The Kindling Hypothesis
The kindling hypothesis describes a neurobiological phenomenon where repeated, initially subthreshold electrical or chemical stimuli progressively increase brain excitability, ultimately leading to spontaneous seizures and permanent alterations in neural function—a model that has been extended conceptually to explain progressive worsening in epilepsy, affective disorders, and chronic pain syndromes. 1, 2
Core Mechanism
The classical kindling model involves the following progressive changes:
Progressive seizure development: Repeated application of initially subconvulsive electrical stimulations (typically 1-second duration) produces seizures of progressively increasing severity, culminating in full-blown tonic-clonic convulsions with rearing and falling 1, 2
Lowered seizure threshold: The after-discharge threshold decreases over time, with lengthening and spatial spread of electrical discharges 1
Permanent state change: Once established, the increased excitability becomes lifelong and animals develop spontaneous seizures even without further stimulation 2, 3
Anatomical sensitivity: The amygdala is the most frequently studied and most sensitive brain region for kindling induction 1
Neurobiological Alterations
Kindling produces persistent molecular and cellular changes:
Synaptic modifications: Changes occur at the synapse level, including increased efficacy at excitatory synapses and/or decreased effectiveness at inhibitory synapses 2
Receptor changes: A novel population of NMDA receptors emerges in hippocampal region CA3, with a 2.8-fold increase in specific receptor binding sites that persists for at least 28 days after the last seizure 4
Gene expression patterns: Evolving spatio-temporal expression of immediate early genes, neurotrophic factors, and late effector genes accompanies the kindling process 1
Neurotransmitter depletion: Catecholamine depletion in kindled tissue supports decreased inhibitory function 2
Absence of gross damage: These changes occur without overt tissue damage, distinguishing kindling from lesion-based models 2, 3
Clinical Relevance and Extensions
Direct Application to Epilepsy
Homologous model: Kindling directly models certain epileptic syndromes and pharmacological seizures induced by agents like cocaine and lidocaine 1
Generalized susceptibility: The increased seizure proclivity generalizes beyond the initial kindling stimulus to other convulsive agents 3
Temporal lobe epilepsy: Kindling shares multiple features with human limbic/temporal lobe epilepsy, including underlying circuits and pathophysiology, though not all findings translate directly to human conditions 5
Conceptual Extension to Other Disorders
Important caveat: The application of kindling principles to non-epileptic conditions represents non-homologous modeling with significant limitations 1
Affective disorders: Recurrent episodes of mood disorders may exhibit kindling-like progression, where episodes become more frequent and severe over time, eventually occurring spontaneously without clear triggers 1, 6
Pain syndromes: Some chronic pain conditions demonstrate progressive sensitization patterns that share conceptual elements with kindling mechanisms 1
Chemical kindling: Low-level repeated exposure to certain pesticides (chlorinated hydrocarbons) can induce kindling-like states 3
Critical Limitations
When applying kindling concepts beyond epilepsy:
Different neuroanatomical substrates: Non-epileptic syndromes involve different brain regions and biochemical processes than classical kindling 1
Indirect inferences only: Conclusions drawn from kindling for affective or pain disorders must be tested directly in clinical populations rather than assumed 1
Distinguishing primary from adaptive changes: Separating genes involved in primary pathological progression from those representing secondary adaptive responses is crucial for therapeutic targeting 1