Neurotherapy is medical treatment
that implements systemic targeted delivery of an energy stimulus or
chemical agents to a specific neurological zone in the body to alter
neuronal activity and stimulate neuroplasticity in a way that develops (or balances) a nervous system in order to treat different diseases, restore and/or to improve patients' physical strength, cognitive functions, and overall health.
Definition
A consensus in the academic community considers this notion within limitations of the contemporary meaning of neuromodulation,
which is "the alteration of nerve activity through targeted delivery of
a stimulus, such as electrical stimulation or chemical agents, to
specific neurological sites in the body" (see Neuromodulation).
While neurotherapy may have a broader meaning, its modern definition
focuses exclusively on technological methods that exert an energy-based
impact on the development of the balanced nervous system in order to address symptom control and cure several
conditions. The definition of neurotherapy relies on evolving scientific concepts from different fields of knowledge, ranging from physics to neuroscience. Four central concepts that underlie the knowledge of neurotherapy are defined here:
Energy stimulus
Energy,
as the ability to do work, cannot be created or destroyed; it can only
be transformed from one form to another (the law of conservation of energy). There are different form of energy. Such forms of energy as radiant energy carried by electromagnetic radiation, electrical energy and magnetic energy,
are of interest to neurotherapy. Medical devices for neuromodulation
exert electrical, magnetic, and/or electromagnetic energy to treat
mental and physical health disorders in patients.
Synaptic plasticity
Synaptic plasticity, a particular type of neuroplasticity is the ability of the nervous system to modify the intensity of interneuronal relationships (synapses),
to establish new ones and to eliminate some. This property allows the
nervous system to modify its structure and functionality in a more or
less lasting way and dependent on the events that influence them such as
experience or neuromodulation.
Neuroplasticity
Brain plasticity refers to the ability of the brain to modify its structure and functionality depending on the activity of its neurons, related for example to stimuli received from the external environment, in reaction to traumatic lesions or pathological changes and in relation to the development process of the individual or neuromodulation.
A balanced nervous system
In the balanced nervous system with required cognitive functions, the sympathetic (SNS) and parasympathetic
nervous systems (PNS) operate in synergy while opposing each other.
Stimulation of the SNS boosts body activity and attention: it raises
heart rate and blood pressure. In contrast, stimulation of the PNS is the rest
and digest state: it reduces blood pressure and heart rate. The nervous system interplays with the immune system. Through these interactions, the nervous and immune systems ensure the nervous system maintains immune homeostasis.
Medical uses
According to the International Neuromodulation Society, neuromodulation-based therapy "addresses symptom control through nerve stimulation" in the following condition categories:
Neurotherapy, as many medical therapy, is based on knowledge from conventional medicine, relying on scientific approach and evidence-based practice. However, some neuromodulation techniques are still attributed to alternative medicine (healthcare procedures "not readily integrated into the dominant healthcare
model") because of their novelty and lack of evidence to support them. The wide range of
neurotherapy techniques can be divided into three groups based on the application of energy stimulus:
Origins
behind the way that an external energy stimulus alters neuronal
activity and stimulates neuroplasticity during various artificial
neurostimulation techniques are still under discussion. It is important
to note that electrical and magnetic energy are two forms of energy that
are closely interconnected: a moving charge induces electrical and
magnetic fields. Electrical current creates a magnetic field, and a
magnetic field induces an electrical charge movement. Neurons are
electrically active cells. Neuronal oscillations have a dual role in synapsis: they are affected by spiking inputs and, in turn, impact the timing of spike outputs. Because of the above facts, both electrical and magnetic fields may induce electrical currents in neuronal circuits.
Therefore, similar mechanisms of altered neuronal activity may underlie
different neuromodulation techniques that use electrical, magnetic, or
electromagnetic energy in treatment.
A variety of hypotheses try to explain the mechanisms that
contribute to synaptic activity during neurostimulation. According to an
influential position, electrical and magnetic fields may alter Ca2+ and Na+ channel activity.
The voltage-gated Ca2+ channels are the primary conduits for the Ca2+
ions that cause a confluence of neurotransmitter-containing vesicles
with the presynaptic membrane.
The altered activity of Ca2+ and Na+ channel changes the timing and
strength of synaptic output, contributing to neuronal excitability.
Another perspective hypothesis stands that electromagnetic fields increase in adenosine receptors release that facilitates neuronal communication. Because A(2A) adenosine receptors control the release of other neurotransmitters (e.g., glutamate and dopamine), this contributes to adjusting neuronal functions.
According to the natural neurostimulation hypothesis, energy stimuli induce mitochondrial stress and micro vascular vasodilation. These promote increasing Adenosine triphosphate (ATP) protein and oxygenation, inducing synaptic strength. This position explains neuromodulation from different scale levels: from interpersonal dynamics to nonlocal neuronal coupling.
According to natural neurostimulation, the innate natural mechanism of
physical interactions between the mother and embryo ensures the balanced
development of the embryonic nervous system. The drivers of these interactions, the electromagnetic properties of the mother's heart, enable brain waves to interact between the mother's and fetal nervous systems.
The electromagnetic and acoustic oscillations of the mother's heart
converge the neuronal activity of both nervous systems in an ensemble,
shaping harmony from a cacophony of separate oscillations. These interactions synchronize brain oscillations, influencing neuroplasticity in the fetus.
During the mother's intentional actions with her environment, these
interchanges provide hints to the fetus's nervous system, binding
synaptic activity with relevant stimuli.
