Elsevier

Psychoneuroendocrinology

Volume 78, April 2017, Pages 203-212
Psychoneuroendocrinology

Exploring the role of testosterone in the cerebellum link to neuroticism: From adolescence to early adulthood

https://doi.org/10.1016/j.psyneuen.2017.01.009Get rights and content

Highlights

  • Cerebellar volumes correlate inversely with neurotic personality traits in adolescents and young adults.

  • In males, higher endogenous testosterone levels is associated with lower scores on neurotic personality traits and larger cerebellar gray matter volumes.

  • Testosterone significantly mediates the relation between cerebellar gray matter and measures of neuroticism.

Abstract

Previous research has found an association between a smaller cerebellar volume and higher levels of neuroticism. The steroid hormone testosterone reduces stress responses and the susceptibility to negative mood. Together with in vitro studies showing a positive effect of testosterone on cerebellar gray matter volumes, we set out to explore the role of testosterone in the relation between cerebellar gray matter and neuroticism. Structural magnetic resonance imaging scans were acquired, and indices of neurotic personality traits were assessed by administering the depression and anxiety scale of the revised NEO personality inventory and Gray’s behavioural avoidance in one hundred and forty-nine healthy volunteers between 12 and 27 years of age. Results demonstrated an inverse relation between total brain corrected cerebellar volumes and neurotic personality traits in adolescents and young adults. In males, higher endogenous testosterone levels were associated with lower scores on neurotic personality traits and larger cerebellar gray matter volumes. No such relations were observed in the female participants. Analyses showed that testosterone significantly mediated the relation between male cerebellar gray matter and measures of neuroticism. Our findings on the interrelations between endogenous testosterone, neuroticism and cerebellar morphology provide a cerebellum-oriented framework for the susceptibility to experience negative emotions and mood in adolescence and early adulthood.

Introduction

Neuroticism refers to the personality trait that is characterized by the tendency to experience negative thoughts and feelings associated with behavioural avoidant behaviour (Eysenck, 1967). An important feature of neuroticism is that individuals typically display lower thresholds for experiencing negative emotions in response to stressors and take more time to recover and regain internal bodily homeostasis (McEwen, 1998). It has been shown that neurotic individuals are inclined to display a systemic bias to behavioural avoidance and experience negative emotions even in the absence of stressors. This observation addsto the clinical view that neuroticism is a risk factor for mood disorders (Clark et al., 1994). Disturbances in internal regulatory functions are increasingly considered to play a leading role in the transition between normal and pathological mood states (Kalisch et al., 2014). In support of this view, research has found abnormal activity in several limbic and cortical brain areas, which are known for their involvement in the regulation of stress, autonomic activity, bodily rhythms and homeostasis (Pruessner et al., 2010). Among these areas, the hypothalamus, amygdala and prefrontal cortex have probably received most attention in scientific research.

A less well researched brain region proposed to be part of the neural machinery dedicated to homeostatic regulation and mood is the cerebellum. Even though the idea of cerebellar contributions to emotion and mood was already postulated in the nineteen-seventies (for a review see Schmahmann, 1997), systematic research on the role of the cerebellum in emotion, mood and psychiatric illnesses has been relatively scarce (Schmahmann and Sherman, 1998, Schutter and Van Honk, 2005). However, increasing evidence confirms the proposed involvement of the cerebellum in the experience and regulation of emotions and mood states (Schutter, 2016). One line of evidence comes from clinical reports that describe difficulties in emotion and mood regulation of patients with neurcognitive deficits due to cerebellar damage that cannot be explained by the presence of neurological impairments (Schmahmann, 2010). Administration of disruptive transcranial magnetic stimulation to the cerebellum of healthy volunteers impairs emotion regulation and causes an increase of negative mood (Schutter and Van Honk, 2009). In a more recent structural 3T magnetic resonance imaging (MRI) association study in adults, we found evidence for an association between cerebellar volumes and neuroticism in a non-clinical community sample (Schutter et al., 2012). More specifically, cerebellar volume corrected for total brain volume inversely related to the proneness to experience anxious and depressive states. Meta-analytic studies of functional magnetic resonance imaging are in support of the structural MRI data (Stoodley and Schmahmann, 2009, Keren-Happuch et al., 2014, Van Overwalle et al., 2014). Cerebellar activation in the detection and evaluation of threat cues coincides with the idea that the cerebellum is part of a brain circuit dedicated to stress regulation (Han et al., 2008, Schutter, 2012). The idea that the cerebellum is part of the autonomic physiological response pattern of the brain to threat cues and controls stress responses relevant for goal-directed behavior received additional evidence by fMRI studies (Schraa-Tam et al., 2012, Eisenbarth et al., 2016).

