Hyperbaric oxygen therapy might improve certain pathophysiological findings in autism

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.     

Increase in cerebral blood flow of right prefrontal cortex in man during orgasm

The functional anatomy of human emotional responses has remained poorly understood, mainly because invasive experiments in humans are unacceptable due to ethical reasons. The new functional imaging techniques such as positron emission tomography and single photon emission computed tomography have made it possible to study the neurophysiology of living humans non-invasively. We studied the regional cerebral blood flow with semi-quantitative ^99mTC-HMPAO single photon emission computed tomography in eight healthy right-handed heterosexual males during orgasm. The results showed decrease of cerebral blood flow during orgasm in all other cortical areas except in right prefrontal cortex, where the cerebral blood flow increased significantly (P < 0.005).     

The use of cerebral blood flow as an index of neuronal activity in functional neuroimaging: experimental and pathophysiological considerations

Over recent years, activation studies that have been undertaken using brain imaging techniques, such as functional magnetic resonance imaging, positron emission tomography or near infrared spectroscopy, have greatly improved our knowledge of the functional anatomy of the brain. Nevertheless, activation studies do not directly quantify the variations of synaptic transmission (neuronal activity) but detect it indirectly either through the visualisation of changes in cerebral blood flow, oxidative or glycolytic metabolism (for positron emission tomography), or through the measurement of a global index that is dependent on both cerebral blood flow and oxidative metabolism (for functional magnetic resonance imaging and near infrared spectroscopy). Such approaches are based on the concept of a tight parallelism — termed coupling — between variations in neuronal activity, metabolism and cerebral blood flow. However, several “uncoupled” situations between these parameters have been reported over the last decade through experimental, pharmacological and pathophysiological studies. The aim of this review is to focus on these data that have to be taken into account for the interpretation of the results obtained in activation paradigms.     

Assessment of brain tissue viability in acute ischemic stroke by BOLD MRI.

The introduction of new neuroprotective treatment strategies for acute stroke patients has provided a requirement for neuroimaging methods capable of identifying salvageable tissue in acute stroke patients. Substantial positron emission tomography evidence points to the fact that a peri-infarct zone with blood flow of 20-45% of normal, metabolic rate of oxygen of >35% of normal and oxygen extraction ratio (OER) of >0.7 are indices of tissue at risk of infarction, yet with potential for recovery. The sensitivity of T(2) to blood oxygen level dependent (BOLD) effects allows the mismatch between oxygen delivery and consumption in the brain to be imaged. Previous evidence from animal models of cerebral hypoperfusion and ischemic stroke strongly suggest that T(2) BOLD MRI highlights viable and salvageable brain regions. The Hahn-echo T(2) and diffusion show distinct flow thresholds in the rat brain so that the former parameter probes areas with high OER and the latter genuine ischemia. In the flow-compromised tissue showing negative T(2) BOLD, substantial residual perfusion is evident as revealed by bolus-tracking perfusion MRI, in agreement with the idea that tissue metabolic viability must be preserved for expression of BOLD. It is concluded that BOLD MRI may have potential for the assessment of tissue viability in acute ischemic stroke.     

Cerebral blood flow and metabolism of oxygen and glucose in young autistic adults

Regional cerebral blood flow, oxygen consumption and glucose consumption were measured by positron emission tomography in six young autistic men. No significant differences were found between patients and normal controls for any of the physiological variables. The results do not substantiate the previous finding of glucose hypermetabolism in autism; the likely reasons for the variance in findings are discussed.     

Does subthalamic nucleus stimulation affect the frontal limbic areas? A single-photon emission computed tomography study using a manual anatomical segmentation method

