Serotonergic hyperactivity as a potential factor in developmental, acquired and drug-induced synesthesia

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.

Abstract

“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.”

Author: Berit Brogaard

Summary

Introduction

Synesthesia is a condition involving experiences of connections between seemingly unrelated sensations, images or thoughts. It can be either projector or associator type, and is automatic, meaning that the subject cannot suppress the association between an inducer and its concurrent.

Synesthesia is a sensory perception that remains relatively stable and systematic over time. It also tends to run in families. Acquired synesthesia is a form of the condition that emerges after brain injury or disease or artificial technologies like sensory substitution. It is often indistinguishable from developmental synesthesia, though it is sometimes less inducer-specific. Drug-induced synesthesia is a blending of sensory or cognitive streams that is experienced during exposure to a hallucinogen. It can range from simple color experiences to complex, surrealistic landscapes. Though synesthesia research has seen a huge growth in recent decades, it is still unclear what causes the onset of the condition and whether the different types of synesthesia have different causes.

Brang and Ramachandran (2007) suggested that serotonin may be functionally implicated in generating synesthetic experience through 5-HT2A receptor activity. I propose that excessive extracellular serotonin (5-HT) can be a trigger of persistent or transient synesthesia in all the groups through excitatory mechanisms.

Serotonin can function both as an inhibitory and an excitatory neurotransmitter. It helps reduce fear processing in the amygdala via GABA modulation, but it also exerts an excitatory effect on cortical brain activity when it binds to 5-HT2A serotonin receptors on layer V pyramidal neurons. Research shows that serotonin levels may be increased after brain injury, which can lead to increased functional or structural interconnectedness among different brain regions, and possibly synesthesia. Developmental synesthesia has been reported as a condition in autism-spectrum disorders, and may be a serotonergic condition resulting from the disorder.

PET scans of people with high-functioning autism reveal that serotonin synthesis is suppressed in the left hemisphere and increased in the right hemisphere, though in some cases it is reversed. Genetic studies furthermore suggest a genetic link between autism spectrum disorder and developmental synesthesia in non-autistic individuals.

Acquired synesthesia

Several studies have hypothesized that acquired synesthesias occur from plasticity of the sensory systems resulting in increased connectivity. In at least one case, a brain lesion may have caused increased connectivity.

Traumatic brain injury causes increased neurotransmitter activity in cortical regions adjacent to the affected site, which leads to membrane degradation of vascular and cellular structures and necrotic or programmed cell death. This causes over-stimulation of serotonin and glutamate receptors.

Brain injury may trigger complex biochemical events that lead to progressive apoptotic and necrotic neuronal cell death. The initially elevated levels of serotonin and glutamate may be sufficient to cause long-lasting functional and possibly also structural changes in the brain.

Brain injury may cause decreased serotonin levels in the ipsilateral hemisphere, which may lead to an upregulation of the serotonergic system in the contralateral hemisphere, which may explain the development of synesthesia and autistic traits in some individuals.

At least one case of acquired synesthesia has been reported to occur shortly after brain injury, indicating that initial neurotransmitter flooding causes the onset.

The first hypothesis may have greater support for synesthesia acquired after frontotemporal dementia, as patients with this condition have deficits in serotonergic and dopaminergic signal-transmission. This could explain some of the cognitive and behavioral impairments of the disease. A small fraction of brain injury patients acquire synesthesia-like experiences. This may be because some subjects are more susceptible to the formation of new neural connections than others, or because sensory regions or neural areas implicated in mental imagery are affected.

Some forms of acquired synesthesia appear to be quite similar to well-known forms of developmental synesthesia, while others appear to be transient and may be a more direct product of excitatory neural activity, similar in many respects to synesthetic experience occurring under the influence of hallucinogens.

Drug-induced synesthesia is a blending of perceptual or cog-nitive experiences, and is often a result of a lack of activity in the visual cortex in response to synesthetic tasks.

Drug-Induced synesthesia

Psychedelic hallucinogens alter perception, mood, and cognitive processes. First-person reports indicate that synesthesia occurs during psychedelic intoxication, with subjects reporting seeing melting windows, breathing walls, and spiraling geometrical figures crawling over the surfaces of objects. The authors characterize this as a hallucination, but it is difficult to distinguish between synesthesia and hallucinations because synesthesia has a phenomenally apparent inducer and most forms of synesthesia are experienced as endogenous images or representations.

The phenethylamines (e.g., mescaline) and the cybin are potent partial agonists at serotonin 5-HT1A/2A/2C receptors, and it is believed that 5-HT2A receptor activation of cortical neurons is responsible for mediating the perceptual effects of psychedelic drugs.

