Neuropsychological Templates for Abnormal Personalities: From Genes to Biodevelopmental Pathways
Adolf Tobeña
The scaffolding of personality
Research on human personality has converged upon a ‘consensual pathway’ indicating that a small number of dimensions can provide the framework for describing the rich variety of human temperaments. These high-level temperamental traits are factorially derived from psychometric measures of individual variation in behaviour, feeling, and thinking,(1,2) and it is assumed that they may reflect the operation of brain systems that are probably multifaceted and multipurpose.(3, 4 and 5) This global outline of the structure of personality depends on the notion that genetic and developmental dispositions combine with critical nurturing and social conditioning events to form the tapestry of human uniqueness within temperamental clusters. In other words, personality types are expressed through relatively clear-cut and stable phenotypic traits that are accessible to objective measurement at behavioural, emotional, and cognitive levels. These depend, in turn, upon the specific and early organization of particular neurocognitive and neuroendocrine templates.
A handful of ‘superfactors’ (broad traits or dimensions) apparently capture the essential components of the mosaic of terms and traits used to describe normal personality. These dimensions are neuroticism, extraversion, agreeableness/friendliness, conscientiousness, and intellectual openness. Neuroticism and extraversion always appear as main stars in these factorial solutions whereas the remaining three superfactors—conscientiousness (reliability/persistence), friendliness (as opposed to aggressiveness/hostility) and intellectual curiosity (openness/creativity)—have less regularity on such high-order taxonomies. A five-dimensional structure is advocated by many researchers though dissent is still strong regarding the nature and scope of these superfactors that would define the ‘core’ of human temperament.(6)
Biological rooting of personality types
Searching for biological substrates of personality dimensions would reinforce their validity as useful constructs but this endeavour was largely neglected by psychometricians devoted to purely descriptive studies and by clinical researchers as well. Some pioneers, like Hans Eysenck at the Institute of Psychiatry, London, tried to root behavioural trait variations within neurobiological concepts(1) following a venerable tradition, which can be traced back as far as Pavlov. These early proposals were rather rudimentary though they served as drivers of subsequent models which focused more tightly on certain brain subsystems as possible sites for the factors underlying normal and abnormal temperaments.(3, 4 and 5,7, 8 and 9) Jeffrey Gray, Robert Cloninger, and Larry Siever’s ideas were among the more fruitful in an area which has grown steadily and is now an lively field of personality research.(9, 10 and 11) Progress in basic neuroscience has made it possible to relate a variety of biological measures to paper and pencil or neurocognitive tests distinguishing normal and anomalous temperaments. Biological screening has also increasingly been applied to patients with personality disorders, using the clinical clusters as defined by Diagnostic Systems. Besides these attempts to build psychobiological profiles of normal and abnormal temperaments, converging evidence is used to advocate that categorical and dimensional models for diagnosing personality disorders should be integrated.(12)
To give a broad overview of an area that may be crucial to illuminate the genesis of personality disorders, I shall discuss the studies that, during the last decade, have tried to find genetic traces for personality traits that are both behaviourally consistent and biologically well rooted. Previous work using classical (familial or twin) methods had found substantial heritability estimates for several personality traits.(13) It was thus unsurprising that genetic tracking methods impulsed research aimed at showing that temperamental traits contribute to personality scaffolding via neuroendocrine targets specified by particular genes. I’ll be discussing the outcome of some of these efforts and I’ll explore afterwards how other basic temperamental traits, rooted within biodevelopmental processes, do mediate enduring neurocognitive organization resulting in long-lasting behavioural styles. Finally I’ll outline new avenues for the neuropsychology of personality. My approach is deliberately selective, discussing relevant evidence rather than performing a systematic assessment of the field. For reasons of convenience and possible clinical relevance, I have selected some of the traits heralding sound biological foundations, although they are not necessarily prominent in the state-of-the-art dimensional ‘solutions’ for normal and abnormal temperaments.