Among the basal ganglia nuclei, the subthalamic nucleus (STN) is considered to play a major role in output modulation. The STN represents a relay of the motor cortico-basal ganglia-thalamo-cortical circuit and has become the standard surgical target for treating Parkinson’s patients with long-term motor fluctuations and dyskinesia. But chronic bilateral stimulation of the STN produces cognitive effects. According to animal and clinical studies, the STN also appears to have direct or indirect connections with the frontal associative and limbic areas. This prospective study was conducted to analyse regional cerebral blood flow changes in single-photon emission computed tomography imaging of six Parkinson’s patients before and after STN stimulation. We particularly focused on the dorsolateral prefrontal cortex and the frontal limbic areas using a manual anatomical MRI segmentation method. We defined nine regions of interest, segmenting each MR slice to quantify the regional cerebral blood flow on pre- and postoperative SPECT images. We normalised the region-of-interest-based measurements to the entire brain volume. The patients showed increased activation during STN stimulation in the dorsolateral prefrontal cortex bilaterally and no change in the anterior cingulate and orbito-frontal cortices. In our study, STN stimulation induced activation of premotor and associative frontal areas. Further studies are needed to underline involvement of the STN with the so-called limbic system.     

Positron emission tomography

Summary Positron emission tomography (PET) allows for the absolute measurement of regional tissue physiological, biochemical and pharmacological processes. This ability is a consequence of the nature of positron emission and the type of tracers which can be labelled with positron emitting radionuclides. The spatial resolution of state of the art scanners is in the order of 4 mm full width at half maximum (FWHM). However, due to statistical limitations, in practice normally a resolution of 7 to 8 mm FWHM is used. For the same reason, although there is no limit to the temporal resolution, studies usually require many seconds to several minutes to obtain a good signal to noise ratio. If a slow kinetic process is followed, studies can be extended to several hours in order to characterise the entire physiological process. A major advantage of PET is its flexibility. Several parameters (e.g., blood flow, oxygen consumption, glucose consumption, receptor density, etc.) can be measured in the same setting. Different aspects of a certain pathology can, therefore, be studied in the same patient.     

Astrocytes degenerate in frontotemporal dementia: possible relation to hypoperfusion

To understand the extent and specificity of astrocyte pathology in sporadic frontotemporal dementia (FTD), we examined several FTD cases for molecular and morphologic characteristics of astrocyte degeneration. We quantified reactive and degenerating astrocytes in sections of frontal, temporal, parietal, and occipital cortex identified using glial fibrillary acidic protein (GFAP) immunoreactivity, terminal deoxynucleotidyl transferase (TdT) labeling, and morphological characteristics and compared them with nondemented, age-matched control brains. Conventional and confocal microscopy revealed that a subpopulation of GFAP(+) astrocytes exhibited positive TdT labeling and beading of their processes in the frontal, temporal, and parietal cortices in 5 of 7 FTD cases that also exhibited gliosis. This morphology was reproduced in cultured astrocytes using ischemic insults. Degenerating astrocytes in FTD correlated inversely with cerebral blood flow as measured by single photon emission computed tomography (SPECT) analysis of (133)Xe inhalation (r = 0.55, p < 0.05). Furthermore, areas of significant astrogliosis corresponded to areas of SPECT hypoperfusion, suggesting that astrocytes may be affected by or perhaps have a causal role in the disturbances of cerebral perfusion in FTD.     

Functional brain imaging of episodic and semantic memory with positron emission tomography

 Human memory is composed of several independent but interacting systems. These include a system for remembering general knowledge, semantic memory, and a system for recollection of personal events, episodic memory. The results of positron emission tomography (PET) studies of regional cerebral blood flow indicate that networks of distributed brain regions subserve episodic and semantic memory. Some networks seem to be generally engaged in memory processes whereas the involvement of others is specific to factors such as the type of information to be remembered or the level of retrieval success. The PET findings help to understand memory dysfunction (a) by showing that multiple brain regions are involved in different memory processes and (b) by sharpening the interpretation of the functional role of different brain regions. Received: 31 January 1997 / Accepted: 28 May 1997     

Technetium-99m HM-PAO SPECT in patients with delayed neurologic sequelae after carbon monoxide poisoning.

