J Clin Psychiatry 75(6):587593, Labonte B, Suderman M, Maussion G, Lopez JP, Navarro-Sanchez L, Yerko V, Mechawar N, Szyf M, Meaney MJ, Turecki G (2013) Genome-wide methylation changes in the brains of suicide completers. Once kindled, the organism is susceptible to seizures from otherwise nonconvulsive drugs such as morphine[51]. Kindling, behavioral sensitization, and related models of neuroplasticity have had considerable theoretical and clinical appeal for investigators struggling to comprehend the complex biopsychosocial interactions that underlie various human neurobehavioral syndromes. It is on this basis that we draw parallels between nociception-induced sensitization at the spinal level and sensitization in corticolimbic pain pathways. What is responsible for this multifaceted symptom complex? The LAPS hypothesis, although framed with reference to the shared neurobiologic substrate of nociception and emotion, should not be construed as biologic reductionism. Treede RD Kenshalo DR Gracely RH Jones AK. Amygdala hijack can happen to anyone and is usually triggered by something, causing the amygdala to 'disable' the frontal lobes and take control of your emotional responses. However, behavioral sensitization (to recurrent stressors and psychomotor stimulants) and kindling of seizures both provide clues to mechanisms in the progressive course of bipolar disorder. Rather, its significance is as a window on the mechanisms of neuroplasticity at molecular and behavioral levels. Gracely also developed the concept of the affective processor that functions as an amplifier of affective outflow, analogous to a gain control mechanism. An estimated 30% to 50% of clinic-based chronic pain patients suffer from major depressive disorder[20]. Pediatrics 136:e1178e1185, PubMed Results: Early life stress is a risk factor for the development of episodes . Three-week-old Wistar rats underwent rapid kindling: 84 initially subconvulsant electrical stimulations of ventral hippocampus . Two points are of particular interest: first, there is evidence that patients with migraine and affective illness show increased vulnerability to stress; and second, both disorders tend to progress from infrequent, discrete episodes to more frequent recurrences and even constancy (i.e., transformed migraine and intercurrent dysthymia). PubMed Early abuse and neglect can deregulate the child's de-veloping neurobiological system by reducing its resistance to stressful events, leading to later problems of emotional regulation. We will now summarize these properties and their relevance to the sensitized pain state we identify as LAPS. When other affective spectrum disorders are included (e.g., anxiety disorders, subacute depression), estimates of psychiatric comorbidity are considerably higher[21]. Neurosurgical Treatment in Psychiatry, Pain, and Epilepsy. Kindling-induced amplification at the corticolimbic level is a mechanism that can account for the disproportionate severity of pain in LAPS in relation to peripheral afferent activity. Birbaumer et al. Fam Process 55(3):483499, Miklowitz DJ, Schneck CD, Singh MK et al (2013) Early intervention for symptomatic youth at risk for bipolar disorder: a randomized trial of family-focused therapy. The development of LAPS, therefore, would seem to be related in part to random events that determine the pattern of noxious stimulation encountered by the person. Expression of c-Fos immunoreactivity in transmitter-characterized neurons after stress. It remains a mainstay of epilepsy related research, but the question remains how the results from kindling experiments further our . Painful illnesses/injuries and stressful life events are ubiquitous. Kindling mechanisms have been considered in the pathophysiology of migraine[7], trigeminal neuralgia[8] and other painful conditions[9]. Google Scholar, Hudziak JJ, Albaugh MD, Ducharme S et al (2014) Cortical thickness maturation and duration of music training: health-promoting activities shape brain development. 1999; Racine, et al. In contrast, pain patients showed similarly high-wave amplitudes with both stimulus conditions. In this article, we draw on research on neuroplastic processes in corticolimbic structures to model the linkage between the sensory and affective domains of pain. kindler n. American Heritage Dictionary of the English Language, Fifth Edition. [1] Symptoms typically include anxiety, shakiness, sweating, vomiting, fast heart rate, and a mild fever. Comparison of human cerebral activation pattern during cutaneous warmth, heat pain, and deep cold pain. Patterns in behavioral neuroanatomy: association areas, the limbic system, and hemispheric specialization. Shared mechanisms in affective illness, epilepsy, and migraine. Any model that would advance