mandag, 25-10-2021

Peter R. Martin: Historical Vocabulary of Addiction




        According to the current electronic version of the Oxford English Dictionary (OED), the noun kindling was formed within English from a combination of the verb kindle and the suffix-ing (used to form a noun of action).  Since there were originally two distinct meanings of the verb kindle, the nouns that were subsequently formed have corresponding senses.  

        The first version of kindle (“With reference to a fire, flame, or flammable substance”) is probably a borrowing from early Scandinavian combined with an English element used as follows: “To start or light (a fire); to set fire to, ignite (something flammable)”; “To begin to burn; to catch fire; to burst into flame”; or “To arouse, give rise to, or inflame (a feeling, emotion, etc.)”.  In early use of this meaning of kindle, it was still difficult to distinguish it from the other sense (“Of a female animal [especially a hare or rabbit]: to bring forth or give birth to [young]).” 

        The meaning of the word kindling formed from the first version of kindle (“The action of kindle…” or “Flammable material [typically small pieces of wood or paper] used in lighting a fire”) is the focus of discussion.  This meaning eventually developed a very specific and intuitive sense in Medicine (“In experimental models of epilepsy: the process of producing seizures by repeated electrical stimulation of an area of the brain, or by repeated administration of chemical agents; the development of seizures following such treatment.”), which evolved to include not only seizures but also facilitation of various behaviors and emotional states.  It is this last meaning that pertains to the neuroscience of addiction.

        The first use of kindling in the English language is from Middle English dated to 1324 as collected in a compendium Reliquiae antiquae scraps from ancient manuscripts, illustrating chiefly early English literature and the English language (Wright and Halliwell-Phillipps 1845): “Iche Edward Kynge Have yeoven of my forest the keping… To Randolph Peperking ant to his kyndlyng.”  This is an example of the word kindling referring to “a brood or litter.”  The first use of the meaning of kindling under discussion here was around 1400 in the poem Cursor mundi also in Middle English (Morris 1874): “His gode werkes ai to þaim ware Bot soru and kindling of care.”  By the 17th century, the current meaning of kindling is easily recognizable (Sandys 1605): “After the kindling of many precursory lights of knowledge.” 

        Graham Goddard (1938—1987), a British immigrant to Canada, received his doctorate in psychology under Donald Olding Hebb (1904—1985) at McGill University.  Hebb has been considered the “father of neuropsychology” because of the way he was able to merge the worlds of psychology and neuroscience.  Goddard <(1967) was the first to recognize that lasting changes within the brain could be generated by repeated electrical stimulation of the same locus, a phenomenon for which he would coin the term kindling (Goddard, McIntyre and Leech 1969).

        Goddard  (1967) believed that his discovery was mechanistically closely related to an earlier observation (1961) by the American neurologist Frank Morrell (1926—1996): “the development of an independent focal discharge (now called a ‘mirror focus’) in the hemisphere contralateral to a dominant epileptic focus.”    It was in the Stanford laboratory of Morrell that Goddard decided to spend a sabbatical year and began to explore the relationship between kindling and learning (Goddard and Douglas 1975; Morrell 1987).  Goddard  published his initial observations in Nature (1967):

        “The experiments to be reported show that daily electrical stimulation of certain sub-cortical areas of the rat brain will eventually cause convulsions even though the intensity of stimulation is relatively low and initially has no such effect.

        “The primary observation is that not one animal [of the 77 rats included in the experiment] had a convulsion on the first day [of stimulation].  …The number of days of stimulation required before the first convulsion varied considerably, the range being between 4 and 136 days.

        “[O]nce convulsions have been elicited in a given animal, subsequent convulsions occur reliably in response to stimulation.  A check on the permanence of this change was made on some animals after a resting interval of several weeks…  At the end of this rest interval each rat was stimulated for a maximum of 15 sec at threshold intensity.  On the first day convulsions were observed in eight of the eighteen animals… Whatever the neural change responsible for the development of convulsions, it is relatively permanent.

        “All the details involved here require a great deal of further study, but one thing is quite clear; there are some areas of the rat brain in which a progressive sensitization, leading to convulsions, will result from daily stimulation for 1 min each day.  It is not clear why some areas of the brain are more disposed to this sensitization than other areas.  In fact, it is not known whether the phenomenon is due to local changes in the area, or to the establishment of connexions with other parts of the brain.  Histological examination of the site of stimulation reveals no gross peculiarities …it can be argued that the phenomenon described in the present note is analogous to learning.  At the very least it is a relatively permanent change in behaviour that depends on repeated experience… It is an appealing notion and deserves the attention of physiologists and psychologists alike.”