The genetic saga for novelty-seeking
In 1996 two independent teams reported(14,15) that a particular chromosomal ‘locus’ was associated with a well-established trait of human temperament—the hunger for novelty and excitement that lies behind sensation-seeking, risk taking, and impulsive behaviours.(5,10) A polymorphism in the sequence of the gene expressing the D4 dopamine receptor (D4DR), located on the short arm of chromosome 11, explained 10 per cent of the genetic variance due to this trait. Individuals with the longer repeat allele at exon III of the D4DR gene scored higher in novelty-seeking
behaviour (explorers, risk-seekers), whereas those with the shorter allele had lower scores (prudent, cautious). The first of these studies(14) investigated a heterogeneous sample of young Israelis, and showed the association to be independent of ethnicity (Ashkenazim versus Sephardim), sex, or age. The second study, carried out in the United States,(15) used a random sample of people who had initially been recruited in a search for chromosomal regions possibly associated with sexual orientation; this sample mainly comprised white men, although some ethnic minorities were also included. The personality questionnaires were different but very popular in personality research: the Israelis were evaluated using Cloninger’s Tridimensional Personality Questionnaire (TPQ),(16) which gives direct scores of novelty-seeking, whereas the American study used the Revised NEO Personality Inventory(17) which measures the five superfactors mentioned above, from which scores for novelty-seeking were derived. The results of the two studies were highly concordant.
behaviour (explorers, risk-seekers), whereas those with the shorter allele had lower scores (prudent, cautious). The first of these studies(14) investigated a heterogeneous sample of young Israelis, and showed the association to be independent of ethnicity (Ashkenazim versus Sephardim), sex, or age. The second study, carried out in the United States,(15) used a random sample of people who had initially been recruited in a search for chromosomal regions possibly associated with sexual orientation; this sample mainly comprised white men, although some ethnic minorities were also included. The personality questionnaires were different but very popular in personality research: the Israelis were evaluated using Cloninger’s Tridimensional Personality Questionnaire (TPQ),(16) which gives direct scores of novelty-seeking, whereas the American study used the Revised NEO Personality Inventory(17) which measures the five superfactors mentioned above, from which scores for novelty-seeking were derived. The results of the two studies were highly concordant.
Despite the modest explanatory power of this reported association, the link between temperamental variability for one trait and a chromosomal polymorphism was the first hint for a direct relationship between a putative ‘genetic marker’ and a core dimension of normal personality. In this case, the potential genetic marker appeared promising because of the amount of basic and clinical research linking dopaminergic function with the regulation of stimulus-seeking and sensitivity to incentives. In theory, if similar degrees of explained variance were assignable to other sound gene markers associated to approach/exploring phenotypes, a substantial part of the heritability of the trait could be explained. Subsequent studies(18,19) failed to replicate these early findings in a consistent way and the optimism receded. The heterogeneity of the samples and the subtleties of the genetics of complex traits were blamed for the disparate results, though the research saga was quite productive: the links between dopamine receptor polymorphisms and novelty-seeking have been intensively searched and the race to find other markers for the same trait was impressive.
Metanalyses suggest that there are subtle connections between dopamine receptor gene variants and approach/exploring propensities as measured by personality questionnaires, though the strength of the contribution of every variant is small and hard to establish.(19,20) Moreover, parallel research has established suggestive connections between gene variants regulating other molecular targets (i.e. tryptophan hydroxylase, dopamine transporter, dopamine-beta-hydroxylase, serotonin transporter, MAOA, COMT) that modulate risk-taking behaviours and impulsivity. A handful of genes, thus contribute to differential vulnerabilities for addictive behaviours, a congruent result at the extreme of stimulus-seeking tendencies. Although further and more refined research is required, these data seem to confirm pioneer work, mostly with twins, which had consistently established that novelty-seeking behaviour was moderately heritable (40 to 50 per cent).
Genetics of fearfulness/neuroticism
The aforementioned American team that reported the first associations between novelty-seeking and variants of D4DR gene informed that there was an association between the neuroticism trait and a chromosomal region linked to serotonin neurotransmission involved in modulating anxiety-related traits.(21) The 5-hydroxytryptamine transporter protein (5-HTT) that promotes the reuptake of serotonin into cell membranes is encoded by a gene (SLC6A4) located in the q11-q12 segment of chromosome 17. The region governing the transcriptional control of the protein shows a polymorphism that influences its expression and functioning. Individuals carrying the short variant of the polymorphism show a reduced efficiency of serotonin reuptake compared with those possessing the longer variant. The study measured these parameters in the lymphoblasts of two independent samples totalling more than 500 volunteers. Using two different personality questionnaires (NEO and Cattell’s 16PF Personality Inventory) and estimated scores on various dimensions of Cloninger’s TPQ, the evidence showed that subjects who carried the short variant in the 5-HTT gene polymorphism had higher neuroticism (NEO), anxiety (16PF), and harm-avoidance (TPQ) scores. The results were equally consistent across and within pedigrees. Across the three personality measures, the 5-HTTLPR contributed a modest 3 to 4 per cent of the total variance and 7 to 9 per cent of the genetic variance in anxiety-related traits. It was suggested that, if other genes contributed similar dosage effects to anxiety traits, approximately 10 to 15 genes might be involved in the heritability of neuroticism.