This hypothesis posits that the physiological processes of
mitochondrial stress induction (affecting neuronal plasticity) and
vasodilation, which cooperatively increase microvascular blood flow and
tissue oxygenation, are the basis of the natural neurostimulation. It is
also thought to be a foundation of many non-invasive artificial
neuromodulation techniques.
Because if the mother-fetus interactions allow the child's nervous
system to grow with adequate biological sentience, similar (while
scaling) environmental interactions can heal the damaged nervous system
in adults.
History
While neurotherapy is a relatively young medical treatment in conventional Western biomedicine (that relies on a scientific approach and evidence-based practice),
different age-old cultural practices of traditional Indian, Egyptian,
and Chinese medicine have been using neuromodulation elements thousands
of years ago. Before the basic processes of neurotherapy were
scientifically studied, humans used the electrical properties of animals
for therapeutic purposes. The Egyptians used the Nile catfish (Synodontis batensoda and Malapterurus electricus) to stimulate tissue electrically, according to an interpretation of frescoes in the tomb of the architect Ti at Saqqara, Egypt. The first documented use of electrical stimulation for pain relief dates back to 46 AD when Scribonius Largus of the ancient Roman Empire used the electric properties of torpedo fish to relieve headaches.
Scientific studies of neuromodulation began in 1745, when German
physician De Haen published “a number of cases of spasmodic, paralytic
and other nervous affections cured by electricity”.
The first implementation of electrocutical apparatus in hospital
medical treatment recorded in Middlesex Hospital of London in 1767.
In 1870, German physicians Gustav Fritsch and Eduard Hitzig reported the modulation of brain activity in dogs by electrical stimulation of the motor cortex.
In 1924, the German psychiatrist Hans Berger attached electrodes to the scalp and detected small currents in the brain.
In the mid-20th century, the scientific study of neuromodulation
in humans expanded significantly. Neurologist Professor Spiegel and
neurosurgeon Professor Weissys of Temple University presented a stereotactic device to perform "ablation procedures" in humans; "intraoperative electrical stimulation"
was introduced to test
the brain's target zone before surgery in 1947. In the 1950s, Professor
Heath reported about subcortical stimulation with precise descriptions
of behavioral changes.
In 1967, Dr. Norm Shealy from Western Reserve Medical School presented
“the first dorsal column stimulator for pain control”. It was developed
based on the Gate Theory of Wall and
Melzack, which stated that pain transmissions from tiny nerve fibers would be blocked if competing transmissions were made along larger sensory nerve fibers.
In 1987, the team of neurosurgeons/neurologists Professor Benabid
and Professor Pollak and their colleagues (Grenoble, France) published
results on this topic about thalamic Deep Brain Stimulation.
Alternative
assumptions for the extrapolation of the cancer risk vs. radiation dose
to low-dose levels, given a known risk at a high dose: supra-linearity
(A), linear (B), linear-quadratic (C) and hormesis (D).
Radiation hormesis is the hypothesis that low doses of ionizing radiation (within the region of and just above natural background levels) are beneficial, stimulating the activation of repair mechanisms that protect against disease,
that are not activated in absence of ionizing radiation. The reserve
repair mechanisms are hypothesized to be sufficiently effective when
stimulated as to not only cancel the detrimental effects of ionizing
radiation but also inhibit disease not related to radiation exposure
(see hormesis). It has been a mainstream concept since at least 2009.
While the effects of high and acute doses of ionising radiation are easily observed and understood in humans (e.g.Japanese atomic bomb
survivors), the effects of low-level radiation are very difficult to
observe and highly controversial. This is because the baseline cancer
rate is already very high and the risk of developing cancer fluctuates
40% because of individual life style and environmental effects, obscuring the subtle effects of low-level radiation. An acute effective dose of 100 millisieverts may increase cancer risk by ~0.8%. However, children are particularly sensitive to radioactivity, with childhood leukemias and other cancers
increasing even within natural and man-made background radiation levels
(under 4 mSv cumulative with 1 mSv being an average annual dose from
terrestrial and cosmic radiation, excluding radon which primarily doses the lung).
There is limited evidence that exposures around this dose level will
cause negative subclinical health impacts to neural development. Students born in regions of higher Chernobyl fallout
performed worse in secondary school, particularly in mathematics.
"Damage is accentuated within families (i.e., siblings comparison) and
among children born to parents with low education..." who often don't
have the resources to overcome this additional health challenge.
Hormesis remains largely unknown to the public. Government and
regulatory bodies disagree on the existence of radiation hormesis and
research points to the "severe problems and limitations" with the use of
hormesis in general as the "principal dose-response default assumption
in a risk assessment process charged with
ensuring public health protection."
Quoting results from a literature database research, the Académie des Sciences – Académie nationale de Médecine (French Academy of Sciences – National Academy of Medicine)
stated in their 2005 report concerning the effects of low-level
radiation that many laboratory studies have observed radiation hormesis. However, they cautioned that it is not yet known if radiation hormesis occurs outside the laboratory, or in humans.
A very low dose of a chemical agent may trigger from an organism the opposite response to a very high dose.
Radiation hormesis proposes that radiation exposure comparable to and just above the natural background level of radiation
is not harmful but beneficial, while accepting that much higher levels
of radiation are hazardous. Proponents of radiation hormesis typically
claim that radio-protective responses in cells and the immune system not
only counter the harmful effects of radiation but additionally act to
inhibit spontaneous cancer not related to radiation exposure. Radiation
hormesis stands in stark contrast to the more generally accepted linear no-threshold model
(LNT), which states that the radiation dose-risk relationship is linear
across all doses, so that small doses are still damaging, albeit less
so than higher ones. Opinion pieces on chemical and radiobiological
hormesis appeared in the journals Nature and Science in 2003.
