Evidence of the link between childhood ADHD and adult brain function adds to the significance of understanding the underlying biological causes of ADHD. Research recently published in the journal Biological Psychiatry addresses one important aspect; the authors state:

“Timing abilities are critical to the successful management of everyday activities and personal safety, and timing abnormalities have been argued to be fundamental to impulsiveness, a core symptom of attention-deficit/hyperactivity disorder (ADHD)…The present study examined subsecond sensorimotor timing and its neural substrates in ADHD adults.”

They used functional magnetic resonance imaging of the blood oxygenation level-dependent contrast response to quantify task-related neural activity in unmedicated adults with ADHD and 19 control subjects. What did the data show?

“The imaging results demonstrated that, relative to control subjects, ADHD adults showed less activity in a number of regions associated with sensorimotor timing, including prefrontal and precentral gyri, basal ganglia, cerebellum, inferior parietal lobule, superior temporal gyri, and insula.”

The authors’ conclusion articulates our concern about the continuity of childhood and adult brain dysfunction:

“Our findings show that subsecond timing abnormalities in ADHD youth persist into adulthood and suggest that abnormalities in the temporal structure of behavior observed in ADHD adults result from atypical function of corticocerebellar and corticostriatal timing systems.”

We can see the link between childhood and adult brain in the genetic potential transmitted from parent to child in a study just published in the Archives of General Psychiatry. The authors investigated the link between parental impairments in serotonin production and ADHD in their offspring:

“Exposure to adverse events during prenatal and postnatal development, as well as serotonin deficiency, have been implicated in disturbances of mood and impulsivity…To investigate the long-term effects of an impaired serotonin synthesis on the developing human brain, we studied the effects of nonsynonymous mutations affecting tryptophan hydroxylase (TPH) enzymes responsible for serotonin production in maternal reproductive tissues (TPH1) and the brain (TPH2).”

They investigated for the relevant genetic mutations among 459 patients with ADHD and 187 controls along with 97 additional family members. This was correlated with psychiatric diagnoses and symptoms obtained from 606 controls, the 459 patients, and their relatives. Their data paint a compelling picture:

“Family analysis of 38 TPH1 mutation carriers and 41 of their offspring revealed that offspring of mothers carrying TPH1 mutations reported 1.5- to 2.5-times-higher ADHD scores and related symptoms during childhood and as adults than did controls or offspring of fathers with the corresponding TPH1 mutations.”

Clinicians and parents should bear in mind that medications that attempt to convert the brain to ‘run’ on insufficient amounts of serotonin do not repair or support the brain’s ability to produce it adequately (as in the functional approach to natural precursor therapy) when contemplating the authors’ conclusion:

“Impaired maternal serotonin production may have long-term consequences for brain development and increase the risk of ADHD-related symptoms and behavior in offspring.“

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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.

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Is depression mainly a disorder of serotonin regulation? A paper just published in Progress in Neuro-Psychopharmacology and Biological Psychiatry reminds us that, of course, it is not. The authors state:

“For many years, a deficiency of monoamines including serotonin has been the prevailing hypothesis on depression, yet research has failed to confirm consistent relations between brain serotonin and depression.“

They observe that there is a relationship between depression a number of other conditions with a common set of underlying causes:

“…depression is one of a family of related conditions sometimes referred to as the “affective spectrum disorders”, and variably including migraine, irritable bowel syndrome, chronic fatigue syndrome, fibromyalgia and generalized anxiety disorder, among many others.”

What do these disorders have in common?

“…we present data from many different experimental modalities that strongly suggest components of mitochondrial dysfunction and inflammation in the pathogenesis of depression and other affective spectrum disorders. The three concepts of monoamines, energy metabolism and inflammatory pathways are inter-related in many complex manners. For example, the major categories of drugs used to treat depression have been demonstrated to exert effects on mitochondria and inflammation, as well as on monoamines. Furthermore, commonly-used mitochondrial-targeted treatments exert effects on mitochondria and inflammation, and are increasingly being shown to demonstrate efficacy in the affective spectrum disorders.”

In the functional approach, the evaluation and treatment of depression is not complete without addressing the factors that contribute to neuroinflammation, neurodegeneration and mitochondrial dysfunction with the appropriate tests and physiological interventions.

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As the authors of this study published in the journal BMC Psychiatry observe:

“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 are equally concerned with the ‘non-celiac’ aspects of gluten sensitivity. Gluten related inflammation in the brain can manifest as a host of cognitive, emotional and neurodegenerative disorders in the absence of intestinal manifestations. This is often referred to as “silent celiac disease”:

“Coeliac disease is an under-diagnosed autoimmune type of gastrointestinal disorder resulting from gluten ingestion in genetically susceptible individuals. Non-specific symptoms such as fatigue and dyspepsia are common, but the disease may also be clinically silent.”

They further note that:

“”Depressive symptoms and disorders are common among adult patients with coeliac disease, and 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.”

