This literature review (2013) evaluates synaesthesia and proposes that the role of excessive serotonin (genetic or drug induced) plays a role through increasing excitability and connectedness of brain regions.
Though synesthesia research has seen a huge growth in recent decades, and tremendous progress has been made in terms of understanding the mechanism and cause of synesthesia, we are still left mostly in the dark when it comes to the mechanistic commonalities (if any) among developmental, acquired and drug-induced synesthesia. We know that many forms of synesthesia involve aberrant structural or functional brain connectivity. Proposed mechanisms include direct projection and disinhibited feedback mechanisms, in which information from two otherwise structurally or functionally separate brain regions mix. We also know that synesthesia sometimes runs in families. However, it is unclear what causes its onset. Studies of psychedelic drugs, such as psilocybin, LSD and mescaline, reveal that exposure to these drugs can induce synesthesia. One neurotransmitter suspected to be central to the perceptual changes is serotonin. Excessive serotonin in the brain may cause many of the characteristics of psychedelic intoxication. Excessive serotonin levels may also play a role in synesthesia acquired after brain injury. In brain injury sudden cell death floods local brain regions with serotonin and glutamate. This neurotransmitter flooding could perhaps result in unusual feature binding. Finally, developmental synesthesia that occurs in individuals with autism may be a result of alterations in the serotonergic system, leading to a blockage of regular gating mechanisms. I conclude on these grounds that one commonality among at least some cases of acquired, developmental and drug-induced synesthesia may be the presence of excessive levels of serotonin, which increases the excitability and connectedness of sensory brain regions.
Papers cited by this study that are also in Blossom
Carhart-Harris, R. L., Erritzoe, D., Williams, T. et al. · PNAS (2012)
Gonza ´lez-Maeso, J., Weisstaub, N. V., Zhou, M. et al. · Neuron (2007)
Nichols, D. E. · Pharmacology and Therapeutics (2004)
Sinke, C., Halpern, J. H., Zedler, M. et al. · Consciousness and Cognition (2012)
Vollenweider, F. X., Leenders, K. L., Maguire, P. et al. · Neuropsychopharmacology (1997)
Brogaard frames synesthesia as a diverse set of conditions in which stimuli in one sensory or cognitive domain (the inducer) automatically elicit an additional, atypical percept or representation (the concurrent). She outlines three broad classes: developmental (lifelong, often familial and systematic), acquired (emerging after brain injury, disease or sensory substitution) and drug-induced (transient experiences during intoxication with psychedelics). Prior work implicates atypical structural or functional connectivity and mechanisms such as direct cross‑projection or disinhibited feedback, but little is known about common causal factors across the three classes. The paper sets out to develop and extend a serotonergic hypothesis: that excessive extracellular serotonin (5‑HT) or serotonergic agonism can trigger persistent or transient synesthesia across developmental, acquired and drug‑induced cases by increasing excitability and connectedness of sensory brain regions, principally via 5‑HT2A receptors on cortical neurons. Brogaard proposes to marshal evidence from studies of psychedelics, brain injury, autism and neuroimaging/genetics to evaluate whether a hyperserotonergic state could provide a unifying mechanistic factor for at least some instances of synesthesia.
This paper is a theoretical synthesis and hypothesis development rather than a primary empirical study. The extracted text does not present a formal Methods section or a documented literature‑search strategy. Instead, Brogaard reviews and integrates findings from empirical domains relevant to synesthesia: case reports and neuroimaging of acquired synesthesia, pharmacology and human reports of psychedelic drug effects, neurochemical and imaging studies in autism, genetic linkage data, and structural/functional imaging (fMRI, DTI) of developmental synesthetes. Evidence is drawn from physiological studies of neurotransmitter dynamics after brain injury, PET and EEG studies of serotonin function and cortical excitability, pharmacological manipulations (e.g. SSRIs, serotonin agonists), neuroimaging reports of altered connectivity or grey matter in synesthetes, and selected case reports documenting drug‑ or disease‑related changes in synesthetic experience. Where mechanistic proposals are advanced (for example, the role of 5‑HT2A receptors on layer V pyramidal neurons), Brogaard synthesises cellular, circuit and systems evidence to connect receptor‑level effects to altered multisensory binding.
Brogaard assembles converging lines of evidence supporting a role for serotonergic hyperactivity in some synesthesia cases. Acquired synesthesia: Traumatic brain injury and other neuropathologies can cause necrosis with massive, transient release of excitatory neurotransmitters, notably serotonin and glutamate. Animal and human data indicate a post‑lesion pattern of decreased activity at lesion borders with a surrounding ring of increased activity for days to weeks; these neurotransmitter elevations typically normalise within about a month. Brogaard outlines two hypotheses for how such transient neurotransmitter flooding could lead to synesthesia: (1) initial hyperactivity leads to later down‑regulation in ipsilateral regions and compensatory upregulation contralaterally, producing altered interhemispheric balance; (2) the early serotonergic/glutamatergic surge triggers disinhibited feedback or opportunistic structural binding among sensory regions. The second hypothesis is favoured for many acquired cases because synesthesia often begins shortly after injury. Individual variability in brain plasticity and lesion location likely explains why only a minority of patients develop synesthesia. Drug‑induced synesthesia: Indoleamine and phenethylamine psychedelics (e.g. LSD, psilocybin, mescaline) are partial agonists at serotonin 5‑HT1A/2A/2C receptors, with hallucinogenic activity most tightly associated with 5‑HT2A activation. Brogaard emphasises a model in which 5‑HT2A activation on layer V pyramidal neurons increases glutamate release and cortical excitability, altering thalamocortical gating and low‑level multisensory integration. This disruption can allow random thalamic activity or aberrant occipital patterns to be bound to concurrent auditory or other inputs, producing vivid, often non‑systematic inducer‑concurrent pairings (for example music perceived as colours or fractal visuals). Increased cortical metabolic activity and modulation of alpha oscillations (8–12 Hz) are cited as correlates. Brogaard predicts drug‑induced synesthesia will usually lack the systematicity characteristic of developmental synesthesia and will tend to be transient because the drug‑driven random pairings are unlikely to form stable one‑to‑one mappings. Developmental synesthesia and autism: Brogaard highlights evidence linking altered serotonergic function to autism, a condition in which synesthesia and savant traits appear more common. Around 30% of autistic individuals show hyperserotonemia (elevated blood serotonin), and PET studies suggest hemispheric asymmetries in serotonin synthesis—typically reduced left‑hemisphere synthesis and increased right‑hemisphere synthesis in many cases. She notes reports that about 15% of people with autism experience synesthesia versus about 4.4% in the general population, and that savant skills occur in roughly 10% of autistic individuals. Two developmental pathways are proposed: early excessive serotonin could alter multisensory processing and thalamocortical development (leading to persistent binding or mnemonic associations), or compensatory increases in serotonin in a spared hemisphere could promote atypical feature binding and associated savant skills. Neuroimaging findings in non‑autistic synesthetes—enhanced functional connectivity, greater intrinsic network connectivity, increased grey matter in parietal and fusiform regions, and increased white matter connections in parietal/temporal/frontal areas—are cited as consistent with local hyperconnectivity models. Genetic linkage work has implicated a locus on chromosome 2 (2q24.1) linked to autism rather than the 5‑HT2A gene on chromosome 13. Pharmacological and case evidence: Mixed pharmacological observations are reported. Some agents that alter serotonergic signalling have been observed to abolish or reduce synesthetic experience in individual case reports (e.g. fluoxetine, bupropion, carbamazepine), but Brogaard notes these drugs also increase GABA or reduce glutamate, which could counteract excitatory serotonergic effects. Taken together, the evidence supports the plausibility that serotonergic excitatory activity contributes to synesthetic binding in at least some cases, but it does not provide definitive causal proof.