We used single photon emission computed tomography (SPECT) with technetium-99m hexamethylpropylene amine oxime (99mTc-HM-PAO) in 14 studies on 6 patients with delayed neurologic sequelae from carbon monoxide (CO) poisoning to determine whether any changes in cerebral blood flow could be correlated with clinical or computed tomographic evidence of delayed deficits. Among the six initial CT brain scans, two showed low density of both basal ganglia and two showed decreased density of the cerebral white matter. There was no correlation between the clinical outcome and the findings of the follow-up CT brain scans. Of the two SPECTS with 99mTc-HM-PAO performed during acute anoxic insult, one showed focal hypoperfusion which appeared 20 days prior to the onset of delayed neurologic sequelae after CO poisoning. Seven SPECTs in the six patients performing the delayed phase showed diffuse patched patterns of hypoperfusion which improved on follow-up images. There was good correlation between the clinical outcome and the findings of the 99mTc-HM-PAO SPECT. In preliminary conclusion, 9Tc-HM-PAO brain SPECT can be used for predicting or evaluating the outcome of delayed neurologic sequelae after CO poisoning. Cerebral vascular changes may be the possible cause of hypoperfusion in patients with CO poisoning.     

SPECT对发作期小儿癫痫诊断价值分析

目的评价单光子发射型计算机断层扫描脑血流灌注显像对发作期小儿癫痫的诊断价值。方法对38例发作期癫痫患儿行单光子发射型计算机断层扫描检查,并同时行CT检查,把二者结果进行比较。结果单光子发射型计算机断层扫描阳性率为84.2%(32/38),CT阳性率为36.8%(14/38)。两者比较有显著性差异。结论发作期单光子发射型计算机断层扫描显像是诊断小儿癫痫灵敏而有效的方法,对小儿癫痫诊断有重要价值。     

Hyperbaric oxygen treatment attenuated the decrease in regional glucose metabolism of rats subjected to focal cerebral ischemia: a high resolution positron emission tomography study

Cerebral hypoxia may be the main component of cell damage caused by ischemia. Previous studies demonstrated a neuroprotective effect of early hyperbaric oxygen (HBO) treatment in various animal models of focal cerebral ischemia. Neuropathologic study showed that exposure of HBO may prevent cell death in ischemic cortex. In the present study, we aimed to assess cellular function of ischemic rat brain after HBO treatment by means of a high-resolution positron emission tomography scanner (microPET) used specifically for small animal imaging. The male Sprague-Dawley rats were subjected to permanent middle cerebral artery occlusion (MCAO), with the regional cerebral blood flow monitored in vivo by laser Doppler flowmetry. One hour after ischemia, HBO therapy (3 atm absolute, 1 h) was initiated. Local cerebral glucose utilization in the ischemic area was measured before, 1 h and 3 h after ischemia, with 2-[(18)F]-fluoro-2-deoxy-d-glucose (FDG) as a tracer. Neurological deficits and infarct volumes were assessed at 24 h after ischemia. Our study showed that early HBO therapy significantly reduced infarct volume of brain 24 h after ischemia. Moreover, glucose utilization in the ischemic area underwent a severe decrease during 1-3 h after MCAO, while the early HBO treatment significantly attenuated the decrease in cerebral metabolic rate of glucose in the ischemic core of the cortex compared with controls. We report for the first time the application of microPET to quantify the rates of glucose metabolism in the ischemic core of rats exposed to HBO. Our results suggest that the early exposure of HBO can partially reverse the downward trend for glucose utilization in the ischemic core, which might contribute to the reported beneficial effects of early HBO therapy on permanent cerebral ischemia.     

Relationship between baseline cerebral blood flow and vascular responses to changes in PaCO2 measured by positron emission tomography in humans: implication of inter-individual variations of cerebral vascular tone

Aim: Inter‐individual variations in normal human cerebral blood flow (CBF) at rest condition have been reported. Inter‐individual variation of cerebral vascular tone is considered to contribute to this, and several determinants of cerebral vascular tone have been proposed. In the present study, the relationship between CBF and cerebral vascular tone to inter‐individual variation at rest condition was investigated using positron emission tomography (PET). Methods: CBF was measured using PET with H₂¹⁵O in each of 20 healthy subjects (20–28 years) under three conditions: at rest (baseline), during hypercapnia and during hypocapnia. The vascular response to change in P_aCO₂ was calculated as the percentage changes in CBF per absolute change in P_aCO₂ in response to hypercapnia and hypocapnia. Results: A significant negative correlation between baseline CBF and the vascular response to hypocapnia was observed in the thalamus, temporal cortex, parietal cortex, occipital cortex and cerebral cortex (P < 0.05). A trend towards negative correlation between baseline CBF and the vascular response to hypocapnia was observed in the cerebellum and putamen (P < 0.1). A significant negative correlation between baseline CBF and the vascular response to hypercapnia was observed in the occipital cortex (P < 0.05). No significant correlation was observed between baseline CBF and haemoglobin concentration, and P_aCO₂. Conclusion: These findings support the assumption that cerebral vascular tone might incline towards vasoconstriction and vasodilatation when baseline CBF is low and high between individuals respectively. Although several determinants of cerebral vascular tone have been proposed, the mechanism of such inter‐individual differences in cerebral vascular tone is unknown.     

