In Search of Biomarkers for Biobehavioural and Psychiatric Taxonomies Free

Lists of temperament and personality traits keep growing, with overlapping descriptors, and so do the lists of psychiatric disorders and their symptoms. Attempts to classify these biologically based biobehavioural differences began right from the start of psychology and psychiatry as sciences, on the threshold of the 20th century, and, a century later, we cannot say that the task of classification has been completed, or even close to being completed [1, 2]. Quite the opposite, it became clear that we cannot have a working taxonomy without knowing, how, biologically speaking, these differences are sustained, despite universal sociocultural pressure for people to be attentive, energetic, social, intelligent, risk averse, empathetic, flexible, patient, and secure. There is obviously something biological going on that makes people respond differently to the same instructions or parenting.

This realization is not new, and we can call it a “biomarkers-first, taxonomy second” approach to biobehavioural taxonomies. This approach is common in medicine: medical scientists first identify systems that regulate the body in health, and then, using this “healthy map,” point to pathological variations of these systems in clinical cases. Similarly, we can identify neurophysiological mechanisms of behavioural regulation in mentally healthy people, identifying the healthy range of neurobiological variations between people. Then, we can present psychopathology as deviations of these neurobiological mechanisms. As highlighted by Sulis [3], Netter [4], and Trofimova [5] in this Theme Issue, this approach allows us to treat temperament traits in healthy people and psychiatric disorders as lying on a continuum of degrees of deviation from an “ideal norm.” The second approach, summarized as “taxonomy first, biomarkers-second,” emerged when psychologists offered their classifications of temperament/personality traits and psychiatric disorders and then started looking for biomarkers that could be linked to those traits.

The first approach is about 20 times older than the 2nd one. In fact, perhaps the oldest theory in differential psychophysiology and psychiatry, is Temperament theory, developed by Hippocrates and Galen. A more modern example is the experimentally derived theory of types of nervous systems developed by Pavlov. These pioneers of the biomarker-based approach had special training in medicine and took the neurobiology of temperament as their starting point for deriving a biobehavioral taxonomy. The second approach emerged mostly in the 20th century in American psychology, with the development of classifications based on lexical methods (sorting long lists of descriptors) or psychiatric observations. Later, this approach was complemented by linear correlational statistical methods (factor analysis and structural equation modelling), still very much detached from neuroscience. Paradoxically, despite the longevity, logical superiority and neuroscientific foundation the first approach, and the well-known superficiality of the second approach [1], models based on the second approach (such as the 5-factor model of personality and DSM/ICD classifications of psychopathology) have come to dominate psychology and psychiatry. Yet, it must be acknowledged that there is a close mutual influence between the second approach, starting from the classification of systems, and the first approach, starting from observations or measurements of biological variables. This means there is a constant mutual enrichment and refinement of classifications as well as of identification and assessment of underlying biological variables resulting in sub-classifications and modifications of theories as well as of methods of assessment. For example, the classification of diseases in medical textbooks according to organs (gut, lung, and heart), body tissues (blood, skin, bones, nervous system, etc.), demographic variables (sex and age groups) or assumed causes (allergies, infections, and degeneration) resulted in improvement of the assessment of several neurochemical, endocrine, and (neuro) physiological “biomarkers.” This led to the development of respective therapeutic substances or procedures. Both experimental and therapeutic results led to changes of theories and to improvement or development of new methods and particularly to new hypotheses for further experiments.

The overall reason for the fact that most psychobiological investigations start from observations-based psychiatric or psychological classifications and not from biomarkers is the complexity of biomarkers underlying biobehavioural traits and psychopathology. It is much harder to disentangle multiple fluid, interconnected psychophysiological systems using time and resource consuming experiments on animals and humans, than to push buttons on statistical software that groups self-rated descriptions of psychological traits or psychiatric descriptions of symptoms to create classifications. Indeed, if we go the first way, that is starting from biological variables, and this is what this Theme Issue illustrates, we are faced with the following challenges.