Brogaard interprets the assembled evidence as consistent with the hypothesis that excessive extracellular serotonin or potent serotonergic agonism can trigger synesthesia by increasing excitability and interconnectivity of sensory regions, principally via 5‑HT2A receptor action on layer V pyramidal neurons. She positions this idea as compatible with three empirical domains: (i) the neurotransmitter flooding that follows necrotic brain injury, (ii) the established hallucinogenic action of classical psychedelics at 5‑HT2A receptors and their frequent induction of synesthesia, and (iii) unilateral serotonergic abnormalities and hyperserotonemia observed in many individuals with autism, where synesthesia appears more prevalent. The author acknowledges important caveats and uncertainties. Not all 5‑HT2A agonists produce hallucinations or synesthesia, and some serotonergic manipulations have opposite effects depending on downstream GABAergic and glutamatergic modulation. Most acquired‑synesthesia research occurs years after onset, limiting insight into immediate post‑injury neurotransmitter dynamics. There is heterogeneity across synesthesia types, so a single mechanism need not account for all cases. Genetic and imaging data are suggestive but not definitive: linkage to chromosome 2 implicates potential shared loci with autism, and DTI/fMRI studies show patterns of hyperconnectivity in some synesthetes, but causality and developmental timing remain unresolved. Brogaard sets out several testable implications. These include pharmacological predictions (5‑HT2A antagonists or SSRIs should diminish serotonergically mediated synesthesia, whereas potent serotonin agonists should enhance it), imaging strategies (performing neuroimaging close to onset of acquired synesthesia to detect transient serotonergic hyperactivity and early network changes), structural connectivity assessments in autistic synesthetes using DTI, and larger population and genetic studies to clarify links among developmental synesthesia, autism and savant phenomena. She calls for systematic empirical work rather than stronger theoretical claims, recognising that the serotonergic hypothesis is intended as a partial, testable explanation for some but not all synesthesia phenomena.
Brogaard concludes that a hyperserotonergic condition is a plausible causal factor for at least some cases of synesthesia. She summarises three lines of supporting evidence: (1) necrosis after brain injury produces transient excessive release of serotonin and glutamate that could trigger atypical feature binding or later disinhibitory changes; (2) classical serotonergic hallucinogens (e.g. psilocybin) reliably induce synesthesia, plausibly via excitatory action on layer V pyramidal neurons and increased glutamate release; (3) autism is frequently associated with unilateral increases in serotonin synthesis and a higher incidence of synesthesia and savant traits, suggesting a potential developmental pathway. The paper advances the hypothesis that excessive serotonin increases excitability and connectedness among sensory regions through 5‑HT2A receptors, thereby promoting synesthetic experiences in developmental, acquired and drug‑induced contexts, while noting that further targeted empirical testing is required.
