Kindling; a model of focal epilepsy
(last updated July 2006)
A page from: Eric Hargreaves'Page O'Neuroplasticity

As the name "Kindling" suggests, a small spark applied to tinder will ignite a flame that eventually can grow into a roaring bonfire. Similarly, a small electrical stimulus, just large enough to trigger a brief "afterdischarge" or burst of epileptiform activity, if repeatedly applied, will eventually generate seizures that can lead to fully generalized behavioral convulsions. As such, kindling is one of the best models of secondary generalized temporal lobe epilepsy, and much of our understanding of how epilepsy works comes from the study of kindling.

Discovery

As in much of science, kindling was stumbled upon by accident, but also as in much of science, the significance and potential of the phenomena was instantly recognized and pursued in its own right. Originally, Graham Goddard was examining electrical stimulation of the amygdaloid complex and its effects on learning. During this examination, he noticed that a number of his rats developed seizures after repeated stimulation. Although it interfered with the current experiment, Goddard recognized that the brain was changing in response to a constant stimulus, and that this change constituted a form of plasticity, which could provide a useful neural model of epilepsy.

Goddard first reported the phenomenon of kindling in the late sixties (Goddard, 1967). In further work Goddard and his students demonstrated that kindling could also be induced chemically (Goddard, McIntyre and Leech, 1969). They also ruled out the pathologies of direct damage, edema, and metal toxicity as causes of kindling, demonstrating that the development of seizures resulted from the repeated stimulations. Another researcher Ron Racine, who had earlier examined the new phenomenon for his Ph.D. work, focused on the lowering of afterdischarge threshold, which appeared to be related to the increased seizure susceptability (Racine, 1972a). He further described the kindling progression in detail, delineating the progression into 5 distinct behavioral stages from motor arrest accompanied by facial automatisms (Stage 1) to fully kindled seizures accompanied by forelimb clonus and hindlimb tonus identified by rearing and bipedal instability (Stage 5) (Racine, 1972b).

Basic Properties of Kindling

But before getting into the full blown behavioral seizures, there are a number of EEG characteristics at the heart of Kindling that help define what is really going on.

Afterdischarge

Hippocampal After Discharge "Afterdischarge" or AD is at the very essence of kindling, whereby cell populations continue to fire in synchronous bursts after the driving stimulation has ceased; discharging after the stimulus, hence afterdischarge. An example of an afterdischarge is pictured at right. There is about a second and a half of normal hippocampal EEG recorded preceding the 1 sec 60Hz kindling train, seen as the solid green block extending beyond the vertical frame of the figure around the two second mark. The train is followed by a brief flattening of the EEG, and then by a growing, 3Hz synchronous bursting. The 3Hz spiking smoothly increases and decreases and increases in amplitude or "waxes and wanes".

Spike-and-Wave

The 3Hz spiking, if expanded to see the resolution clearly, also has a characteristic "spike-and-dome" or "spike-and-wave" shape, in which a high amplitude fast wave (spike) is followed by a much lower amplitude slow wave (dome), as depicted immediately below. Spike and Wave form of Hippocampal After Discharge Both the 3Hz frequency and the "waxing and waning" are characteristic of afterdischarge or epileptiform activity, which also is of a much greater amplitude than the normal EEG. Since the synchronous spiking involves a large majority of the cells discharging all at once, it is naturally larger than the normal asynchronous firing of the neurons, which frequently are silent for long periods of time. When the synchronous spiking dies out, the EEG is again flat, whereafter it recovers regaining its characteristic amplitude and seemingly "asynchronous" or random firing.

The AD in this case is very brief, lasting less than 10 seconds. In fact this was a first AD generated in the CA3-CA1 part of the "trisynaptic circuit" of the hippocampus, which with the amygdala and several other cortical regions make up the limbic system. The limbic system is overall fairly susceptible to seizures and is where much of kindling is studied, and where much of focal epilepsy can originate. Near the beginning of the AD train a few spikes are more complex and called "hyper-spikes".

