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Neuroselectivity, Hyperesthesia and Pain
Neuroselectivity Overview
Hyperesthesia and Allodynia
Pain Tolerance Threshold (PTT)
and the Percentile Allodynia Test
Direct Nerve Fiber Stimulation
fMRI and Neurometer
Evoked Sensation and Pain
[PDF
version with References]
Neuroselectivity
Overview
(website references)
The Neurometer generates a constant alternating current (AC) stimulus to
evoke nerve selective responses from major sub-populations of sensory nerve
fibers. The
three major sub-populations of sensory nerve
fibers are defined by their morphologic, electrophysiologic and functional
(e.g. pain vs. non-pain transmission) characteristics. The smallest diameter
unmyelinated fibers comprise greater than eighty percent of the total
fibers, possess the longest refractory periods and the slowest average
conduction velocities (CV) of 1 m/s. In contrast, large diameter myelinated
fibers comprise less than ten percent of the total fibers, have the briefest
refractory periods and fastest average CV of 60 m/s. Neuroselectivity is
achieved by using three different frequencies of an electrical sinewave
stimulus (2000 Hz, 250 Hz and 5 Hz), taking advantage of this waveform’s
frequency dependent rate of depolarization. Large diameter fibers can
generate action potentials in response to the rapid 2000 Hz stimulus but
small fibers require several milliseconds of continuous depolarization (i.e.
low frequency stimulation, e.g., 5 Hz), to reach threshold potential. Large
fibers will generate action potentials to the 5 Hz stimulus, but not at
physiologically significant rates. Additionally, the quantity of electrons
or charge per depolarization of a 5 Hz sinewave (100 msec) is 400 times the
charge and duration of a 2000 Hz sinewave depolarization (0.25 msec).
Together, these factors result in the 2000 Hz stimulus selectively evoking
physiologically significant large myelinated fiber responses and the 5 Hz
stimulus selectively evoking physiologically significant unmyelinated fiber
responses.
The neuroselective nature of the sinusoid waveform electrical stimulus was
first demonstrated in a study comparing the application of a variety of
waveform types on healthy individuals at Johns Hopkins in the 1980's.
Neurometer measures have been compared with the results of other
physiological /imaging, diagnostic, histologic and pharmaceutical studies.
These and other studies involving nerve regeneration, ischemia and
neuroselective pathological conditions have corroborated the neuroselective
nature of this stimulus. The CPT measures also have the unique ability of
evaluating pathologies such as hyperesthesia and hypoesthesia that may
selectively occur in one or more subpopulations of sensory fibers while
sparing the others.
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Hyperesthesia and Allodynia
Hyperesthesia, as measured by abnormally low neuroselective Current
Perception Threshold (CPT) measures, reflects an increased electrical
excitability of sensory nervous tissue for the evocation of responses. The
resting membrane potential of the sensory nerve fiber increases as the
result of stresses such as hyperglycemia. An elevated resting membrane
potential decreases the intensity of the excitatory electrical stimulus
required to reach the threshold required to evoke an action potential
response. In other words, less electrical energy is required to evoke a
neuronal response.
Hyperesthesia is reported in the early stages of progressive neuropathy
affecting both pre-diabetics and newly diagnosed diabetics. Other early
occurrences of hyperesthesia are present in alcoholism, Carpal Tunnel
Syndrome (CTS) and radiculopathy. A different type of
hyperesthesia results
from chronic hereditary sensory neuropathies associated with lysosomal
storage disorders and primary biliary cirrhosis, demyelinating
polyneuropathies and infectious conditions (eg. HIV, Lyme Disease). Other
neurodiagnostic tests, (e.g. sensory nerve conduction velocity, quantitative
tactile, vibration and thermal thresholds) are insensitive to the
hyperesthetic condition which is often sub-clinical.