Synesthesia is an extraordinary way of perceiving the world, involving experiences of connections between seemingly unrelated sensations, images or thoughts. For example, seeing the number 7 may lead to an experience of navy blue, hearing the word "bliss" may flood the mouth with the flavor of bread soaked in tomato soup and hearing the key of C# minor may elicit a bright purple spiral radiating from the center of the visual field. The trigger of the experience is called "the inducer," whereas the additional experience to which it gives rise is called"the concurrent". In visual synesthesia, the concurrent may be projected out into space and experienced as located in the visual scene outside the subject's mind, or it may be merely imagistically or semantically associated with the inducer. The two key characteristics of synesthesia regardless of whether it is of the projector or associator type is that it involves an aberrant binding of features from different sensory or cognitive streams that are associated with atypical conscious experiences or thoughts and that these experiences or thoughts are automatic, that is, synesthetes cannot suppress the association between an inducer and its concurrent. Other characteristics of the condition are specific to the different forms. According to, there are three different types of synesthesia: (1) Developmental, or genuine, synesthesia (2) Acquired synesthesia (3) Drug-induced synesthesia Developmental synesthesia, the most common type, is a form of the condition that has persisted since birth or early childhood and that remains relatively stable and systematic over time: each inducer has a highly specific concurrent.. It also tends to run in families. For the most common forms of developmental synesthesia, the Synesthesia Battery, an automated online test, allows for rigorous testing of both the tightness of the synesthetic association and its stability and systematicity over time (www.synaesthete.org;. Acquired synesthesia is a form of the condition that emerges after brain injury or disease or artificial technologies like sensory substitution. It has been reported following stroke, traumatic brain injury, neuropathology involving the optic nerve and/or chiasm, seizures, migraine, post-hypnotic suggestionand sensory substitution. Audiovisual synesthesia has been reported to be the most common acquired type. Like developmental synesthesia, acquired synesthesia tends to be automatic and systematic over time, though in some cases it only persists for a limited time period. Experientally, acquired synesthesia may be indistinguishable from developmental synesthesia, though it is sometimes less inducer-specific, that is, the same concurrent may have several different inducers. Cases have also been reported in which the acquired experience is simpler than the developmental counterpart, often similar to light flashes (phosphenes) or pure color experiences. Drug-induced synesthesia is a blending of sensory or cognitive streams that is experienced during exposure to a hallucinogen (psilocybin, LSD, mescaline, peyote;. Unlike the developmental and acquired varieties, the drug-induced form is usually limited to the most intense phases of intoxication, though in some cases it continues for weeks or months after exposure to the drug. Experientally, drug-induced synesthesia can vary from simple color experiences to complex, surrealistic landscapes consisting of, for example, oddly shaped objects with multicolored contours or images with ornamental or kaleidoscopic compositions. Though synesthesia research has seen a huge growth in recent decades, and tremendous progress has been made in terms of understanding the mechanism and cause of the condition, we are still left mostly in the dark when it comes to the mechanistic commonalities (if any) among developmental, acquired and drug-induced synesthesia. It is widely believed that most forms of the condition involve functional or structural aberrant brain connectivity. The proposed mechanisms include direct or indirect projection through increased structural connectivity, functionally driven disinhibited-feedback mechanisms, and mixed models. However, it is unclear what causes the onset of the condition and whether the different types of synesthesia have different causes. One proposal bysuggests serotonin (5-HT) as a causal factor. Their specific suggestion is that "serotonin S2a receptors are the 'synesthesia receptors' in the brain" (p. 903). In support of this hypothesis they list four pieces of evidence: (i) LSD produces synesthesia by selectively activating serotonin 5-HT2A receptors. (ii) Prozac (fluoxetine), a selective serotonin reuptake inhibitor that increases 5-HT1 receptor activity thereby inhibiting 5-HT2A, blocked synesthesia in two subjects. (iii) the anxiolytic drug Wellbutrin (bupropion), which presumably inhibits 5-HT2A receptor activity, temporarily abolished synesthesia in one subject, (iv) melatonin, a brain hormone derived from serotonin that can disinhibit 5-HT2A receptor activity, temporarily induced grapheme-color synesthesia in a subject with number-form synesthesia. Thus,suggestion is that serotonin may be functionally implicated in generating synesthetic experience through 5-HT2A receptor activity. In the formulation of the hypothesisdo not specify which of the 5-HT2A receptors in the brain cause synesthesia, whether the serotonin receptors that are"synesthesia receptors"are inhibitory or excitatory, whether serotonin could be structurally implicated in causing synesthesia through altered structural connectivity during brain development and whether the serotonin hypothesis may also explain cases of acquired synesthesia. My aim in this paper is to develop the serotonin hypothesis to tentatively answer these questions by looking at a wider range of evidence. More specifically, my proposal is that excessive extracellular serotonin (5-HT) can be a trigger of persistent or transient synesthesia in all the groups through excitatory mechanisms. Though serotonin traditionally has been considered an inhibitory neurotransmitter, more recent evidence suggests a more complex picture according to which serotonin can function both as an inhibitory and an excitatory neurotransmitter. For example, serotonin helps reduce fear processing in the amygdala via GABA modulation but it exerts an excitatory effect on cortical brain activity when it binds to 5-HT2A serotonin receptors on layer V pyramidal neurons. As indicated by, the suggestion that serotonergic activity may be a trigger of synesthesia has the greatest degree of evidential backing in the case of druginduced synesthesia. It has been shown in several studies that psychedelic hallucinogens that function primarily as serotonin agonists, such as psilocybin, LSD and mescaline, often induce transient, often auditory-visual synesthesia, presumably through an alteration of functional brain connectivity. Though not all serotonin agonists elicit synesthetic experience, it is widely agreed that the mechanism of action for the class of serotonergic hallucinogens is through binding of serotonin to the 5-HT2A serotonin receptor. Excessive serotonin levels may also play a role in synesthesia acquired after brain injury. Research has shown that necrosis following tissue damage leads to local neurotransmitter flooding caused by an excessive release of serotonin and glutamate, a phenomenon that can have long-range consequences even when the injury is minor. This flooding appears to lead to increased functional or structural interconnectedness among different brain regions in some individuals, and in some cases this increased connectivity may be a cause of synesthesia. Developmental synesthesia has been reported as a condition in autism-spectrum disorders, and is believed to be more frequently occurring in individuals with autism compared to the general population. It is suggested below that synesthesia accompanying autism may be a serotonergic condition, resulting from excessive serotonin levels in early childhood that could possibly lead to decreased extracellular levels of serotonin in one hemisphere and compensatory increased levels in the other hemisphere. One piece of evidence for this comes from PET scans of people with high-functioning autism which have revealed that in the majority of cases serotonin synthesis is suppressed in the left hemisphere and increased in the right hemisphere, though in some cases it is reversed. Recent genetic studies furthermore suggest a genetic link between autism spectrum disorder and developmental synesthesia in non-autistic individuals. Whether there is a mechanistic link between autism and cases of developmental synesthesia in non-autistic individuals remains to be established. In what follows I will provide detailed evidence for the hypothesis that one commonality among at least some cases of acquired, developmental and drug-induced synesthesia is the presence of excessive levels of serotonin or serotonin-agonists, which increase the excitability and connectedness of sensory brain regions through 5-HT2A receptors in cortical neurons.
