Acquired Synesthesia

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Artistic rendition of synesthesia
Retrieved March 26, 2014, from

Acquired synesthesia is a phenomenon which is most commonly induced by physical trauma, neuropathology, or stroke leading to sensory deafferentation[1]. In most cases, it is believed this deafferentation leads to the rewiring of neural pathways such that stimulation of other sensory systems are able to elicit a response in the deafferentated sensory system[2]. The creation of these new associations are generally limited to regions of the brain close to the deafferentated sensory region[2]. Due to the many forms of acquired synesthesia, there are some exceptions that do not appear to fit this model, thus the exact cause of synesthesia still remains unknown. Other factors have been suggested as possible candidates for eliciting synesthetic experiences, such as the serotonin S2a receptor which appears to play a role in all three forms of synesthesia (developmental, acquired, and drug-induced)[1]. A form of synesthesia which appears to be exclusive in acquired synesthetes is the experience of pain in response to seeing or thinking about pain[3]. Specific research into the phenomenon of synesthesia for pain and phantom limbs may give insight into human perception of pain and the role of empathy in the processing of pain. More recently, there has been research into whether synesthesia can be artificially developed in individuals either through reading in coloured letters or through sensory substitution[4][5]. However, there has been some debate over whether these experiences constitute as genuine synesthetic experiences[4][5].

Quick Overview of the Types of Synesthesia (Genuine, Acquired, Drug-induced)

Synesthesia can be seperated into three general types, genuine (also referred to as developed and constitutional), acquired, and drug-induced. Genuine synesthesia is present at birth and persists throughout adulthood, staying relatively stable in terms of associations between inducer and concurrent.[1] Studies have suggested that there is a genetic component associated with this type of synesthesia, meaning that it is heritable.[1] Acquired synesthesia usually develops after sensory deaffentation due to brain injury, stroke, or disease affecting the brain or optic nerves.[1] Depending on the cause, acquired synesthesia may be temporary as in the case of acquired synesthesia where removal of a cystic tumour ended the person's synesthetic experiences.[6]Acquired cases of synesthesia may elicit experiences that are simpler in nature than those experienced in genuine synesthesia, though in some cases these experiences may be indistinguishable.[1] Drug-induced synesthesia arises while under the effects of hallucinogenic substances such as LSD or psilocybin.[7] Unlike the previous two types, drug-induced synesthesia tends to be temporary and generally only manifests itself during the most intense phases of intoxication.[7]Additionally, inducer-concurrent couplings are not static.[7] For example, a drug-induced synesthete might see blue upon hearing a tone but, hearing the same tone a second time might invoke the colour orange, they may feel a sensation on their skin, or they might not experience anything at all.[7]

Drug-Induced Synesthesia

At first glance, drug-induced synesthesia appears to share commonalities with genuine and acquired synesthesia. However, on closer inspection, differences become apparent leading some researchers to question if the similarities between these types of synesthesia are merely superficial.[7] This could mean that though hallucinogens cause a association of sensory modalities similar to what a synesthete might experience, this change in state may be caused by a different underlying mechanism which is not shared with the other two types of synesthesia.[7] However, that is not to say that drug-induced synesthesia is a completely separate process from genuine synesthesia. Though there has not been much research into the effects of hallucinogenic drugs on genuine synesthesia, smoking cannabis has, in one particular case, induced the return of synesthetic experiences in one genuine synesthete whose experiences had faded over time.[7] In another case, a genuine synesthete experienced auditory-visual synesthesia which seemed to be built onto their pre-exsisting grapheme-colour synesthesia while under the influence of LSD.[7] Hallucinogenic drugs also appear to be able to "override" existing inducer-concurrent pairings as in the case of one audio visual-synesthete.[7] Finally, it has also been proposed that serotonin levels may play an active role in all three forms of synesthesia.[1]

Role of Serotonin S2a Receptors

A recent paper has suggested that increased serotonin levels can be partially responsible for the development of synesthesia, both in permanent (as in genuine and acquired cases) and temporary (as in drug-induced cases).[1] Serotonin is generally thought to act as an inhibitor, but some studies (have) revealed that serotonin has the potential to function as an excitatory neurotransmitter.[8] It is hypothesised that through the action of these excitatory mechanisms that synesthesia is induced.[1] Much of the research in this field has implicated the involvement of the serotonin S2a receptor. For example, hallucinogens which can trigger synesthesia, such as LSD, have been found to activate serotonin S2a receptors.[1][9] Melatonin, a hormone derived from serotonin, can disinhibit S2a receptors and in one case, induced grapheme-colour synesthesia.[1][9] It has also been found that some drugs are able to block synesthetic experiences, likely through interaction with the S2a receptor.[1][9] Prozac, a selective serotonin reuptake inhibitor (SSRI) acts by activating serotonin S1 receptors which inhibits serotonin S2a activation, stopped synesthetic experiences in an individual.[1][9] Wellbutrin, a norepinephrine and dopamine reuptake inhibitor, which also inhibits S2a activity was also able to temporarily abolish synesthesia.[1][9]