To further understand the relation between cerebellar volume and neurotic personality traits, the monosynaptic reciprocal connections between the cerebellum and hypothalamus are particularly notable (Haines et al., 1997). By controlling the release of hormones, the hypothalamus is a critical brain structure responsible for the regulation of stress responses, autonomic activity, bodily homeostasis and mood (Haines et al., 1984, Haines et al., 1997, Kelts and Hoehn, 1978, Ramnani, 2006). In addition to the hypothalamus-pituitary-adrenal axis which is linked to the release of stress hormone cortisol, the hypothalamic-pituitary-gonadal axis also plays an important role in governing the release of sex steroids as part of the fight-flight reaction (Toufexis et al., 2014). The discovery of sex steroid receptor binding sites on the cerebellum offers an additional feedback mechanism by which the sex steroid testosterone is able to influence the cerebello-hypothalamic coupling. Recent empirical findings show that androgen receptors in the Purkinje (output) cells are modulated by endogenous testosterone levels in male rats and further underscore the link between the cerebellum and the neuro-endocrine system (Perez-Pouchoulen et al., 2016). Moreover, in vitro studies have established that testosterone reduces oxidative stress-induced cell death of cerebellar gray matter (Ahlbom et al., 1999, Tsutsui et al., 2013). The association between low levels of testosterone and smaller gray matter volume agrees with clinical findings involving male participants with Klinefelter syndrome (Bryant et al., 2011) and effects of testosterone deprivation therapy on gray matter volumes of patients with prostate cancer (Chao et al., 2013).

The presence of steroid hormone receptors in cerebellar tissue offers a physiological basis for steroid hormonal modulation of cerebellar functions. In addition to the cerebello-hypothalamic link, recent debates on the involvement of the cerebellum in cognition and emotion are inspired by existing neuro-anatomical connections. In particular, the cerebello-cortical loops provide a basis for contributions of the cerebellum to processes associated with motivational direction and cognitive control (Schutter and van Honk, 2005). This is further supported by evidence of a topographical map in the cerebellum of motor control on the one hand, and cognitive and affective processes on the other hand (Stoodley and Schmahmann, 2010). Because of its uniform anatomical microstructure, the cerebellum is well suited to process signals from all parts of the brain. This so-called universal cerebellar transform (UCT) function is argued to promote internal homeostasis by monitoring and regulating signals coming from the autonomic, limbic and cortical regions of the brain (Schmahmann, 2004). The UCT has its origins in the processing of multimodal inputs stemming from the existing cerebellar connections with cortical and limbic parts of the brain. In particular, with the direct reciprocal connections to the hypothalamus, the cerebellum acts as a monitor of central and peripheral (bodily) information processing related to internal homeostasis. Disruption of internal homeostasis, that is a mismatch between central and bodily state, activates the UCT for coordinating internal neural processes to restore equilibrium. From this perspective, anxiety and depression are the experiential correlates of disrupted bodily homeostasis. Suboptimal UCT function or chronic overstimulation may contribute to difficulties in establishing and maintaining homeostasis leading to neurotic traits (Schutter, 2012, Schutter, 2016).

On the phenomenological level, testosterone has anxiolytic and antidepressant properties as evidenced by animal and human research (Carrier et al., 2015, Giltay et al., 2012, Höfer et al., 2013). In agreement, experimentally reducing endogenous testosterone and oestrogen levels in healthy female adults reduced reward-related brain activity and increased self-reported depression ratings (Macoveanu et al., 2016). Although results do not provide conclusive evidence on the efficacy of testosterone treatment in mood disorders, some studies suggest that testosterone protects against the development and progression of mood disorders, and acts as a primer for subsequent pharmaceutical interventions (Carrier and Kabbaj, 2012, Frye and Walf, 2009). Furthermore, there is increasing evidence that the onset and development of mood disorders starts during adolescence (Zahn-Waxler et al., 2008). Adolescence is a developmental stage roughly between 10 and 18 years of age characterized by a sharp rise in sex steroid hormones. Adolescence is proposed to be a sensitive period for sex steroid-induced brain maturation (Cunningham et al., 2007, Koolschijn et al., 2014, Peper and Dahl, 2013, Peper et al., 2015). In adolescents, lower levels of testosterone have been associated with the presence of anxious and depressive symptoms (Granger et al., 2003; but see Duke et al., 2014). It has been suggested that sex steroid levels in combination with environmental stress and neurotic temperament constitute a vulnerability factor for the onset of mood disorders during adolescence (Mueller et al., 2014, Zinbarg et al., 2016). The findings suggest that the associations between cerebellar volumes, neurotic personality traits and endogenous testosterone levels may already be present in the adolescent period. Finally, earlier research has shown a significant positive relation between gray matter volumes and testosterone in adolescent boys, but not in girls suggesting that testosterone may have a different effect on brain morphology in male as compared to female adolescents (for review see Peper et al., 2011).

