The specific aims of this project are to:
- Developed functional magnetic resonance imaging (fMRI) protocols to demonstrate brain activity in adults diagnosed with synesthesia.
- Investigate the distribution and localization of brain activity following an auditory or visual (A&V) stimulus.
- Investigate the effects of hallucinogens on the A&V responses of the same subjects. Functional MR imaging of the brain can provide reliable, predictable responses in a population of adults with synesthesia, given proper screening for the type of synesthesia each has.
- Differences in synesthesia types correlate to distinct brain activation patterns to auditory and visual stimuli.
- The effects of hallucinogenic substances altering auditory and visual input responses are independent of the type of synesthesia of the subject.
- Hallucinogens can be used to mimic hallucinatory brain disorders in synesthetes. Demonstrate predictable or recurrent activation patterns in the brains of synesthesia subjects to provide diagnostic tools to assess synesthesia.
- Dynamic imaging of responses to auditory and visual stimuli with and in the absence of a hallucinogenic substance will provide insight into signaling systems of healthy and disordered individuals.
- Localized responses in the hallucinogenic state can be used as markers to differentiate between hallucinogenic disorders like schizophrenia and synesthesia. Synesthesia is defined as the condition where one sensory domain often, but not always, evokes experiences in another. Synesthetic associations are often involuntary, recursive, and arbitrary. Traditional forms of synesthesia include cross-modal correspondence, cross-modal imagery, sensory autobiographical memory, empathic perception, hallucination, and doppler illusion [1]. To distinguish synesthesia from imagination, however, it is necessary to understand the neural correlates behind each type of synesthesia. For example, in a synesthete that experiences bimodal color and sound associations, a higher note may correspond to a brighter color. This correlation can be due to extra neuronal connections across neighboring brain regions (cross-modality) or from differences in signal transmission magnitude and frequency across the same. Prior magnetic resonance imaging (MRI) meta-analyses of synesthesia have concluded that differences in signaling occur at the cortical level [2]. However, much debate remains about the significance of these results due to response quantification on a per voxel basis as well as questions on the appropriate protocol. This study seeks to focus on a specific subset of synesthetic patients to quantify changes in, rather than a standard profile for, brain behavior.
In a similar vein, neuroimaging of schizophrenia has revealed underlying structural differences which reflect neuronal abnormalities [3]. These structural brain changes are often gradual and result in auditory or visual hallucinations. Additional markers for schizophrenia include cognitive impairment, such as memory loss and attention deficit, or a variety of emotional and psychological delusions which lead to negative symptoms and severe life impairment [4]. Upon diagnosis, schizophrenia may require lifelong treatment and intervention. Generating new imaging markers for schizophrenia will be a useful tool in identifying the condition for earlier treatment applications.
The focus of this study is to scrutinize signaling and activation differences between severe hallucinogenic diseases, which significantly perturb quality of life and synesthesia. Furthermore, this study wishes to explore synesthesia as less of a “perception-based experience” and more as an indicator for differential synaptic alignment. For the purposes of this research, schizophrenia shall be mimicked by the controlled delivery of hallucinogens to synesthetic subjects: hence, each synesthete shall serve as his own control for baseline brain activity. I shall seek to identify global changes in brain activity while the subject is at rest with and without drug delivery. Audio-visual alterations are of special interest, as both parameters are easier to control within a study. Subjects shall experience the same audio-visual stimulus and their brain activity response shall be recorded in altered and resting brain states. Applying functional MR imaging techniques to synesthesia in the presence of hallucinogens could produce a brain signature for disease versus a benign neurological condition. The oldest brain imaging technique, electroencephalography (EEG), was one of the first methods purported for the measurement of synesthetic responses. EEGs directly record the electrical activity of depolarization by tracking transient electrical dipoles during ion flux across the cellular membrane [5]. The method is non-invasive and relies upon electrodes placed on the scalp of the subject, recording the overall activity of post-synaptic currents. Particularly, EEG was useful in tracking synesthesia during rest and free-viewing stimulation and revealed distinct activity patterns in the visual LPIT/BA37 brain region of grapheme synesthetes [6]. Non- and pseudo-synesthete control subjects were used as baseline activity comparisons. Spatial resolution is lacking, however, as the method relies upon a summed signal of currents for measurement. Additionally, it would be difficult to track the effect of an active agent like a hallucinogen, which diffuses into the brain via the bloodstream, with direct electric imaging methods.
