Research paperSize matters – The olfactory bulb as a marker for depression
Introduction
The majority of mental disorders is currently diagnosed by behavioral symptom descriptions. Objective biomarkers may improve the treatment of mental disorders by enhancing the precision of diagnosis and prognosis and thus making allocation of patients to the most effective treatment more efficient. Additionally, there are situations where it is necessary to obtain objective and reliable information of a person's mental health and to control for distorted or socially desirable depictions. The ongoing pursuit for neural markers of mental disorders (Lener and Iosifescu, 2015) has revealed numerous descriptions of the structural and functional alterations in the depressed brain (Fitzgerald et al., 2008, Sacher et al., 2012). Still, there are only few investigations where an evaluation of the diagnostic accuracy of objective biomarkers for depression was carried out (for an overview compare (Fu and Costafreda, 2013)) and to date they are not used regularly in clinical practice. It is assumed that the olfactory bulb (OB) volume could act as such a biomarker.
In rodents, bilateral destruction of the OB leads to depression-like behavior (Kelly et al., 1997, Song and Leonard, 2005) and evokes altered serotonin and dopamine concentrations (Masini et al., 2004, Redmond et al., 1997), which is why bulbectomized rats are seen as an animal model for depression. It is suggested that, in the rodent, the loss of afferent impulses of the olfactory system may cause neuronal degeneration in subsequent structures, such as the habenular nuclei (Oral et al., 2013). It is not clear if those findings can be directly transferred to humans as the link between olfaction and emotion processing structures may be less strong here (Heimer et al., 2007).
In anology to the bulbectomized rats, humans with congenital anosmia, a disorder characterized by aplastic OB, report enhanced symptoms of depression (Croy et al., 2012). In line with this finding, structural MR Imaging observed a reduced volume of the OB in depression (Negoias et al., 2010) that especially affects depressed patients with a history of childhood maltreatment (Croy, Negoias et al., 2013) and a reduced depth of the olfactory sulcus (Takahashi et al., 2016).
The connection between the OB-based olfactory disruptions and depression is not surprising from an evolutionary point of view. Evolving about 500 million years ago, olfaction is considered as one of the earliest sensory systems (Stoddart, 2012). The need to motivate avoidance and approaching behavior according to olfactory stimuli led to the evolution of the ancient limbic system (Joseph, 2013). This central brain system was conserved in all mammals (Northcutt, 2002) as a network of neural structures responsible for emotion and salience processing. Due to the coevolution, olfactory, salience and emotion neural structures are still highly interwoven (LeDoux, 2000). The olfactory bulb, as the first central olfactory processing structure projects within 1–2 synapses into the limbic system (Wilson et al., 2015). The tight functional and anatomical connections between olfactory, salience and emotion processing networks, which persist in humans (LeDoux, 2000, Gottfried, 2006) may explain why human mental disorders like depression are often associated with abnormalities of olfactory processing (Croy and Hummel, 2016, Kohli et al., 2016).
More support for the association between depression and olfaction comes from psychophysiological studies showing that depressed patients exhibit reduced olfactory functioning (Negoias et al., 2010, Lombion-Pouthier et al., 2006, Pause et al., 2001), which most consistently affects the olfactory sensitivity. Accordingly, functional investigations revealed that depressed patients exhibit reduced insula activation (Croy et al., 2014) and prolonged and reduced neural processing (Croy et al., 2014, Pause et al., 2003) after olfactory stimulation.
The association between olfaction and mental disorders is not limited to depression. Alterations of olfactory function are also present in other mental disorders characterized by emotion and salience processing deficits: for instance in anxiety disorders like posttraumatic stress disorder (Dileo et al., 2008, Vasterling et al., 2000) or obsessive-compulsive disorder (Barnett et al., 1999), eating disorders (Lombion-Pouthier et al., 2006, Aschenbrenner et al., 2008), alcohol and drug dependence (Lombion-Pouthier et al., 2006) and schizophrenia (Sirota et al., 1999; Kohler et al., 2001; Rupp et al., 2005, Atanasova et al., 2008). However, data for these disorders are less consistent and show weaker effect sizes (Atanasova et al., 2008).
To sum up, mental disorders are often accompanied by alterations in olfactory function which was hence assumed as a potential objective marker of psychiatric disorders that could represent an increased vulnerability to disease (Atanasova et al., 2008). Most consistently a link between olfaction and depression was reported (Croy and Hummel, 2016, Kohli et al., 2016) and connections between the olfactory bulb and the olfactory-limbic circuit may play a role here. To date, it remains unclear if OB reduction is specific to depression or whether it may also be associated to other mental disorders.
We hypothesized that the human OB volume could serve as a biomarker for depression. As alterations of olfactory function are also present in other mental disorders, we furthermore examined whether the assumed reduction of OB volume is specific to depression. Hence, we not only compared OB volume between patients and healthy controls, ruled out multiple regression analysis to test if OB volume reductions were specific to depression, but additionally evaluated the diagnostic accuracy of the OB volume for depression.
