Summary: Neuroinflammatory signaling molecules are elevated in bipolar disorder patients compared to controls. Marked increases in proinflammatory cytokines are also observed in the brains of teen suicide victims. Brain inflammation, immune system dysregulation and the loss of self-tolerance are key factors in the management of BP and major depression.

A paper just published in the Journal of Psychiatric Research offers further evidence for the role of neuroinflammation resulting from immune system dysregulation in bipolar disorder. The authors state:

“Bipolar disorder (BD) is associated with considerable higher chronic medical comorbidities, overweight and obesity. Adipokines are adipocyte-derived secretory factors which have functions in immune response and seem to be associated with both BD and overweight. The aim of this study was to evaluate the plasma levels of adipokines (adiponectin, resistin and leptin) and TNF-α and its receptors (sTNFR1 and sTNFR2) in BD overweight patients in comparison with overweight controls.”

The authors measured plasma levels of adiponectin, resistin, leptin, TNF-α and TNF-α soluble receptors in thirty bipolar patients along with thirty controls matched by age, gender and body-mass index (BMI). The subjects were also assessed by Mini-International Neuropsychiatric Interview, Young Mania and Hamilton Depression rating scales. What did the data show?

“BD patients presented increased plasma levels of adiponectin, leptin and sTNFR1.”

This is but one drop in a sea of emerging evidence for the role of brain inflammation and immune dysregulation in neuropsychiatric disorders that clinicians should consider in comprehensive case management. The authors conclude:

“This study provides further support to the hypothesis of the immune/inflammatory imbalance in BD.”

Another study in the same journal documents a marked increase in proinflammatory cytokines in the frontal lobes of teenagers attempting suicide. The authors observe:

“”Proinflammatory cytokines play an important role in stress and in the pathophysiology of depression—two major risk factors for suicide. Cytokines are increased in the serum of patients with depression and suicidal behavior; however, it is not clear if similar abnormality in cytokines occurs in brains of suicide victims.”

So they evaluated 24 teenage suicide victims and 24 matched normal control subjects for gene and protein expression levels of the proinflammatory cytokines interleukin (IL)-1β, IL-6, and tissue necrosis factor (TNF)-α in the prefrontal cortex (PFC). Again we see the markers for brain inflammation:

“Our results show that the mRNA and protein expression levels of IL-1β, IL-6, and TNF-α were significantly increased in Brodmann area 10 (BA-10) of suicide victims compared with normal control subjects.”

This is the deepest biological expression of the loss of self-tolerance in these disorders. Autoimmune inflammatory conditions require evaluation of all the known underlying causal factors that may contribute to the loss of self and chemical tolerance in order to design the most helpful treatment plan. The authors conclude:

“These results suggest an important role for IL-1β, IL-6, and TNF-α in the pathophysiology of suicidal behavior and that proinflammatory cytokines may be an appropriate target for developing therapeutic agents.”

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Those interested in the management of autoimmune hepatitis as a condition in itself or as a complication of infectious hepatitis will appreciate a study just published in the journal Hepatology Research.

“This study investigated the relationship between circulating cytokines in the pretreatment phase and remission following corticosteroid therapy phase in Japanese AIH [autoimmune hepatitis] patients.”

The authors measured 28 cytokines by multiple bead array technology in 40 patients with AIH during pretreatment and remission phases. A particular pattern stood out:

“Interleukin (IL)-12p40, interferon-γ-inducible protein (IP-10), macrophage inflammatory protein (MIP)-1α, MIP-1β, IL-17F and IL-18 were significantly decreased during remission from pretreatment stage levels. The level of IP-10 in the pretreatment phase was correlated with serum levels of alanine aminotransferase.”

An assay of these cytokines can help to answer two important questions: (1) does this patient have an autoimmune component to their hepatitis, and (2) are they responding to treatment? The authors’ conclusion is worth bearing in mind when these kinds of cases come up:

“Our results suggest that a complex interplay of several cytokines, especially pro-inflammatory and T-helper 17 cytokines and regulatory T-cell suppression by IL-12p40 may play a pivotal role in the pathogenesis of AIH.”

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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.

