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 Table of Contents  
Year : 2021  |  Volume : 7  |  Issue : 2  |  Page : 87-93

Neurobiological correlates of burnout

1 Consultant Psychiatrist, Sterling Hospital, Vadodara, India
2 Department of Psychiatry, Lokmanya Tilak Municipal Medical College, Mumbai, Maharashtra, India

Date of Submission06-Dec-2021
Date of Decision06-Dec-2021
Date of Acceptance10-Dec-2021
Date of Web Publication12-Jan-2022

Correspondence Address:
Dr. Avinash De Sousa
Department of Psychiatry, Lokmanya Tilak Municipal Medical College, Mumbai, Maharashtra
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/tjp.tjp_44_21

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Introduction: Maslach defined burnout syndrome first time as a syndrome involving (i) exhaustion, (ii) “depersonalization” – lack of empathy for or detachment from service recipients, and (iii) a reduced sense of professional accomplishment. Burnout leads to changes in autonomic system, immune and endocrine system. The aim of this paper was therefore to provide an overview of the literature on clinically significant burnout and their potential neurobiological and physiological correlates.
Methods: All English articles published between till October 2021 were searched in PubMed, Science-Direct, Medline, GoogleScholar, using the keywords, burnout, hypothalamic-pituitary-adrenal-axis, cortisol, stress, neurobiology, neurogenesis, BDNF, immune, biological, sympathetic, parasympathetic, autonomic nervous system, endocrine, metabolic, cognition, sleep, and neuroimaging in various combinations. The full text of relevant articles was obtained and their reference lists were reviewed for additional studies.
Results: Burnout leads to alteration in autonomic, endocrine and immune system marked by deranged levels of various hormones and immune markers. It is also reflected as neuroimaging changes in various brain structures and may manifest as cognitive changes. Accelerated aging, increased risk of cardiovascular diseases and type II diabetes mellitus, increased allosteric load are some other manifestations of burnout that needs clinical attention.
Conclusion: Future research with more homogeneous clinical samples, prospective experimental designs and challenge tests will help to delineating the underlying biological mechanisms of burnout. This will help to point to potential treatment targets.

Keywords: Burnout, cognition, endocrine system, hypothalamic-pituitary-adrenal-axis, metabolic system, neurobiology, sleep and neuroimaging, stress

How to cite this article:
Sail DB, De Sousa A. Neurobiological correlates of burnout. Telangana J Psychiatry 2021;7:87-93

How to cite this URL:
Sail DB, De Sousa A. Neurobiological correlates of burnout. Telangana J Psychiatry [serial online] 2021 [cited 2023 Jun 5];7:87-93. Available from: https://tjpipstsb.org/text.asp?2021/7/2/87/335648

  Introduction Top

The term “Acedia” was used in the fourth century AD to describe states of listlessness and mental torpor in monastics.[1] The American psychologist Freudenberger introduced the term “burnout.”[2] Maslach defined burnout syndrome first time as a syndrome involving (i) exhaustion, (ii) “depersonalization”– lack of empathy for or detachment from service recipients, and (iii) a reduced sense of professional accomplishment.[3] Emotional exhaustion implies to the depletion of positive emotions towards the recipients of one's care. Depersonalization refers to an excessively callous, detached and cynical attitude towards them. The reduced professional accomplishment indicates an increase in self-appraisals as ineffective, incompetent and/or inadequate for the job. The International Statistical Classification of Diseases and Related Health Problems, 11th revision, listed burnout as a “syndrome resulting from chronic workplace stress that has not been successfully managed” though only as a residual factor that may affect health status, and “is not in itself a current illness or injury.[4] Melamed, Kushnir and Shirom[5],[6] described burnout as the chronic depletion of an individual's energetic resources as a consequence of chronic stress. According to them, burnout consists of the three dimensions: physical fatigue, emotional exhaustion and cognitive weariness. Burnout can be a consequence of long-term exposure to any situation that is emotionally demanding.[7],[8] In milder form of burnout symptoms that are not sufficiently incapacitating to prevent the employee from working while in clinical burnout there is clinically significant exhaustion and impaired performance, which motivates seeking professional help.[9] Typically, chief complaints can be longstanding fatigue, sleep impairments, and problems with memory and concentration.[10] In nonclinical populations, high burnout scores have shown association with impaired sleep[11],[12] and some longitudinal studies concluded that poor sleep can be a risk factor for subsequent exhaustion.[13],[14] Cognitive impairment is observed to be associated with burnout mainly in the field of difficulties with working memory, episodic memory and executive functions.[15] Furthermore, burnout vital exhaustion[16] have been linked to somatic morbidity in few studies.[17],[18] This led multiple studies aiming sought to find the physiological mechanisms that may explain the symptomatology of burnout, as well as the links between burnout and bodily disease.[19] The aim of this paper was therefore to provide an overview of the literature on clinically significant burnout and their potential neurobiological and physiological correlates.