our understanding of chronic pain disorders must address this complexity because unidimensional theories of causation of biopsychosocial illnesses invariably lead to oversimplifications. The NMDA antagonist, MK-801, suppresses long-term potentiation, kindling, and kindling-induced potentiation in the perforant path of the unanesthetized rat. Thalamic and extrathalamic pathways then carry nociceptor-derived signals to limbic and paralimbic regions and continue rostrally through projections to prefrontal and motor cortices. The second component (secondary pain affect) in the 2-stage model involves affective/cognitive responses that are triggered by the composite (primary) unpleasant sensory event. In one example, if electrical stimulation of the amygdala varies significantly from the optimal frequency of once daily at the requisite amplitude, then either kindling does not evolve or inhibition (LTD) is registered[108,109]. Does kindling model anything clinically relevant? Prevailing theories have explained the linkage between the affective, cognitive, and sensory dimensions of pain in several ways: (1) gating mechanisms in the dorsal horn[1] (2) cognitive- and behavioral-mediating factors[113]; (3) psychophysiologic mechanisms such as muscle tension[105]; and (4) shared neurobiologic substrates[32]. In the standard model of kindling, continued subthreshold stimulation eventually produces a quantum-like increase in response (i.e., the development of seizures). Neocortical and limbic sites show different behavioral manifestations of kindling, but not all involve ictal discharge. It appears that some form of sensitization in response to noxious stimulation can occur at multiple levels in the neuraxis. Anyone you share the following link with will be able to read this content: Sorry, a shareable link is not currently available for this article. In patients who have recurrent affective illnessmajor depression, bipolar disorder, post-traumatic stress disorderthe clinical features indicative of sensitization can be conceptualized within an endogenous versus reactive framework. The medial pain system has limited somatotopic organization. The kindling effect occurs due to changes in the brain due to multiple relapses by a person trying to quit drugs or alcohol. Lenz and colleagues[80] have proposed that deep brain stimulation in a region of the somatosensory thalamus reproduces pain with strong affective loading only in patients who had previously experienced such affectively charged pain. This indicates that cross-sensitization extends to psychosocial stressors. Springer, Cham. According to Vogt et al. Hirayama T Dostrovsky JO Gorecki J Tasker RR Lenz FA. Giesler et al. At the end stage of illness, cycling of mood may occur many times a day without apparent external triggers. Post and Silberstein[7] proposed that the excitatory amino acidmediated cascade giving rise to chronic neuropathic pain has features also found in the progression of neurobiologic events in kindling. It is hoped that a better understanding of sensitization and kindling-like mechanisms will add neurobiological rationales for the importance of prevention and sustained prophylactic intervention in rendering bipolar disorder a more benign illness. The Organization of Behavior; A Neuropsychological Theory. Both factors have been shown to influence kindling susceptibility[15,60]. The kindling model of corticolimbic sensitization allows us to describe in neurobiologic terms the mechanisms of cellular/synaptic memory that register the ebb and flow of experience. Therefore, inFigure 1 we have included a gain mechanism within the sensory pain pathway that projects from the ventral posterolateral and ventral posteromedial thalamic nuclei to primary and secondary somatosensory cortices. Perlin JB Gerwin CM Panchision DM Vick RS Jakoi ER DeLorenzo RJ. Their distress is multifaceted. Melzack[77] has proposed an overarching construct that he has termed the neuromatrix and has described how disruptions in the integrity of the neuromatrix can account for symptoms such as phantom limb pain. The full significance of these overlapping neuroanatomic and neurochemical findings awaits further study. Addictive behavior and kindling: relationship to alcohol withdrawal and cocaine. This result underscores the point that various amplitudes and frequencies of stimulation may lead to either sensitization or inhibition, and a resulting element of chance is introduced[108]. Howard P. Rome, Jr, PhD , Jeffrey D. Rome, MD, Limbically Augmented Pain Syndrome (LAPS): Kindling, Corticolimbic Sensitization, and the Convergence of Affective and Sensory Symptoms in Chronic Pain Disorders, Pain Medicine, Volume 1, Issue 1, March 2000, Pages 723, https://doi.org/10.1046/j.1526-4637.2000.99105.x. Taken