Hyper-spikes

Hyper-spikes are spikes of lesser amplitude occurring in between or immediately following standard 3Hz spikes. Expanded on the right, as before, are a few spikes from near the beginning of the AD train that have double or hyper-spikes. Hyper-Spike form of Hippocampal After Discharge Hyper-spikes are echoes of other brain structures being recruited by the epileptiform activity. Hyper-spikes can also occur at the begininng of a seizure, when more than one structure may compete to be the dominant seizing foci, ultimately supressing the non-dominant structures activity temporarily. Alternately hyper-spikes can occur towards the middle or end of and AD, when other structures are being recruited by the initial seizing foci.

Secondary AD

At times the synchronous 3Hz spiking can wax and wane until it vanished, only to return seconds later in whats known as a "secondary AD", indicative of spreading seizure activity, and another hallmark of the kindling process. In contrast to hyper-spikes, where multiple structures are recruited simultaneously by the seizure, a single structure at a time holds the seizing activity. Secondary AD reflects the epileptiform activity being shunted from one structure to another and back again. Kinda' like a hot potato being passed around. This is in contrast to hyper-spikes where multiple structures can be recruited simultaneously. If the kindling process were to be continued in the above example, both processes would be evident as subsequent evoked ADs would grow in duration and complexity and eventually give rise to behavioral manisfestations.

Behavioral Manifestations

The spreading of seizure activity to the motor cortex is what leads to the later stages of kindling characterized by the obvious and observable behavioral manifestations of clonic jerking of the limbs and eventually the tonic rigidity as all muscle groups are simultaneously activated. Prior to the full seizure which literally can engulf the whole body are isolated seizure movements typically starting with facial automatisms and then spreading to include the hands. Homunculus Figurine

Jacksonian March

The spreading seizure activity at these stages often follow what is known as a "Jacksonian March", after Hughlings Jackson a pioneer in epilepsy from the 1800s. The principle of a "Jacksonian March" is that the seizure activity will engulf the motor cortex seemingly in stages, which will follow the body's sequence and degree of representation of the motor cortex. The form and degree of the body's brain representation is known as the "homunculous", or the little man inside and often is depicted much like the distorted little creature on the right.

Motor Homunculus

Penfield and Rasmussen (1950) Summary Motor Homunculus From stimulation studies The distortion represents the degree of cortex devoted to the representation. We have a large degree of motor control over very fine movements in our faces, allowing the complexity of communicative expressions, as well as communication, via speech itself. We also have very fine motor control over our fingers and hands, far more so than over our toes or feet. Subsequently, the motor cortex regions representing our face and hands are disproportionately large in comparison to the motor cortex regions representing our feet. As a result, behavioral manifestations of seizure activity are first detected in the face, and subsequently in the hands, as the seizure activity literally "marches" across the motor cortex recruiting more and more regions, and therefore more and more of the body's participation in the convulsions. On the right, is the "classic" mapping of the homunculus to a coronal slab of the motor cortex I've stolen from Wilder Penfield Portrait Penfield and Rasmussen's 1950 book: The cerebral cortex of man: a clinical study of localization of function. This was the summary figure of many years worth of work mapping out the motor cortex and other cortical functions in humans during neurosurgery, by electrically stimulting, with a small probe the opened surface of the brain, often during surgeries to specifically remove epileptic tissue. Although the mapping has proved invaluable to our understanding of cortical organization, it was done more importantly, case by case, to avoid removing important controlling areas, regardless, of whether they were epileptic foci or not. Historically, this brain mapping done by Wilder Penifield and his team is worth a page unto itself, and the Montreal Neurological Institue or MNI is often referred to as "The house that Wilder Built". However as I said, thats another story, for another time, and another page yet to be written (possibly by myself, although many others have already done so...).

Stages of Kindling

Returning to Kindling... ...All of these properties, particularl;y the behavioral manifestations of seizure activity...

