Hyperbaric oxygen therapy might improve certain pathophysiological findings in autism

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Summary

Autism is a neurodevelopmental disorder currently affecting as many as 1 out of 166 children in the United States. Numerous studies of autistic individuals have revealed evidence of cerebral hypoperfusion, neuroinflammation and gastrointestinal inflammation, immune dysregulation, oxidative stress, relative mitochondrial dysfunction, neurotransmitter abnormalities, impaired detoxification of toxins, dysbiosis, and impaired production of porphyrins. Many of these findings have been correlated with core autistic symptoms. For example, cerebral hypoperfusion in autistic children has been correlated with repetitive, self-stimulatory and stereotypical behaviors, and impairments in communication, sensory perception, and social interaction. Hyperbaric oxygen therapy (HBOT) might be able to improve each of these problems in autistic individuals. Specifically, HBOT has been used with clinical success in several cerebral hypoperfusion conditions and can compensate for decreased blood flow by increasing the oxygen content of plasma and body tissues. HBOT has been reported to possess strong anti-inflammatory properties and has been shown to improve immune function. There is evidence that oxidative stress can be reduced with HBOT through the upregulation of antioxidant enzymes. HBOT can also increase the function and production of mitochondria and improve neurotransmitter abnormalities. In addition, HBOT upregulates enzymes that can help with detoxification problems specifically found in autistic children. Dysbiosis is common in autistic children and HBOT can improve this. Impaired production of porphyrins in autistic children might affect the production of heme, and HBOT might help overcome the effects of this problem. Finally, HBOT has been shown to mobilize stem cells from the bone marrow to the systemic circulation. Recent studies in humans have shown that stem cells can enter the brain and form new neurons, astrocytes, and microglia. It is expected that amelioration of these underlying pathophysiological problems through the use of HBOT will lead to improvements in autistic symptoms. Several studies on the use of HBOT in autistic children are currently underway and early results are promising.

Section snippets

Background

Autism is a neurodevelopmental disorder currently affecting as many as 1 out of 166 children in the United States [1] and as many as 1 in 86 in certain areas of England [2]. Over 1.5 million children and adults in the United States alone are affected with some form of autism [3]. Autism is characterized by impairments in social interaction, difficulty with communication, and restrictive and repetitive behaviors [4]. Traditionally, autism has been considered a highly genetic disorder, yet the

Hypothesis

Recent analysis has furthered our understanding of the underlying pathophysiology of autism that was not apparent even several years ago. Novel clinical findings in autism have lately been described, including cerebral hypoperfusion, neuroinflammation and gastrointestinal inflammation, immune dysregulation, oxidative stress, relative mitochondrial dysfunction, neurotransmitter abnormalities, impaired detoxification enzymes, dysbiosis, and impaired production of porphyrins. Many of these

Cerebral hypoperfusion in autism

Numerous independent single photon emission computed tomography (SPECT) and positron emission tomography (PET) research studies have demonstrated hypoperfusion to several areas of the autistic brain, most notably the temporal lobes [10], [11], [12], [13], [14], [15], [16], [17], [18], [19], [20], [21], [22], [23]. In one study, this hypoperfusion typically worsened as the age of the autistic child increased, and become “quite profound” in older children compared to younger [11]. The maximal

HBOT and cerebral hypoperfusion

HBOT can overcome the effects of cerebral hypoperfusion (see Table 2) by providing more oxygen to the brain [55], [56], and by causing angiogenesis of new blood vessels over time by increasing VEGF levels [57]. Furthermore, if cerebral hypoperfusion is causing hypoxia that is also driving inflammation through the induction of HIF-1α, the oxygen delivered by HBOT can improve hypoxia, and thus downregulate HIF-1α. Hypoxia can lead to apoptosis [58] regulated by HIF-1α [59]. HBOT has been shown to

Neuroinflammation in autism

Several recent studies have revealed that children with autism have evidence of neuroinflammation [31], [78], [79]. Marked activation of microglia and astroglia with elevations in IL-6 and macrophage chemoattractant protein-1 (MCP-1) were found in autistic brain samples upon autopsy, along with increased proinflammatory cytokines in the cerebral spinal fluid (CSF) of living autistic children [31]. Activated microglia have been shown to release inflammatory mediators such as IL-1 and TNF-α, and

