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Brain–behavior interactions are imperative across a wide range of medical practices and are commonly probed by neuropsychological assessments. These assessments are carried out in order to support diagnosis of congenital or acquired neurological conditions or to assist in treatment planning or tracking. Recent advancements include standardization of tools and norms, the development of computer-based tests, and incorporation of test performance with neuroimaging tools for clinical prediction. However, current practices are challenged by cultural biases, time-consuming procedures, and relying on commercial testing tools. These factors may limit assessments’ quality and prevalence in clinical and research settings, widening health disparities and hindering scientific advancement. In the era of precision medicine, optimizing neuropsychological assessments is a necessity. The current chapter will suggest how and why a precision medicine approach should be applied in the field of neuropsychological assessment, and how applying this framework will increase sensitivity and specificity of existing diagnoses and improve treatment selection and outcome. By using an illustrative case study, we describe current discrepancies and suggest ways to implement and embrace the following changes: (1) explore behavior using a dimensional cross-diagnostic approach integrating different information levels (e.g., biology, cognition, and behavior); (2) study brain atrophy and brain connectivity as potent markers of brain–behavior interactions; (3) adopt an open-science approach by creating open databases with neuroanatomical and behavioral records of different patient populations; and (4) incorporate technology in the assessment by using computerized tests and ecological momentary assessment tools to complement the traditional tests and measures. Combining novel neurocognitive indexes with advanced genomics and state-of-the-art neuroimaging will allow creating individual profiles spanning the brain–behavior interaction. These profiles would guide personalized diagnostic and prognostic treatment strategies.

Number and space are spontaneously linked in human cognition and have been metaphorically described as a ‘mental number line’. In number–space synesthetes (NSS), numbers are visualized in specific spatial arrays, in an idiosyncratic and explicit manner. Here we tested whether the numerical–spatial association that characterizes NSS has the potential to affect individual’s actions when the number is not a task-relevant feature. We used a Simon task that implies stimulus–response matching. Task-irrelevant Arabic numerals (1, 4, 6, 9) appeared simultaneously at the same location as a colored target. A group of 15 age-matched controls and 4 NSS completed a 2 × 2 within-subjects design consisting of Simon (compatible and incompatible) and number–space (congruent and incongruent) trials. Mean reaction time (RT) and RT cumulative distribution functions across Simon and number–space conditions for both NSS and controls were analyzed. Relative to controls, synesthetes’ RTs were overall affected by the number–space mapping. Moreover, synesthetes’ Simon effects occurred at later response times. These results provide strong evidence that numbers are cognitively represented as action codes and that the strength of the association shapes the impact of the numerical representation on individuals’ actions.

In the study of basic and high-level cognitive functions, neuroscientists, psychologists, and philosophers have tended to focus on normal psychological processes and on deficits in these processes, whereas the study of exceptional abilities has been largely neglected. Here the authors emphasize the value of researching exceptional abilities. They make the case that studies of exceptional representations, such as of time, number, and space in synesthesia, can provide us with insights regarding the nature of the neurocognitive mechanisms of these dimensions, as well as their developmental, evolutionary, and cultural origins.

Number-form synesthetes consciously experience numbers in spatially-defined locations. For non-synesthete individuals, a similar association of numbers and space appears in the form of an implicit mental number line as signified by the distance effect-reaction time decreases as the numerical distance between compared numbers increases. In the current experiment, three number-form synesthetes and two different non-synesthete control groups (Hebrew speaking and English speaking) performed a number comparison task. Synesthete participants exhibited a sizeable distance effect only when presented numbers were congruent with their number-form. In contrast, the controls exhibited a distance effect regardless of congruency or presentation type. The findings suggest that: (a) number-form synesthesia impairs the ability to represent numbers in a flexible manner according to task demands; (b) number-form synesthesia is a genuine tangible experience, triggered involuntarily; and (c) the classic mental number line can be more pliable than previously thought and appears to be independent of cultural-lingo direction.