In Drug-Induced Synesthesia

Interaction Between Psilocybin and Layer V Pyramidal Neurons
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Proposed Pathway of how Psilocybin Elicits Synesthetic Experiences[1]

Many aspects of drug-induced synesthesia are similar to that of hallucinations experienced while under the influence of hallucinogenic drugs.[1] Unlike in other types of synesthesia, the person is not able tell if the concurrent exists in reality.[1] For example, an individual with auditory-visual synesthesia understands that what they see in response to what they hear is not actually there whereas the person experiencing drug-induced synesthesia would not. As such, it is thought that this type of synesthesia is elicited much in the same way that hallucinations are.[1] It has been proposed that hallucinogens bind serotonin to the S2A receptors of layer V pyramidal cells triggering glutamate release through an excitatory response.[1] This change in glutamate levels increases cortical metabolic activity, which can be tied to changes in perception.[1] Additionally, this binding causes hyperactivation of layer V pyramidal cells, which process multisensory information through projections into the thalamus and prefrontal cortex.[1] Hyperactivity in these neurons causes destabilisation of the projections which may lead to the coupling of unrelated stimuli resulting in the synesthetic experiences.[1]

In Acquired Synesthsia

In most cases, acquired synesthesia occurs after injury to the brain or brain region. Tissue damage due to this brain injury has been shown to cause cells to shift into anaerobic glycolysis, a process which is not enough to maintain ATP levels used to fuel membrane ion-pumps.[1] Failure of these pumps leads to cell death either through necrosis or apoptosis.[1] Cell death results in local flooding of neurotransmitters, including serotonin and glutamate.[1] This may lead to hyperactivity of sensory neurons or increased interaction between neighbouring brain regions resulting in the development of synesthesia.[1] In addition, this elevation of neurotransmitter levels causes the down-regulation of receptors which has been implicated in the development of autistic and savant-like traits which may help to explain the correlation between the increased incident levels of the two conditions with genuine synesthesia.[1] This increase of extracellular neurotransmitters has been shown to occur even in milder cases of brain injury and following stroke.1 Further studies have shown that the levels of serotonin and glutamate only remain elevated for a short period of time following injury, suggesting that temporary elevation might be enough to cause the changes dramatic changes in the brain.[1]

Acquired Synesthesia

Can Synesthesia be Acquired?

It is hypothesised that acquired synesthesias are the result of sensory deafferentation leading to the reorganization of cortical maps.[10] Loss of the sensory input can cause unmasking of pre-existing pathways, limiting the remapping to pre-existing connections the deafferentated system has with other modalities.[10] Cells involved in the development of acquired synesthesia may have dual inputs, one from the deafferentated system and one from the inducer.[7][10] The time between the onset of synesthesia and the deafferenetation of the sensory modality varies greatly, indicating that perhaps different changes in the brain can lead to the same outcome.[11] Unmasking of pre-existing pathways is a relatively short-term change in the brain and does not adequately explain why some synesthesias take years to manifest which further supports the idea that there are long-term plastic changes which also play a role in acquired synesthesia.[12]

It has been noted that the large majority of acquired synesthesias arise as a result of deafferentation of visual modality.[12] As such there are a larger number of acquired visual synesthesias.[12] This might be explained by the theory that the visual cortex tends to get remapped after losing visual input to help process information from other modalities.[13]

Acquired Auditory-Visual Synesthesia

Acquired auditory-visual synesthesia is the most common acquired type.[11] This form often arises after damage to the optic nerve.[11] has been proposed that the are post-synaptic projections originating from the auditory cortex leading indirectly into the visual cortex which are normally dormant, and it is the unmasking of these connections that can lead to the development of synesthesia.[14] These connections have been found to be present in macaque monkeys though it is not known if these connections are also found in humans.[11][14]