Assessing the risk of radiation at low doses (<100 mSv) and low dose rates (<0.1 mSv.min−1) is highly problematic and controversial. While epidemiological studies on populations of people exposed to an acute dose of high level radiation such as Japanese atomic bomb survivors (hibakusha (被爆者)) have robustly upheld the LNT (mean dose ~210 mSv), studies involving low doses and low dose rates have failed to detect any increased cancer rate.
This is because the baseline cancer rate is already very high (~42 of
100 people will be diagnosed in their lifetime) and it fluctuates ~40%
because of lifestyle and environmental effects,
obscuring the subtle effects of low level radiation. Epidemiological
studies may be capable of detecting elevated cancer rates as low as 1.2
to 1.3 i.e. 20% to 30% increase. But for low doses (1–100 mSv)
the predicted elevated risks are only 1.001 to 1.04 and excess cancer
cases, if present, cannot be detected due to confounding factors, errors
and biases.
In particular, variations in smoking prevalence or even accuracy
in reporting smoking cause wide variation in excess cancer and
measurement error bias. Thus, even a large study of many thousands of
subjects with imperfect smoking prevalence information will fail to
detect the effects of low level radiation than a smaller study that
properly compensates for smoking prevalence.
Given the absence of direct epidemiological evidence, there is
considerable debate as to whether the dose-response relationship <100
mSv is supralinear, linear (LNT), has a threshold, is sub-linear, or whether the coefficient is negative with a sign change, i.e. a hormetic response.
The radiation adaptive response
seems to be a main origin of the potential hormetic effect. The
theoretical studies indicate that the adaptive response is responsible
for the shape of dose-response curve and can transform the linear
relationship (LNT) into the hormetic one.
While most major consensus reports and government bodies currently adhere to LNT, the 2005 French Academy of Sciences-National Academy of Medicine's report concerning the effects of low-level radiation rejected LNT as a scientific model of carcinogenic risk at low doses.
Using LNT to estimate the carcinogenic effect at doses of
less than 20 mSv is not justified in the light of current radiobiologic
knowledge.
They consider there to be several dose-effect relationships rather
than only one, and that these relationships have many variables such as
target tissue, radiation dose, dose rate and individual sensitivity
factors. They request that further study is required on low doses (less
than 100 mSv) and very low doses (less than 10 mSv)
as well as the impact of tissue type and age. The Academy considers the
LNT model is only useful for regulatory purposes as it simplifies the
administrative task. Quoting results from literature research,
they furthermore claim that approximately 40% of laboratory studies on
cell cultures and animals indicate some degree of chemical or
radiobiological hormesis, and state:
...its existence in the laboratory is beyond question and its mechanism of action appears well understood.
They go on to outline a growing body of research that illustrates that the human body is not a passive accumulator of radiation damage but it actively repairs the damage caused via a number of different processes, including:
Radiation-induced tumorigenesis may have a threshold related to damage density, as revealed by experiments that employ blocking grids to thinly distribute radiation.
A large increase in tumours in immunosuppressed individuals illustrates that the immune system efficiently destroys aberrant cells and nascent tumors.
Furthermore, increased sensitivity to radiation induced cancer in the inherited condition Ataxia-telangiectasia like disorder, illustrates the damaging effects of loss of the repair gene Mre11h resulting in the inability to fix DNA double-strand breaks.
The BEIR-VII report argued that, "the presence of a true dose
threshold demands totally error-free DNA damage response and repair."
The specific damage they worry about is double strand breaks (DSBs) and
they continue, "error-prone nonhomologous end joining (NHEJ) repair in
postirradiation cellular response, argues strongly against a DNA
repair-mediated low-dose threshold for cancer initiation". Recent research observed that DSBs caused by CAT scans
are repaired within 24 hours and DSBs may be more efficiently repaired
at low doses, suggesting that the risk of ionizing radiation at low
doses may not be directly proportional to the dose.However, it is not known if low-dose ionizing radiation stimulates the repair of DSBs not caused by ionizing radiation i.e. a hormetic response.
Radon gas in homes is the largest source of radiation dose for
most individuals and it is generally advised that the concentration be
kept below 150 Bq/m³ (4 pCi/L).
A recent retrospective case-control study of lung cancer risk showed
substantial cancer rate reduction between 50 and 123 Bq per cubic meter
relative to a group at zero to 25 Bq per cubic meter.
This study is cited as evidence for hormesis, but a single study all by
itself cannot be regarded as definitive. Other studies into the effects
of domestic radon
exposure have not reported a hormetic effect; including for example the
respected "Iowa Radon Lung Cancer Study" of Field et al. (2000), which
also used sophisticated radon exposure dosimetry.
In addition, Darby et al. (2005) argue that radon exposure is
negatively correlated with the tendency to smoke and environmental
studies need to accurately control for this; people living in urban
areas where smoking rates are higher usually have lower levels of radon
exposure due to the increased prevalence of multi-story dwellings.
When doing so, they found a significant increase in lung cancer
amongst smokers exposed to radon at doses as low as 100 to 199 Bq m−3 and warned that smoking greatly increases the risk posed by radon exposure i.e. reducing the prevalence of smoking would decrease deaths caused by radon. However, the discussion about the opposite experimental results is still going on, especially the popular US and German studies have found some hormetic effects.