Gastrointestinal inflammation in autism

In addition, some patients with autism have chronic ileocolonic lymphoid nodular hyperplasia (LNH) and enterocolitis characterized by mucosal inflammation of the colon, stomach, and small intestine [92], [93], [94]. These findings might represent a “new variant inflammatory bowel disease” [93], and have been described as a “panenteric IBD-like disease” [95]. As many as 90% of autistic children with gastrointestinal symptoms have evidence of ileal LNH, with 68% having moderate to severe ileal

HBOT and inflammation

HBOT has potent anti-inflammatory tissue effects [57] as revealed by several recent animal studies [105], [106], with equivalence to diclofenac 20 mg/kg noted in one study [107]. HBOT has been shown to attenuate the production of proinflammatory cytokines including TNF-α [108], [109], [110], [111], IL-1 [108], [112], IL-1β [110], [111], and IL-6 [108], and increase the production of anti-inflammatory IL-10 [113]. HBOT has also been shown to reduce neuroinflammation in a rat model after traumatic

Immune function in autism

There is mounting evidence of immune dysregulation in autistic individuals (see Table 5), and new research is revealing the link between the immune system and the nervous system [131]. An increased number of autoimmune diseases exist in autistic families compared to control families [132], [133] with as much as a 6–8 fold increased incidence [134]. Some researchers believe that autistic children might have “an underlying autoimmune disorder” [135] and that a “genetic relationship” exists

HBOT and immune function

HBOT might be useful in some autoimmune diseases [157], and has shown promise in rheumatic diseases, including lupus and scleroderma [158], and rheumatoid arthritis [159]. HBOT has been used in animal models to completely suppress autoimmune encephalomyelitis by blocking mononuclear infiltration and demyelination of the CNS [160], and acted as an immunosuppressive agent to delay skin allograft rejection [161]. HBOT has been shown to suppress immune responses such as proteinuria, facial

Oxidative stress in autism

Autistic children have evidence of increased oxidative stress including lower serum glutathione levels [170], [171]. Some autistic children have increased red blood cell nitric oxide, which is a known free radical and toxic to the brain [172]. Of note, HIF-1α increases the production of nitric oxide [45]. Lower serum antioxidant enzyme, antioxidant nutrient, and glutathione levels, as well as higher pro-oxidants have been found in multiple studies of autistic children [173]. Autistic children

HBOT and oxidative stress

Concerns have been previously raised that HBOT might increase oxidative stress through the production of reactive oxygen species [182]. This is a relevant concern because of the increased oxidative stress just described in autistic children. However, oxidative stress from HBOT appears to be less of a concern at pressures under 2.0 atm [183] which are often used clinically. Oxidative stress is caused by an imbalance of oxidants and antioxidants. With long-term and repeated administration, HBOT

Mitochondrial dysfunction in autism

Lombard hypothesized that autism might be caused by mitochondrial dysfunction [199]. Several recent case reports supporting this concept have been published including two autistic children with hypotonia, lactic acidosis and abnormal mitochondrial enzyme assays on muscle biopsy [200], an autistic child with developmental regression and mitochondrial dysfunction [201], and an autistic child with mitochondrial dysfunction [202]. A larger case series of 12 children with hypotonia, epilepsy, and

HBOT and mitochondrial dysfunction

Hypoxia can impair mitochondrial function [212]. Since only approximately 0.3% of inhaled oxygen is ultimately delivered to the mitochondria [213], increasing the oxygen delivery to dysfunctional mitochondria by HBOT might aid in improving function [214], [215]. In a mouse model with an intrinsic impairment of mitochondrial complex IV, HBOT at 2 atm “significantly ameliorate[d] mitochondrial dysfunction” and delayed the onset of motor neuron disease when compared to control mice [215]. In