In one case of acquired auditory-visual synesthesia, an individual was involved in a car accident which destroyed both optic nerves.[14] Preliminary CT and EEG scans showed no damage to the brain.[14] After a year, the individual found that being exposed to loud and sudden sounds produced visual phosphenes.[14] Sounds which reminded him of the traffic accident and those associated with war were particularly efficient at inducing the visual sensations.[14] This suggests that these sounds associated with meaningful memories to the individual are able to better activate his primary visual cortex, activation of which, by auditory input, is thought to be the cause of his synesthesia.[14] It has been shown that stimulation of other sensory modalities can lead to activation of the visual cortex of blind individuals, though this activation does not lead to actual perception.[13] Electrical stimulation of the primary visual cortex is able to induce visual phosphenes.[13] Studies into the areas of brain activation in acquired auditory-visual synesthetes in response to sounds which evoked synesthetic experiences showed activation in the same areas of the visual cortex.[13] In particular, it was noted that areas V4 and V8 were activated in response to words triggering visual experiences.[13] These areas are associated in the processing of images that an individual perceives rather than what a person would imagine, revealing that synesthetes are actually seeing colours as opposed to imagining colours.[13] The results of these studies show that the visual cortex of the blind are able to retain their ability to process visual information, as producing genuine visual perception.[13] There have also been reported cases of individuals with acquired auditory-visual synesthesia but have intact visual pathways.[6][11] Though the visual pathways appeared undamaged, a gliotic mass was found in the brain and removal of this mass resulted in the abolishment of the acquired synesthesia.[11] This shows that the development of acquired synesthesia is not solely dependent on remapping due to sensory deafferentation. There have also been some cases of non-synesthetes acquiring auditory-visual synesthesia only when blindfolded suggesting that there may be another factor present in the development of synesthesia which is fast-acting and reversable.[11]

Acquired Auditory-Tactile Synesthesia

Acquired auditory-tactile synesthesia developed after damage to the ventrolateral nucleus as a result of a stroke.[11] This damage disrupted pathways between the thalamus and cortex resulting in impairment of the individual's sight and touch.[11][15] Initial MRI scans showed no significant difference in white matter between the two hemispheres.[12] Later scans, after the onset of synesthesia, showed changes between the two hemispheres in terms of white matter and connectivity between brain regions.[11] In particular, there appeared to be new connections between the auditory and somatosensory cortices.16 It has been hypothesised that is due to plasticity in the brain, such as axonal sprouting that causes reorganization of regions after loss of its original inputs.[15] As such, perhaps stimulation of the deafferentated system could prevent the formation of these new connections between sensory systems.[15] Using fMRI it was found that sounds activated the parietal operculum, which is involved in processing somatosensory information and can be activated by just seeing images of humans touching others.[16] There also appeared to be a linear relationship between the reported intensity of the tactile sensations and activation of this area.[16] Similar to the cases of acquired auditory-visual synesthesia, the stroke disrupted normal connections between the cortices and allowed for the short-term unmasking of pre-existing pathways and eventual development of long-term plastic changes.[16]

Acquired Synesthesia in an Individual with Intact Sensory Pathways

Geometric Shapes Seen in Response to Mathematical Equations
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Geometric shape seen when exposed to the equation hf=mc2.
Images are drawn roughly three months apart showing that
the inducer concurrent pairing remains stable.[17]

Statistical Parametric Map (SPM) of Brain Activity
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Comparison of regions of brain activation in response to equations which
induce synesthetic responses (left) versus equations which do not (right)[17]

After sustaining an injury to the head, the individual (previously diagnosed with savant syndrome) began to see geometric figures in response to mathematical equations and perceived objects as being bound by tangent lines.[17] MRI revealed no significant brain damage as a result of this injury after the accident and during the time of this study.[17] fMRI showed activation of the left hemisphere, largely the inferior frontal, middle frontal, and precentral gyrus.[17] This increased activation in the left hemisphere suggests that the individual's synesthetic experiences are more conceptual in nature than actual sensory perceptual.[17] The left hemisphere has been shown to be involved in creating novel mental images compared to the other visual areas which were not activated in response to the inducers in this case of synesthesia.[17] This suggests that there might be two forms of visual synesthesia, one which involves sensory perception and another which is largely dependent on the generation of images.[17]

Synesthetic Pain

Are you a Mirror Touch Synesthete?
Mirror touch synesthetes feel a sensation on their own
bodies when they see someone else being touched

Some amputees may develop a form of acquired synesthesia wherein they feel phantom sensations where their limb used to be, in some cases these sensations can manifest themselves as pain.[11] Often times, seeing or even thinking about other people in pain is enough to trigger pain in the phantom limb.[3][18] This projection of someone else's sensation onto oneself is similar to those with mirror-touch synesthesia.[3] As such, it has been proposed that these two types of synesthesia are activated in much the same way.[3] A mirror system is proposed to be responsible for these sensations.[3][18] It is suggested that these mirror neurons activate neurons which process tactile sensations, while normally this activation is not able to reach a threshold to elicit conscious sensations, increased sensitivity in mirror-touch synesthetes allow the threshold to be reached thus causing the synesthete to feel tactile sensation in response to seeing someone else being touched.[3] In the case of amputees, this increased sensitivity may be related to the pain they had experienced before the amputation.[3] It has been found that phantom pain is more likely to develop in individuals who experienced intense pain before the operation.[3] This hypothesis is supported by the finding that pain is largely due to the individual's awareness of pain cues, for example, an individual who has experienced more pain will be more vigilant of possible threats and better able to empathize with those experiencing pain.[3] In addition, these individuals will tend to have a lower pain threshold than those who have not experienced intense pain.[3] Though these mirror neurons have been found to exist in monkeys, it is still unclear as to if these mirror systems exist in humans.[3]