Furthermore, particle microbeam studies show that passage of even
a single alpha particle (e.g. from radon and its progeny) through cell
nuclei is highly mutagenic,
and that alpha radiation may have a higher mutagenic effect at low
doses (even if a small fraction of cells are hit by alpha particles)
than predicted by linear no-threshold model, a phenomenon attributed to bystander effect. However, there is currently insufficient evidence at hand to suggest that the bystander effect promotes carcinogenesis in humans at low doses.
Statements by leading nuclear bodies
Radiation hormesis has not been accepted by either the United States National Research Council, or the National Council on Radiation Protection and Measurements (NCRP).
In May 2018, the NCRP published the report of an interdisciplinary
group of radiation experts who critically reviewed 29 high-quality
epidemiologic studies of populations exposed to radiation in the low
dose and low dose-rate range, mostly published within the last 10 years. The group of experts concluded:
The recent epidemiologic studies support the continued
use of the LNT model for radiation protection. This is in accord with
judgments by other national and international scientific committees,
based on somewhat older data, that no alternative dose-response
relationship appears more pragmatic or prudent for radiation protection
purposes than the LNT model.
Until the [...] uncertainties on low-dose response are
resolved, the Committee believes that an increase in the risk of tumour
induction proportionate to the radiation dose is consistent with
developing knowledge and that it remains, accordingly, the most
scientifically defensible approximation of low-dose response. However, a
strictly linear dose response should not be expected in all
circumstances.
This is a reference to the fact that very low doses of radiation have
only marginal impacts on individual health outcomes. It is therefore
difficult to detect the 'signal' of decreased or increased morbidity and
mortality due to low-level radiation exposure in the 'noise' of other
effects. The notion of radiation hormesis has been rejected by the
National Research Council's (part of the National Academy of Sciences)
16-year-long study on the Biological Effects of Ionizing Radiation. "The
scientific research base shows that there is no threshold of exposure
below which low levels of ionizing radiation can be demonstrated to be
harmless or beneficial. The health risks – particularly the development
of solid cancers in organs – rise proportionally with exposure" says
Richard R. Monson, associate dean for professional education and
professor of epidemiology, Harvard School of Public Health, Boston.
The possibility that low doses of
radiation may have beneficial effects (a phenomenon often referred to as
"hormesis") has been the subject of considerable debate. Evidence for
hormetic effects was reviewed, with emphasis on material published since
the 1990 BEIR V study on the health effects of exposure to low levels
of ionizing radiation. Although examples of apparent stimulatory or
protective effects can be found in cellular and animal biology, the
preponderance of available experimental information does not support the
contention that low levels of ionizing radiation have a beneficial
effect. The mechanism of any such possible effect remains obscure. At
this time, the assumption that any stimulatory hormetic effects from low
doses of ionizing radiation will have a significant health benefit to
humans that exceeds potential detrimental effects from radiation
exposure at the same dose is unwarranted.
Studies of low-level radiation
Cancer rates and very high natural background gamma radiation at Kerala, India
Kerala's monazite sand (containing a third of the world's economically recoverable reserves of radioactive thorium) emits about 8 microsieverts
per hour of gamma radiation, 80 times the dose rate equivalent in
London, but a decade-long study of 69,985 residents published in Health
Physics in 2009 "showed no excess cancer risk from exposure to
terrestrial gamma radiation. The excess relative risk of cancer
excluding leukemia was estimated to be −0.13 per Gy (95% CI: −0.58,
0.46)", indicating no statistically significant positive or negative
relationship between background radiation levels and cancer risk in this
sample.
Cultures
Studies
in cell cultures can be useful for finding mechanisms for biological
processes, but they also can be criticized for not effectively capturing
the whole of the living organism.
A study by E. I. Azzam suggested that pre-exposure to radiation causes cells to turn on protection mechanisms.
A different study by de Toledo and collaborators has shown that
irradiation with gamma rays increases the concentration of glutathione,
an antioxidant found in cells.
In 2011, an in vitro study led by S. V. Costes showed in
time-lapse images a strongly non-linear response of certain cellular
repair mechanisms called radiation-induced foci (RIF). The study found
that low doses of radiation prompted higher rates of RIF formation than
high doses, and that after low-dose exposure RIF continued to form after
the radiation had ended. Measured rates of RIF formation were 15 RIF/Gy at 2 Gy, and 64 RIF/Gy at 0.1 Gy. These results suggest that low dose levels of ionizing radiation may not increase cancer risk directly proportional to dose and thus contradict the linear-no-threshold standard model. Mina Bissell,
a world-renowned breast-cancer researcher and collaborator in this
study stated: "Our data show that at lower doses of ionizing radiation,
DNA repair mechanisms work much better than at higher doses. This
non-linear DNA damage response casts doubt on the general assumption
that any amount of ionizing radiation is harmful and additive."
Animals
An early study on mice exposed to low dose of radiation daily (0.11 R per day) suggest that they may outlive control animals. A study by Otsuka and collaborators found hormesis in animals.
Miyachi conducted a study on mice and found that a 200 mGy X-ray dose
protects mice against both further X-ray exposure and ozone gas. In another rodent study, Sakai and collaborators found that (1 mGy/h) gamma irradiation prevents the development of cancer (induced by chemical means, injection of methylcholanthrene).