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We’re always on the lookout for physiological agents that have the potential to calm the activity of pro-inflammatory cytokines when they are elevated in autoimmune disease. An exciting finding was reported in a paper just published in the European Journal of Clinical Nutrition:

“The purpose of this study was to investigate whether vitamin B6 supplementation had a beneficial effect on inflammatory and immune responses in patients with rheumatoid arthritis (RA).”

The control group of patients was given 5 mg/day of folic acid only while the study group was given 100 mg/day of vitamin B6 in addition for 12 weeks. Indicators of inflammation (C-reactive protein (hs-CRP), erythrocyte sedimentation rate (ESR), interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α) and lymphocyte subsets were measured on day 1 (week 0) and after 12 weeks (week 12) of the intervention.

At the end of twelves the data painted this picture:

“In the group receiving vitamin B6, plasma IL-6 and TNF-α levels significantly decreased at week 12. Plasma IL-6 level remained significantly inversely related to plasma PLP (pyridoxal 5′-phosphate, B6) after adjusting for confounders.”

The bottom line conclusion is worth bearing in mind when evaluating any autoimmune disorder because underlying causal factors are similar regardless of the specific tissue under attack:

“A large dose of vitamin B6 supplementation (100 mg/day) suppressed pro-inflammatory cytokines (that is, IL-6 and TNF-α) in patients with RA.”

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Surgeons are routinely surprised at the speed of recovery and reduction of complications and discomfort when they operate on our patients who have a surgical support program based on their individual needs. This interesting study published recently in the Journal of Clinical Endocrinology & Metabolism describes why supporting insulin function and regulation of the inflammatory response help so much.

“The mechanisms behind postoperative insulin resistance and impaired glucose utilization are not fully understood…In this study, we aimed to specifically evaluate the transcription profile of genes in the insulin and adipokine signaling pathways…after surgical injury.”

Adipokines are cytokines such as IL-6 and TNFα secreted by fat cells. The authors measured changes in the messenger RNA (mRNA) levels that code for insulin signaling and inflammatory cytokines to define how genes alter their expression in response to a surgical trauma. Their data showed a signficant effect:

“After surgery…adipose tissue mRNA levels of genes involved in the IL6 and nicotinamide phosphoribosyltransferase pathways were increased, whereas mRNA levels of insulin receptor substrate 1 and adiponectin were reduced.”

Their conclusion is important for surgeons and their patients:

“The transcriptional output of pivotal inflammatory and insulin signaling pathway genes is altered after surgery…This could be of importance for the metabolic aberrations associated to postsurgical complications, such as insulin resistance and hyperglycemia.”

If you are anticipating an elective procedure and your surgeon is not trained to design a supportive protocol based on an evaluation using the appropriate tests, you may wish to seek out a practitioner experienced in the functional approach.

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The therapeutic use of non-invasive, low level (cold) laser and and infrared has not crossed the gap into clinical practice to the degree that the rich body of scientific research justifies. The laser and infrared therapies we use here appear to help even though you can’t feel them (at the time of application); but what evidence is there that they really do anything? And by what mechanisms? Consider this study published in the journal Photomedicine and Laser Surgery a few years ago that documents the effect of visible and infrared light on inflammatory cytokines (immune system messenger molecules). The authors state:

“The aim of this randomized, placebo-controlled, double-blind trial was to investigate changes in the content of 10 cytokines in the human peripheral blood after transcutaneous [through the skin] and in vitro [to blood removed from the body] irradiation with polychromatic visible and infrared (IR) polarized light…”

The magnitude of the effect that they observed by just applying the light to the sacral area of the study subjects is surprising:

“A dramatic decrease in the level of pro-inflammatory cytokines TNF-α, IL-6, and IFN-γ was revealed: at 0.5 h after exposure of volunteers (with the initial parameters exceeding the norm), the cytokine contents fell, on average, 34, 12, and 1.5 times. The reduced concentrations of TNF-α and IL-6 were preserved after four daily exposures, whereas levels of IFN-γ and IL-12 decreased five and 15 times. At 0.5 h and at later times, the amount of anti-inflammatory cytokines was found to rise: that of IL-10 rose 2.7–3.5 times (in subjects with normal initial parameters) and of TGF-β1 1.4–1.5 times.”

But if you expose just the area over the sacrum, what happens when that blood mixes with the rest of the circulation?