The acquired form of synesthesia usually emerges subsequent to traumatic brain injury or neuropathologic insult to the brain. Several studies have hypothesized that these acquired synesthesias occur from plasticity of the sensory systems resulting in increased connectivity. This theory has additionally been studied in at least one case of acquired synesthesia.found that connections between the auditory and somatosensory cortices in healthy controls were strengthened in a subject with auditory-tactile synesthesia acquired after a right ventrolateral thalamic lesion that deprived her somatosensory cortex of normal somatosensory input. It remains largely unknown how a brain lesion may give rise to the plastic changes that lead to the increased connectivity. One possibility is that it is caused by increased neurotransmitter activity in cortical regions adjacent to the affected site. This increase is believed to contribute to the pathophysiology and neurological dysfunction after traumatic brain injury. In traumatic brain injury tissue damage makes the cells shift to anaerobic glycolysis, resulting in an accumulation of lactic acid. The anaerobic metabolism cannot by itself maintain the energy levels, so ATPstores are depleted and the membrane ion-pumps, which depend on ATP, fail. This leads to membrane degradation of vascular and cellular structures and necrotic or programmed cell death (apoptosis), resulting in excessive release of excitatory neurotransmitters, particularly serotonin and glutamate. This excess in extracellular serotonin and glutamate availability affects neurons and astrocytes and results in over-stimulation of serotonin and glutamate receptors. It is believed that this over-stimulation effect can happen even in mild traumatic brain injury, as the release of neurotransmitters is vast even with minor lesions. Other types of brain injury that have been reported to trigger synesthesia, such as stroke, also cause neurotransmitter flooding after necrosis. It has been found, for example, that even a brief ischemic stroke may trigger complex biochemical events that lead to progressive apoptotic and necrotic neuronal cell death. The increased levels of serotonin and glutamate immediately following brain injury do not normally stay elevated for very long.induced 1.5 to 2 mm lesions in the striate cortex of cats using surface photocoagulation or ibotenic acid injections. Single cell measurements revealed that activity was decreased at the border of the lesion and increased in a ring around the lesion during the first days to weeks following the induction but it returned to normal after about a month. Despite the fact that serotonin does not seem to stay elevated for more than one month following a brain lesion, there is suggestive evidence that the temporary elevation may suffice for creating long-lasting functional, and possibly also structural, changes. It has furthermore been reported that initial increases in neurotransmitter levels following brain injury or disease may be followed by down-regulation of receptors in ipsilateral brain regions. One hypothesis for how brain injury or disease may cause synesthesia, then, is that the initially elevated neurotransmitter levels down-regulate serotonin receptors in neural regions in the ipsilateral hemisphere, leading to decreased serotonin levels. Individuals who acquire synesthesia also sometimes develop autistic traits and savant-like abilities of the sort seen in 10 percent of autistic individuals. Emerging savant skills have also been reported in many other cases of central nervous system injury or disease later in life. As is known from studies of autistic savants, downregulation of the serotonergic system in one hemisphere may result in an upregulation of the serotonergic system in contralateral brain regions, which might explain the development of savant skill and synesthesia following brain injury. A second hypothesis is that the elevation in serotonin and glutamate levels in the days or weeks after brain injury can trigger disinhibited feedback or a structural binding of features through serotonergic hyperactivity in sensory neurons or neurons in parietal cortex involved in mental imagery. The latter have been found to be plausible neural correlates in at least one case of acquired synesthesia. The second hypothesis is more plausible than the first when synesthesia is acquired after brain injury. It would explain the increased ipsilateral connectivity found in at least one case of acquired synesthesia. It gains further support from the fact that the onset of synesthesia following brain injury has been reported to occur shortly after the injury rather than months later, which indicates that it is the initial neurotransmitter flooding that causes the onset. Furthermore, if the first hypothesis were correct, then the affected region would have to be crucially implicated if the down-regulation triggers an upregulation in other areas, an assumption that cannot be confirmed at the present time. The first hypothesis may have a greater degree of support for synesthesia acquired after frontotemporal dementia. Cell death in frontotemporal dementia does not normally occur via necrosis that leads to neurotransmitter flooding. However, it is well known that patients with this condition have deficits in serotonergic and dopaminergic signal-transmission. These deficits may account for some of the cognitive and behavioral impairments of the disease. As prefrontal areas are known to exert inhibitory control over other brain regions, decreased activity in these neural regions could lead to a disinhibitory enhancement of neural activity and connectivity in unaffected cortical regions, which could also explain why this type of dementia frequently is reported as a cause of savant skills. Regardless of whether the synesthesia is acquired after brain injury or dementia, neuroimaging might help reveal whether the unusual binding is functional or structural. For example, if it is functional, we should expect to find increased connectivity in functional connectivity analyses on fMRI data. The above considerations raise the question of why only a small fraction of brain injury patients acquire synesthesia-like experiences. One possible answer is that individual differences originate in variance in the degree of plasticity of the subject's brain prior to the incident. Research on brain injury in children has shown that alterations in neurotransmission during the critical period when a brain region is most plastic can promote outgrowth of abnormal neural connections. Since it is likely that there are significant individual differences in the plasticity of the mature brain, it is possible that some subjects are more susceptible to the formation of new neural connections than others. Individual differences are no doubt also grounded in variance in the location of the injury. Synesthesia-like experiences may be much more likely to develop if sensory regions or neural areas implicated in mental imagery are affected. Given the broad range of conditions that can trigger acquired synesthesia it is unlikely that there is a single mechanism underlying all cases. Some cases appear to be quite similar in persistence and phenomenology to well-known forms of developmental synesthesia and are likely to share a neurological basis with some of these varieties of synesthesia. For example, autistic savant Daniel Tammet describes in his book Born on a Blue Day that he acquired synesthesia after childhood seizures. Though his grapheme-color synesthesia appears unusually rich, it may have neurological underpinnings akin to more typical developmental forms. Other forms of acquired synesthesia appear to be transient and may well be a more direct product of excitatory neural activity, similar in many respects to synesthetic experience occurring under the influence of hallucinogens (see below). An example would be synesthesia experienced during occipital and temporal lobe seizures, which can lead to brief experiences quite similar to psychedelic experiences. Some forms of acquired synesthesia could be undergird by a different mechanism not typically found after drug intoxication or aberrant neural development. In cases in which synesthesia and savant syndrome are acquired in the same incident, the two conditions may well be triggered in similar ways. This could be the case for Tammet, who reports having synesthesia matching not only digits but also the product of digits. His synesthesia could possibly be an imagistic manifestation of number processing in the parietal cortex. One observation that supports this hypothesis is that the lack of increased activity in the visual cortex in response to synesthetic tasks found in an imaging study comparing brain activity in Tammet and controls. But more research needs to be done to settle these questions. In most cases of acquired synesthesia the research component has taken place several years after the onset of the condition. If we could perform the research (e.g., neuroimagining studies) closer to the onset, we might be able to determine whether serotonergic hyperactivity in sensory neurons is implicated in the sudden, unusual binding of features.