In addition to EEG experiments, one PET study analyzed grapheme-color synesthetes and normal controls. Positron emission tomography (PET) is a nuclear imaging methodology that tracks small radioactive metabolites called radiotracers and models radioactive signals with mathematical equations [7]. The advantage of this method is that metabolic rates can be deduced from different tissues concerning specific metabolites, and the metabolites (or portions of them) can be tracked within the tissue sample. Using PET, however, derived no statistical difference between grapheme-word synesthetes and normal controls when introducing them to words and tones [8]. Hence, fMRI remains the most popular synesthesia imaging method by far.
Additional studies have centered upon functional magnetic resonance imaging, the main method applied in this proposal. Following these experiments, two major theories have been proposed to explain the neural basis for A&V-based synesthesia. First, it is believed that a region in the visual cortex (fourth visual area V4) preferentially processes color and cross-communicates with the motion processing region, called “MT” [9]. It is surmised that cross-activation comes as a result of reduced synaptic pruning, a process of ensuring synaptic plasticity during brain development. The second predominant theory is that of “Disinhibited Feedback,” a more signaling-based rather than structural explanation for synesthesia. Disinhibited Feedback assumes a reduction in the amount of inhibition signaling between brain regions, causing signaling to travel from “higher” to “lower” order areas about the signaling pathway. Synesthesia would be a result of an overall abundance of excitatory over inhibitory signaling, causing an over-activation of visual cortical brain regions in synesthetes [10]. It is under the second theory that synesthetic experiences can be induced with hallucinogens such as LSD, the main hypothesis of this proposal [11]. Functional MR imaging (fMRI) applies the magnetic properties of select nuclei to generate a comprehensive, temporal image of the brain as a response to small changes in blood flow. fMRI contrast is dependent upon blood-oxygen-level (BOLD): deoxygenated and oxygenated hemoglobin exhibit different magnetic properties, producing a high-resolution, specialized map of brain activity [12]. Brain activity in fMRI is based on the proportional relationship between energy usage and increases in localized cerebral blood flow, volume, and oxygenation. Active regions will display an influx of blood, increasing the concentration of oxygenated hemoglobin and decreasing that which is deoxygenated.
Quantitative analysis of the MR imaging data can then extract changes in concentrations of deoxygenated and oxygenated blood. Statistical filtering separates the signal of interest from noise in each voxel and produces a portrait of brain metabolism [13]. Additionally, because of its dependence on the change in blood flow, the method is noninvasive, hence it will not perturb the effect of any introduced hallucinogens for the second portion of this study. fMRI is also relatively accessible (can be performed on a 1.5 T scanner), low cost, and provides good spatial resolution [14]. Typical fMRI experiments display regional, time-dependent changes in metabolism over an average period of an hour or less [15]. All stimuli delivered must be artificial, as the patient will be lying within the scanner and therefore cannot receive real-life sensory input. The subject shall be provided goggles and earphones through which they shall receive a controlled auditory and visual stimulus that would elicit synesthesia.
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Due to the subjective nature of the synesthesia experience, the study shall rely upon the synesthetes themselves to control for their hallucinogenic stages. Hence, brain activity measurements will be recorded at rest and audio-visual stimulus states both before and after hallucinogen introduction. The baseline activity level shall be determined relative to the non-hallucinogen synesthete data.
As voluntary motion control cannot be guaranteed after the introduction of the hallucinogen, the subject shall be asked to remain as still as possible during the control portion of the experiment (i.e. undergoing no motor tasks). Speech data may also be recorded during the control portion, as a precaution against any speech elicited by the subject in the non-control phase. After the introduction of the hallucinogen, the subject shall be secured comfortably to the scanning bed, to reduce head and body motion as much as possible without restricting natural involuntary movement. A sequence of the same auditory and visual stimulus shall be relayed. Subjects shall be awake during the examination. Drug dosage shall be low enough to not require additional sedatives or anesthesia to provide a relatively motionless environment and to ensure proper capture of brain activation. Due to the complexity of schizophrenia, the hallucinogen of choice will be selected to model only the audio-visual aspect of the mental disease, rather than elicit all symptoms. Though an ideal schizophrenia model would simulate all biological changes and lead to very predictive symptoms, the scope of this study contains only responses at the audio-visual sensory level. It should also be noted that it is not the interest of this study to explore long-term brain changes in schizophrenia, but rather instant neurobiological changes that may occur at the beginning of disorder diagnosis.