First, there are several types of biomarkers for biobehavioural individual differences, each associated with a specific methodology of research: neurochemical (identified in studies of neurotransmitters, hormones, and other biochemical systems), neuroanatomic (identified in neuroimaging studies), and electrophysiological (identified in studies of EEG and evoked potentials). These branches of neuroscience rarely compare their notes and findings, due to differences in their units of measurement. To illustrate this, this Theme Issue included articles that represented several different approaches to studying these biomarkers: an overview of the results from a specific neurochemical experimental tradition using humans [4], electrophysiological methods, and measurement of physical touch [6] in infants, comparison of different age groups in children with a psychiatric disorder [7], conceptual review of functional neurochemistry [5], neurochemical experiments on animals [8], insights into mathematical modelling of the dynamical nature of biobehavioural biomarkers [3], and a neuroimaging study investigating a specific temperament trait [9].

Second, neurochemical biomarkers (neurotransmitter and hormonal systems) receive less attention in the search for biomarkers of traits and psychopathology in comparison to neuroimaging, often due to the fluid and complex nature of neurochemical systems. Moreover, the methods of studies in neurochemistry are more invasive than in neuroimaging [4, 10], and the multiplicity of neurochemical systems creates another puzzle in sorting out their mechanisms of behavioural regulation [4, 5, 10-12]. There are additional challenges associated with age and sex, 2 biochemical factors proven to affect consistent behavioural patterns (CBPs, a term proposed to abbreviate temperament traits and symptoms of psychopathology [5]). It is well known that several psychiatric disorders have uneven age distributions and specific age ranges for their typical onset. Temperament traits, such as sensation seeking, impulsivity, sociability, and tempo of speech, tend to have higher expression in younger ages and lower expression in older ages. Sex differences in sensation seeking and impulsivity (higher in males) and in social-verbal traits (higher in females) are most profound before age 30 years. After that, these sex differences seem to level off, suggestive of a “middle age – middle sex” phenomenon [13] linked to systemic biological factors [14]. Age is, therefore, a factor that should be taken into account. In fact, the study of Zvereva and colleagues [7] demonstrates that even in the cases of delusional disorders, children aged 8–11 differ from teenagers by their temperament profiles. Sex differences are regulated, to a large extent, by hormonal systems, which do show not only different levels in males and females, but also different relationships with and experimental effects on psychological behaviour and temperament traits (as demonstrated for oxytocin [15] or testosterone [16]). Hormones and neurotransmitters are also governed by circadian and/or lunar cycles, which, in addition, may be changed by external stimuli [4]. This increases the difficulty in synchronizing phases and time of day of assessment and in comparing males and females.

The third group of challenges comes from the interaction between neurochemical systems, or between neuroanatomic systems, or between these 2 classes of biomarkers. Obviously, due to these interactions, we cannot use correlational methods only (such as factor analysis) that look for independent, non-interacting dimensions. Instead, we had better apply techniques of pattern analysis. Primary neurotransmitters regulate each other’s release using a diversity of mechanisms. An important part of neuroscientific knowledge is based on the cascade of functional relationships [17] that starts from the release of monoamine neurotransmitters (dopamine, noradrenaline, and serotonin), that co-release neuropeptides (e.g., corticotropin-releasing hormone) in the hypothalamus. These act on the pituitary, which can have 2 types of actions. It either produces further peptides (like the adrenocorticotropic hormone), which, in turn, releases hormones (like cortisol or gonadal hormones) from the adrenal cortex in the periphery; or, alternatively, the pituitary releases peptides (like prolactin and growth hormone) directly into the bloodstream. The benefit for studies on humans is that the reactivity of each transmitter system can be assessed by their indirect actions on peripheral hormone levels accessible in plasma. There are benefits and limitations of this methodology [10] as it provides an indirect approach to identifying differences in neurotransmitters’ responsiveness in temperament research [4, 10].

As emphasized above, the neurophysiological systems are not independent, dominated by complex feedback mechanisms and, therefore, a “dimensional” approach has rather limited content validity [1]. This brings another challenge of identifying biomarkers of psychopathology. A psychiatric disorder rarely comes as a problem involving a single biomarker. When one neurophysiological system of behavioural regulation goes out of balance, multiple feedback mechanisms from other systems restore the balance. It is only when 2 or more systems go out of balance that they amplify each other’s dysfunctionality and affect many aspects of the integration of behaviour. These changes, in turn, receive feedback from multiple levels of the environment, reinforcing them. This suggests that looking for single, specific biomarkers for specific psychiatric diagnoses might not be very fruitful [18]. However, if we go with a biomarkers-by-bunches approach, it is useful still to know what each member of the “bunch” has to contribute to behavioural regulation.