Drug-induced synesthesia is a blending of perceptual or cognitive streams that emerges in subjects under the influence of psychedelic hallucinogens, psychoactive substances that alter perception, mood, and a variety of cognitive processes. A myriad of first-person reports indicate that synesthesia occurs during psychedelic intoxication. Some reports suggest an altered perception of the world that blends normally distinct senses. Reports of colored music are particularly frequent. In other cases external objects appear to the perceiver as having an unusual wealth of colors, textures and shapes that undergo rapid changes. Subjects report seeing melting windows, breathing walls and spiraling geometrical figures crawling over the surfaces of objects. Reflecting on a DMT session one subject, described by, reported that "The room erupted in incredible neon colors, and dissolving into the most elaborate incredibly detailed fractal patterns that I have ever seen." The authors characterize this as a hallucination, and it is admittedly difficult to distinguish synesthesia and hallucinations, particularly because some forms of synesthesia probably are best characterized as hallucinations. A crucial difference seems to be that hallucinations proper do not have a phenomenally apparent inducer, whereas synesthesia does. Another difference is that most forms of synesthesia are experienced as endogenous images or representations (i.e., associator synesthesia,). Yet another difference is that synesthetes know that the concurrent experience is not a veridical perception, whereas hallucinations tend to evoke the experience of the veridicality of the perception. It is by now fairly well established that two major classes of psychedelic hallucinogens, the indoleamines (e.g., LSD and psilocybin) and the phenethylamines (e.g., mescaline), are potent partial agonists at serotonin 5-HT1A/2A/2C receptors, with 5-HT2A receptor activation directly correlated with hallucinogenic activity; though see e.g., Previc, 2011 for a different perspective). Though the mechanism of action varies for different hallucinogens, it is believed that 5-HT2A receptor activation of cortical neurons is responsible for mediating the signaling pattern and behavioral response to hallucinogens. However, the activation of the cortical serotonergic system does not fully explain the perceptual effects of psychedelic drugs, as not all 5-HT2A agonists (or partial agonists) have an excitatory mechanism of action and not all 5-HT2A agonists have psychedelic effects (e.g., methysergide). So, this raises the question of what other factors need to be present for drug-induced hallucinations to occur. A promising suggestion for how the hallucinatory effects occur is that hallucinogens activate layer V pyramidal neurons in the cortex, which engage in gating functions in communication between the cortex and subcortical brain regions. When a hallucinogen binds to the 5-HT2A receptor, this gives rise to an excitatory response. Recent research suggests that co-transmission of glutamate and monoamines is a frequent occurrence in the central nervous system. The 5-HT2A receptors, specifically, have been found to increase glutamate release. There is furthermore evidence suggesting that the hallucinogen psilocybin targets a cortical receptor complex that forms when the glutamate mGluR2 receptor interacts with the serotonin 5-HT2A receptor. Increased release of glutamate in response to hallucinogen administration should enhance cortical metabolic activity, a finding that has been confirmed by. Perceptual changes have been found to correlate with increased metabolic activity in the frontomedial and frontolateral cortices, anterior cingulate, and temporomedial cortex. There is also some evidence from EEG studies that activation of 5-HT2A receptors increases the excitability of cortical sensory networks by modulating alpha oscillations (8-12 Hz;. Brain waves in the alpha frequency range have been shown to regulate the excitability levels of cortical sensory networks through inhibition. The increased excitatory action of serotonin and glutamate in sensory regions might explain why hallucinogens mimic aspects of psychosis during intoxication. The view that the hallucinatory effects of hallucinogens are primarily a result of enhanced neural activity may appear inconsistent with a recent fMRI study showing that psilocybin causes decreased activity in the ACC/medial prefrontal cortex and a significant decrease in the positive coupling between the medial prefrontal cortex and the posterior cingulate cortex, and that these findings were correlated with subjective effects. Aspoint out, however, these results are consistent with the observation that 5-HT2A receptors are found on both layer V glutamatergic neurons and GABAergic interneurons. Furthermore, there is also a direct activation of GABAergic interneurons through the synapses of pyramidal cells onto the interneurons. So, a large excitatory response in a pyramidal neuron will lead to a large inhibitory response in the interneuron.propose that the effects of psilocybin could be due to both excitatory (e.g., pyramidal) and inhibitory (e.g., GABAergic interneuronal) neuronal circuits and that it may be the effects on the inhibitory neuronal circuits that gave rise to the measured BOLD response (see Figure). To my knowledge, no model of how hallucinogens trigger synesthesia has yet been proposed. One natural proposal would be that the mechanisms in developmental and drug-induced synesthesia are similar. There is, however, some reason to doubt this suggestion. The phenomenological differences between developmental and drug-induced synesthesia are quite striking (seefor a review). As experiences causally supervene on neurological processes, experiences that are significantly different in their phenomenology are bound to have significantly different neurological underpinnings. So, we should expect some differences in the underlying mechanisms. One tentative suggestion is that drug-induced synesthesia, like hallucinations, originates in the hyperactivity of layer V pyramidal cells resulting from the binding of hallucinogens to 5-HT2A receptors in the cells' dendrites, which then increases local glutamate levels. Layer V pyramidal cells bind multisensory information through feedback loops that synchronize oscillatory neural responses. In the visual and the auditory cortices layer V neurons form feedback loops with local neurons as well as neurons in the thalamus and prefrontal cortex. Projections to thalamus play a role in discriminating among incoming information and integrating information from different sensory channels, whereas projections to the prefrontal cortex play a role in higher-order processes and the generation