Glutamatergic NMDA receptors play a central role in synaptic plasticity and serve as fair targets for schizophrenia modeling. Glutamate signaling hypofunction is generally reported in schizophrenia, a possible cause for the pathogenic reduction of gray matter over time [16]. The molecule itself is an excitatory glucose derivative which promotes the influx of sodium atoms during depolarization and action potential propagation. Hence, the model assumes the perturbation of the neurotransmission signaling pathway following an A&V stimulus. NMDA post-transcriptional NR1 subunit mRNA is also shown to be reduced in schizophrenia [17].
Ketamine shall be applied in controlled dosages as a glutamatergic NMDA uncompetitive antagonist to mimic schizophrenic hallucinations. These dosages will follow pediatric sedation recommendations of a single bolus of 1.5 mg/kg, with an average recovery time of approximately 20 minutes [18]. The drug itself weighs approximately 237.72 g/mol and is a parenterally administered anesthetic used commonly for short-term surgical procedures. Among other effects, ketamine increases functional connectivity and prefrontal glutamate levels due to a reduction in GABAergic interneuron function (possibly through preferential binding of ketamine on GABAergic cells) [19]. The chemical structure of the molecule is provided below. Prior studies have shown that ketamine exacerbates schizophrenic symptoms and induces them in healthy subjects in acute dosages [21]. Hallucinations induced by the molecule are primarily visual and mimic earlier stages of schizophrenia onset, preferential for the profile this study would generate. Generally, ketamine administration shall mimic schizophrenia pathogenic onset via inducing temporary NMDA receptor dysfunction. The study shall be conducted in two stages: one without the hallucinogen, and one with the hallucinogen. These stages shall in turn be subdivided into a rest-state experiment and another with audio-visual synesthetic stimulus, for a total of four experiments. The rest state experiment will have the participant rest within the scanner, awake, with no stimulus for the duration of the experiment (around 20 minutes depending on hallucinogen clearance time). A scanner with EPI capability and appropriate receiver coils shall be used for data collection during these 4 sessions. Basic auditory and visual stimulus shall be controlled in intensity and frequency throughout the study.
Regions of Interest (ROIs) for the functional MR imaging portion of the experiment shall likely rest in the auditory cortex in the upper side of the temporal lobe, as well as regions of the occipital lobe which show increased activation or significant activation patterns.
Standard statistical techniques for the determination of average baseline and stimulation voxel signals shall be applied for differentiating brain region activation. Auditory stimuli will be tones, voices, or musical sounds which the subject has proclaimed triggers a synesthesia response. Tones shall be present at an appropriate level to ensure listening, with intermittent bouts of the silence of approximately 200 milliseconds between each sound bite. Audio shall be delivered via headphones the subject shall be wearing. A minimum of ten sets of sounds, each less than a minute long, shall be played in succession with intermittent pauses. The sequence shall be repeated for the duration of the experiment. The audio shall be played in two stages: once alone, and once with visual input after the first set of sounds alone has been played. Subjects shall experience visual stimuli via LED goggles placed over the eyes. The number of images shall be concurrent with the sound sequence described in the auditory paradigm and correspond to audio-visual synesthesia triggers reported by the subject. Hence, images shall only be played after the first set of audios has occurred. This study proposes a representative sample of sound-to-color synesthetes with no concurrent mental diseases which are above the age of 21. As in all functional MR imaging studies, subjects with metallic clips or metallic objects within their bodies shall be rejected. Insufficient sedation or any indication of significant adverse response to the hallucinogen shall stop any experimental tasks immediately and warrant medical review. Informed consent shall be required of all subjects. In the interest of time and resource management, this study has proposed an analysis of sound-to-color synesthetes with short-term hallucinogen influence. Future studies may strive to track hallucinogens if introduced to synthetic subjects or otherwise explore hallucinogens that mimic long-term schizophrenic behavior. The study could be additionally enriched through PET tracking of these hallucinogens during the introduction: a traced pathway of drug interaction within the brain would introduce another level of completeness to the signaling pathway I plan to develop.
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