End Stage of Kindling

Although by convention the 5th stage of kindling is considered to be its end state, kindling can be pushed beyond this level resulting in the development of spontaneous seizures (Pinel and Rovner, 1978). The changes caused by kindling also persist over long periods of time, and are generally viewed as being semi-permanent (Wada, Sato, and Corcoran, 1974; Dennison, Teskey, and Cain, 1995). Kindling is also a fairly general phenomenon, and has been demonstrated in all species in which it has been attempted, from the frog to the baboon (McNamara, 1986; Review). Kindling has also been found in humans, where a similar progression of seizures was triggered by tumours (Morrell, 1985). Kindling is also fairly general in that it can be induced throughout the brain (Racine, 1978; Review), with the possible exception of the cerebellum (Maiti and Snider, 1975). Thus, by describing in detail, kindling's progression and its parameters, and further demonstrating its universality across species and throughout the brain, kindling's usefulness as a model of human epilepsy was well established (Racine, 1978; Review).

Mechanisms of Kindling

Naturally, much work has gone into understanding the underlying mechanisms of kindling, allowing a better understanding of epilepsy. Over the years the involvement of the various neurotransmitter systems has been worked out, as well as much of the intracellular mechanisms (Reviews:Corcoran, 1988; Racine, 1978; Racine and Burnham, 1984; Wada, 1990). More recently, some of the research strives to understand the genetic mechanisms underlying kindling, through genetic expression (Review: McNamara, 1995) and through direct manipulation of the genetic code (Cain, et al., 1995; Watanabe et al., 1996).

Kindling and Learning

Kindling was also the first neuroplasticity phenomenon suggested to be useful for studying memory processes (Goddard and Douglas, 1975). It may sound odd to suggest that epileptic seizure activity could relate to learning, but its possible that the separate cascade of mechanisms constituting kindling and learning intersect and share a number of common mechanisms. For this reason both kindling and learning are viewed as phenomena of neuroplasticity.

In the end, kindling was surpassed by LTP as the neuroplasticity phenomena of choice for modelling memory processes, largely because LTP more closely approximated normal neural activity. However, although closer to normal firing patterns then kindling, LTP is still far from normal neural activity. As such, LTP may eventually be surpassed as a model of learning by plasticity phenomena that are even more subtle like PBP. This succession of neuroplasticity phenomena has made it important to understand how the various forms of plasticity like LTP and kindling are related (Reviews: Baudry, 1986; Cain, 1989). Similarly, some of the research examines the effects of kindling on learning and memory (Leung and Shen, 1991; Cain et al., 1993; McNamara et al., 1993; Sutula et al., 1995).

In a odd way, kindling research has come full circle, re-connecting with Graham Goddard's original discovery of the phenomenon while studying learning. Kindling's return to its point of origin is not without differences however, and much of the understanding provided by kindling has led to direct advancements in the development of effective treatments for the neurological disease of epilepsy. As such, the study of kindling continues to play one of the more important roles in neuroplasticty research.

Links to Canadian Scientists, who do Kindling Research...


(last updated July 2007)

Not too surprisingly, there is a lot of overlap between scientists who study LTP and scientists who study Kindling. I make no claim that this is a full and comprehensive list of all the individuals doing Kindling, just my list. If you wish to be included, just e-mail me.

  • Bob Adamec, Memorial University, Newfoundland, Canada.
  • Mac Burnham, Professor Emeritus, University of Toronto, Ontario, Canada.
  • Peter Cain, Full Professor, University of Western Ontario, London Ontario, Canada.
  • Mike Corcoran, University of Saskatchewan, Saskatchewan, Canada.
  • Stan Leung, University of Western Ontario, London Ontario, Canada.
  • Dan McIntyre, Carleton University, Ontario, Canada.
  • John Pinel, University of British Columbia, Vancouver B.C., Canada.
  • Ron Racine, McMaster University, Hamilton Ontario, Canada.
  • Cam Teskey, University of Calgary, Alberta, Canada.

Kindling References...

Baudry, M. (1986). Long-term potentiation and kindling: similar biochemical mechanisms? In A.V. Delgago-Escueto, A.A. Ward Jr., D.M. Woodbury, and R.J. Porter (Eds) Advances in Neurology, 44, 401-410.

Cain, D.P. (1989). Long-term potentiation and kindling: how similar are the mechanisms? Trends in Neuroscience, 12, 6-10.