Mapping of Perceived Tactile Stimulation of Others onto Self
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There is increased incidence of preserved somatatopy in those with mirror-touch synesthesia[18]

Recent studies have shown the existence of human brain mirror neuron-like behaviour which seem to involve more sensory areas than in the monkey, specifically it appears to be implicated in emotion and touch.[3][18] Experimental findings support the claim that empathy and emotion are important in mirror-touch synesthesia as well as the manifestation of phantom pain.[18] fMRI has revealed that the act of observing someone else being touched or in pain activates the same regions of the brain when the individual is touched or in pain.[18] This activation was not as strong when viewing a rubber hand or someone the individual considered part of an "out-group" suggesting that the ability to empathize with the person being stimulated is important the activation of the mirror system.[18] The study also implicated emotion in the activation of this mirror system, if the inducer appeared more painful, it was more likely to induce a sensation.[18] This study also revealed that somatotopy, that is the sensation felt on the viewer's body is in the same area where they saw the other person being stimulated, is preserved in mirror-touch synesthetes.[18] Somatotopy is also preserved in some amputees but in general, the elicited sensation tends to be felt in the phantom limb.[18] This suggests that in the development of phantom limbs is dependent on a combination of the individual's predisposition to pain as well as the rewiring of connections as a result of sensory deaffernetation.[18]

Development of Artificial Synesthesia

Coloured Magnets
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One individual's grapheme-colour synesthesia largely maps
onto magnets they had when they were young[21]

It has been suggested that young children often display synesthetic tendencies, perhaps due to an increased interconnectivity in the brain.[3] It is also during this time period that genuine synesthesias develop, leading to the hypothesis that strengthening of these pathways may lead to genuine synesthesia later in life.[3] This also brings into the question of the environmental factors associated with the development of synesthesia. Studies have shown that though graphemes are not identical from synesthete to synesthete there does appear to be a tendency for certain letters to appear as certain colours, even in the case of identical twins.[3][19] There was a case of one synesthete whose grapheme colours match those of refrigerator magnets they had in their childhood.[20][21] However, it is unclear as to how these pairings are made as this is not true for all synesthetes. For example, with the increased exposure to advertising, it is interesting to note that most grapheme-colour synesthetes do not associate the letter "M" with yellow as in the McDonald's logo.[4]

Reading in Coloured Letters

One study looked to see if strengthening of letter-colour associations in non-synesthetes can cause the development of synesthetic-like traits.[4] This was done by having subjects read in coloured letters and tested with a Stroop test.[4] Though they were somewhat successful, these associations were weakened and forgotten in the subjects a few months later.[4] This suggests that the subjects most likely did not experience true synesthetic experiences as a result of this training.[4] There is some controversy over what should be considered as synesthetic experiences.[22] It is argued that though there appear to be some commonalities between associations, such as in this case when you associate the letter "A" with the colour red, and synesthetic experiences, the underlying neuromechanisms are extremely different.[22] Difference between these two processes are apparent, even when examining them on a superficial level. For example, synesthetic pairings tend to remain stable and these connections between inducer and concurrent are automatic.[7][22] In cases of association, the associated colour may change over time and these pairings are not formed instantaneously.[22]

Sensory Substitution

Sensory Substitution Device
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How the vOICe converts visual information into auditory information
Retrieved March 26, 2014, from

Sensory substitution devices (SSD) turn input from one sensory modality into another.[5][23] For example, one such device, "the vOICe" turns visual information and converts this into auditory information.[23] A camera picks up the visual information where it is relayed to a computer where it converts the input from the camera into sounds and sends that through to the user through headphones.[23] Proficient users of SSDs report being able to see their surroundings using this audio input.[23] For example, some develop the ability to perceive depth and in some, even colour.[23] This development sounds similar to the phenomenon of auditory-visual synesthesia and raises the question if these experiences are a form of acquired synesthesia.[5] It has been suggested that the images that are elicited in response to the SSD are the result of imagery rather than actual perception.[5] For instance, things that the user has memory of before losing their vision are much clearer in their mind than things they have never seen.[23] Much like in the case of the previous study, it is possible that prolonged use has just helped to solidify the associations between what the sounds mean and what is in their environment. [5][23]

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