“Similar regularities of the light effects were recorded after in vitro irradiation of blood, as well as on mixing the irradiated and non-irradiated autologous blood at a volume ratio 1:10 (i.e., at modeling the events in a vascular bed of the exposed person when a small amount of the transcutaneously photomodified blood contacts its main circulating volume).”

In other words, a small limited application causes system-wide effects. Considering how much we need therapies that physiologically modulate the inflammatory response without side effects, the authors’ conclusion is extremely compelling:

“Exposure of a small area of the human body to light leads to a fast decrease in the elevated pro-inflammatory cytokine plasma content and to an increase in the the anti-inflammatory factor concentration, which may be an important mechanism of the anti-inflammatory effect of phototherapy. These changes result from transcutaneous photomodification of a small volume of blood and a fast transfer of the light-induced changes to the entire pool of circulating blood [!].”

Here’s a little more from the large body of research published in the same journal:

• LLLT can modulate inflammatory processes in a dose-dependent manner and can be titrated to significantly reduce acute inflammatory pain in clinical settings.
• Laser therapy was effective in preventing and treating oral effects induced by radiotherapy and chemotherapy, thus improving the patient’s quality of life.
• LLLT reduces inflammatory signs (more effectively than LED) in arthritis.
• Salivary levels of inflammatory cytokines TNF-α and IL-6 are reduced in patients with stomatitis (mouth sores).

By the way, this is interesting in connection with the earlier post on the infrared treatment of depression.

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Those interested in how image and perception modify gene expression and immune function will appreciate this paper recently published in the journal Psychological Science.

“An experiment…tested the hypothesis that the mere visual perception of disease-connoting cues promotes a more aggressive immune response.”

The experimental subjects were exposed to either photographs depicting symptoms of infectious disease or photographs of guns.

“After incubation with a model bacterial stimulus, participants’ white blood cells produced higher levels of the proinflammatory cytokine interleukin-6 (IL-6) in the infectious-disease condition, compared with the control (guns) condition.”

This may not be the first study to demonstrate this effect, but the authors assert…

“These results provide the first empirical evidence that visual perception of other people’s symptoms may cause the immune system to respond more aggressively to infection.”

It’s well known that though we can cognitively discriminate between a photo depicting infection and the immediate material presence of it, our autonomous physiological response does not. Now consider the significance for autoimmune disease when there is hyperarousal of attention to the possibility of infection. This is one of the reasons why I am convinced that dogmatically insisting on a diagnosis of chronic infection (such as Lyme disease) when the most sensitive and advanced tests provide zero evidence—and at the same time demonstrable autoimmune phenomena are present—is doing patients a disservice.

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The authors of this paper published in the journal Minerva Ginecologica frame the problem:

“Endometriosis is classically described as the presence of both endometrial glandular and stromal cells outside the uterine cavity, mainly in the pelvis. The pathogenesis of this enigmatic disorder still remains controversial despite extensive research. Although multiple theories have been put forth to explain the pathophysiology and pathogenesis of endometriosis, the retrograde menstruation theory of Sampson is the most widely accepted. However, since retrograde menstruation occurs in most of the reproductive age women, it is clear that there must be other factors which may contribute to the implantation of endometrial cells and their subsequent development into endometriotic disease.”

The authors argue that immune dysfunction must be playing an important role:

“There is substantial evidence to support that the alterations in both cell-mediated and humoral immunity contribute to the pathogenesis of endometriosis.

They note that immune dysregulation is associated with inadequate removal of ectopic endometrial cells from the peritoneal cavity.

“Moreover, increased levels of several cytokines and growth factors which are secreted by either immune and endometrial cells seem to promote implantation and growth of ectopic endometrium by inducing proliferation and angiogenesis.”

Finally, they make important observation:

“Endometriosis has also been considered to be an autoimmune disease, since it is often associated with the presence of autoantibodies, other autoimmune diseases, and possibly with recurrent immune-mediated abortion.”

This review published recently in the journal Reproduction concentrates on the role of inflammation:

“It is well recognised that many physiological reproductive events such as ovulation, menstruation, implantation and onset of labour display hallmark signs of inflammation. …Moreover, initiation and maintenance of inflammatory pathways are the key components of many pathologies of the reproductive tract and elsewhere in the body. The onset of reproductive disorders or disease may be the result of exacerbated activation and maintenance of inflammatory pathways or their dysregulated resolution.”