The fourth type of challenge relates to the transient nature of the neurophysiological processes that we consider as biomarkers of CBPs. Most neurotransmitters are created from precursors before they are used for transmission and are decomposed soon after that by special enzymes. Similarly, dendritic associations appear to be plastic [19] and task dependent. Moreover, most cortical neurotransmission (regulating high-complexity behaviour) does not use “secured” synapses but rather neurotransmitters present in the extracellular space (volume transmission) [20-22]. Similarly, a compositional nature was noted in the behaviour itself [5], supporting the constructivism approach. When everything is constructed “on the go” depending on available resources and demands, how can we find anything consistent in behavioural regulation? Nevertheless, some behavioural patterns, such as symptoms of psychopathology or temperament traits in healthy individuals, show remarkable consistency. It is, therefore, challenging to identify and classify biomarkers in line with the generative and transient features of behaviour.

The fifth group of challenges comes from the fact that CBPs, such as temperament traits or psychiatric disorders, are never solely the product of the brain of an individual. Instead, they are products of body-environment interactions, including the social environment. The study of Hardin and colleagues illustrates the epigenetic influence of a mother’s touch and breastfeeding on an infant’s development, highlighting the importance of considering environmental factors in childhood [6]. One way of a rough classification of the degrees, to which an individual is tuned to environmental reinforcers, was offered since the mid 1980s by the activity-specific approach to temperament [21]. This approach suggests a separation between behavioural regulators related to body systems, social relations and abstract-cultural reinforcers (i.e., physical, social, and intellectual aspects of activities) [5, 11, 18, 23-26]. As Acevedo and colleagues [9] have shown, sensitivity to specific types of reinforcers can be a temperament trait linked to specific biomarkers. A possible impact of early childhood experience on the activity of the left hemisphere, as shown by Hardin and colleagues [6], can, therefore, affect future sensitivity to sociocultural reinforcers. The review by Netter highlights [4] the contribution of responsiveness of neurotransmitter systems in fatigue (low endurance), anhedonia, and impulsivity. Similarly, Rezaei and colleagues shows that the endurance of behaviour diminished with a decrease in hypothalamic serotonin and BDNF, suggesting possible biomarkers for this trait [8]. For these reasons, the neurochemical model Functional Ensemble of Temperament distinguishes between physical, social, and mental, as well as between endurance, speed of integration and orientation aspects of behaviour [5]. This differentiation is in line with functional specificity of neuromodulatory systems [5, 11, 12, 24-26], Finally, probably the sixth, biggest challenge, is that we likely cannot rely on help from mathematics or statistics, to identify variables and structure of our taxonomies. In studying even the most “straight-forward” traits or symptoms such as impulsivity or depression, we rely on self-reports promising to measure specific CBPs objectively, and so we use scores from the testing as independent variables to study associations with biomarkers. However, our “rules” are far from perfect and often include arbitrarily chosen statements and markers. More importantly, mathematical operators are suitable for “counting heads” of identical items and for static, well-defined spaces of possible states of the system under study. Neurophysiological systems do not behave this way; they change their possible states, losing them and getting new ones [27]. This “misbehaviour” limits the applicability of classical mathematics and statistics and calls for new, dynamical approaches to formal descriptions of these systems [3, 5, 28]. Moreover, the use of words, verbal descriptions, takes too much space and is not efficient in scientific exchanges. There is, therefore, a need for new formal languages for the description of biomarkers of CBPs [3, 5].

Overall, we advocate for the “biomarkers-first” approach and for more transparency concerning what is going on in the development of consistent biobehavioural patterns. Undoubtedly, much more work needs to be done before we settle on taxonomies of temperament and psychopathology, and this volume is a small step forward in this direction.

The authors have no conflicts of interest to declare.

The authors had no funding for preparation of this paper.

I.T. wrote the main body of the first draft, edited the second draft and part of the references, formatted, and submitted the article; P.N. wrote several sections of the first draft and edited the second draft and a part of references.

This editorial highlights six challenges in search for biomarkers underlying biobehavioural traits (temperament) and symptoms of psychiatric disorders. These challenges were illustrated by the contributions to the current Theme Issue.