In a 2006 paper,
a dose of 1 Gy was delivered to the cells (at constant rate from a
radioactive source) over a series of lengths of time. These were between
8.77 and 87.7 hours, the abstract states for a dose delivered over 35
hours or more (low dose rate) no transformation of the cells occurred.
Also for the 1 Gy dose delivered over 8.77 to 18.3 hours that the
biological effect (neoplastic transformation) was about "1.5 times less
than that measured at high dose rate in previous studies with a similar
quality of [X-ray] radiation". Likewise it has been reported that
fractionation of gamma irradiation reduces the likelihood of a
neoplastic transformation.
Pre-exposure to fast neutrons and gamma rays from Cs-137 is reported to
increase the ability of a second dose to induce a neoplastic
transformation.
Caution must be used in interpreting these results, as it noted
in the BEIR VII report, these pre-doses can also increase cancer risk:
In chronic low-dose experiments
with dogs (75 mGy/d for the duration of life), vital hematopoietic
progenitors showed increased radioresistance along with renewed
proliferative capacity (Seed and Kaspar 1992). Under the same
conditions, a subset of animals showed an increased repair capacity as
judged by the unscheduled DNA synthesis assay (Seed and Meyers 1993).
Although one might interpret these observations as an adaptive effect at
the cellular level, the exposed animal population experienced a high
incidence of myeloid leukemia and related myeloproliferative disorders.
The authors concluded that "the acquisition of radioresistance and
associated repair functions under the strong selective and mutagenic
pressure of chronic radiation is tied temporally and causally to
leukemogenic transformation by the radiation exposure" (Seed and Kaspar
1992).
However, 75 mGy/d cannot be accurately described as a low dose rate –
it is equivalent to over 27 sieverts per year. The same study on dogs
showed no increase in cancer nor reduction in life expectancy for dogs
irradiated at 3 mGy/d.
Humans
Effects of slightly increased radiation level
In long-term study of Chernobyl disaster liquidators
was found that: "During current research paradoxically longer telomeres
were found among persons, who have received heavier long-term
irradiation." and "Mortality due to oncologic diseases was lower than in
general population in all age groups that may reflect efficient health
care of this group." Though in conclusion interim results were ignored
and conclusion followed LNT
hypothesis: "The signs of premature aging were found in Chernobyl
disaster clean-up workers; moreover, aging process developed in heavier
form and at younger age in humans, who underwent greater exposure to
ionizing radiation."
In an Australian study which analyzed the association between solar UV exposure and DNA damage, the results indicated that although the frequency of cells with chromosome breakage increased with increasing sun exposure, the misrepair of DNA strand breaks decreased as sun exposure was heightened.
Effects of cobalt-60 exposure
The health of the inhabitants of radioactive apartment buildings in Taiwan has received prominent attention. In 1982, more than 20,000 tons of steel was accidentally contaminated with cobalt-60,
and much of this radioactive steel was used to build apartments and
exposed thousands of Taiwanese to gamma radiation levels of up to
>1000 times background (average 47.7 mSv, maximum 2360 mSv excess
cumulative dose). The radioactive contamination was discovered in 1992.
A seriously flawed 2004 study compared the building's younger
residents with the much older general population of Taiwan and
determined that the younger residents were less likely to have been
diagnosed with cancer than older people; this was touted as evidence of a
radiation hormesis effect. (Older people have much higher cancer rates even in the absence of excess radiation exposure.)
In the years shortly after exposure, the total number cancer
cases have been reported to be either lower than the society-wide
average or slightly elevated. Leukaemia and thyroid cancer were substantially elevated. When a lower rate of "all cancers" was found, it was thought to be due to the exposed residents having a higher socioeconomic status, and thus overall healthier lifestyle. Additionally, Hwang, et al. cautioned in 2006 that leukaemia
was the first cancer type found to be elevated amongst the survivors of
the Hiroshima and Nagasaki bombings, so it could be decades before any
increase in more common cancer types is seen.
Besides the excess risks of leukaemia and thyroid cancer, a later
publication notes various DNA anomalies and other health effects among
the exposed population:
There have been several reports concerning the radiation effects on
the exposed population, including cytogenetic analysis that showed
increased micronucleus frequencies in peripheral lymphocytes in the
exposed population, increases in acentromeric and single or multiple
centromeric cytogenetic damages, and higher frequencies of chromosomal
translocations, rings and dicentrics. Other analyses have shown
persistent depression of peripheral leucocytes and neutrophils,
increased eosinophils, altered distributions of lymphocyte
subpopulations, increased frequencies of lens opacities, delays in
physical development among exposed children, increased risk of thyroid
abnormalities, and late consequences in hematopoietic adaptation in
children.
People living in these buildings also experienced infertility.
Intentional exposure to water and air containing increased amounts of radon
is perceived as therapeutic, and "radon spas" can be found in United
States, Czechia, Poland, Germany, Austria and other countries.
Effects of no radiation
Given
the uncertain effects of low-level and very-low-level radiation, there
is a pressing need for quality research in this area. An expert panel
convened at the 2006 Ultra-Low-Level Radiation Effects Summit at
Carlsbad, New Mexico, proposed the construction of an Ultra-Low-Level
Radiation laboratory. The laboratory, if built, will investigate the effects of almost no radiation on laboratory animals and cell cultures, and it will compare these groups to control groups exposed to natural radiation levels. Precautions would be made, for example, to remove potassium-40 from the food of laboratory animals. The expert panel believes that the Ultra-Low-Level Radiation laboratory is the only experiment
that can explore with authority and confidence the effects of low-level
radiation; that it can confirm or discard the various radiobiological
effects proposed at low radiation levels e.g. LNT, threshold and radiation hormesis.
