Neurotransmitters in pediatric disorders of learning, behavior and development

Posted on September 22, 2010 by Dr. Jonathan

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

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

Moreover, from the remedial perspective:

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

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

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

The author sums up his findings by stating:

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

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

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

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

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

The authors conclude by stating:

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

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

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

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

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

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

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

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

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

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

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

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

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

The authors sum up the significance of their findings:

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

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

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

Effects of suboptimal oxygen and iron on learning and behavior

Posted on September 11, 2010 by Dr. Jonathan

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-disorderedbreathing] 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.”

One way to prevent having a schizophrenic child

Posted on July 3, 2010 by Dr. Jonathan

An important research article was just published in PLoS One (Public Library of Medicine) that shows a connection between the disruption of dopamine neurons when a maternal infection causes the iron supply of the fetus to drop and schizophrenia. The authors give some background:

“Maternal infection during pregnancy has been associated with increased incidence of schizophrenia in the adult offspring. Mechanistically, this has been partially attributed to neurodevelopmental disruption of the dopamine neurons, as a consequence of exacerbated maternal immunity. In the present study we sought to target hypoferremia, a cytokine-induced reduction of serum non-heme iron, which is common to all types of infections. Adequate iron supply to the fetus is fundamental for the development of the mesencephalic dopamine neurons and disruption of this following maternal infection can affect the offspring’s dopamine function.”

The authors measured the adverse behavioral and neurochemical changes from challenging the dopamine circuits with turpentine to trigger an inflammatory immune response, both with and without maternal iron supplementation. They demonstrated that…

“Both the behavioral and neurochemical changes were prevented by maternal iron supplementation.“

We already know that iron is a critical nutrient for dopamine production in the adult. Their conclusion sums up why prenatal iron status is important in preventing neurodevelopmental disorders including schizophrenia in the offspring.

ADHD and the dopamine reward pathway

Posted on June 3, 2010 by Dr. Jonathan

JAMA This paper published not long ago in the Journal of the American Medical Association provides more evidence for the association of deficiencies of dopamine function with ADHD. The authors first note:

“Attention-deficit/hyperactivity disorder (ADHD)—characterized by symptoms of inattention and hyperactivity-impulsivity—is the most prevalent childhood psychiatric disorder that frequently persists into adulthood, and there is increasing evidence of reward-motivation deficits in this disorder.”

The authors used positron emission tomography (PET) to image the brain dopamine reward pathway. Specifically they measured dopamine synaptic markers (transporters and receptors). What did their data show?

“A reduction in dopamine synaptic markers associated with symptoms of inattention was shown in the dopamine reward pathway of participants with ADHD.”

This has great practical significance when we consider that physiological precursor therapy naturally and without side-effects provides the resources for the body to increase its own dopamine levels and up-regulate the reward pathways.

Fibromyalgia, iron and neurotransmitters

Posted on May 15, 2010 by Dr. Jonathan

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.

Compulsive eating and dopamine receptor dysfunction

Posted on May 11, 2010 by Dr. Jonathan

As most of you well know, the neurotransmitter dopamine and its receptors are critical to the brain’s reward pathways, and dysfunction of these pathways is associated with addictive behaviors. This paper recently published in the journal Nature Neuroscience elucidates the role of dopamine receptors in compulsive eating with obesity. The authors first noticed that…

“…development of obesity was coupled with emergence of a progressively worsening deficit in neural reward responses. Similar changes in reward homeostasis induced by cocaine or heroin are considered to be crucial in triggering the transition from casual to compulsive drug-taking.”

On investigating the underlying mechanism they found that compulsive feeding was present in obese but not lean rats because…

“Striatal (corpus striatum of the brain) dopamine D2 receptors (D2Rs) were downregulated in obese rats, as has been reported in humans addicted to drugs.”

What did they conclude from their data?

“These data demonstrate that overconsumption of palatable food [which produces insulin resistance] triggers addiction-like neuroadaptive responses in brain reward circuits and drives the development of compulsive eating. Common hedonic mechanisms may therefore underlie obesity and drug addiction.”

Journal of Neuorendocrinology A paper published in the Journal of Neuroendocrinology adds further support to the importance of dopamine in appetite regulation. Ghrelin is a peptide produced in the stomach that increases appetite by stimulating a part of the brain (VTA = ventral tegmental area) that is rich in dopamine producing neurons:

“Interestingly, ghrelin infusions into the VTA increase food intake dramatically, and stimulate dopamine release from the VTA…ghrelin increases food intake by modulating the activity of dopaminergic neurones in the VTA.“

The author offers this conclusion:

“On the basis of these data as well as the fact that VTA dopamine cells respond to other metabolic hormones such as insulin and leptin, it is proposed that VTA dopamine cells…are first-order sensory neurones that regulate appetitive behaviour…”

Pharmacology Biochemistry Behavior Blood sugar and insulin have such a powerful effect on the brain and energy (nutrient) seeking behavior it’s no wonder there’s abundant evidence that they are associated with dopamine in the regulation of appetite. This paper published in Pharmacology Biochemistry and Behavior notes that:

“The hormones insulin, leptin, and ghrelin have been demonstrated to act in the central nervous system (CNS) as regulators of energy homeostasis…CNS circuitry that subserves reward and is also a direct and indirect target for the action of these endocrine regulators of energy homeostasis.”