Specifically in regard to endometriosis they observe:

“Recent reports suggest that dysregulation of inflammatory factors play a role in endometriosis-associated reproductive failure…The concentration of inflammatory cytokines (IL1B and TNF) and PGs (PGE2 and PGF2{alpha}) produced by peritoneal macrophages and pro-inflammatory chemokines for monocyte/macrophages and for granulocytes is elevated in women with endometriosis…”

What other evidence might we find of inflammatory and autoimmune phenomena in endometriosis? This paper published in the journal Gynecological Endocrinology begins by noting how common a problem this is:

“Endometriosis affects 10–20% of women during reproductive age and is a common cause of infertility and pain leading to work absenteeism and reduced quality of life.”

The authors studied the correlation of the cytokines interleukin-8 (IL-8), tumor necrosis factor alpha (TNF-α), glycodelin and other factors in the peritoneal fluid with pain reported by patients undergoing laparoscopy, and pain during menstruation and intercourse. The presence of endometriosis was histologically confirmed (microscopic examination of the cellular structure).

What did their data show?

“TNF-α and glycodelin correlated positively with the level of menstrual pain…Patients with severe dysmenorrhoea had increased PF cytokine and marker levels; the difference was significant for TNF-α and glycodelin…TNF-α and glycodelin may thus play a role in endometriosis and the severity of menstrual pain.”

If you are treating or you suffer from endometriosis (or severe dysmenorrhea without a diagnosis of endometriosis), is it important to investigate the autoimmune inflammatory components? This and other evidence indicates that it is.

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An interesting study just published in the journal Cell demonstrates one mechanism by which immunological dysfunction causes obsessive-compulsive disorder (OCD). The authors show that microglia (the immune cells in the brain) when abnormal can cause compulsive behaviors in mice that correspond to OCD in humans:

“Mouse Hoxb8 mutants (with faulty microglia) show unexpected behavior manifested by compulsive grooming and hair removal, similar to behavior in humans with the obsessive-compulsive disorder spectrum disorder trichotillomania.”

They then showed that transplanting normal microglia eliminated their pathological OCD behavior.

“Immunological dysfunctions have been associated with neuropsychiatric disorders…In this mouse, a distinct compulsive behavioral disorder is associated with mutant microglia.”

The author of a report on this study published in Science Now comments:

“Previous studies have implied a link between the immune system and obsessive-compulsive disorder and other neuropsychiatric conditions, Capecchi says. “Here, we say there is a direct connection.”…The results raise the possibility of treating obsessive-compulsive disorder by targeting the immune system rather than the brain.”

What other evidence might there be that OCD in humans is an autoimmune disease? A paper published a year and a half ago in Neuroscience Letters shows how an immune cytokine abnormality also contributes to OCD. The authors begin by observing:

“Several lines of evidence support an immunologic involvement in obsessive-compulsive disorder (OCD): the increased prevalence of OCD in patients with rheumatic fever (RF), and the aggregation of obsessive-compulsive spectrum disorders among relatives of RF probands [affected persons studied in a genetic investigation]. Tumor necrosis factor alpha is a proinflammatory cytokine involved in RF and other autoimmune diseases…the goal of the present study was to investigate a possible association between polymorphisms within the promoter region of TNFA and OCD.”

They studied two polymorphisms of the genes for TNF-alpha and found that:

“Significant associations were observed between both polymorphisms and OCD.”

The theme is carried forward in a paper more recently published in the journal Neuropsychopharmacology that reports the presence of anti-brain autoantibodies that derange excitatory neurotransmitters with OCD. The authors begin by observing:

“…serum autoantibodies directed against basal ganglia (BG) implicate autoimmunity in the pathogenesis of obsessive–compulsive disorder (OCD),…We examined this by investigating the presence of autoantibodies directed against the BG or thalamus in the serum as well as CSF of 23 OCD patients compared with 23 matched psychiatrically normal controls.”

They also measured several neurotransmitters including the most abundant excitatory neurotransmitter glutamate. What did their data show?