of a conscious representation. In normal multisensory perception, low-level multisensory binding of incoming signals from visual and auditory channels occurs spontaneously in the auditory cortex via thalamocortical feedback loops, when the spatial and temporal attributes of incoming signals match (Schroeder and Foxe, 2005). Excessive excitatory activity in layer V pyramidal neurons, however, results in a destabilization of layer V projections to the thalamus through GABAergic neuronal circuits. This has a number of consequences, such as decreased attentional discrimination among incoming stimuli, allowing more information to flood the sensory cortices, a loss of stimulus-specific inhibition, an resultant increase of random (or environmentally under-constrained) activity in the thalamus, and a disruption of low-level, spontaneous integration of multisensory stimuli on the basis of actually matching spatial and temporal attributes. The disruption of low-level integration mechanisms can result in incongruent experiences, such as hearing an object hit the floor prior to seeing it fall. Another result of this disruption of low-level integration may be a coupling of stimuli that do not belong together. A common synesthetic experience during hallucinogen intoxication is colored, geometrical grids, matrices or fractals induced by music (seefor a review). These types of visual experience also frequently occur without an inducer, probably as a result of random activity in the thalamus. One possible mechanism for drug-induced synesthesia, then, is that the brain assumes that an experience that results from occipital processing of random thalamic activity matches auditory stimuli, leading to an unusual low-level binding in the auditory cortex (see Figure). As a result of this aberrant binding, the two inputs may be experienced as an inducer-concurrent pair, for example colored, geometrical music. The proposed mechanism leads to the testable prediction that drug-induced synesthesia will not usually be systematic. In developmental cases sound-color synesthesia is systematic in the sense that very specific sounds normally trigger very specific colors. Given the aberrant binding proposed, however, it appears that drug-induced sound-color synesthesia will not tend to be systematic because random activity will be paired with available auditory information. So, we should expect that the same sound may have many different colors and shapes. There are only few reports of drug-induced synesthesia that endures post-exposure, though there is evidence that other practices that can induce altered states of consciousness, such as meditation and posthypnotic suggestion, frequently cause enduring synesthesia. The suggested mechanism may help explain why drug-induced synesthesia is seldom persistent over time. The hypothesis proposed is that occipitally processed random activity is coupled with available auditory information during drug-induction. The random activity does not persist in the same magnitude after drug exposure, which may explain why the synesthetic experiences and hallucinations tend to subside. But what further decreases the chance that the synesthesia persists would be the lack of a one-one mapping or even a many-one mapping from inducer to concurrent, which we might expect will make the unusual synesthetic binding less likely to be retained as a neural connection. The proposed mechanism of hyperexcitability followed by disruption may appear to be inconsistent with a related finding for developmental synesthesia. It is believed that enhanced cortical excitability at an early developmental stage might contribute to atypical grapheme-color binding, even though it does not appear to be a direct cause of synesthesia at later stages. A recent study reported data that were consistent with the idea that at later stages the hyperexcitability can hinder synesthesia by producing excess noise in the visual cortex and thereby reducing conscious awareness of the atypical binding of features. However, I think that this suggestion can be reconciled with the proposed mechanism for drug-induced synesthesia. It is plausible that hyperexcitability may no longer play a functional role at later stages of developmental synesthesia. Hallucinogenic serotonin agonists, however, appear to introduce a significant amount of hyperexcitability that can offset normal binding by disrupting low-level integration mechanisms. It is possible that some varieties of developmental synesthesia form in early childhood in a way similar to the way druginduced synesthesia is here hypothesized to form temporarily later in life, but there would be certain differences: developmental synesthesia is systematic so if synesthesia develops in childhood as a result of a disruption of low-level integration, it is not a result of random activity in the thalamus. Furthermore, the presence of the hyperexcitability during brain development must somehow make it more likely that the unusual binding persists over time than when the hyperexcitability is drug-induced. A version of the proposed model also appears consistent with the findings of Cohen. The team induced strong projector grapheme-color synesthesia using posthypnotic suggestion in a group of highly suggestible college students. In most cases the synesthesia was found to endure and to display the phenomenal characteristics of developmental grapheme-color synesthesia. Cohenprovide evidence suggesting that the induced synesthesia resulted from posthypnotically triggered disinhibited feedback. However, their results seem equally consistent with a model that proposes disruption of lowlevel integration. One shortcoming of both mechanistic proposals for synesthesia induced post hypnosis is that they do not explain why the condition tends to endure much longer than drug-induced synesthesia. A further interesting question is whether the above model could be adapted to explain acquired synesthesia in which necrosis leads to neurotransmitter flooding and elevated local serotonin levels. Though we do not have enough data on acquired synesthesia to make any firm conclusions at this point, it remains a possibility that some forms of developmental synesthesia are acquired in childhood in the same way as the persistent cases of acquired synesthesia, whereas temporarily acquired synesthesia is mechanistically akin to drug-induced synesthesia. If this is correct, then we should expect drug-induced synesthesia and temporarily acquired synesthesia to both lack systematicity, as they would result from pairing features with random information. We should furthermore expect persisting forms of acquired synesthesia to have the same patterns of permanence and systematicity as at least some forms of developmental synesthesia.