together, these studies . The origin of tic douloureux: a unified view. ILAR 55(2):221232, CAS The kindling phenomenon is first described. Nociception-induced c-fos immunoreactivity has been observed in rats in these limbic and interconnected cortical and brainstem regions: (1) cingulate, retrosplenial, insular, perirhinal, and entorhinal cortices; (2) periaqueductal gray matter; (3) locus ceruleus; (4) several thalamic nuclei; (5) lateral septal area; (6) dorsomedial hypothalamus; and (7) amygdala[8891]. A heightened sensitivity to even minor traumatic events ensues. Cocaine: Clinical and Biobehavioral Aspects. https://doi.org/10.1007/7854_2020_172, DOI: https://doi.org/10.1007/7854_2020_172, eBook Packages: Biomedical and Life SciencesBiomedical and Life Sciences (R0). We suggest that kindling is a cogent model for nociception-induced neuroplastic changes that can develop in the limbic system and other supraspinal structures (i.e., corticolimbic sensitization) and can produce a clinical picture of persistent pain, affective dysregulation, and behavioral disturbance. J Psychiatr Res 81:6370, Post R, Leverich G, Kupka R et al (2016b) Age of onset of bipolar disorder related to parental and grandparental illness burden. The correlation between the number of cells expressing c-fos and pain behavior is strong[92]. Contingent tolerance to the anticonvulsant effects of carbamazepine: relationship to loss of endogenous adaptive mechanisms. Oxford University Press, New York, Post RM (2016a) Epigenetic basis of sensitization to stress, affective episodes, and stimulants: implications for illness progression and prevention. Such patients tend to gravitate to pain clinics and have been written about extensively[2224]. Neuroanatomy and neurochemical mechanisms of time-dependent sensitization. PubMed Central Long-term depression of excitatory synaptic transmission and its relationship to long-term potentiation. Neuroendocrine effects of limbic activation by electrical, spontaneous, and pharmacological modes: relevance to the pathophysiology of affective dysregulation in psychiatric disorders. The recognition of this cluster of symptoms is far from new. Lancet Psychiatry 4:208217, Clinical Professor of Psychiatry, George Washington University School of Medicine, Bipolar Collaborative Network, Bethesda, MD, USA, You can also search for this author in Kindling produces long-lasting and selective changes in gene expression of hippocampal neurons. First, kindling offers a neurobiologic model for investigating the mechanisms and pathways that mediate the relationship between the organism and its environment. This has proven especially useful in developing alternative pharmacologic treatments for bipolar disorder[98,99]. Each stressful event in her life, whether a disagreement with her spouse, doing too much work in her garden, or worrying about a new swelling sensation in the affected limb is accompanied by a generalized flare in her sensory/affective/behavioral symptom complex. Amplification at the spinal level transmits a message to cerebral regions that includes not only information about the activity of peripheral nociceptors, but also additional information contributed by sensitized spinal circuitry. Ophoff RA Terwindt GM Vergouwe MN et al. J Clin Psychiatry 71(7):864872, Post RM, Fleming J, Kapczinski F (2012) Neurobiological correlates of illness progression in the recurrent affective disorders. Pain affect encoded in human anterior cingulate but not somatosensory cortex. The similarities among neuroplastic processes at different levels of the CNSand across speciesare underscored by the fact that windup, central (spinal) sensitization, and corticolimbic sensitization share molecular mechanisms, including mediation by the n-methyl- d-aspartate (NMDA) receptor[66]. Sensitization to stressors, episodes, and substances of abuse each appear driven by epigenetic mechanisms and their accumulation on DNA, histones, and microRNA. KINDLING: "Kindling is often used as an experimental model for epilepsy ." However, since the amygdala has been found to be . equilibrium can be reliably elicited (Racine, 1972a). It also suggests that learned associations linking substantially separate sensory and affective pathways are formed in such a way as to be reproduced as an ensemble (i.e., a composite of sensation, affect, and cognition) by stimulation of a single brain region. The term connotes a sensitized cerebral condition characterized by amplified responses to stimuli, spontaneity (autonomy) of centrally driven processes, the recruitment of additional features through neuroanatomic spreading, and pathologic responsiveness to novel/non-nociceptive stimuli (cross-sensitization). Coderre TJ Katz J Vaccarino AL Melzack R. Fishbain DA