxiety problems were associated with greater cortisol reactivity, whereas boys’ comorbid DBD and oppositional problems predicted diminished adrenocortical activity. Reactive cortisol increases were greatest in boys with ADHD and comorbid AnxD, but without DBD…comorbid DBD predicted decreased cortisol reactivity in boys with inattentive and hyperactive subtypes of ADHD, but not in boys with combined subtype of ADHD. The results clarify previous patterns of distinct and divergent dysregulations of HPA function associated with boys’ varying kinds of psychopathology.”

By the way, note that venipuncture (drawing blood) was used elicit a cortisol-modifying stress response. This is one reason why we use saliva instead of blood tests for cortisol.

We can add to this a study published in the journal Child Psychiatry & Human Development that further examines HPA axis dysregulation in a specific subtype of ADHD. The authors set out…

“To investigate the hypothalamic pituitary adrenal (HPA) axis response to a stressor in adolescents with inattentive type attention-deficit hyperactivity disorder symptoms (ADHD-I).”

They too used salivary cortisol measurements as a metric in response to a social/cognitive stressor for threshold inattentive (TI), moderately inattentive (MI) and no symptom groups of healthy adolescents. A distinction was present in this study as well:

“The TI group displayed a significant decrease in cortisol post stressor whereas both the MI and comparison groups showed an increase in cortisol.”

We can also appreciate a study published in the journal Psychiatry Research that looks specifically at aggressive behavior and cortisol. The authors state:

“We examined the relationship between the cortisol response to stress and aggression in patients with attention deficit hyperactivity disorder (ADHD). Based on a report stating that only some of the patients with ADHD retain their hypothalamic-pituitary-adrenal axis reactivity to stress, we separately analyzed the relationship between aggression and the cortisol response to stress in two groups according to their reactivity to stress.”

Their data included psychological testing as a stress indicator with salivary cortisol measurements made before and after psychological test administration. Behavioral problems and aggression were assessed with the local (Korean) version of the Child Behavior Checklist. Their findings also showed the connection:

“The increase of the cortisol level was inversely correlated with aggression in patients who retained their reactivity to stress. The absolute value of the decrease was negatively correlated with the attention score of the CBCL for the patients who showed decreases in cortisol after stress. For the patients who showed increases in their concentration of cortisol in reaction to stress, cortisol may play a protective role against aggression.”

In other words, when cortisol went down aggression went up and attention scored worse. As we can see, there is a large body of evidence showing that we must consider the possibility of hypothalamic-pituitary-adrenal dysregulation in pediatric disorders of learning and behavior. This is best assessed by the functional approach that encompasses the multiple factors such as blood sugar dysregulation, inflammation from allergy or autoimmunity, etc. that can be contributing causes to HPA axis dysfunction, along with experienced assessment of salivary cortisol levels together with associated laboratory findings.

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.

Environmental risk factors for neurodevelopmental, learning and behavioral disorders

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Brain development, structure and function can suffer from a number of adverse environmental influences. A paper published in the journal Acta Pædiatrica review some of the environmental risk factors for ADHD.

“Converging evidence from epidemiologic, neuropsychology, neuroimaging, genetic and treatment studies shows that ADHD is a valid medical disorder…The majority of studies performed to assess genetic risk factors in ADHD have supported a strong familial nature of this disorder…However, several biological and environmental factors have also been proposed as risk factors for ADHD, including food additives/diet, lead contamination, cigarette and alcohol exposure, maternal smoking during pregnancy, and low birth weight.“

The authors review numerous studies that examine some these extraneous risk factors. They conclude by stating:

“Although a substantial fraction of the aetiology of ADHD is due to genes, the studies reviewed in this article show that many environmental risk factors and potential gene–environment interactions also increase the risk for the disorder.”

A study published in the journal Neuropediatrics investigates specifically the association between blood levels of mercury and ADHD in Hong Kong children:

“Fifty-two children with ADHD aged below 18 years diagnosed by DSM IV criteria without perinatal brain insults, mental retardation or neurological deficits were recruited from a developmental assessment center. Fifty-nine normal controls were recruited from a nearby hospital. Blood mercury levels were measured by cold vapor atomic absorption spectrophotometry.”

The authors uncovered a significant difference in blood mercury levels between the children with ADHD and the controls (‘normal’ children) which remained apparent after adjusting for age, gender and parents’ occupations:

“Children with blood mercury level above 29 nmol/L had 9.69 times higher risk of having ADHD after adjustment for confounding variables.”