Their research demonstrates that insulin and leptin can dampen reward satisfaction through an effect on dopamine signaling:

“Specifically, insulin and leptin can decrease food reward behaviors and modulate the function of neurotransmitter systems and neural circuitry that mediate food reward, the midbrain dopamine (DA) and opioidergic pathways.”

Another study published in Acta Diabetologica also confirms the profound effect of insulin on dopamine signaling:

“Administration of various doses of glucose to rats produced a significant decrease of dopamine turnover…a close connection between 3,4-dihydroxyphenylacetic acid (DOPAC) (metabolite of dopamine) variation and insulin plasma level was demonstrated. However, glucose did not affect dopamine metabolism in starved or streptozotocin-treated rats (rats made to be diabetic). This indicates that the effect of glucose on the central dopaminergic system is mediated by pancreatic insulin, even in the presence of endogenous brain insulin.”

Moreover, dopamine gives the message that the cells are satisfied and shuts down pancreatic production of insulin as described in this paper published in The Journal of Biological Chemistry:

“Both dopamine and insulin actions in the brain modulate appetite and feeding behaviors. In this work we show for the first time that pancreatic beta cells express dopamine receptors mediating inhibition of glucose-stimulated insulin secretion.”

They go on to further describe the close association of dopamine with insulin and problems related to blood sugar regulation and obesity:

“Moreover, antipsychotic (neuroleptic) drugs blocking dopamine receptors may cause hyperinsulinemia, hypoglycemia, increase appetite, and obesity and are associated with diabetes. Therefore, dopamine action on beta cells (of the pancreas that secrete insulin)might have relevant implications for the study of obesity and diabetes, in particular in situations where dopamine transmission is altered.”

As if that wasn’t enough, the effect of insulin on dopamine signaling is so strong that it can even block the effects of amphetamine as described in this study published in PLoS Biology:

“Amphetamines mediate their behavioral effects by stimulating dopaminergic signaling throughout reward circuits of the brain. This property of amphetamine relies on its actions at the dopamine transporter (DAT)…we and others have revealed the novel ability of insulin signaling pathways in the brain to regulate DAT function as well as the…actions of amphetamine…by depleting insulin, or…insulin signaling, we can severely attenuate amphetamine-induced dopamine release and impair DAT function. Our findings demonstrate in vivo the novel ability of insulin signaling to dynamically influence the neuronal effects of amphetamine-like psychostimulants.”

The bottom line: compulsive eating (and other addictive behaviors) occurs when the reward (satisfaction) circuits are not functioning. To feel satisfied, we need adequate dopamine production and healthy insulin regulation. For the former we have natural precursor therapy to replenish exhausted dopamine resources. Healthy insulin and blood sugar regulation is, of course, a fundamental to any health strategy.

Fibromyalgia, iron and neurotransmitters

Posted on March 30, 2010 by Dr. Jonathan

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.

Restless Leg Syndrome and Erectile Dysfunction

Posted on January 10, 2010 by Dr. Jonathan

Sleep Those of you interested in how brain function is significant for virtually all aspects of health will like this study just published in the medical journal Sleep. It’s also another example of the importance of healthy dopamine signalling. The investigators note that “Dopaminergic hypofunction in the central nervous system may contribute to restless legs syndrome (RLS) and erectile dysfunction (ED). We therefore examined whether men with RLS have higher prevalences of ED.” After analyzing the data on a group of 23,119 men they conclude: “Men with RLS had a higher likelihood of concurrent ED, and the magnitude of the observed association was increased with a higher frequency of RLS symptoms. These results suggest that ED and RLS share common determinants.” The take home message here is that dopamine function can play a role in both Restless Leg Syndrome and Erectile Dysfunction. This can be helped with a functional medicine approach to restoring dopamine regulation.

Coincidentally, a related paper has also just been published in the journal Sleep Medicine examining the role of dopaminergic dysfunction and treatment in Restless Leg Syndrome. Here the authors conclude their observations by stating: “Since dopaminergic treatment can reverse delayed facilitation in RLS, we hypothesized that cortical plasticity related to dopaminergic systems may play a crucial role in RLS pathophysiology.”

The brain’s role in obesity and the importance of dopamine

Posted on January 9, 2010 by Dr. Jonathan

JAMA (the Journal of the American Medical Association) reports on research recently presented at the annual meeting of the Society for Neuroscience where researchers discussed their studies of the biological causes of overeating and obesity. One interesting comment of great practical importance: “Brain imaging of volunteers drinking a shake suggests that overweight persons with a gene variant associated with fewer dopamine receptors may be prone to impulsive eating.” Functional medicine patients know better than most people how important dopamine signalling is for calm contentment, focus, satisfaction, etc. and how deficits can result in compensatory compulsive behaviors and addictions that are in fact attempts to self-medicate. How do we fix dopamine signalling? By restoring the resources the body needs to manufacture its own dopamine and the brain’s capacity to respond to its stimulus.

Restless Legs Syndrome & Iron

Posted on October 20, 2009 by Dr. Jonathan

This study adds more evidence that functionally low iron is one of the causes of Restless Legs Syndrome. The investigators documented significant improvement in individuals if they had a low-normal serum ferritin to begin with. Interestingly, dopamine deficiency is another cause of RLS—low iron is among the factors that can cause insufficient dopamine production. RLS is a brain problem.