In musical–space synesthesia, musical pitches are perceived as having a spatially defined array. Previous studies showed that symbolic inducers (e.g., numbers, months) can modulate response according to the inducer’s relative position on the synesthetic spatial form. In the current study we tested two musical–space synesthetes and a group of matched controls on three different tasks: musical–space mapping, spatial cue detection and a spatial Stroop-like task. In the free mapping task, both synesthetes exhibited a diagonal organization of musical pitch tones rising from bottom left to the top right. This organization was found to be consistent over time. In the subsequent tasks, synesthetes were asked to ignore an auditory or visually presented musical pitch (irrelevant information) and respond to a visual target (i.e., an asterisk) on the screen (relevant information). Compatibility between musical pitch and the target’s spatial location was manipulated to be compatible or incompatible with the synesthetes’ spatial representations. In the spatial cue detection task participants had to press the space key immediately upon detecting the target. In the Stroop-like task, they had to reach the target by using a mouse cursor. In both tasks, synesthetes’ performance was modulated by the compatibility between irrelevant and relevant spatial information. Specifically, the target’s spatial location conflicted with the spatial information triggered by the irrelevant musical stimulus. These results reveal that for musical–space synesthetes, musical information automatically orients attention according to their specific spatial musical-forms. The present study demonstrates the genuineness of musical–space synesthesia by revealing its two hallmarks—automaticity and consistency. In addition, our results challenge previous findings regarding an implicit vertical representation for pitch tones in non-synesthete musicians.

Synesthesia is a peculiar condition that involves an atypical binding between two seemingly independent sensory modalities or within the same one. All synesthetic bindings are characterized by an inducing stimulus (i.e., inducer) and a subjective sensation triggered concurrently (i.e., concurrent). Synesthetic inducers can be sensory (e.g., sound) or conceptual (e.g., graphemes, time units) while the concurrent sensation is, in the majority of cases, a sensory one (e.g., smell, touch). In numerical synesthesia, numbers (i.e., inducer) automatically and consistently trigger an ancillary experience of color, texture, spatial location, or personification (i.e., concurrent). For example, for a given synesthete, an audition of the number 5 may trigger a sensation of the color shiny yellow, be mapped on a vertical meridian above four and beneath six in his/her peripersonal space or elicit a cognitive awareness of “a young man, ordinary, and common in his tastes and appearance …” (Simner et al., 2011). Until recently, numerical synesthesia was almost unquestionably viewed as a symbolic-based phenomenon. This was mainly because most synesthetes report their synesthetic experience is elicited solely by symbolic content (i.e., Arabic numbers) but not by non-symbolic ones (i.e., size, quantity) (Cohen Kadosh and Gertner, 2011). Furthermore, some researchers showed that non-symbolic magnitudes (i.e., random clusters of dots) or less familiar symbolic numerals (i.e., Roman numbers) were ineffective in evoking the synesthetic concurrent (Ramachandran and Hubbard, 2001, Experiment 3; Ward and Sagiv, 2007), suggesting that Arabic numbers per se (i.e., their form, ordinality, etc.) and not their semantic meaning or numerosity are the critical factors for inducing synesthetic experience (Hubbard et al., 2009). However, when considering two main findings in the domain of numerical cognition—(a) that symbolic content is intimately associated with non-symbolic dimensions (e.g., size, quantity, brightness) (e.g., Schwarz and Heinze, 1998; Fias et al., 2003; Pinel et al., 2004; Ansari, 2008; Cohen Kadosh et al., 2008a), and (b) that magnitude is assumed to be automatically activated whenever we are presented with numbers (Dehaene et al., 1993; Dehaene and Akhavein, 1995)—one must wonder whether synesthetic experience can also be elicited by different magnitude dimensions. In this opinion paper we present some recent observations from the literature on numerical synesthesia indicating that magnitude representation may play a role in mediating synesthetic effects found under experimental settings. Based on this evidence we suggest that synesthetic experiences induced by numbers may be produced also by non-symbolic magnitudes, due to the cognitive and neuronal overlap of these two dimensions. In other words, we propose that numerical synesthesia is more than a symbol-induced phenomenon per se. Furthermore, we speculate that this suggested association between a non-symbolic inducer and a synesthetic concurrent may manifest at different levels of awareness, resulting in an explicit, reportable experience for some synesthetes but a more non-conscious or implicit representation in others. Before presenting our arguments, it is important to note that we use the phrase “numerical synesthesia” to include the subtypes of synesthesia that share numerical inducers (i.e., number-color and number-space synesthesia). We acknowledge that in spite of a common inducer (i.e., number), different mechanisms may mediate the various inducer-concurrent associations (Novich et al., 2011), yet we argue that both types discussed here illustrate the suggested involvement of magnitude representation in inducing synesthetic concurrents (i.e., color, spatial location).

In spatial-sequence synesthesia, ordinal sequences are visualized in explicit spatial locations. We examined a recently documented subtype in which musical notes are represented in spatial configurations, to verify consistency and automaticity of musical pitch-space (M-S) synesthesia. An M-S synesthete performed a mapping pre-task (Exp. 1) used to indicate the locations of 7 auditory or visually presented notes, in 2 sessions a month apart. Results revealed strong correlations between sessions, suggesting the synesthete’s musical forms were consistent over time. Experiment 2 assessed automaticity of M-S synesthesia. The same synesthete and matched controls preformed a spatial Stroop-like task. Participants were presented with an auditory or visual musical note and then had to reach for an asterisk (target) with a mouse cursor. The target appeared in a compatible or incompatible location (according to the synesthete’s spatial representation). A compatibility effect was found for the synesthete but not for controls. The synesthete was significantly faster when the target appeared in compatible locations than in incompatible ones. Our findings show that for synesthetes, auditory and visually presented notes automatically trigger attention to specific spatial locations according to their specific M-S associations.