Positron emission tomography and migraine]

Positron emission tomography (PET) is a brain imaging technique that allows in vivo studies of numerous physiological parameters. There have been few PET studies in migraine patients. Cerebral blood flow changes with no variations in brain oxygen consumption have been reported in patients with prolonged neurologic manifestations during migraine attacks. Parenteral administration of reserpine during migraine headache has been followed by a fall in the overall cerebral uptake of glucose. The small sample sizes and a number of methodologic problems complicate the interpretation of these results. Recent technical advances and the development of new PET tracers can be expected to provide further insight into the pathophysiology of migraine. Today cerebral cortex 5 HT2 serotonin receptors can be studied in migraine patients with PET.     

Alzheimer's disease: a review concerning immune response and microischemia

Alzheimer's disease (AD), as we think of it today, is the idiopathic progressive loss of cognitive function over a period of several years. The risk of late onset dementia increases significantly with each decade of life such that half of the population over the age of 80 is vulnerable to this disease (1). We know that proper functioning of the central nervous system is dependent on adequate blood flow to remove harmful metabolic products and supply nutrients such as glucose and oxygen to the brain. It has been suggested that cerebral hypoperfusion causes AD (2). Mean cerebral blood flow decreases with age and with sclerosis of cerebral blood vessels. Blood flow appears to increase in stimulated areas of the brain during different activities. However, there is a derangement of blood flow in disease states; this has been documented in the temporal lobes of AD patients, (3,4). English language journal articles located by a MEDLINE search (1960-1999) were reviewed with consideration to the hypothesis that Alzheimer's disease is an autoimmune disease initiated by low oxygen tension and microischemia. Inflammation is thought to be a known contributor to the pathology of AD (5,6). Recent reports support the concept of autoimmunity as a final common pathway of neuron death, particularly for cholinergic in Alzheimer's disease (6). A model of Alzheimer's disease is proposed and related research and treatment modalities are discussed.     

HIV: reactive oxygen species, enveloped viruses and hyperbaric oxygen

This paper demonstrates that there are many examples in the literature of contradictory data concerning reactive oxygen intermediates (ROIs), responsible for producing cellular oxidative stress (OS), and their enhancement or diminution of viral replication. Nevertheless, ROIs repeatedly have been shown to be virucidal against enveloped-viruses, like the human immunodeficiency virus (HIV). Hyperbaric oxygen therapy (HBOT) increases the production of ROIs throughout the body, leaving no safe harbor for the virus to hide outside the genome. This technique already has been tried on acquired immune deficiency syndrome (AIDS) patients, with exciting results. Historically, the biggest setback to demonstrating HBO's antiviral effects has been the investigator's folly of studying non-enveloped viruses or failing to initiate ROI production. ROIs specifically attack areas of unsaturation occurring in the polyunsaturated fatty acids of cell membranes and viral envelopes. Moreover, it consistently has been shown that a peroxidized viral envelope breaches, and a breached viral envelope causes viral disintegration.     

Sentence comprehension and word repetition: a positron emission tomography investigation.

Using positron emission tomography, visual presentation of sentences was shown to cause increased regional cerebral blood flow relative to word lists in the left lateral anterior superior and middle temporal gyri, attributable to cognitive processes that occur during sentence comprehension in addition to those carried out during word comprehension. Additional comparisons showed that repeating words (in a different context, when subjects did not attempt to learn the initial lists) led to significant patterns of both increased blood flow (left putamen and right caudate) and decreased blood flow (left posterior temporal lobe). Increases are argued to reflect retrieval of memory traces, whereas decreases reflect diminished necessity for processing of input. A decrease in the left inferior parietal lobe was attributable to other factors.     