        In his subsequent publication, Goddard, McIntyre and Leech (1969) concluded that the “kindling effect”:

        “was due to neuronal activation by the electrical stimulus.  This conclusion receives further support from experiments showing that repeated chemical activation of the rat amygdala, with low doses of locally injected carbachol, will also mimic the kindling effect and increase the likelihood of seizure development.  If it is accepted that the necessary condition for kindling is electrical activation, it is then appropriate to consider which regions of the brain can be altered in this fashion, what types of change are involved, and what types of activation are necessary… it was seen that the effect was produced mainly from the limbic system and closely associated structures...  Differences in the rate of kindling were observed between different structures within the limbic system, with amygdala being the most responsive.  The majority of the neocortex, thalamus and brain stem were refractory to the kindling procedures.”

        As Goddard predicted, mechanistic understanding of the kindling effect and its similarities with learning, such as its relative permanence, positive and negative transfer effect, and involvement of the limbic system, became a fertile area of investigation (Gaito 1974). 

        Interestingly, Frank Morrell had also trained at the Montreal Neurological Institute (MNI).  During his time in Montreal with the eminent epileptologist Herbert Jasper (1906–1999), Morrell had an opportunity to become involved in some of the first electrophysiological approaches to understanding the neuronal substrates of  conditioning, brain plasticity and mechanisms of learning.  One area of early interest for Morrell was the relationship of epileptic neural activity and conditioning (Engel 2001).

        Jasper was an important collaborator of Wilder Penfield (18911976), the American-Canadian neurosurgeon who established the MNI at McGill University with Rockefeller Foundation philanthropy.  Under Penfield the MNI became a mecca for pioneering intraoperative neural stimulation studies in patients undergoing surgical ablation of seizure foci (Hebb and Penfield 1940; Penfield, Erickson, Jasper and Harrower 1941).  This work led to neuronatomic localization of brain functions, including the cortical homunculus and a variety of mental processes such as hallucinations, illusions and déjà vu.  Studying some of these neurosurgical patients, Brenda Milner (1918—), who also received her doctorate under Hebb, began to elucidate the specific role of the temporal lobes in conjunction with the limbic system in learning and memory (Scoville and Milner 1957; Penfield and Milner 1958). 

        Both the American neuroscientist James Olds (1922–1976) and his collaborator Peter Milner (1919–2018), a British electrical engineer who immigrated to Canada, had advanced training under Hebb.  Analogous to human neurostimulation studies conducted by Penfield and colleagues at the MNI and those at other centers in awake animals (MacLean and Delgado 1953), Olds and Milner (1954) devised experiments which allowed laboratory animals to signal by their behavior which brain regions they found reinforcing on stimulation:

        “A preliminary study was made of rewarding effects produced by electrical stimulation of certain areas of the brain... needle electrodes were permanently implanted at various points in the brain. Animals were tested in Skinner boxes where they could stimulate themselves by pressing a lever.  They received no other reward than the electrical stimulus in the course of the experiments.  The primary findings may be listed as follows: (a) There are numerous places in the lower centers of the brain where electrical stimulation is rewarding in the sense that the experimental animal will stimulate itself in these places frequently and regularly for long periods of time if permitted to do so. (b) It is possible to obtain these results from as far back as the tegmentum, and as far forward as the septal area; from as far down as the subthalamus, and as far up as the cingulate gyrus of the cortex, (c) There are also sites in the lower centers where the effect is just the opposite: animals do everything possible to avoid stimulation.  And there are neutral sites: animals do nothing to obtain or to avoid stimulation. (d) The reward results are obtained more dependably with electrode placements in some areas than others, the septal area being the most dependable to date. (e) In septal area preparations, the control exercised over the animal's behavior by means of this reward is extreme, possibly exceeding that exercised by any other reward previously used in animal experimentation.” 

        Through these experiments, Olds and Milner determined in the rat brain that the medial forebrain bundle (the mesolimbic pathway, a collection of dopaminergic neurons that projects from the ventral tegmental area to the nucleus accumbens) was characterized by a unique capacity to sustain self-stimulation.  These brain regions became known as “reward pathways” and have become a focus in elucidation of the pathophysiologic underpinnings of addiction (Olds 1958; Kornetsky and Esposito 1981; Wise 1996; Kalivas and Volkow 2005).  Moreover, these brain regions that support self-stimulation in animal models are also highly susceptible to the kindling effect

        This convergence of cellular properties supports the roles of learning, conditioning and brain plasticity in mechanistic understanding of addiction (Kalant, LeBlanc and Gibbins 1971; O’Brien 1975) and provide insight into the neuroanatomic locations at which the molecular machinery involved in its pathogenesis should be investigated (Hyman, Malenka and Nestler 2006).