The 5-HT2A receptors are involved in the co-transmission of glutamate and monoamines in the cortex and subcortical brain regions. The hallucinogen psilocybin targets this receptor complex. Hallucinogens increase cortical metabolic activity and perceptual changes are correlated with increased metabolic activity in the frontomedial and frontolateral cortices, anterior cingulate, and temporomedial cortex. Increased excitability of cortical sensory networks may explain why hallucinogens mimic aspects of psychosis during intoxication.

A recent fMRI study showed 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.

Drug-induced synesthesia is similar to hallucinations in that layer V pyramidal cells hyperactivate, which increases local glutamate levels and synchronizes oscillatory neural responses. These neurons form feedback loops with local neurons as well as neurons in the thalamus and prefrontal cortex.

Intoxication can cause a disruption of low-level integration mechanisms in the thalamus, which can lead to incongruent experiences such as colored, geometrical grids, matrices or fractals induced by music, or experiences without an inducer, such as hearing an object hit the floor prior to seeing it fall.

Drug-induced sound-color synesthesia may not be systematic because random activity is paired with available auditory information, and the random activity does not persist in the same magnitude after drug exposure, which may explain why the synesthesia tends to subside.

At later stages, hyperexcitability may hinder synesthesia by producing excess noise in the visual cortex, but the mechanism for drug-induced synesthesia is different because the hyperexcitability is introduced earlier in life and the unusual binding persists over time.

A group of highly suggestible college students experienced strong projector grapheme-color synesthesia, which endured and displayed the phenomenal characteristics of developmental grapheme-color synesthesia. The authors propose that the synesthesia results from posthypnotically triggered disinhibited feedback, but the condition also endures much longer than drug-induced synesthesia.

Development syenthesia in autistic and NON-autistic individuals

A statistical correlation as well as a possible genetic connection between autism and synesthesia has been suggested. However, a systematic population study of the correlation between autism and synesthesia has not yet been completed. Despite the lack of solid evidence, the statistical and genetic correlations suggest that serotonin may be related to synesthesia in autistic individuals. The evidence that serotonin plays a crucial role in autism is overwhelming. High blood levels of serotonin in young children may indicate high levels of serotonin in the brain, and high levels of serotonin may negatively affect the development of serotonin neurons through negative feedback.

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). The asymmetry of serotonin synthesis may be caused by a lesion or birth defect in the dominant left hemisphere, which results in overcompensation in the right hemisphere, leading to a general hypoexcitability of the left hemisphere and underdeveloped long-range connections between different brain areas. The lateralization hypothesis and the high frequency of synesthesia in autistic individuals point to the possibility that increased extracellular levels of serotonin in the autistic brain may be a causal influence on the genesis of synesthesia. Multiple ways exist for elevated serotonin levels to lead to synesthesia in autistic individuals, including serotonin-triggered hyperactivity in glutamatergic neurons in layer V and resulting destabilization of thalamic connections. If the onset of synesthesia in autism occurs at an early age, structural or functional synesthetic connections may still form. Structural connectivity mechanisms have been proposed for grapheme-color synesthesia and sound-color synesthesia, and increased anatomical connectivity near the fusiform gyrus has been reported in individuals with synesthesia. Whether a hyperactive serotonergic system can contribute to synesthesia in autism remains to be investigated.

Autism could be partly defined by sensory processing deficits, and synesthesia could be a consequence of altered functional connectivity. Pharmacological evidence suggests that serotonin may be involved in generating synesthetic experience either through a disinhibited feedback mechanism or by making unusual structural binding available for conscious processing. The pharmacological evidence supports a disinhibited feedback mechanism, which suggests that synesthesia is not a result of altered structural connectivity but arises from altered functional feedback connections. There is also suggestive evidence of mixed mechanisms, including enhanced visual memory associations with hyper-reinstantiation in the visual cortex.

A whole-genome linkage scan and family-linkage analysis in 43 multiplex families with auditory-visual synesthesia did not confirm the hypothesis that synesthesia is caused by overexpression of the 5-HT2A receptor gene on chromosome 13.

Studies have found that some synesthetes have greater cognitive and memory capacities specific to the concurrent of the individual’s synesthesia compared to the general population. These results may be due to serotonin-induced hyperconnected neural networks without the down-regulated neural regions found in people with autism.

Conclusion

Serotonin may be involved in synesthesia through excitatory neurotransmitter action, and this connection could be explored by using drugs that inhibit 5-HT2A receptors and serotonin-agonists that only cause hallucinations with excessive use.

The mechanisms underlying drug-induced synesthesia plausibly involve 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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