Their data revealed abnormalities in tryptophan assimilation (tryptophan is the amino acid precursor to serotonin) and prolactin levels in adolescents with celiac disease and depression prior to treatment. Consequently…

“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…”

They also make a fascinating observation that links gluten sensitivity, inflammation, and the serotonergic aspect of depression unrelated to malabsorption:

“…increased production of interferon-γ (IFN-γ), known to be the predominant cytokine produced by gluten-specific T-cells in active coeliac disease, can suppress serotonin function both directly and indirectly by enhancing tryptophan and serotonin turnover…even without malabsorption.”

To diagnose gluten sensitivity in the absence of celiac disease the gluten gene sensitivity test is the most reliable method for a number of reasons.

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Most readers are aware that low iron reduces oxygen delivery to tissues, and this degrades the ability of every cell to produce energy for function. Naturally this can contribute to chronic pain of various kinds. This valuable paper published in the European Journal of Clinical Nutrition about fibromyalgia brings up another important point: low neurotransitters (dopamine, norepinephrine, serotonin) are a contributing cause of the pain and dysfunction of fibromyalgia, and adequate iron is necessary for their production. The authors begin by observing:

“Iron is essential for a number of enzymes involved in neurotransmitter synthesis. Analysis of cerebrospinal fluid in fibromyalgia syndrome (FMS) has shown a reduction in the concentration of biogenic amine metabolites, including dopamine, norepinephrine and serotonin. This study aimed to investigate the association of ferritin with FMS.”

To investigate this association serum ferritin, vitamin B12 and folic acid were measured in 46 patients with primary FMS and 46 healthy controls. Their data paints a very interesting picture:

“Binary multiple logistic regression analysis…showed that having a serum ferritin level <50 ng/ml caused a 6.5-fold increased risk for FMS.”

Here’s what the authors concluded from their findings:

“Our study implicates a possible association between FM and decreased ferritin level, even for ferritin in normal [see note below] ranges. We suggest that iron as a cofactor in serotonin and dopamine production may have a role in the etiology of FMS.”

Important: there is earlier research that validates 50 ng/ml as the correct low point for serum ferritin, but many labs have not caught up and still have a report with a reference range for ferritin that is too low. This is a key point in clinical practice.

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You might think that functionally low iron would contribute to the pain and fatigue of fibromyalgia through its effect on the oxygen carrying capacity of the blood, which would not be incorrect. But as this study just published in the European Journal of Clinical Nutrition reveals, there is another very important effect of suboptimal iron levels.

“Iron is essential for a number of enzymes involved in neurotransmitter synthesis. Analysis of cerebrospinal fluid in fibromyalgia syndrome (FMS) has shown a reduction in the concentration of biogenic amine metabolites, including dopamine, norepinephrine and serotonin. This study aimed to investigate the association of ferritin with FMS.”

Ferritin, a protein that stores iron, is the most accurate single quantifier for iron stores in the body. Adequate iron is mandatory for the production of neurotransmitters including dopamine and serotonin (one of the reasons why depression occur around the time of menses). What did their data show?

“…having a serum ferritin level <50 ng/ml caused a 6.5-fold increased risk for FMS.”

Doctors (and everyone), notice the serum ferritin level. Many practitioners are not aware of other research showing that the common laboratory reference ranges for ferritin are too low and that 50 ng/ml should be the cut-off point. Additionally, there are a number of mechanisms by which suboptimal dopamine and/or serotonin production can affect the experience of pain and fatigue with FMS.

The authors’ conclusion is consonant with the existing evidence:

“Our study implicates a possible association between FM and decreased ferritin level, even for ferritin in “normal” ranges [quotation marks added]. We suggest that iron as a cofactor in serotonin and dopamine production may have a role in the etiology of FMS.”

If there is a question about iron, have your serum ferritin checked (at least) and make sure that it is not lower than 50 ng/ml.

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If you’re wondering whether you should take the hormone melatonin for a sleep disorder, bear in mind that melatonin is synthesized from the neurotransmitter serotonin (as described in this paper published in the journal Cell & Tissue Research). The functional approach avoids taking melatonin (except temporarily for extensive time zone travel) because of the possibility of suppressing native hormone pathways. This is only one of a number of factors that can cause or contribute to insomnia, but the possible need for physiological support with precursors and co-factors to normalize serotonin production and conversion to melatonin shouldn’t be overlooked since they can be depleted by stress.

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Disturbingly, there are still doctors who misinform their patients by telling them that progesterone is not necessary after menopause. Progesterone is crucial for numerous functions throughout the body (for men too). The brain is rich in progesterone receptors, and it plays an important role in immune system regulation and nervous system health. Here are a few citations from the sciencific literature. There are many more:

• Progesterone modulates neuroendocrine functions in the central nervous system
• Progesterone’s role in inflammatory, autoimmune and infectious disease
• Progesterone regulates neuronal activities
• Progesterone protects against Parkinson’s disease
• Progesterone-neurotransmitter interactions
• Progesterone modulates serotonin transporter

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