The first preliminary results of the effects of almost
no-radiation on cell cultures was reported by two research groups in
2011 and 2012; researchers in the US studied cell cultures protected
from radiation in a steel chamber 650 meters underground at the Waste Isolation Pilot Plant in Carlsbad, New Mexico
and researchers in Europe proposed an experiment design to study the
effects of almost no-radiation on mouse cells (pKZ1 transgenic
chromosomal inversion assay), but did not carry out the experiment.
The autonomic nervous system (ANS), sometimes called the visceral nervous system and formerly the vegetative nervous system, is a division of the nervous system that operates internal organs, smooth muscle and glands. The autonomic nervous system is a control system that acts largely unconsciously and regulates bodily functions, such as the heart rate, its force of contraction, digestion, respiratory rate, pupillary response, urination, and sexual arousal. The fight-or-flight response, also known as the acute stress response, is set into action by the autonomic nervous system.
Although conflicting reports about its subdivisions exist in the
literature, the autonomic nervous system has historically been
considered a purely motor system, and has been divided into three
branches: the sympathetic nervous system, the parasympathetic nervous system, and the enteric nervous system. Some textbooks do not include the enteric nervous system as part of this system. The sympathetic nervous system is responsible for setting off the fight-or-flight response. The parasympathetic nervous system is responsible for the body's rest and digestion response.
In many cases, both of these systems have "opposite" actions where one
system activates a physiological response and the other inhibits it. An
older simplification of the sympathetic and parasympathetic nervous
systems as "excitatory" and "inhibitory" was overturned due to the many
exceptions found. A more modern characterization is that the sympathetic
nervous system is a "quick response mobilizing system" and the
parasympathetic is a "more slowly activated dampening system", but even this has exceptions, such as in sexual arousal and orgasm, wherein both play a role.
There are inhibitory and excitatorysynapses between neurons. A third subsystem of neurons has been named as non-noradrenergic, non-cholinergic transmitters (because they use nitric oxide as a neurotransmitter) and are integral in autonomic function, in particular in the gut and the lungs.though the ANS is also known as the visceral nervous system and
although most of its fibers carry non-somatic information to the CNS,
many authors still consider it only connected with the motor side. Most autonomous functions are involuntary but they can often work in conjunction with the somatic nervous system which provides voluntary control.
Structure
Autonomic nervous system, showing splanchnic nerves in middle, and the vagus nerve as "X" in blue. The heart and organs below in list to right are regarded as viscera.
The autonomic nervous system is unique in that it requires a
sequential two-neuron efferent pathway; the preganglionic neuron must
first synapse onto a postganglionic neuron before innervating the target
organ. The preganglionic, or first, neuron will begin at the "outflow"
and will synapse at the postganglionic, or second, neuron's cell body.
The postganglionic neuron will then synapse at the target organ.
The sympathetic nervous system consists of cells with bodies in the lateral grey column from T1 to L2/3. These cell bodies are "GVE" (general visceral efferent) neurons
and are the preganglionic neurons. There are several locations upon
which preganglionic neurons can synapse for their postganglionic
neurons:
paravertebral ganglia (3) of the sympathetic chain (these run on either side of the vertebral bodies)
chromaffin cells of the adrenal medulla (this is the one exception to the two-neuron pathway rule: the synapse is directly efferent onto the target cell bodies)
These ganglia provide the postganglionic neurons from which innervation of target organs follows. Examples of splanchnic (visceral) nerves are:
cervical cardiac nerves and thoracic visceral nerves, which synapse in the sympathetic chain
The parasympathetic nervous system consists of cells with bodies in one of two locations: the brainstem
(cranial nerves III, VII, IX, X) or the sacral spinal cord (S2, S3,
S4). These are the preganglionic neurons, which synapse with
postganglionic neurons in these locations:
The
intricate process of enteric nervous system (ENS) development begins
with the migration of cells from the vagal section of the neural crest.
These cells embark on a journey from the cranial region to populate the
entire gastrointestinal tract. Concurrently, the sacral section of the
neural crest provides an additional layer of complexity by contributing
input to the hindgut ganglia. Throughout this developmental journey,
numerous receptors exhibiting tyrosine kinase activity, such as Ret and
Kit, play indispensable roles. Ret, for instance, plays a critical role
in the formation of enteric ganglia derived from cells known as vagal
neural crest. In mice, targeted disruption of the RET gene results in
renal agenesis and the absence of enteric ganglia, while in humans,
mutations in the RET gene are associated with megacolon. Similarly, Kit,
another receptor with tyrosine kinase activity, is implicated in Cajal
interstitial cell formation, influencing the spontaneous, rhythmic,
electrical excitatory activity known as slow waves in the
gastrointestinal tract. Understanding the molecular intricacies of these
receptors provides crucial insights into the delicate orchestration of
ENS development.
Structure of the enteric nervous system
The
structural complexity of the enteric nervous system (ENS) is a
fascinating aspect of its functional significance. Originally perceived
as postganglionic parasympathetic neurons, the ENS earned recognition
for its autonomy in the early 1900s. Boasting approximately 100 million
neurons, a quantity comparable to the spinal cord, the ENS is often
described as a "brain of its own." This description is rooted in the
ENS's ability to communicate independently with the central nervous
system through parasympathetic and sympathetic neurons. At the core of
this intricate structure are the myenteric plexus (Auerbach's) and the
submucous plexus (Meissner's), two main plexuses formed by the grouping
of nerve-cell bodies into tiny ganglia connected by bundles of nerve
processes. The myenteric plexus extends the full length of the gut,
situated between the circular and longitudinal muscle layers. Beyond its
primary motor and secretomotor functions, the myenteric plexus exhibits
projections to submucosal ganglia and enteric ganglia in the pancreas
and gallbladder, showcasing the interconnectivity within the ENS.