“There was evidence of significantly more binding of CSF autoantibodies to homogenate of BG as well as to homogenate of thalamus among OCD patients compared with controls. …CSF glutamate and glycine levels were also significantly higher in OCD patients compared with controls…”

Thus their conclusion:

“The results of our study implicate autoimmune mechanisms in the pathogenesis of OCD and also provide preliminary evidence that autoantibodies against BG and thalamus may cause OCD by modulating excitatory neurotransmission.”

This post would not be complete without including the recognized association of OCD with Tourette’s disorder (TD). The authors of this clinically useful study published not long ago in the journal Progress in Neuro-Psychopharmacology and Biological Psychiatry linked TD and OCD in their investigation of the cytokines promoting the autoimmune attack on brain tissue:

“This study examined the potential role of cytokines, modulators of the immune system. We hypothesized that children with TD would have increased levels of tumor necrosis factor (TNF)-α, interleukin (IL)-12, IL-1β and IL-6, and decreased IL-2. We also explored whether comorbid [happening together] obsessive compulsive disorder (OCD) had an effect on the cytokine profile of TD patients.”

They found that both TD and OCD had abnormal elevations of cytokines associated with their immune dysfunction, only those who had OCD comorbid with TD had significantly elevated IL-12.

“Findings suggest a role for IL-12 and IL-2 in TD, and that the TD+OCD subgroup may involve different neuroimmunological functions than the TD−OCD subgroup.”

Their conclusion confirms both the autoimmune etiology and that each patient must be precisely evaluated and treated as in individual for their autoimmune disorder.

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As readers here know, inflammation is a fundamental factor in chronic disease and accelerated aging (neurodegeneration). A functional approach to treatment requires an objective understanding of how this system is working for each patient. Here are several of the many studies that illustrate how nervous system function and inflammation can be evaluated with heart rate variability (HRV) analysis and cytokine (‘messenger molecules’ of inflammation) levels.

The practical focus is on restoring parasympathetic nervous system (PNS) activity which inhibits inflammation. (PNS resources decline with disease, stress and age resulting in a state of ‘sympathetic nervous system dominance’.) This paper just published in the journal  Shock shows how autonomic nervous system activity (sympathetic and parasympathetic) as measured by HRV corresponds to inflammatory cytokine activity, in this case when stimulated by endotoxins (poisons produced by bacterial infections):

“Autonomic inputs from the sympathetic and parasympathetic nervous systems, as measured by heart rate variability (HRV), have been reported to correlate to the… responses to infectious challenge… In addition, parasympathetic/vagal activity has been shown experimentally to exert anti-inflammatory effects via attenuation of splanchnic tissue TNF-α [cytokine] production. We sought… to determine if baseline HRV parameters correlated with endotoxin-mediated circulating cytokine responses.”

They documented a strong correspondence regardless of gender, body mass index and resting heart rate:

“…we found a significant correlation of several baseline HRV parameters…on TNF-α release after endotoxin exposure.”

This is not a new observation. An interesting study published a few years ago in the journal Psychosomatic Medicine documents the HRV expression of autonomic activity in response to an inflammatory challenge and its correspondence to cytokine production. They begin by noting that:

“…the autonomic nervous system plays a key role in regulating the magnitude of immune responses to inflammatory stimuli. Signaling by the parasympathetic system inhibits the production of proinflammatory cytokines by activated monocytes/macrophages and thus decreases local and systemic inflammation.”

They examined the relationship of HRV to lipopolysaccharide-induced production of the inflammatory cytokines interleukin (IL)-1ß, IL-6, tumor necrosis factor (TNF)-{alpha}, and IL-10. What did the data show?

“Consistent with animal findings, higher derived estimates of vagal activity measured during paced respiration* were associated with lower production of the proinflammatory cytokines TNF-{alpha} and IL-6…These associations persisted after controlling for demographic and health characteristics, including age, gender, race, years of education, smoking, hypertension, and white blood cell count.”

Their conclusion has profound implications for the biological mechanism by which stress causes inflammation:

“These data provide initial human evidence that vagal activity is inversely related to inflammatory competence, raising the possibility that vagal regulation of immune reactivity may represent a pathway linking psychosocial factors to risk for inflammatory disease.”

How might this show up in heart disease? This paper published not long ago in the journal Brain, Behavior, and Immunity investigates the links between HRV, inflammatory cytokines, coronary heart disease and depression:

“Studies show negative correlations between heart rate variability (HRV) and inflammatory markers [less variability = more inflammation]…We investigated links between short-term HRV and inflammatory markers in relation to depression in acute coronary syndrome (ACS) patients.”