To address these questions, we conducted an exploratory study to examine the interrelations between endogenous testosterone levels, cerebellar volumes and neuroticism in adolescent and adult healthy volunteers. Consistent with our previous findings and existing literature on the role of testosterone in structural brain anatomy and mood, we tested the following three hypotheses: (1) Cerebellar volumes are inversely correlated with neuroticism (Schutter et al., 2012); (2) Endogenous testosterone levels are inversely correlated to neuroticism; (3) The association between cerebellar volume and neuroticism is mediated by endogenous testosterone levels.

Section snippets

Participants

This study was part of a two-year follow-up MRI scan in the longitudinal ‘BrainTime’ research project (e.g., Braams et al., 2016, Peters et al., 2016). Of the 254 participants that were enrolled in the follow-up, ninety one healthy adolescents (♀ = 46, ♂ = 45) aged between 12 and 17 years and fifty eight adults (♀ = 30, ♂ = 28) aged between 18 and 27 years, mean age ± SD, 17.4 ± 3.3 years, had complete data records and were included in the current study. Reasons for exclusion were (1) MRI scan could not be

Results

Descriptives of the main variables of the study are depicted in Table 1.

Discussion

The aim of this study was to investigate the relation between cerebellar volume, measures of neuroticism and endogenous testosterone levels in a non-clinical sample of adolescents and young adults.

Results show that the association between larger cerebellar volumes and lower levels of neuroticism remains present in a fourfold sample size − compared to our previous study restricted to adults only (Schutter et al., 2012). Here, we show that gray and not white matter volumes account for the earlier

Conclusion

This is, to our knowledge, the first study that has successfully integrated predictions from both the animal and human literature to demonstrate associations between cerebellar morphology, testosterone and neuroticism. Our findings provide an empirical basis for establishing the direction of the correlations in future work. The interrelations between testosterone, behavioural indices of emotional vulnerability and cerebellar morphology provide a cerebellum oriented framework for hormone-brain

Competing financial interests

Author declares no competing financial interests.

Acknowledgements

This work was supported by NWO Innovational research grants 452-07-012 (D.S.) and 451-10-007 (J.P.) and an ERC Starting Grant 2010-StG-263234 (E.C.). The authors thank dr. P.C. Koolschijn for making the cerebellum reconstruction figure.

References (100)

  • S.A. Duke et al.

    Testosterone and its effects on human male adolescent mood and behavior: a systematic review

    J. Adolesc. Health.

    (2014)
  • D. Enter et al.

    Alleviating social avoidance: effects of single dose testosterone administration on approach-avoidance action

    Horm. Behav.

    (2014)
  • B. Fischl et al.

    Cortical surface-based analysis. II: Inflation flattening, and a surface-based coordinate system

    Neuroimage

    (1999)
  • B. Fischl et al.

    Whole brain segmentation: automated labeling of neuroanatomical structures in the human brain

    Neuron

    (2002)
  • C.A. Frye et al.

    Depression-like behavior of aged male and female mice is ameliorated with administration of testosterone or its metabolites

    Physiol. Behav.

    (2009)
  • E.J. Giltay et al.

    Salivary testosterone: associations with depression, anxiety disorders, and antidepressant use in a large cohort study

    J. Psychosom. Res.

    (2012)
  • P. Höfer et al.

    Testosterone in the brain: neuroimaging findings and the potential role for neuropsychopharmacology

    Eur. Neuropsychopharmacol.

    (2013)
  • D.E. Haines et al.

    The cerebellar-hypothalamic axis: basic circuits and clinical observations

    Int. Rev. Neurobiol.

    (1997)
  • V.L. Hedges et al.

    The cerebellum as a target for estrogen action

    Front. Neuroendocrinol.

    (2012)
  • E.J. Hermans et al.

    A single administration of testosterone reduces fear-potentiated startle in humans

    Biol. Psychiatry

    (2006)
  • J.S. Ide et al.

    A cerebellar thalamic cortical circuit for error-related cognitive control

    Neuroimage

    (2011)
  • C.H. Lai et al.

    The gray matter alterations in major depressive disorder and panic disorder: putative differences in the pathogenesis

    J. Affect. Disord.

    (2015)
  • M. Mihm et al.