Cain, D.P., Grant, S.G.N., Saucier, D.M., Hargreaves, E.L., and Kandel, E.R. (1995). Fyn tyrosine kinase is required for normal amygdala kindling. Epilepsy Research, 22, 107-114.

Cain, D.P., Hargreaves, E.L., Boon, F., and Dennison, Z. (1993). An examination of the relations between hippocampal long-term potentiation, kindling, afterdischarge, and place learning in the water maze. Hippocampus, 3, 153-164.

Corcoran, M.E. (1988). Characteristics and mechanisms of kindling. In P. Kalivas and C. Barnes, (Eds) Sensitization of the Nervous System, pp81-116.

Dennison, Z., Teskey, G.C., and Cain, D.P. (1995). Persistence of kindling: effect of partial kindling, retention interval, kindling site, and stimulation parameters. Epilepsy Research, 21 171-82.

Goddard, G.V. (1967). Developnment of epileptic seizures through brain stimulation at low intensity. Nature, 214, 1020-1021.

Goddard, G.V. and Douglas, R.M. (1975). Does the engram of kindling model the engram of normal long term memory. Jounral of Canadian Science and Neurology, Nov, 385-394.

Goddard, G.V., McIntyre, D.C., and Leech, C.K. (1969). A permanent change in brain function resulting from daily electrical stimulation. Experimental Neurology, 25, 295-330.

Leung LS. and Shen B. (1991). Hippocampal CA1 evoked response and radial 8-arm maze performance after hippocampal kindling. Brain Research. 555 353-7.

McNamara, R.K., Kirkby, R.D., dePape, G., Skelton, R.W., and Corcoran, M.E. (1993). Differential effects of kindling and kindled seizures on place learning in the morris water maze. Hippocampus, 3, 149-152.

McNamara, J.O. (1986). Kindling model of epilepsy. In A.V. Delgago-Escueto, A.A. Ward Jr., D.M. Woodbury, and R.J. Porter (Eds) Advances in Neurology, 44.

McNamara J.O. (1995).Analyses of the molecular basis of kindling development. Psychiatry & Clinical Neurosciences, 49, S175-8.

Maiti, A and Snider, R.S. (1975). Cerebellar control of basal forebrain seizures: amygdala and hippocampus. Epilepsia, 16, 521-533.

Morrell, F. (1985). Secondary epileptogenesis in man. Archives of Neurology, 42, 318-335.

Pinel, J.P.J, and Rovner, L.I. (1978). Experimental epileptogenesis: Kindling-induced epilepsy in rats. Experimental Neurology, 58, 190-202.

Racine, R.J. (1972a). Modification of seizure activity by electrical stimulation. I. After-discharge threshold. Electroencephalography and Clinical Neurophysiology, 32, 269-279.

Racine, R.J. (1972b). Modification of seizure activity by electrical stimulation. II. Motor seizure. Electroencephalography and Clinical Neurophysiology, 32, 281-284.

Racine, R.J. (1978). Kindling. The first decade. Neurosurgery, 3, 234-252.

Racine, R.J. and Burnham, W.M. (1984). The Kindling model. In P.A. Schwartzkroin and H. Wheal (Eds) Electrophysiology of Epilepsy pp153-171.

Sutula T., Lauersdorf S., Lynch M., Jurgella C. and Woodard A. (1995). Deficits in radial arm maze performance in kindled rats: evidence for long-lasting memory dysfunction induced by repeated brief seizures. Journal of Neuroscience, 15, 8295-8301.

Wada, J.A. (Ed) (1990). Kindling 4. Plenum Press:New York.

Wada, J.A., Sato, M. and Corcoran, M.E. (1974). Persistent seizure susceptability and recurrent spontaneous seizures in kindled cats. Epilepsia, 15, 465-478.

Watanabe Y., Johnson RS., Butler LS., Binder DK., Spiegelman BM.Papaioannou VE., McNamara JO. (1996). Null mutation of c-fos impairs structural and functional plasticities in the kindling model of epilepsy. Journal of Neuroscience, 16 3827-36.