Hemodynamic changes during aging associated with cerebral blood flow and impaired cognitive function

This study investigates the age associated changes in hemorheological properties and cerebral blood flow. Partial correlations indicate that part of the age-dependent decrease in flow velocities can be attributed to a hemorheological decrement resulting in part from enhanced oxidative stress in the aged. A possible link with Alzheimer's pathology is suggested by the augmented hemorheological impairment resulting from in vitro incubation of red cells with amyloids. These results suggest that in aging, oxidative stress as well as amyloids may influence the fluid properties of blood, resulting in a potential decrement in blood flow and oxygen delivery to the brain. Animal intervention studies further demonstrate that altered hemorheological properties of blood can actually influence cognitive function. The relationships shown to exist between hemorheology, blood flow, amyloids, oxidative stress, and cognitive function suggest that these factors may be one of the mechanisms operating in the complex etiology of Alzheimer's disease.     

SPECT changes and their correlation with EEG changes in tuberculous meningitis

OBJECTIVE: In tuberculous meningitis (TBM) blood flow may be altered due to associated vasculitis, hydrocephalus and raised intracranial pressure. Electroencephalography (EEG) and single photon emission computed tomography (SPECT) provide information about electrical activity and regional cerebral blood flow respectively. This study aims at the correlation of EEG and SPECT changes in patients with TBM. METHOD: Sixteen patients with TBM whose age ranged between 5 and 62 years and 3 of whom were females were subjected to clinical, radiological (CT and/or MRI), EEG and SPECT studies using 99mTc ethylene cystine dimer (ECD). Ten patients were in stage III and 3 each in stage II and stage I meningitis. Cranial CT scan was carried out in 15 and MRI in 4 patients. Hydrocephalus was present in 9, infarction in 7 and tuberculoma in 5 patients. RESULTS: SPECT studies were abnormal in all except 2 patients revealing basal ganglionic hypoperfusion in 14 and focal cortical hypoperfusion in 9 patients. The EEG was abnormal in 11 patients which included delta slowing in 5, theta slowing in 6, frontal intermittent rhythmic delta activity (FIRDA) in 3 and epileptiform discharges in 2 patients. All the patients with abnormal EEG had abnormal SPECT study except 1. In 4 patients, EEG was normal although there was subcortical hypoperfusion on SPECT. In spite of high frequency of focal cortical hypoperfusion (9 patients), EEG revealed focal abnormality in 3 patients only. CONCLUSION: It can be concluded that the SPECT reveals more frequent abnormalities compared to EEG and CT scan. Cortical hypoperfusion with or without basal ganglia hypoperfusion is associated with FIRDA and diffuse delta slowing on EEG.     

Impact of acute hypobaric hypoxia on blood flow distribution in brain

Aim: Acute hypobaric hypoxia is well known to alter brain circulation and to cause neuropsychological impairment. However, very few studies have examined the regional changes occurring in the brain during acute exposure to extreme hypoxic conditions. Methods: Regional cerebral blood flow (rCBF) response to hypoxia was investigated in six healthy subjects exposed to either normobaric normoxia or hypobaric hypoxia with ambient pressure/inspired oxygen pressure of 101/21 kPa and 50/11 kPa respectively. After 40 min at the desired pressure they were injected ^99mTc‐HMPAO and subsequently underwent single photon emission computed tomography. Regional cerebral blood flow distribution changes in the whole brain were assessed by Statistical Parametric Mapping, a well established voxel‐based analysis method. Results: Hypobaric hypoxia increased rCBF distribution in sensorymotor and prefrontal cortices and in central structures. PCO₂ correlated positively and SatO₂ negatively with rCBF in several temporal, parahippocampal, parietal and central structures. Conclusions: These findings underscore the specific sensitivity of the frontal lobe to acute hypobaric hypoxia and of limbic and central structures to blood gas changes emphasizing the involvement of these brain areas in acute hypoxia.