The average blood mercury levels were higher for both the inattentive and combined subtypes of ADHD. Let’s bear in mind that this is one possible causal factor among many, not ‘THE’ cause. The authors conclude by stating:

“High blood mercury level was associated with ADHD. Whether the relationship is causal requires further studies.”

We can see a similar biological mechanism at play when we consider research recently published in Pediatric Allergy and Immunology that examines the association of heavy metals and Tourette syndrome. The authors state:

“Tourette syndrome (TS) is a childhood-onset and relapsing disorder characterized by involuntary simple or complex tics and high co-morbidity with behavioral anomalies…We investigated immunologic alternations and serum heavy metal levels in patients with TS to elucidate the unclarified mechanisms.”

Their findings illuminate a key point:

“In exacerbation, there were reverse CD4/CD8 (in two), higher percentages of natural killer cells (in five) and memory T cells (in eight), diminished lymphocyte activation CD69 marker (in three) and impaired NK cytotoxicity (in six) that showed a trend of lower inhibitory CD94 (NKG2A), activating NKp46, and perforin expression compared to those of patients with stable TS and healthy controls…Serum ASLO, mycoplasma antibody and the levels of heavy metals were not significantly different.”

In other words, the levels of heavy metals were pretty much the same but the immune system reaction to them was different. This is why it is impossible to make absolute statements about sub-acute levels of any heavy metal or toxin. Whether it elicits a dysregulated immune response leading to brain inflammation depends on the individual. The authors note this in their conclusion:

“Our study demonstrated that, in some patients with TS, consistently higher memory T cells and lower cytotoxicity in exacerbation status reflect immune alterations and underscore the potential for immunomodulation or immunosuppressive treatment.”

A paper published not long ago in Annals of Clinical Psychiatry carries the point further. The authors summarize the laboratory findings and other data in evidence for an autoimmune pathogenesis for autism:

“ Autoimmune markers were analyzed in the sera of autistic and normal children, but the cerebrospinal fluid (CSF) of some autistic children was also analyzed. Laboratory procedures included enzyme-linked immunosorbent assay and protein immunoblotting assay.”

Their findings certainly revealed the fire behind the smoke:

“Autoimmunity was demonstrated by the presence of brain autoantibodies, abnormal viral serology, brain and viral antibodies in CSF, a positive correlation between brain autoantibodies and viral serology, elevated levels of proinflammatory cytokines and acute-phase reactants, and a positive response to immunotherapy. Many autistic children harbored brain myelin basic protein autoantibodies and elevated levels of antibodies to measles virus and measles-mumps-rubella (MMR) vaccine. Measles might be etiologically linked to autism because measles and MMR antibodies (a viral marker) correlated positively to brain autoantibodies (an autoimmune marker)—salient features that characterize autoimmune pathology in autism. Autistic children also showed elevated levels of acute-phase reactants—a marker of systemic inflammation.”

Here again we see why it is impossible to argue for an environmental factor (heavy metal, virus, vaccine) as an absolute cause for autism or any other condition. Children at risk are those whose immune system is dysregulated and predisposed to an autoimmune triggering agent.

The authors state in their conclusion:

“The scientific evidence is quite credible for our autoimmune hypothesis, leading to the identification of autoimmune autistic disorder (AAD) as a major subset of autism. AAD can be identified by immune tests to determine immune problems before administering immunotherapy.”

We can also consider mild traumatic brain injury as a kind of ‘environmental risk factor’ for disorders neurodevelopment, learning and behavior. A study just published in the journal Pediatrics tests the link between postconcussion syndrome (PCS) and brain injury:

“Much disagreement exists as to whether postconcussion syndrome (PCS) is attributable to brain injury or to other factors such as trauma alone, preexisting psychosocial problems, or medicolegal issues. We investigated the epidemiology and natural history of PCS symptoms in a large cohort of children with a mild traumatic brain injury (mTBI) and compared them with children with an extracranial injury (ECI).”

The authors followed 670 children with mTBI and 197 children with ECI (non-cranial injury) and used the the Post Concussion Symptom Inventory, Rivermead Postconcussion Symptom Questionnaire, Brief Symptom Inventory, and Family Assessment Device to determine outcomes. Their data led to this conclusion:

“Among school-aged children with mTBI, 13.7% were symptomatic 3 months after injury. This finding could not be explained by trauma, family dysfunction, or maternal psychological adjustment. The results of this study provide clear support for the validity of the diagnosis of PCS in children.“

Environmental factors can be so severe that anyone would be affected. For most, however, the response depends on the individual. A skilled and experienced clinician knows when and where to focus suspicion. In the functional medicine model there are numerous resources available to test objectively when a question about environmental factors needs an answer, followed by the appropriate therapies when indicated.

