Thanks for the reference. I am familiar with Post's work and I have seen
papers on the quenching procedure that employed low frequency stimulation as
a means to depotentiate epileptogenic foci before, however. I haven't read
any of his low intensity current work. The low frequency paradigm they
adopted is routinely employed to study long-term depression in the
hippocampus, neocortex, cerebellum, etc. I think 15 microAmp stimulation
had the most advantageous effect for retarding the development of kindling.
In the reference you provided, the authors suggested that the quenching
effects did not depend upon low frequency stimulation especially since
low-frequency stimulation did not appear to change or diminish the
ameliorative effects of DC stimulation. (This is an extremely important
point because this suggestion contradicts their own previous work and the
work of others on this matter).
I thought it was interesting to note that they have reported a dense silver
staining surrounding the foci region. The silver staining at least suggests
the possibility of degrading neurons within the region, but it is quite
unfortunate that they did not assess necrosis or apoptosis in their animals.
What I thought was interesting was that there unpublished studies showed
increased GFAP (a glial cell marker) within this silver staining "halo".
Considering that the most likely labeled cells would be astrocytes and
considering the homeostatic and regulatory role that these cells play
especially during epilepsy, it seems very likely that these could be the
targets that may be actively responsible for modulating the responsiveness
of these "epileptic" neurons during their kindling procedure.
I don't buy the gap junction possibility that was suggested earlier simply
because gap junctions are not that ubiquitous within the basolateral
amygala. Perhaps if the AD threshold changes were recorded in the dentate
or CA1, then perhaps gap junctions would be at least partially responsible.
Moreover, it has been well-established that continual low frequency
stimulation can cause significant changes to the GABA receptor, such that
increased binding can occur at the benzodiazepine binding site in the
GABA(A) receptor. Perhaps receptor changes similar to this can occur during
the DC stimulation.
I am quite surprise that they never considered that these low threshold
currents may in fact activate different calcium channels during stimulation.
They basically ignored the possibility that gene transcription and
subsequent protein synthesis may be one of the causal factors involved in
mediating this effect, especially in light of the long-lasting effect that
this DC stimulation paradigm had. Specific frequencies of stimulation and
even different intensities of current have all been shown to activate,
modulate, and suppress voltage-dependent calcium channels differently.
Moreover, spatiotemporal modulation of these channels would evoke different
signal cascades within the cell that could lead to transient enhancement or
transient suppression in excitatory properties of neurons (see Johnston and
Magee).
As far as clinical efficacy goes it seems really interesting and promising.
I did a very quick first-order calculation of habituation that would occur
from these cells in response to the 15 min. DC current stimulations daily.
Habituation to this stimulation protocol would occur around 96 days. That is
theoretically the neurons should stop responding to the DC current by this
time point. If the scaring can be prevented this might serve as an extremely
useful adjunctive treatment.
NMF
"Klenow" <bakedbeans at spam.not> wrote in message
news:afkXb.32855$9U3.29342 at fe09.usenetserver.com...
> In our journal club, we were discussing their chapter in the book Kindling
5
> where they describe the Quenching effect on kindling. We're pretty
> skeptical about it so we looked to see what else they had done on it. I'm
> curious to know what people think of this.
>> Here's the article...
>> 1: Exp Neurol. 1998 Nov;154(1):185-92.
>> Quenching revisited: low level direct current inhibits amygdala-kindled
> seizures.
>> Weiss SR, Eidsath A, Li XL, Heynen T, Post RM.
>> Biological Psychiatry Branch, National Institute of Mental Health,
Bethesda,
> Maryland 20892, USA.
>> We have reported that low frequency stimulation (1 Hz for 15 min), applied
> after
> kindling stimulation of the amygdala, inhibited the development and
> expression
> of amygdala-kindled seizures, an effect we termed quenching. Subsequently,
> we
> discovered that this effect could only be achieved when certain
stimulators
> were
> used that also emitted a low-level direct current (DC). The studies
reported
> here indicate that DC, applied once daily for 15 min at intensities of
5-15
> microA, produced an intensity-related attenuation of kindling development
> and an
> increase in the afterdischarge threshold. This effect persisted in some
> animals
> for at least 1 month after discontinuation of the DC. In fully kindled
> animals,
> a robust increase in seizure threshold and persistent seizure inhibition
> were
> also observed using 10 microA of DC administered for 14 days. These
results
> clarify and extend our original findings of a quenching effect; however,
the
> mechanisms by which low level DC induces quenching require further
> elucidation.
>>> "NMF" <nm_fournier at ns.sympatico.ca> wrote in message
> news:JEjXb.17152$sO4.1541938 at news20.bellglobal.com...> > Your right that really is a low current, however, depending on where
they
> > implanted the electrode you might be able produce an electrolytic lesion
> > with extremely low current. It might depend on whether they were using
> > monophasic, biphasic fast ramps to deliever the stimulus current.
> However,
> > I think you said it was a low but constant current intensity, so square
> wave
> > currents (which can elicit lesions at very low current intensities) are
> out
> > of the picture. For example, in the dentate with a low intensity
current
> > many cells have been shown to readily elicit prolonged burst firing.
The
> > prolonged period of burst firing will allow for greater calcium entrance
> > into the cell and the potential for deleterious accumulations of
> > intracellular calcium, activation of internal stores, and consequential
> > secondary messenger cascades.
> >
> > Generally the microcurrents used in many peripheral nerve stimulation
> > experiments are in the 50-100 microAmp range. Moreover, they elicit
> potent
> > analgesic responses. (This is the premise of electroacupuncture
> paradigms).
> > So definitely potent cellular responses are likely at the low currents
you
> > suggest. As an aside point, even picotesla intensity magnetic fields
have
> > been shown to elicit profound neuronal responses. (no evidence of cystic
> > lesions though). So definitely low intensity currents can elicit potent
> > biological effects.
> >
> > Technically, it doesn't surprise me all that much that you can get a
> > deleterious effect with such low intensity. The cellular responses to
> > electrical stimulation is often a U-shaped curve. With extremely minimal
> > currents eliciting similar effects to that of high intensity currents.
In
> > this case its probably the temporal component (the fact that its a long
> > duration low intensity current) that is causing the effect similar to
what
> > would be encountered at higher intensity currents but have short time
> range.
> > That is also a common finding in sensory and motoric systems. But its
> also
> > a routine finding in the literature involving learning and LTP vs. LTD
> > (long-term potentation vs. long-term depression), where the specific
level
> > of current intensity determines which type of behavioral (physiological)
> > response occurs.
> >
> > I wouldn't mind if you provided the citation to that paper.
> >
> > Thanks,
> >
> > NMF
> >
> >
> >
> > "Klenow" <bakedbeans at spam.not> wrote in message
> > news:PxiXb.9020$%h1.7659 at fe24.usenetserver.com...> > >
> > > I've recently read a paper looking at the effects of 15 minutes of
> direct
> > > current stimulation (5-15 uA) through a chronic indwelling electrode
on
> > > kindled seizure thresholds in rats. Can this type of stimulation
cause
> an
> > > electrolytic lesion at the electrode tip even with such low current?
> I've
> > > been looking through brain stimulation books and can't find an answer.
> > >
> > > --
> > > -----
> > >
> > >
> > >
> >
> >
>>>