    The normal menstrual cycle in women

    Anim. Reprod. Sci.

    (2011)
  • S.C. Mueller et al.

    Assessing gonadal hormone contributions to affective psychopathologies across humans and animal models

    Psychoneuroendocrinology

    (2014)
  • M. Napolitano et al.

    17β-estradiol protects cerebellar granule cells against β-amyloid-induced toxicity via the apoptotic mitochondrial pathway

    Neurosci. Lett.

    (2014)
  • R.L. O’Gorman et al.

    Personality factors correlate with regional cerebral perfusion

    Neuroimage

    (2006)
  • J. Peng et al.

    Cerebral and cerebellar gray matter reduction in first-episode patients with major depressive disorder: a voxel-based morphometry study

    Eur. J. Radiol.

    (2011)
  • J.S. Peper et al.

    Sex steroids and brain structure in pubertal boys and girls: a mini-review of neuroimaging studies

    Neuroscience

    (2011)
  • M. Perez-Pouchoulen et al.

    Androgen receptors in Purkinje neurons are modulated by systemic testosterone and sexual training in a region-specific manner in the male rat

    Physiol. Behav.

    (2016)
  • S. Peters et al.

    The link between testosterone and amygdala-orbitofrontal cortex connectivity in adolescent alcohol use

    Psychoneuroendocrinology

    (2015)
  • S. Peters et al.

    Longitudinal development of frontoparietal activity during feedback learning Contributions of age, performance, working memory and cortical thickness

    Dev. Cogn. Neurosci.

    (2016)
  • J.C. Pruessner et al.

    Stress regulation in the central nervous system: evidence from structural and functional neuroimaging studies in human populations

    Psychoneuroendocrinology

    (2010)
  • J.D. Schmahmann

    Rediscovery of an early concept

    Int. Rev. Neurobiol.

    (1997)
  • D.J. Schutter

    The cerebello-hypothalamic-pituitary-adrenal axis dysregulation hypothesis in depressive disorder

    Med. Hypotheses

    (2012)
  • F. Segonne et al.

    A hybrid approach to the skull stripping problem in MRI

    Neuroimage

    (2004)
  • C.J. Stoodley et al.

    Functional topography in the human cerebellum: a meta-analysis of neuroimaging studies

    Neuroimage

    (2009)
  • C.J. Stoodley et al.

    Evidence for topographic organization in the cerebellum of motor control versus cognitive and affective processing

    Cortex

    (2010)
  • A. Torvik et al.

    The prevalence of alcoholic cerebellar atrophy: a morphometric and histological study of an autopsy material

    J. Neurol. Sci.

    (1986)
  • J. Van Honk et al.

    Testosterone reduces unconscious fear but not consciously experienced anxiety: implications for the disorders of fear and anxiety

    Biol. Psychiatry

    (2005)
  • F. Van Overwalle et al.

    Social cognition and the cerebellum: a meta-analysis of over 350 fMRI studies

    Neuroimage

    (2014)
  • L. Wei et al.

    The synchronization of spontaneous BOLD activity predicts extraversion and neuroticism

    Brain Res.

    (2011)
  • M. Adamaszek et al.

    Consensus paper: cerebellum and emotion

    Cerebellum

    (2016)
  • E. Ahlbom et al.

    Androgen treatment of neonatal rats decreases susceptibility of cerebellar granule neurons to oxidative stress in vitro

    Eur. J. Neurosci.

    (1999)
  • D.M. Bryant et al.

    Neuroanatomical phenotype of Klinefelter syndrome in childhood: a voxel-based morphometry study

    J. Neurosci.

    (2011)
  • C.S. Carver et al.

    Behavioral inhibition, behavioral activation, and affective responses to impending reward and punishment: the BIS/BAS scales

    J. Pers. Soc. Psychol.

    (1994)
  • H.H. Chao et al.

    Effects of androgen deprivation on cerebral morphometry in prostate cancer patients–an exploratory study

    PLoS One

    (2013)
  • L.A. Clark et al.

    Temperament, personality, and the mood and anxiety disorders

    J. Abnorm. Psychol.

    (1994)
  • C.R. Cloninger et al.

    A psychobiological model of temperament and character

    Arch. Gen. Psychiatry

    (1993)
  • S.L. Dean et al.

    Steroids, sex and the cerebellar cortex: implications for human disease

    Cerebellum

    (2008)
  • M. Ebinger et al.

    Is there a neuroendocrinological rationale for testosterone as a therapeutic option in depression?

    J. Psychopharmacol.

    (2009)
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