        The underlying physiological mechanism of the kindling effect began to be elucidated within a decade after its first description.  Specifically, what are the lasting changes that occur either locally within the stimulated neuron or through neural inputs to the neuron through formation of connections with other parts of the brain?  The Norwegian physiologist Terje Lømo (1935—) and the British neuroscientist Timothy Bliss (1940—) reported (Bliss and Lømo 1973; Lømo 2003) evidence for long-lasting enhancement of signal transmission between repeatedly stimulated neurons which they called long-term potentiation (LTP).  Interestingly, Bliss received his undergraduate (1963) and doctoral (1967) education at McGill University where he likely was influenced by Hebb’s theory of synaptic changes with learning. 

        Hebb hypothesized in The Organization of Behavior: A Neuropsychological Theory (1949) that permanent memory traces could be laid down by the sustained activation of reverberatory circuits, or neural networks that would echo and in effect hold the information after the event itself had passed. A permanent change in the reverberatory circuit would occur if activated to sufficient levels, thereby allowing the information to be more easily retrieved or remembered.  Enhanced synaptic efficacy in LTP discovered by Bliss and Lømo was essentially as first propsed by Hebb.  

        Electrical stimulation of the pre-synaptic cell makes the synapse more responsive to future stimulation by enhancing efficacy of signal transduction between cells through both pre- and post-synaptic changes (Nicoll 2017).   The enhanced efficacy of the synapse by LTP results from a cascade of molecular signals within relevant neurons, most importantly resulting in increased permeability of the N-Methyl-D-aspartate (NMDA) receptor channel complex and the entry of the Ca2+ ion into the cell (Bliss and Collingridge 1993).   Associated changes occur in the expression of genes in neurons within the brain network that mediates drug reward (Hyman, Malenka and Nestler 2006; Galaj and Ranaldi 2021). 

        LTP is the most extensively studied model of memory at the cellular level in hippocampus (Morris, Anderson, Lynch and Baudry 1986) and has become the paradigm within which kindling-related phenomena, especially those underpinning addiction, are specifically studied at the molecular level in neurons of the reward pathway (Estill, Ribeiro, Francoeur et al. 2021).  

        As conduction in the nervous system is neurochemical, it is hardly surprising that the kindling effect can also be elicited by brain stimulation using proconvulsant pharmacologic agents (Baxter 1967; Goddard and Douglas 1975).  So-called chemical kindling is exemplified by progressive decreases in seizure threshold of neurons with repeated administration of the proconvulsant psychostimulant cocaine (Stripling and Ellinwood 1977).  Post and Kopanda (1975) proposed that chemical kindling effects may contribute to development of cocaine use disorder as learning-related cumulative changes in reward circuits are caused by repeated self-administration of initially subconvulsant doses of cocaine. 

        Of note, the stimulant cocaine is not only reinforcing by enhancing dopamine neurotransmission in the reward pathways but is also proconvulsant by effects on sodium channels and excitatory neurotransmission (Martin and Patel 2017).  It has been demonstrated that even a single dose of cocaine induces LTP in dopamine cells in the ventral tegmental area (Ungless, Whistler, Malenka and Bonci 2001). 

        Post and colleagues (Post, Uhde, Putnam et al. 1982; Post, Weiss, Smith et al. 1997) have suggested that kindling mechanisms, so called behavioral sensitization, may also apply to increasing behavioral responses with repetition of the same stimulus over time during a lifetime.  This model may have important implications for the progressive development of psychopathology in a variety of neuropsychiatric syndromes as for example in bipolar disorder and posttraumatic stress disorder (Adamec 1990), disorders that often co-occur with drug use disorders (Martin, Weinberg and Bealer 2007).  

        Carbamazepine, an effective anticonvulsant for treatment of temporal lobe and limbic seizures, also inhibits the kindling effect and has been demonstrated useful as a treatment of affective illness and PTSD  (Post  1982; Post, Weiss, Smith et al. 1997), also cocaine use disorder (Halikas, Crosby, Pearson and Graves 1997).  

        The chemical kindling effect may also provide as a heuristic explanation for progression of alcoholism throughout the course of a lifetime of drinking (Ballenger and Post 1978).  Since alcohol is a central nervous system depressant, its pharmacological actions do not per se facilitate chemical kindling as do proconvulsant stimulants.  Rather, repeated episodes of intoxication with alcohol are followed by widespread neuronal excitation during the withdrawal syndrome.  Accordingly, withdrawal from central nervous system depressants can be conceptualized as resembling the kindling effect and thereby may contribute to neuroadaptive changes associated with progression of the disorder (Martin and Patel 2017).  

        Interestingly, chemical kindling has also been proposed to contribute to the addictive effects of cannabinoids (Karler, Calder, Sangdee and Turkanis 1984) and opioids (Tanaka, Takeshita, Kawahara and Hazama 1989), although the role of this mechanism in the respective use disorders are not as fully developed.  Kindling effects with all drugs of abuse whether or not they are proconvulsant per idem may operate via learning associated mechanisms of behavioral sensitization or the increasing behavioral responses with repetition of the same stimulus (Robinson and Berridge 1993).



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July 8,  2021