Cutler R Rosomoff HL Rosomoff RS. This complication was compared to the kindling phenomenon described by Goddard. The influence of prior synaptic activity on the induction of long-term potentiation. Casey KL Minoshima S Morrow TJ Koeppe RA. Systemic morphine suppresses noxious stimulus-evoked Fos protein-like immunoreactivity in the rat spinal cord. The nexus of cerebral circuitry that gives rise to consciousness of painor for that matter, consciousness of any kindis the subject of much conjecture. Neuroplastic changes have been reported in the somatosensory thalamus of patients with denervation injuries. For example, Matsuda et al. It is now well established in syndromes such as thalamic pain, phantom limb, and deafferentation pain that pathologic changes in sensory processing occur not only at the spinal level but also in supraspinal structures[81]. In the spontaneous phase, seizures occur in the absence of exogenous stimulation. Neurobiological sensitization models of post-traumatic stress disorder: their possible relevance to multiple chemical sensitivity syndrome. Biol Psychiatry 65:790769, Shonkoff JP, Garner AS (2012) The lifelong effects of early childhood adversity and toxic stress. Biol Psychiatry 84:803809, Yatham L, Mackala S, Basivireddy J, Ahn S, Walji N, Hu C (2017) Lurasidone versus treatment as usual for cognitive impairment in euthymic patients with bipolar I disorder: a randomised, open-label, pilot study. [30], using electrophysiologic tracing methods in rats, have demonstrated direct and indirect (polysynaptic) nociceptor-responsive projections to key limbic and basal ganglia structures, including the hypothalamus, central nucleus of the amygdala, nucleus accumbens, infralimbic cortex, ventral pallidum, and globus pallidus. They also suggested that phantom limb pain might represent dysfunction in this compensatory mechanism, possibly related to a lasting hyperexcitability of nociceptive pathways induced by previous pain. Plasticity in the cortical homunculus has been demonstrated in human phantom limb pain and central pain syndromes[46,47]. Biol Psychiatry 83:886894, Danese A, Moffitt TE, Harrington H, Milne BJ, Polanczyk G, Pariante C, Poulton R, Caspi A (2009) Adverse childhood experiences and adult risk factors for age-related disease: depression, inflammation, and clustering of metabolic risk markers. The clinical end points of windup and central (spinal) sensitization are noted to share NMDA receptormediated mechanisms with kindling, and both processes can be interrupted by NMDA antagonists[66]. Over several months after the initial injury, symptoms of a complex regional pain syndrome (CRPS) began to emerge and included features of allodynia, hyperalgesia, and skin and temperature changes. A case example illustrates how these properties offer a neurobiologic framework for understanding the sensory/affective/behavioral symptom complex seen in a subset of chronic pain patients. (eds) Bipolar Disorder: From Neuroscience to Treatment. There is a well-established rationale for dividing the pain system into two distinct processing networks: (1) the lateral pain system (involved in localization and sensory discrimination of painful stimuli), and (2) the medial pain system (involved in affective-motivational responses to painful stimuli)[2628]. A painful sensory event gives rise simultaneously to an awareness that has the affective valence unpleasant, which at times can be unbearably intense. The kindling properties of amplification, spontaneity, neuroanatomic spreading, and cross-sensitization offer an intriguing bridge between the realms of bio and psychosocial. Whether kindling-related mechanisms per se are operative in the human cerebrum in certain chronic pain states remains to be proven. The role of the medial prefrontal cortex (cingulate gyrus) in the regulation of hypothalamic-pituitary-adrenal responses to stress. Explaining high rates of depression in chronic paina diathesis-stress framework. Even in presumed high-risk populations (i.e., persons with a history of recurrent affective illness and/or painful medical conditions), the relatively infrequent occurrence of LAPS suggests that physical and psychologic trauma usually induce neurobiologic events that ultimately produce a net quenching effect[109]. In this regard, Kandel[100] has noted that the plasticity of neurons is derived from the properties of specific proteins such as the NMDA receptor and adenylyl cyclase, which are common to neurons throughout the CNS. The authors point out that there are other homologies involving neurotransmitters, receptors, and gene products that support kindling as a heuristic model[7]. The Kindling/Sensitization Model and Early Life Stress. Nat Rev Neurosci 8(5):355367, Weber MD, Godbout JP, Sheridan