Additionally, the myenteric plexus plays a unique role in innervating
motor end plates with the inhibitory neurotransmitter nitric oxide in
the striated-muscle segment of the esophagus, a feature exclusive to
this organ. Meanwhile, the submucous plexus, most developed in the small
intestine, occupies a crucial position in secretory regulation.
Positioned in the submucosa between the circular muscle layer and the
muscularis mucosa, the submucous plexus's neurons innervate intestinal
endocrine cells, submucosal blood arteries, and the muscularis mucosa,
emphasizing its multifaceted role in gastrointestinal function.
Furthermore, ganglionated plexuses in the pancreatic, cystic duct,
common bile duct, and gallbladder, resembling submucous plexuses,
contribute to the overall complexity of the ENS structure. In this
intricate landscape, glial cells emerge as key players, outnumbering
enteric neurons and covering the majority of the surface of enteric
neuronal-cell bodies with laminar extensions. Resembling the astrocytes
of the central nervous system, enteric glial cells respond to cytokines
by expressing MHC class II antigens and generating interleukins. This
underlines their pivotal role in modulating inflammatory responses in
the intestine, adding another layer of sophistication to the functional
dynamics of the ENS. The varied morphological shapes of enteric neurons
further contribute to the structural diversity of the ENS, with neurons
capable of exhibiting up to eight different morphologies. These neurons
are primarily categorized into type I and type II, where type II neurons
are multipolar with numerous long, smooth processes, and type I neurons
feature numerous club-shaped processes along with a single long,
slender process. The rich structural diversity of enteric neurons
highlights the complexity and adaptability of the ENS in orchestrating a
wide array of gastrointestinal functions, reflecting its status as a
dynamic and sophisticated component of the nervous system.
The visceral sensory system - technically not a part of the autonomic
nervous system - is composed of primary neurons located in cranial
sensory ganglia: the geniculate, petrosal and nodose ganglia, appended respectively to cranial nerves VII, IX and X. These sensory neurons monitor the levels of carbon dioxide, oxygen
and sugar in the blood, arterial pressure and the chemical composition
of the stomach and gut content. They also convey the sense of taste and
smell, which, unlike most functions of the ANS, is a conscious
perception. Blood oxygen and carbon dioxide are in fact directly sensed
by the carotid body, a small collection of chemosensors at the
bifurcation of the carotid artery, innervated by the petrosal (IXth)
ganglion.
Primary sensory neurons project (synapse) onto "second order" visceral
sensory neurons located in the medulla oblongata, forming the nucleus of the solitary tract
(nTS), that integrates all visceral information. The nTS also receives
input from a nearby chemosensory center, the area postrema, that detects
toxins in the blood and the cerebrospinal fluid and is essential for
chemically induced vomiting or conditional taste aversion (the memory
that ensures that an animal that has been poisoned by a food never
touches it again). All this visceral sensory information constantly and
unconsciously modulates the activity of the motor neurons of the ANS.
Innervation
Autonomic nerves travel to organs throughout the body. Most organs receive parasympathetic supply by the vagus nerve and sympathetic supply by splanchnic nerves. The sensory part of the latter reaches the spinal column at certain spinal segments. Pain in any internal organ is perceived as referred pain, more specifically as pain from the dermatome corresponding to the spinal segment.
Autonomic nervous system's jurisdiction to organs in the human bodyedit
Motor neurons of the autonomic nervous system are found in "autonomic
ganglia". Those of the parasympathetic branch are located close to the
target organ whilst the ganglia of the sympathetic branch are located
close to the spinal cord.
The sympathetic ganglia here, are found in two chains: the
pre-vertebral and pre-aortic chains. The activity of autonomic
ganglionic neurons is modulated by "preganglionic neurons" located in
the central nervous system. Preganglionic sympathetic neurons are
located in the spinal cord, at the thorax and upper lumbar levels.
Preganglionic parasympathetic neurons are found in the medulla oblongata
where they form visceral motor nuclei; the dorsal motor nucleus of the
vagus nerve; the nucleus ambiguus, the salivatory nuclei, and in the sacral region of the spinal cord.
Function
Function of the autonomic nervous system
Sympathetic and parasympathetic divisions typically function in
opposition to each other. But this opposition is better termed
complementary in nature rather than antagonistic. For an analogy, one
may think of the sympathetic division as the accelerator and the
parasympathetic division as the brake. The sympathetic division
typically functions in actions requiring quick responses. The
parasympathetic division functions with actions that do not require
immediate reaction. The sympathetic system is often considered the "fight or flight" system, while the parasympathetic system is often considered the "rest and digest" or "feed and breed" system.
However, many instances of sympathetic and parasympathetic
activity cannot be ascribed to "fight" or "rest" situations. For
example, standing up from a reclining or sitting position would entail
an unsustainable drop in blood pressure if not for a compensatory
increase in the arterial sympathetic tonus. Another example is the
constant, second-to-second, modulation of heart rate by sympathetic and
parasympathetic influences, as a function of the respiratory cycles. In
general, these two systems should be seen as permanently modulating
vital functions, in a usually antagonistic fashion, to achieve homeostasis.