Section snippets
Participants
Eighty-four in-patients of the Department of Psychosomatic and Psychotherapy of the Dresden University Hospital were recruited. They had been previously diagnosed by structured anamnestic interviews (German version of the SCID-I (Wittchen, 1997)) which were performed by trained psychotherapists. The patient group included 65 females and 19 males, aged between 19 and 62 (M ± SD = 40.2 ± 12.0) years. Further demographic and illness-related parameters are shown in Table 1. The median of the number
Reduced OB volume in mental disorders
In line with the hypothesis, a significant effect of group on OB volume was found (F[2135] = 4.2; p < .05; η2 = .03). Patients exhibited a 13.5% smaller OB volume than healthy controls (patients: 64.2±18.5 mm³, healthy controls: 74.2 ± 17.5 mm3, compare Table 1 and Fig. 2). In women, we found an OB volume reduction of 13% (F[2,44] = 4.0; p < .05), in men we found an OB volume reduction of 7% which misses significance (F[2,91] = 1.1; p > .05). We explain the insignificant OB volume reduction in
Discussion
We found OB volume reduction of 14% in patients with mental disorders compared to healthy controls. Regression analyses showed that these volume reductions were - amongst all mental diagnoses included in the sample - most strongly related to depressive symptomatology. Direction and amount of the OB volume reduction are in line with previously published results obtained in a different sample of patients (Negoias et al., 2010, Croy et al., 2013). By now, Major Depression is mainly related to
Conclusion
The OB volume differs significantly between groups of depressed and non-depressed individuals and seems to be a promising marker for depression vulnerability. Hence, the OB should be considered as one of the altered brain structures in depression. However, diagnostic accuracy of the OB alone is insufficient to reliably detect depression.
Acknowledgments
We would like to thank Cornelia Hummel for her help with the analysis of the olfactory bulb measurement.
References (56)
Gustatory and olfactory sensitivity in patients with anorexia and bulimia in the course of treatment
J. Psychiatr. Res.
(2008)Olfaction: a potential cognitive marker of psychiatric disorders
Neurosci. Biobehav Rev.
(2008)Gray matter abnormalities in major depressive disorder: a meta-analysis of voxel based morphometry studies
J. Affect. Disord.
(2012)Correlation between olfactory bulb volume and olfactory function
Neuroimage
(2008)Olfaction as a marker for depression in humans
J. Affect. Disord.
(2014)Pattern classification of sad facial processing: toward the development of neurobiological markers in depression
Biol. Psychiatry
(2008)Prognostic prediction of therapeutic response in depression using high-field MR imaging
Neuroimage
(2011)- et al.
The olfactory bulbectomized rat as a model of depression: an update
Pharmacol. Ther.
(1997) Odor perception in patients with mood disorders
J. Affect. Disord.
(2006)Altered cerebellar–cerebral resting-state functional connectivity reliably identifies major depressive disorder
Brain Res.
(2013)
Dopamine overflow is increased in olfactory bulbectomized rats: an in vivo microdialysis study
Physiol. Behav.
Large-scale brain networks and psychopathology: a unifying triple network model
Trends Cogn. Sci.
Reduced olfactory bulb volume and olfactory sensitivity in patients with acute major depression
Neuroscience
How olfaction disorders can cause depression? The role of habenular degeneration
Neuroscience
Reduced olfactory performance in patients with major depression
J. Psychiatr. Res.
Behavioural and neurochemical effects of dizocilpine in the olfactory bulbectomized rat model of depression
Pharmacol. Biochem. Behav.
Olfactory functions and volumetric measures of orbitofrontal and limbic regions in schizophrenia
Schizophr. Res.
Mapping the depressed brain: a meta-analysis of structural and functional alterations in major depressive disorder
J. Affect. Disord.
Anomalous gray matter structural networks in major depressive disorder
Biol. Psychiatry
Increased olfactory sensitivity in first episode psychosis and the effect of neuroleptic treatment on olfactory sensitivity in schizophrenia
Psychiatry Res.
The olfactory bulbectomised rat as a model of depression
Neurosci. Biobehav. Rev.
Olfactory sulcus morphology in patients with current and past major depression
Psychiatry Res.: Neuroimaging
Emotion Regulation Questionnaire–Eine deutschsprachige Fassung des ERQ von Gross und John
Diagnostica
Impairment of olfactory identification in obsessive–compulsive disorder
Psychol. Med.
Prognostic and diagnostic potential of the structural neuroanatomy of depression
PLoS One
Learning about the functions of the olfactory system from people without a sense of smell
PLoS One
Reduced olfactory bulb volume in adults with a history of childhood maltreatment
Chem. Senses
Olfaction as a marker for depression
J. Neurol.
Cited by (38)
Momentary gustative-olfactory sensitivity and tonic heart rate variability are independently associated with motivational behavior
2023, International Journal of PsychophysiologyACR Appropriateness Criteria® Cranial Neuropathy: 2022 Update
2022, Journal of the American College of RadiologyOlfactory training – Thirteen years of research reviewed
2022, Neuroscience and Biobehavioral ReviewsCitation Excerpt :Reduced olfactory sensitivity is also connected with depressive symptoms (Croy and Hummel, 2017; Kohli et al., 2016) and disturbs social interactions (reviewed by Blomkvist and Hofer, 2021). People with major depressive disorder have reduced olfactory bulbs and decreased smell sensitivity (Negoias et al., 2010; Rottstaedt et al., 2018) whereas patients facing difficulties with adjustment to smell loss are likely to exhibit symptoms of depression (Croy et al., 2011). This bidirectional relationship between smell loss and depression might arise directly from alterations of the central nervous system that impacts olfactory and affective domains or might be mediated by other consequences of smell loss, e.g., decreased enjoyment of food or difficulties in close social relationships (Croy et al., 2014).
Infiltration of peripheral immune cells into the olfactory bulb in a mouse model of acute nasal inflammation
2022, Journal of Neuroimmunology