Though it is difficult to say whether alterations in the serotonergic system play a role in the development of the most common forms developmental synesthesia, such as week-color and graphemecolor, developmental synesthesia seen in autism spectrum disorder is plausibly triggered by unilateral changes in the serotonergic system. There is not yet any solid evidence that autism and synesthesia are mechanistically related but there appears to be a statistical correlation as well as a possible genetic connection between the two conditions: synesthesia as well as sensory and perceptual abnormalities, such as hyper-responsiveness to sensory stimulation, are often reported as significant symptoms in autism-spectrum disorders.states that 15 percent of people with autism experience synesthesia, which would be significant compared to the 4.4 percent of the general population. However, a systematic population study of the correlation between autism and synesthesia has not yet been completed. About 10 percent of individuals with autism also have savant syndrome, and all three conditions have frequently been reported to occur together. Recently, a genetic link between synesthesia and autism was suggested. Despite the lack of solid evidence for a mechanistic connection between autism and synesthesia, the existing statistical and genetic correlations give us reason to explore how serotonin may be related to synesthesia in autistic individuals. I will look at the evidence for the serotonin hypothesis for autism and then propose some testable predictions about how serotonin may give rise to synesthesia in autistic individuals. The evidence that serotonin plays a crucial role in autism is overwhelming. About 30 percent of autistic individuals have a 25 to 70 percent increase in blood levels of serotonin, also known as hyperserotonemia. Hyperserotonemia has also been found to a similar degree in first-degree healthy relatives. As serotonin cannot normally cross the blood-brain barrier in adults, high blood levels of serotonin are not necessarily a good indicator of high extracellular serotonin in the brain. High blood levels of serotonin, however, may indicate brain levels of serotonin in young children, as the blood-brain barrier is not fully developed until the age of two. Higher rates of autism have also been found in children exposed in utero to drugs that increase 5-HT levels, such as cocaine. The high levels of serotonin in young children can negatively affect the development of serotonin neurons through negative feedback. As serotonin neurons develop and the extracellular levels of the neurotransmitter increase, growth of serotonin neurons is normally curtailed through a negative feedback mechanism, leading to a loss of serotonin terminals. This decrease in serotonin terminal development has also been found in animal studies administering monoamine oxidase A and B inhibitors or serotonin reuptake inhibitors during gestation. Several PET imaging studies have suggested that autism may be a lateralized syndrome, with decreased serotonin release from raphe terminals in one hemisphere (typically the left) and elevated serotonin release in the contralateral hemisphere. Significantly increased language impairment was found in subjects with decreased serotonin synthesis in the left hemisphere compared to individuals with right-hemisphere abnormalities and those without cortical asymmetry. Further evidence for the lateralization theory comes from studies indicating functional improvement with selective serotonin reuptake inhibitors (SSRIs), such fluoxetine. SSRIs block serotonin transporters, preventing extracellular serotonin from being transported back into the cell. When children with autism are treated with SSRIs, the symptoms they share in common with individuals with major depressive disorder and anxiety disorders drastically improve. The children's range of interests broaden, their perceptual experiences normalize, their memory and cognitive functions improve and anxiety and phobias become less prominent. Depleting brain serotonin in a tryptophan depletion paradigm, on the other hand, results in a worsening of the mood-related symptoms of autism as well as behaviors such as whirling, flapping, rocking and pacing, though it does not affect the other symptoms of autism. One possible explanation of the asymmetry is that the early serotonin depletion in the dominant left hemisphere leads to overcompensation in the right hemisphere. It has been reported that a decrease in extracellular serotonin over time may lead to an excessive spread of thalamocortical axon branches, resulting in lower information-transmission and structural changes in affected cortical regions as well as underdeveloped long-range connections between different brain areas. When the decrease in serotonin is left-lateralized, this leads to a general hypoexcitability of the left hemisphere and a wider right parietooccipital region compared to individuals with mental retardation or miscellaneous neurological disorders. The reversal of the asymmetry may be the result of initial right-hemisphere dominance, as indicated by a higher incidence of left-handedness and improved language skills in autistic individuals with decreased serotonin synthesis in the right hemisphere. These results may explain why savant syndrome occurs in ten percent of autistic individuals. The leading hypothesis is that savant syndrome is caused by a lesion or birth defect in one hemisphere that results in overcompensation by the other hemisphere. A hemispheric effect does not provide clear evidence for a role of serotonin in synesthesia, as not all individuals with autism have synesthesia. But the expected high frequency of synesthesia in autistic individuals together with the lateralization hypothesis point to the possibility that increased extracellular levels of serotonin in the autistic brain may be a causal influence on the genesis of synesthesia in individuals with this disorder. There appears to be two ways in which serotonin could be implicated in synesthesia in autistic individuals. One possibility is that the high serotonin levels in very young children with autism sometimes trigger altered multisensory processing. Another possibility is that compensatory high serotonin levels in the contralesional hemisphere sometimes cause unusual feature binding. If the former hypothesis is correct, then we should expect to find evidence of synesthesia in autistic individuals at a very young age. There are multiple ways that elevated serotonin levels may lead to synesthesia in autistic individuals. If the onset of synesthesia in autism occurs at an early age, it could be the result of serotonintriggered hyperactivity in glutamatergic neurons in layer V and resulting destabilization of thalamic connections. If this hypothesis is correct for synesthesia in autistic individuals, then we should expect that the synesthetic connections can persist only in the form of tight memory connections after the subsequent loss of serotonin-terminals in large areas of the brain. Accordingly, on the assumption that projector synesthesia is not normally mnemonic, we should not expect to find a significant number of projector synesthetes among autistic individuals. Another way synesthetic connections could form would be through the early excessive formation of neural pathways. Persisting synesthesia in this case would require that the early formed structural connections could survive the extensive pruning that appears to take place when serotonin-terminals are lost. If the onset of the synesthesia does not occur at an early age, structural or functional synesthetic connections could still form in the spared right-hemisphere regions that are also believed to be responsible for the savant skills founds in 10 percent of autistic individuals. Structural connectivity mechanisms have been proposed for standard cases of grapheme-color synesthesia, suggesting unusual connectivity between the color area and the fusiform gyrus. Enhanced anatomical connectivity near the fusiform gyrus confirming this hypothesis has been reported for grapheme-color synesthesiaand sound-color synesthesia. Whether a structural connectivity mechanism also underlies synesthesia in autism could fairly easily be tested by using a DTI paradigm to look at whether there are similar patterns of localized hyper-corticalconnectivity in autistic individuals with