Nutritional and metabolic requirements for pediatric brain health

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Numerous micro and macronutrients are required to grow and sustain a human brain in both structure and function. A paper published in the Journal of Nutrition, Health & Aging presents evidence for some of the key micronutrients:

“…most micronutrients (vitamins and trace-elements) have been directly evaluated in the setting of cerebral functioning. For instance, to produce energy, the use of glucose by nervous tissue implies the presence of vitamin B1; this vitamin modulates cognitive performance…Vitamins B6 and B12, among others, are directly involved in the synthesis of some neurotransmitters…Supplementation with cobalamin…frequently improves the functioning of factors related to the frontal lobe, as well as the language function of those with cognitive disorders. Adolescents who have a borderline level of vitamin B12 develop signs of cognitive changes.“

Revisiting the importance of iron for the brain:

“Iron is necessary to ensure oxygenation and to produce energy in the cerebral parenchyma (via cytochrome oxidase), and for the synthesis of neurotransmitters and myelin; iron deficiency is found in children with attention-deficit/hyperactivity disorder. Iron concentrations in the umbilical artery are critical during the development of the foetus, and in relation with the IQ in the child; infantile anaemia with its associated iron deficiency is linked to perturbation of the development of cognitive functions.“

Moreover, even subclinical deficiencies of micronutrients can have profound effects:

“…the full genetic potential of the child for physical growth and mental development may be compromised due to deficiency (even subclinical) of micronutrients.”

Macronutrients for the brain are addressed by the same author in an accompanying paper, starting with another look at fats:

“DHA (docosahexaenoic acid) is one for the major building structures of membrane phospholipids of brain and absolutely necessary for neuronal function…ALA acid deficiency alters the course of brain development…the nature of polyunsaturated fatty acids (in particular omega-3, ALA and DHA) present in formula milks for infants (premature and term) conditions the visual, neurological and cerebral abilities, including intellectual…Low fat diet may have adverse effects on mood.“

Regarding protein:

“The nature of the amino acid composition of dietary proteins contributes to cerebral function; taking into account that tryptophan plays a special role. In fact, some indispensable amino acids present in dietary proteins participate to elaborate neurotransmitters (and neuromodulators).”

The importance of blood sugar stability cannot be overstated:

“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…some cognitive functions appear sensitive to short term variations in glucose availability.”

The author concludes:

“[A] number of findings show that dietary factors play major roles in determining whether the brain ages successfully or experiences neurodegenerative disorders.”

Research recently presented in Psychosomatic Medicine (Journal of Biobehavioral Medicine) investigates:

“……the association between dietary folate, riboflavin, vitamin B-6, and vitamin B-12 and depressive symptoms in a group of adolescents.“

The authors correlated data on dietary intake with scores for depressive symptoms in 3,067 boys and 3,450 girls aged 12 to 15 years as defined by the Center of Epidemiologic Studies Depression Scale. What were the results?

“The prevalence of depressive symptoms was 22.5% for boys and 31.2% for girls. Folate intake was inversely associated with depressive symptoms in both boys and girls. Vitamin B-6 intake was inversely associated with depressive symptoms in both boys and girls. Riboflavin intake was inversely associated with depressive symptoms in girls, but not in boys. No clear association was seen between vitamin B-12 intake and depressive symptoms in either sex.”

Other studies have show an association between low vitamin B12 and depression in adults. We can speculate that this may be due to declining gastric digestive and absorptive capacity with age.

The authors conclude:

“This study suggests that higher intake of dietary B vitamins, particularly folate and vitamin B-6, is independently associated with a lower prevalence of depressive symptoms in early adolescence.“

There is interesting evidence for the importance of zinc in the clinical management of ADHD in a paper published in the journal Progress in Neuro-Psychopharmacology and Biological Psychiatry. The authors state:

“Some studies suggest that deficiency of zinc play a substantial role in the aetiopathogenesis of ADHD. Therefore, to assess the efficacy of zinc sulfate we conducted treatment trial.”