Number-space synesthetes visualize numbers in specific spatial configurations. Their spatial-numerical perceptions are assumed to be automatic in nature and have been found to affect performance in various numerical tasks. The current study tested whether synesthetic number-space associations can modulate the well-established Size Congruency Effect (SiCE), which is considered to be an indication for the automaticity of numerical processing. Two groups, number-space synesthetes and matched controls, were tested on a numerical Stroop task (Henik and Tzelgov, 1982). In separate blocks, participants were presented with two digits and asked to make comparative judgments regarding either numerical values (numerical comparison) or physical size (physical comparison). Both dimensions were manipulated orthogonally, creating three congruency levels: congruent (e.g., 2 7), incongruent (e.g., 2 7) and neutral (e.g., 2 2 and 2 7 for physical and numerical blocks, respectively). For the numerical block, both synesthetes and controls showed the classic SiCE, indicating similar automatic processing of physical magnitude. However, in the physical block, synesthetes showed a lack of automatic numerical magnitude processing when the numbers to be compared were presented incompatibly with their relative position on the synesthetic number-form. This finding strongly suggests that synesthetes' number-space perceptions affect their ability to automatically process the semantic meaning of numerals. The involvement of space in automatic magnitude processing for number-space synesthetes and non-synesthetes is discussed. © 2012 Elsevier Ltd.

Month-space synaesthetes experience months as sequences arranged in spatially defined configurations. While most works on synaesthesia have studied its perceptual implications, this study focuses on the synaesthetic influence on a synaesthete's action behaviour. S.M., a month-space synaesthete, and 5 matched controls performed a spatial Stroop-like task in a haptics and virtual reality combined environment, which was especially designed to simulate S.M.'s three-dimensional synaesthetic experience. In the experiment, a circle and a word were presented simultaneously. The word consisted of either a month name or a direction name and was located at the centre of the screen, while the circle was displayed in one of four peripheral positions-top, bottom, right, or left. When S.M. was asked to ignore the word and reach for the circle, no effects were found. In contrast, when she was asked to ignore the circle and reach for a location indicated by the word, a congruency effect was found for both months and direction words. Crucially, these effects were evident in all measurements of reaching performance (i.e., path, velocity, and trajectory of movement). Our findings revealed that for month-space synaesthetes, months trigger spatial shifts of attention in a similar manner as directions do. Moreover, these shifts of attention affected not only latent cognitive processes (i.e., reaction time) but also overt behaviour (i.e., entire hand movements).

Number comparison tasks produce a distance effect e.g., Moyer & Landauer (Nature 215: 1519-1520, 1967). It has been suggested that this effect supports the existence of semantic mental representations of numbers. In a matching task, a distance effect also appears, which suggests that the effect has an automatic semantic component. Recently, Cohen (Psychonomic Bulletin & Review 16: 332-336, 2009) suggested that in both automatic and intentional tasks, the distance effect might reflect not a semantic number representation, but a physical similarity between digits. The present article (1) compares the distance effect in the automatic matching task with that in the intentional number comparison task and suggests that, in the latter, the distance effect does include an additional semantic component; and (2) indicates that the distance effect in the standard automatic matching task is questionable and that its appearance in previous matching tasks was based on the specific analysis and design that were applied.

Publisher Summary This chapter describes the phenomenon of time and/or number, space (TNS) synesthesia, its possible neural mechanisms and its effect on everyday life functioning. The account for the allegedly contrasting evidence relies on the idea that both synesthetes and non-synesthetes share the same cognitive and neural mechanisms and the differences between them are down to different levels of conscious awareness and the intensity of the TNS association. Namely, synesthetes who visualize early months on the left and late months on the right were faster to make left-hand responses to the former and right-hand responses to the latter than vice versa, while synesthetes who represent early months on the right and late months on the left showed the opposite pattern. A better understanding of the neural bases might offer a lead toward its origin, including the developmental stages at which it might occur. Therefore, a careful investigation of the individual differences in the experience of TNS together with a better understanding of its neural mechanisms will provide a means for the delineation of these types of synesthesias and consequently a better knowledge of the neurocognitive mechanisms behind the implicit interaction of time, number, and space in non-synesthetes.