synesthesia. If the onset of the synesthesia does not occur at an early age, there is also the possibility that it is the result of impaired higher-order multisensory integration associated with decreased functional and structural connectivity. This would make developmental synesthesia in autism very different from other cases, which appear to be a result of increased structural or functional connectivity. There is, however, a fairly strong reason against this mechanism as explanatory of synesthesia in autistic individuals. Impaired multisensory integration in autism amounts to a failure to associate two high-level sensory input that neurotypical individuals would associate, not a persistent success in associating two input that neurotypical individuals do not associate. Whether a hyperactive serotonergic system can contribute to developmental synesthesia in non-autistic individuals is unknown. As autism is partly defined by sensory processing deficits, the emergence of synesthesia in autism could be a consequence of other sensory alterations and originate from a unique set of mechanisms distinct from those present in other cases of developmental synesthesia. But some data points indicate that serotonin may be mechanistically involved in producing synesthetic experience through altered functional connectivity. Asobserved, there is some reported pharmacological evidence suggesting that developmental synesthesia in non-autistic individuals could sometimes be a serotonergic condition. Pharmacological evidence for the serotonin hypothesis was also reported by. He describes a patient with life-long synesthesia who developed epilepsy as an adult and subsequently experienced less vivid synesthetic experiences when treated with the anti-epileptic drug Tegretol (carbamazepine), which is known to increase extracellular levels of serotonin. The reports fromandmay seem to provide evidence against serotonin triggering synesthesia via excitatory activity, as the increased serotonin levels apparently inhibited synesthesia. However, both fluoxetine and carbamazepine have been shown to significantly increase GABA and reduce glutamate levels, which would block the excitatory effects of serotonin in cortical areas. So, these data suggest that serotonin may be functionally involved in generating synesthetic experience either through a disinhibited feedback mechanism or by making unusual structural binding available for conscious processing. The pharmacological evidence thus lends some support to a disinhibited feedback mechanism, which suggests that synesthesia is not a result of altered structural connectivity but arises from altered functional feedback connections. This type of mechanism has received prior support from psychophysical and neuromagining studies of non-autistic synesthetes. A recent imaging study of 14 auditory-visual non-autistic synesthetes, for example, found increased functional connectivity of the left inferior parietal cortex with the left primary auditory and right primary visual cortex, suggesting that the aberrant synesthetic binding takes place in parietal cortex. There is also suggestive evidence of mixed mechanisms. For example, some forms of grapheme-color synesthesia appear to involve enhanced visual memory associations with hyper-reinstantiation in the visual cortex (see. Drawing on evidence that the 5-HT2A receptor may be involved in generating synesthetic experience,suggest that synesthesia might occur from overexpression of the 5-HT2A receptor gene on chromosome 13. A whole-genome linkage scan and a family-linkage analysis in a sample of 43 multiplex families with auditory-visual synesthesia did not confirm this hypothesis. Instead the study suggested that synesthesia may be traceable to a region on chromosome 2 (2q24.1) that has been implicated in autism, indicating that there may be genetic link between developmental synesthesia and autism. Other evidence gives some credit to the hypothesis that synesthesia in non-autistic individuals could be related in terms of brain structure to autism and savant syndrome and hence that a particular brain structure may underlie all of these conditions. Population studies suggest that there may be a higher incidence of synesthesia among people with creative talent. Conversely, some synesthetes appear to have greater cognitive and memory capacities specific to the concurrent of the individual's synesthesia compared to the general population. The possible association between synesthesia and cognitive talent might suggest that synesthetes without autism have serotonin-induced hyperconnected neural networks without the down-regulated neural regions found in people with autism. Recent neuroimaging studies further point to enhanced functional connectivity or increased gray matter density in synesthesia. A recent functional MRI study found increased intrinsic network connectivity in 12 grapheme-color synesthetes that reflected the strength of their synesthetic experiences.further reported greater gray matter volume in the left intraparietal sulcus and right fusiform gyrus in 18 synesthetes compared to 18 controls. Several DTI studies have confirmed increased white matter connections in the superior parietal cortex, right inferior temporal cortex and frontal regions in grapheme-color synesthesia, though at more liberal thresholds;and sound-color synesthesia. Although these lines of evidence do not provide evidence of a causal connection among developmental synesthesia, autism and savant syndrome, results are suggestive that local hyperconnectivity is a common feature of these conditions. However, we do not yet have enough data to draw any firm conclusions about the role of serotonin in developmental synesthesia in non-autistic individuals or the connection between developmental synesthesia and autism. More systematic population studies as well as whole-genome linkage scans and family linkage analyses may be able to shed more light on this connection. The extent to which serotonin is mechanistically involved in developmental synesthesia could be tested more systematically in pharmacological studies using drugs known to inhibit 5-HT2A receptors, such as SSRIs, and serotonin-agonists, such as cocaine, that are only reported to cause hallucinations with excessive use. If serotonin is functionally implicated in synesthesia, we should expect 5-HT2A inhibitors to block or reduce synesthesia and serotonin-agonists to augment the experiences. A negative result would rule out that serotonin is functionally involved in synesthesia but would leave open the possibility that the neurotransmitter is involved in the onset of developmental synesthesia by leading to an early change in structural connectivity.
The primary aim here has been to defend the hypothesis that synesthesia is at least sometimes a hyperserotonergic condition that triggers synesthesia through excitatory neurotransmitter action. The main evidence in favor of this hypothesis can be summarized as follows: First of all, brain injury that gives rise to acquired synesthesia leads to necrosis and excessive release of serotonin and glutamate. Though this increase in excitatory neurotransmitter activity leads to lower excitability in local areas through negative feedback within weeks, decreased activity in affected neural regions could lead to a disinhibitory enhancement of neural activity and connectivity in unaffected cortical regions. Alternatively, the early increase in serotonin levels could lead to the formation of unusual feature binding. Secondly, administration of certain hallucinogenic serotonin agonists (e.g., psilocybin) induces synesthesia. The mechanism underlying drug-induced synesthesia plausibly involves serotonergic excitatory activity in layer V pyramidal neurons implicated in multisensory binding. Thirdly, serotonin synthesis is typically increased unilaterally in individuals with autism, about 15 percent of which are believed to experience synesthesia compared to about 4 percent population-wide. In terms of a potential mechanism, one possibility is that serotonin causes aberrant structural binding in the spared neural regions that are also responsible for the savant skills found in 10 percent of autistic individuals.
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Vollenweider, F. X., Vollenweider-Scherpenhuyzen, M. F. I., Bäbler, A. et al. · NeuroReport (1998)
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