They examined the effect of double-blind treatment with zinc sulfate or placebo on 72 girls and 328 boys with a diagnosis of ADHD. Efficacy was assessed with a triad of rating scales. What did the data show?

“Zinc sulfate was statistically superior to placebo in reducing both hyperactive, impulsive and impaired socialization symptoms, but not in reducing attention deficiency symptoms, as assessed by ADHDS. However, full therapeutic response rates of the zinc and placebo groups remained 28.7% and 20%, respectively. It was determined that the hyperactivity, impulsivity and socialization scores displayed significant decrease in patients of older age and high BMI score with low zinc and free fatty acids (FFA) levels.“

The benefit of carnitine has been investigated for ADHD in boys and presented in a paper published in the journal Prostaglandins, Leukotrienes and Essential Fatty Acids:

“The ADHD behavior was observed by parents completing the Child Behavior Checklist (CBCL) and by teachers completing the Conners teacher-rating score, in a randomized, double-blind, placebo-controlled double-crossover trial.”

Significant improvements in behavior at home and at school were documented:

“Before treatment, the CBCL total and sub-scores were significantly different from those of normal Dutch boys. Responders showed a significant improvement of the CBCL total scores compared to baseline…responders showed higher levels of plasma-free carnitine and acetylcarnitine.“

The authors state in their conclusion:

“Treatment with carnitine significantly decreased the attention problems and aggressive behavior in boys with ADHD.“

An important paper also published in Progress in Neuro-Psychopharmacology and Biological Psychiatry disruption of the metabolism of tryptophan by inflammation can contribute to major depressive disorder (MDD) in adolescents. For background the authors state:

“Cytokine induction of the enzyme indoleamine 2,3-dioxygenase (IDO) has been implicated in the development of major depressive disorder (MDD). IDO metabolizes tryptophan (TRP) into kynurenine (KYN), thereby decreasing TRP availability to the brain. KYN is further metabolized into several neurotoxins…The aims of this pilot were to examine possible relationships between plasma TRP, KYN, and 3-hydroxyanthranilic acid (3-HAA, neurotoxic metabolite) and striatal total choline (tCho, cell membrane turnover biomarker) in adolescents with MDD. We hypothesized that MDD adolescents would exhibit: i) positive correlations between KYN and 3-HAA and striatal tCho and a negative correlation between TRP and striatal tCho…”

The authors employed high resolution proton magnetic resonance spectroscopic imaging to examine fourteen adolescents with MDD, seven of whom had melancholic features, and six healthy controls.

“Positive correlations were found only in the melancholic group, between KYN and 3-HAA and tCho in the right caudate and the left putamen, respectively…These preliminary findings suggest a possible role of the KYN pathway in adolescent melancholic MDD.“

In other words, the authors’ evidence shows that for the melancholic subset of adolescents with major depressive disorder, pro-inflammatory cytokines are disrupting the metabolism of tryptophan into serotonin. This brings into focus special considerations for the management of diet and nutritional precursor supplementation.

Environmental toxins also place a burden on brain metabolism that can disrupt neurodevelopment. A paper published in the journal Neurotoxicology describes the importance of the redox/methylation pathways in the brain. The authors state:

“Autistic children exhibit evidence of oxidative stress and impaired methylation, which may reflect effects of toxic exposure on sulfur metabolism. We review the metabolic relationship between oxidative stress and methylation, with particular emphasis on adaptive responses that limit activity of cobalamin and folate-dependent methionine synthase.”

Methionine synthase activity is required for the dopamine metabolic activity and dopamine receptor function that promotes neuronal synchronization and attention (synchrony is impaired in autism).

“Genetic polymorphisms adversely affecting sulfur metabolism, methylation, detoxification, dopamine signaling and the formation of neuronal networks occur more frequently in autistic subjects…oxidative stress, initiated by environment factors in genetically vulnerable individuals, [can lead] to impaired methylation and neurological deficits secondary to reductions in the capacity for synchronizing neural networks.”

Here we see the possibility of environment conditions demanding extraordinary metabolic support to prevent disruption of developing neural networks.

None of the research presented here implies that a specific nutritional or metabolic intervention is correct for any given individual. In all cases the parents and clinician should keep in mind the possibility that any of these factors may play a role. However, a “try this, try that” approach should be avoided in favor of objectively determining the needs of the individual with the appropriate laboratory tests. While the experienced clinician will have an abundant toolbox, the urinary assessment of organic acids is an indispensable resource.

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.”