The implication of the serotonin transporter in the potential genetic predisposition towards emotionality traits agrees with many other results. Serotonergic neurotransmission is involved in multiple brain functions with little or no relationship with fear/anxiety regulation, but there is a large body of evidence linking it with the modulation of adaptive responses to serious conflict and emotionally demanding situations.(3) Moreover, many drugs currently used to treat anxious/depressive dysphorias and personality disorders depend on mending serotonergic function. Finally, several studies have shown that variants of the 5-HTTLPR predict differential response on anxious phenotypes: fear-driven amygdala activation(22) and response to pharmacological challenges.(23) Therefore, although the exact role of serotonergic systems in the modulation of emotionality is not fully understood, it is improbable that the neurohormonal adaptations that participate in individual responses to serious emotional conflicts would not include serotonin modulation either through the cell transporter or through the extended family of serotonin receptors and their intracellular targets. Defensive adaptations require however the participation of other central neuromodulators: the CRH-ACTH regulatory cascade, γ-aminobutyric acid, neuropeptide Y, and substance P,(3) are major contenders in this respect and they can be expected to contribute to the genetic mediation of neuroticism.
Polymorphisms in anxious humans versus QTL-genes for fearful rodents
Dozens of studies investigated whether the particular polymorphism in the 5-HTT gene contributes to the tendency for individuals who score higher on neuroticism, in personality tests, to be at higher risk for ‘internalizing disorders’ (anxiety/depression) and personality disorders (anxiety/affective clusters). The global outcome of that research has been unreliable: though stringent metanalyses confirmed the original association with a modest relevance at explaining the trait variance,(23) subsequent results in large samples of siblings and singletons have been negative.(24) There are other lines of evidence, however, mainly from animal research, that support the claim of a possible genetic basis for fearfulness/emotionality. This evidence is derived from studies of the
psychogenetics of emotional susceptibility searching for chromosome loci. In many biological and behavioural tests, comparisons of several reactive and non-reactive strains of mice and rats obtained through artificial selection (forced interbreedings) have narrowed the search for genetic loci thanks to increasingly powerful methods of chromosomal mapping. In a pioneer work with progeny obtained by crossing two strains of mice selected for activity and defecation in an open-field test, three loci (QTLs) which explained most of the genetic variance in emotionality were found on chromosomes 1, 12, and 15 of the murine genome.(25) These data were confirmed and extended by measuring fear responses towards particular cues: the same segment of chromosome 1 was identified as a relevant ‘locus’ for emotional susceptibility besides other murine chromosomal zones.(9) The importance of the loci at chromosome 1 has been established in studies using heterogeneous and inbred stocks, combining techniques which have permitted to focus the suspicious segment to less than 1 cM and leading to the identification of the first gene linked to murine emotionality: Rgs2, a regulator of G-protein functioning which is highly expressed in the brain.(26) The complexities are nevertheless tremendous because even a QTL like that contains several genes each contributing a very modest part of variation on the phenotype of interest.(9,26)
psychogenetics of emotional susceptibility searching for chromosome loci. In many biological and behavioural tests, comparisons of several reactive and non-reactive strains of mice and rats obtained through artificial selection (forced interbreedings) have narrowed the search for genetic loci thanks to increasingly powerful methods of chromosomal mapping. In a pioneer work with progeny obtained by crossing two strains of mice selected for activity and defecation in an open-field test, three loci (QTLs) which explained most of the genetic variance in emotionality were found on chromosomes 1, 12, and 15 of the murine genome.(25) These data were confirmed and extended by measuring fear responses towards particular cues: the same segment of chromosome 1 was identified as a relevant ‘locus’ for emotional susceptibility besides other murine chromosomal zones.(9) The importance of the loci at chromosome 1 has been established in studies using heterogeneous and inbred stocks, combining techniques which have permitted to focus the suspicious segment to less than 1 cM and leading to the identification of the first gene linked to murine emotionality: Rgs2, a regulator of G-protein functioning which is highly expressed in the brain.(26) The complexities are nevertheless tremendous because even a QTL like that contains several genes each contributing a very modest part of variation on the phenotype of interest.(9,26)
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