Progressive peripheral
neuropathy can be characterized by stages of development. The earliest stage
is most often sensory hyperesthesia, defined as abnormally low sensory
thresholds or increased ability to respond to stimulation. This condition
that represents, for example, the neuritis that can precede neuropathy or
the radiculitis that can precede radiculopathy. The sensory Nerve Conduction
Threshold (sNCT) Current Perception Threshold (CPT) measure is unique
because it is the only neurodiagnostic test capable of detecting
hyperesthesia. This is sometimes sub-clinical condition (eg. insulin
resistance without diabetes, metabolic syndrome). Hyperesthetic conditions
may be quantified in both large and small fibers. This condition may
coexists with hypoesthetic measures from the same test site in different
sub-populations of nerve fibers. Other Quantitative Sensory Tests (QSTs) and
electrodiagnostic tests also lack this capability. The hyperesthetic measure
does not imply a loss of function. This condition may precede symptomatology
or be the most symptomatic. The pathological progression of sensory nerve
hyperesthetic pathology may progress to hypoesthesia or, ultimately,
anesthesia. Hypoesthesia is defined as abnormally elevated sensory
thresholds or decreased ability to respond to stimulation. The advanced
stages of neuropathy may also be associated with the loss of motor nerve
function and symptoms of weakness. Treatment of the condition causing the
neuropathy at the earliest stages, when it is limited to the sensory nerves
should allow for a better prognosis. Sensory nerves can regenerate. Motor
neuropathy resulting in muscle denervation (atrophy) is essentially an
irreversible condition. There will be some collateral sprouting of axons but
complete return of function, without surgical intervention, is rare. Early
detection is the key to successful intervention.
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Pain Tolerance Threshold (PTT)
and the Percentile Allodynia Test
When the Neurometer stimulus is administered at intensities greater than the
painless CPT sensory threshold it is possible to evoke painful sensation.
Under patient control, the maximum tolerable intensity neuroselective
stimulus is defined as the Pain Tolerance Threshold (PTT). The PTT has been
demonstrated to be a reliable measure for the evaluation of pain and select
analgesic agents. Allodynia is characterized by increased sensitivity to a
non-noxious stimulus which the subject characterizes as "painful". Allodynia
may be evaluated by neuroselective Pain Tolerance Threshold (PTT) measures
as well as the less painful “Percentile Allyodynia Test”. CPT hyperesthesia
and PTT allodynia may occur as neuroselective and independent sensory
conditions. For example, spinal opiates do not affect the 2000 Hz, 250 Hz or
5 Hz painless CPT measures or the 2000 Hz and 250 Hz PTT measures but they
selectively elevate 5 Hz PTT measures in humans. Similar Neurometer neuroselective response measures have been reported from rats.
Direct Nerve Fiber Stimulation
Neurometer CPT and PTT measures are not receptor or end-organ mediated. The
electrical stimulus bypasses the end-organs and directly excites the nerve
fibers. Skin freeze or burn lesions precipitate the local release of an
“inflammatory broth” (e.g. bradykinins, prostaglandins, leukotrienes,
substance P, etc.) which bind to receptors resulting in local sensory
thermal and tactile threshold changes. Thermal allodynia (pain evoked by
normally painless heat stimulus) and tactile allodynia (pain evoked by a
normally painless tactile stimulus, e.g., Von Frey filament stimulus) occurs
with these lesions. Research has demonstrated that sNCT electrical
allodynia, however, does not occur with the skin freeze model and other
differences between these types of stimuli that may be due to their
different site of stimulation, i.e.,
end-organ vs direct nerve stimulation.
fMRI and Neurometer
Evoked Sensation and Pain
Functional magnetic resonance imaging studies from the Massachusetts General
Hospital demonstrate that heat pain and 5 Hz sNCT evoked pain increase
metabolic activity in the same areas of the brain; however, there is a
habituation to the heat pain stimulus that does not occur with the
electrical pain stimulus. Studies from the University of California at
Irvine using high field functional Magnetic Resonance Imaging (hfMRI) in
healthy subjects brains using the 5 Hz CPT and PTT stimuli, demonstrated
distinct CNS localizations for the discrimination of the stimulus intensity
(primary somatosensory cortex, insula) versus the its pain intensity
(secondary somatosensory cortex). Using shielded electrode cables the
Neurometer and fMRI are combined using an external computer control program
for the functional/imaging evaluation of painless and pain evoked responses in the CNS.
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