JF (2017) Repeated social defeat, neuroinflammation, and behavior: monocytes carry the signal. Nevertheless, there is a subgroup of patients whose symptoms tend to break through previously effective medication regimens, and in these patients a syndrome of cyclicity and resistance to medication develops. Limbic structures are particularly susceptible to kindling and related sensitization mechanisms, although other brain structures can also be kindled[6]. Psychiatry Res 210(3):880886, Post R, Chang K, Frye M (2013b) Preliminary categorization of ultra-high risk for childhood bipolar disorder on clinical grounds so that preventive strategies can be studied. Other theories highlight shared neurobiologic substrates. Third, it has been used to study neuropharmacology, specifically issues such as drug efficacy and tolerance, in relation to the spatiotemporal cascade of intracellular messenger systems. Yet it seems safe to assume that consciousness represents some form of superordinate neuropsychologic phenomenon that is based largely in the heteromodal association cortices and paralimbic regions of the frontal, parietal, and temporal lobes[102,103]. Rainville et al. Hsieh JC Belfrage M Stone-Elander S Hansson P Ingvar M. Derbyshire SW Jones AK Gyulai F Clark S Townsend D Firestone LL. There is abundant evidence that nociception-induced neuroplasticity occurs within third-order corticolimbic neurons. Acta Psychiatr Scand 135:5164, Kessing LV, Hansen HV, Hvenegaard A et al (2013) Treatment in a specialised out-patient mood disorder clinic v. standard out-patient treatment in the early course of bipolar disorder: randomised clinical trial. [93] have shown that rats exposed to species-specific intermale aggression on a chronic but not acute basis showed lasting c-fos expression in cingulate cortex, hippocampus, hypothalamus, septal nuclei, amygdaloid complex, central gray matter, and raphe nuclei. With the passage of time, however, cycling becomes more frequent and the connection to external stressors becomes less evident. The affective-motivational dimension of pain: a two-stage model. Psychiatric history was positive for at least 3 previous episodes of major depression with intercurrent dysthymia. Am J Psychiatry 163(2):240246, Lo Iacono LCC, Martini A, Valzania A, Viscomi MT, Chiurchi V, Guatteo E, Bussone S, Perrone F, Di Sabato P, Aric E, D'Argenio A, Troisi A, Mercuri NB, Maccarrone M, Puglisi-Allegra S, Casella P, Carola V (2018) From traumatic childhood to cocaine abuse: the critical function of the immune system. The distinguishing features of LAPS, as we conceptualize it, include (in the prototypic case) alterations in pain perception that are chronic, often atypical, and resistant to analgesic treatments in association with disturbances of mood, sleep, energy, libido, memory/concentration, behavior, and stress intolerance. PubMed The sensory-limbic model of pain memory: connections from thalamus to the limbic system mediate the learned component of the affective dimension of pain. Lenz FA Kwan HC Dostrovsky JO Tasker RR. The illustrative case history below helps to identify the subgroup of chronic pain patients of interest to this discussion. For full access to this pdf, sign in to an existing account, or purchase an annual subscription. The kindling model proposes an additional avenue for this linkage through neuroplastic changes, acquired in the course of life experience, that under certain circumstances may lead to a state of corticolimbic sensitization. Introduction: Few animal models address the characteristics of the longitudinal course of bipolar disorder. It is concluded that studies of the effects of kindling on emotional behavior may offer a model of how limbic seizures in humans increase the vulnerability of patients to external . J Psychiatr Res 41(12):979990, Post RM (2015) In: Kapczinski F (ed) Clinical staging in bipolar disorder: a historical perspective. This phenomenon is termed cross-sensitization and has been demonstrated to occur among electrical, chemical, and other environmental stimuli[50]. 1 Emotions have a strong influence on our daily lives. Kindling of the right-side amygdala of animals elicits anxietylike behavior (Adamec and Morgan, 1994;Helfer et al., 1996;Hannesson et al., 2008). These patients are characterized by atypical and treatment-refractory pain complaints, in association with disturbances of mood, sleep, energy, libido, memory/concentration, behavior, and stress intolerance. Plasticity of sensory and motor maps in adult mammals. Cereb Cortex 23:17841797, Hodes GE, Menard C, Russo SJ (2016) Integrating interleukin-6 into depression diagnosis and treatment. The phenomenon of kindling was first discovered in 1967 by a scientist in Halifax, Nova Scotia, named Graham Goddard.