They measured C-reactive protein (CRP), interleukin-6 (IL-6, a cytokine), depression symptoms and heart rate variability determinants of autonomic function. What did their data show?

“…all HRV measures were negatively and significantly associated with both inflammatory markers…HRV independently accounted for at least 4% of the variance in CRP in the depressed, more than any factor except BMI.”

Interestingly, they also noted that:

“Relationships between measures of inflammation and autonomic function are stronger among depressed than non-depressed cardiac patients. Interventions targeting regulation of both autonomic control and inflammation may be of particular importance.”

The research of another group published in the Journal of Critical Care used sepsis as their model.

“The aim of the study was to investigate possible associations between different heart rate variability (HRV) indices and various biomarkers of inflammation in 45 septic patients.”

They examined the correlation between HRV, C-reactive protein, and the cytokines  interleukin 6 and interleukin 10:

“Our data suggest that low HRV and sympathovagal balance during septic shock are associated with both an increased hyperinflammatory and antiinflammatory response.”

The antiinflammatory response corresponds to high HRV and interleukin-10, the cytokine that is also increased by vitamin D.

How can we reduce inflammation by increasing HRV and reducing inflammatory cytokines? There are numerous methods; one is to increase cholinergic activity in the nervous system (parasympathetic activity mediated by the neurotransmitter acetylcholine). We can increase this with natural precursor support for acetylcholine. This study published recently in the Journal of Internal Medicine shows the connection between vagal parasympathetic function (as shown by HRV), inflammatory cytokines, cholinergic activity and rheumatoid arthritis:

“The central nervous system regulates innate immunity in part via the cholinergic anti-inflammatory pathway, a neural circuit that transmits signals in the vagus nerve that suppress pro-inflammatory cytokine production…Vagus nerve activity is significantly suppressed in patients with autoimmune diseases, including rheumatoid arthritis (RA). It has been suggested that stimulating the cholinergic anti-inflammatory pathway may be beneficial to patients…”

They found that increasing cholinergic signaling in stimulated whole blood cultures suppressed cytokine production in rheumatoid arthritis patients whose vagal activity was deficient:

“These findings suggest that it is possible to pharmacologically target the α7nAChR dependent control of cytokine release in RA patients with suppressed vagus nerve activity.”

In a functional medicine practice, of course, we use natural acetylcholine precursors.

This is a drop in the bucket, but here’s one more fascinating paper published recently in the journal Brain, Behavior, and Immunity that shows how acetylcholine activity in the brain (the upper level of autonomic regulation) controls systemic cytokine levels through vagal function:

“The excessive release of cytokines by the immune system contributes importantly to the pathogenesis of inflammatory diseases. Recent advances in understanding the biology of cytokine toxicity led to the discovery of the “cholinergic anti-inflammatory pathway,” defined as neural signals transmitted via the vagus nerve that inhibit cytokine release…Vagus nerve regulation of peripheral functions is controlled by brain nuclei and neural networks…Here we report that brain acetylcholinesterase activity controls systemic and organ specific TNF [cytokine] production during endotoxemia.”

They demonstrated that inhibiting the breakdown of acetylcholine† markedly reduced proinflammatory serum TNF levels through the resulting increasing vagus nerve signaling which prevented inflammatory damage. What do they conclude from their research?

“These findings show that inhibition of brain acetylcholinesterase [that breaks down acetylcholine] suppresses systemic inflammation through a central…mediated and vagal…dependent mechanism. Our data also indicate that a clinically used centrally-acting acetylcholinesterase inhibitor† can be utilized to suppress abnormal inflammation to therapeutic advantage.”

* There are numerous therapies to reduce inflammation by increasing parasympathetic function. Breathing is a powerful stimulus to the autonomic nervous system. We train breathing with biofeedback while simultaneously monitoring for CO2 (capnography) and coherence in HRV to hit the physiological “sweet spot”.

† Agents that inhibit the breakdown of neurotransmitters including reuptake inhibitors do not restore the body’s ability to make its own. Precursor therapy provides the natural ingredients that have been depleted or are insufficient to meet genetic needs so neurotransmitters can be increased naturally.

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