Neurotransmitter abnormalities in autism

Early childhood is typified by an increased production of serotonin when compared to adulthood; however, one study showed that autistic children synthesized less serotonin during childhood when compared to control children [220]. Another study demonstrated lower levels of serotonin in both autistic children and their mothers [221]. Plasma levels of tryptophan, which is the precursor to serotonin, are lower in autistic children compared to control children, and are suggestive of a serotonergic

HBOT and neurotransmitter abnormalities

HBOT has also been shown to reduce the uptake of serotonin by pulmonary endothelial cells [233], [234], and thus might function like an SSRI. In one study, HBOT demonstrated “antidepressant-like activity” similar to that seen with some SSRI antidepressants like fluoxetine [235]. In another study on patients with cluster headaches, HBOT improved pain and was shown to act through serotonergic pathways [236]. Furthermore, in an animal model, HBOT was shown to decrease the release of dopamine after

Toxin exposure in autism and HBOT

Recent data has shown that organophosphate poisoning can cause atypical autism [239]. Paraoxonase is the enzyme responsible for organophosphate detoxification in humans. In North America, autism has been associated with variants in the paraoxonase gene which can decrease the activity of this enzyme by 50 percent [177]. This was recently confirmed in another study that demonstrated reduced activity of paraoxonase in some autistic children [198].

HBOT has been shown to increase the activity of

Dysbiosis in autism

Significant alterations in intestinal flora, with increased amounts of Clostridia bacteria [240], [241], [242], and overgrowth of other abnormal bacteria [241], exist in some autistic children when compared to control children. In fact, one author has hypothesized that Clostridia infection in the gut might cause autistic-like symptoms [243]. Furthermore, treatment of these abnormal gut bacteria with antibiotics has led to improvements of autistic symptoms as measured by a clinical psychologist

HBOT and dysbiosis

HBOT has been shown to decrease the amount of abnormal bacteria in the gut and therefore can function as an antibiotic [246]. In animal studies, HBOT decreased intestinal bacterial colony counts after bacteria overgrowth in the distal ileum associated with bile duct ligation [247]. HBOT is also bactericidal against many bacteria [248], including Pseudomonas [249], [250], Salmonella and Proteus [249], Staphylococcus [251], Mycobacterium tuberculosis [248], and anaerobic bacteria such as

Porphyrin production in autism and HBOT

Children with autism might have impaired production of some porphyrins [260] which are involved in the synthesis of heme, which carries oxygen in the body. Therefore, the ability to deliver oxygen on hemoglobin could be compromised in some autistic children [261], and HBOT might help overcome this by increasing the amount of oxygen dissolved in plasma.

Stem cells and HBOT

Recently, HBOT at 2.0 atm was shown to mobilize stem/progenitor cells from the bone marrow of humans into the systemic circulation. Elevations were found in the number of colony-forming cells as demonstrated by an increase in the number of CD34+ cells by 8-fold after 20 HBOT sessions [262]. Since stem cells are also produced in the brain, this gives rise to the possibility of neuropoiesis [263], which might aid in reversing chronic neurodegenerative disorders. Furthermore, in two human case

HBOT pressure considerations

Previous studies have shown improvements of symptoms in children with autism and cerebral palsy (CP) at hyperbaric pressures of 1.3 atm with or without additional oxygen [72], [73], [266]. The use of HBOT in children appears generally safe, even at pressures up to 2.0 atm for 2 h per day for 40 sessions [267]. Many of the potential benefits of HBOT as described above were found in studies at higher hyperbaric pressures. Further study is necessary to determine if these benefits also hold true at

Conclusions

Numerous studies of autistic individuals have revealed evidence of cerebral hypoperfusion, neuroinflammation and gastrointestinal inflammation, immune dysregulation, oxidative stress, relative mitochondrial dysfunction, neurotransmitter abnormalities, impaired detoxification of toxins, dysbiosis, and impaired production of porphyrins. HBOT has been shown to increase oxygen delivery to hypoperfused or hypoxic tissues, decrease inflammation and oxidative stress, and increase the production of

Acknowledgement

The author thanks Mr. Michael Haynes for reviewing this manuscript and offering editorial advice.

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