Higher organisms maintain their integrity via homeostasis which relies
on negative feedback regulation which, in turn, typically depends on the
autonomic nervous system. Some typical actions of the sympathetic and parasympathetic nervous systems are listed below.
Target organ/system
Parasympathetic
Sympathetic
Digestive system
Increase peristalsis and amount of secretion by digestive glands
Decrease activity of digestive system
Liver
No effect
Causes glucose to be released to blood
Lungs
Constricts bronchioles
Dilates bronchioles
Urinary bladder and Urethra
Relaxes sphincter
Constricts sphincter
Kidneys
No effects
Decrease urine output
Heart
Decreases rate
Increase rate
Blood vessels
No effect on most blood vessels
Constricts blood vessels in viscera; increase BP
Salivary and lacrimal glands
Stimulates; increases production of saliva and tears
Inhibits; result in dry mouth and dry eyes
Eye (iris)
Stimulates constrictor muscles; constrict pupils
Stimulate dilator muscle; dilates pupils
Eye (ciliary muscles)
Stimulates to increase bulging of lens for close vision
Inhibits; decrease bulging of lens; prepares for distant vision
Adrenal medulla
No effect
Stimulate medulla cells to secrete epinephrine and norepinephrine
Sweat gland of skin
No effect
Stimulate sudomotor function to produce perspiration
The parasympathetic nervous system has been said to promote a "rest
and digest" response, promotes calming of the nerves return to regular
function, and enhancing digestion. Functions of nerves within the
parasympathetic nervous system include:
Dilating blood vessels leading to the GI tract, increasing the blood flow.
Constricting the bronchiolar diameter when the need for oxygen has diminished
Constriction of the pupil and contraction of the ciliary muscles, facilitating accommodation and allowing for closer vision
Stimulating salivary gland secretion, and accelerates peristalsis, mediating digestion of food and, indirectly, the absorption of nutrients
Sexual. Nerves of the peripheral nervous system are involved in the erection of genital tissues via the pelvic splanchnic nerves 2–4. They are also responsible for stimulating sexual arousal.
The enteric nervous system is the intrinsic nervous system of the gastrointestinal system. It has been described as the "second brain of the human body". Its functions include:
Sensing chemical and mechanical changes in the gut
A
flow diagram showing the process of stimulation of adrenal medulla that
makes it release adrenaline, that further acts on adrenoreceptors,
indirectly mediating or mimicking sympathetic activity
Acetylcholine
is the preganglionic neurotransmitter for both divisions of the ANS, as
well as the postganglionic neurotransmitter of parasympathetic neurons.
Nerves that release acetylcholine are said to be cholinergic. In the
parasympathetic system, ganglionic neurons use acetylcholine as a
neurotransmitter to stimulate muscarinic receptors.
At the adrenal medulla, there is no postsynaptic neuron. Instead, the presynaptic neuron releases acetylcholine to act on nicotinic receptors. Stimulation of the adrenal medulla releases adrenaline
(epinephrine) into the bloodstream, which acts on adrenoceptors,
thereby indirectly mediating or mimicking sympathetic activity.
Recent
studies indicate that ANS activation is critical for regulating the
local and systemic immune-inflammatory responses and may influence acute
stroke outcomes. Therapeutic approaches modulating the activation of
the ANS or the immune-inflammatory response could promote neurologic
recovery after stroke.
History
The specialised system of the autonomic nervous system was recognised by Galen.
In 1665, Thomas Willis used the terminology, and in 1900, John Newport Langley used the term, defining the two divisions as the sympathetic and parasympathetic nervous systems.
Caffeine effects
Caffeine is a bioactive ingredient
found in commonly consumed beverages such as coffee, tea, and sodas.
Short-term physiological effects of caffeine include increased blood pressure
and sympathetic nerve outflow. Habitual consumption of caffeine may
inhibit physiological short-term effects. Consumption of caffeinated
espresso increases parasympathetic activity in habitual caffeine
consumers; however, decaffeinated espresso inhibits parasympathetic
activity in habitual caffeine consumers. It is possible that other
bioactive ingredients in decaffeinated espresso may also contribute to
the inhibition of parasympathetic activity in habitual caffeine
consumers.
Caffeine is capable of increasing work capacity while individuals
perform strenuous tasks. In one study, caffeine provoked a greater
maximum heart rate while a strenuous task was being performed compared to a placebo.
This tendency is likely due to caffeine's ability to increase
sympathetic nerve outflow. Furthermore, this study found that recovery
after intense exercise was slower when caffeine was consumed prior to
exercise. This finding is indicative of caffeine's tendency to inhibit
parasympathetic activity in non-habitual consumers. The
caffeine-stimulated increase in nerve activity is likely to evoke other
physiological effects as the body attempts to maintain homeostasis.
The effects of caffeine on parasympathetic activity may vary
depending on the position of the individual when autonomic responses are
measured. One study found that the seated position inhibited autonomic
activity after caffeine consumption (75 mg); however, parasympathetic
activity increased in the supine position. This finding may explain why
some habitual caffeine consumers (75 mg or less) do not experience
short-term effects of caffeine if their routine requires many hours in a
seated position. It is important to note that the data supporting
increased parasympathetic activity in the supine position was derived
from an experiment involving participants between the ages of 25 and 30
who were considered healthy and sedentary. Caffeine may influence
autonomic activity differently for individuals who are more active or
elderly.