  Methods Top

All English articles published between till October 2021 were searched in PubMed, Science-Direct, Medline, GoogleScholar, using the keywords, burnout, hypothalamic-pituitary-adrenal (HPA)-axis, cortisol, stress, neurobiology, neurogenesis, BDNF, immune, biological, sympathetic, parasympathetic, autonomic, nervous system, endocrine, metabolic, cognition, sleep, and neuroimaging in various combinations. Reference lists of papers were hand searched for further studies. Inclusion of papers was based on English language, published in peer review journals and whether burnout was primarily examined in relation to a biological parameter. The full text of relevant articles was obtained and their reference lists were reviewed for additional studies.

  Results and Discussion Top

The role of the hypothalamic-pituitary-adrenal axis

During stressful situations, HPA axis gets activated in the limbic system mainly the amygdala and hippocampus. As a result corticotropin releasing hormone is released from the hypothalamus which in turn stimulates adrenocortotropic hormone release from the pituitary which further stimulates glucocorticoids secretion from the adrenal cortex.

Cortisol awakening response and Cortisol levels

Due to diurnal and ultradian variation in cortisol levels make it difficult to measure the same. This led to the development of various approaches including examining the cortisol awakening response (CAR), undertaking serial measures across the day, and probing HPA function through challenge tests. Reduced CAR levels found in majority of studies making burnout a hypocortisolemic state. However, other studies in clinical[20],[21],[22] and nonclinical samples[23],[24] have failed to find impaired CAR. In a study done by Grossi et al.[25] patients on sick leave due to burnout found to have hypocortisolism compared to low and moderate burnout groups. Higher CAR levels observed in female patients with clinical burnout compared to the low burnout group. Whereas these results were less clear in males, as only moderate burnout patients found to have elevated morning cortisol. Chida et al. in their meta-analysis found a positive association between CAR and psychological distress as well as depression while a negative association was observed between CAR and burnout, suggesting that the former displays a hypercortisolemic picture while burnout more displays a hypocortisolemic picture.[26]

Other cortisol measures

An association of emotional exhaustion and global burnout with lower cortisol at time points between 2 pm and bedtime was observed in a study that examined cortisol levels at five different time points across the day.[27] Cross-sectional hair cortisol concentrations provide retrospective examination of HPA activity over the preceding months. Severe burnout group found to have hypercortisolism in the compared to “no burnout” or moderate burnout groups in a population study examining hair cortisol.[28]

The dexamethasone suppression test

This test examines feedback sensitivity of the HPA axis in response to exogenous administration of dexamethasone. Stronger suppression of cortisol in response to the dexamethasone suppression test (DST) was noted in a people with severe burnout symptoms when study was conducted in clinically-defined burnout participants.[21] Intact HPA axis functioning using the DST was found in other studies.[29],[30],[31]

Anabolic hormones

Dihydroepiandrosterone sulfate (DHEA-S) is a hormone produced by the adrenal cortex in response to stress and is considered a cortisol “counterbalancing” product. It stimulates neurogenesis, enhances memory, has anxiolytic and antidepressant properties.[32],[33] Some studies have found no differences in DHEA-S levels between burnout and healthy control groups[34],[35],[36] while some studies found elevated DHEAS levels in a burnout group compared to controls.[21] A study of clinical burnout sample concluded that more severe burnout symptoms higher the DHEA-S levels.[21] Lennartsson et al. found attenuated DHEA-S production in their study comparing DHEA-S levels before and after an acute psychosocial stress test in comparing a clinical burnout group than healthy controls.[37]

Other hormones

Serum prolactin

Increase in prolactin level in those with psychosocial stressors with a postulated protective role against psychological stress.[38] In a study of healthy individuals who reported burnout, serum prolactin levels were higher in men with burnout (vs. those without burnout), although prolactin levels did not differ between these two groups in women.[38]

Thyroid hormones

Limited studies have examined thyroid hormones with mixed findings.[39]

Brain changes


Various animal models linked reduced neuroplasticity to stress.[40] Inhibited neurogenesis was observed in monkeys who were exposed to stress by Gould et al. in their study.[41] The possible underlying mechanism can be stress-induced limbic activation causing HPA hyperactivity as downstream release of glucocorticoids affects limbic system by crossing the blood brain barrier.[42]

Neuroimaging findings

Thinning of the medial frontal cortex and a bilateral increase in amygdala volumes were found in various neuroimaging studies.[43] Also reduced gray matter volumes found in the anterior cingulate cortex (ACC) and dorsolateral prefrontal cortex (dlPFC).[44] The caudate and putamen volumes were also reduced, with volume reduction correlated to the level of perceived stress, possibly due to excitotoxic mechanisms.[44] However, no difference in hippocampal and prefrontal volumes was observed by Sandström e et al.[45] In a positron emission tomography study by Jovanovic et al.[46] reported a functional disconnection between the amygdala and ACC/medial prefrontal cortex in the chronic stress group.

Functional magnetic resonance imaging

In a functional magnetic resonance imaging (fMRI) study reported those with occupational burnout was less able to downregulate negative emotions, with reduced functional connectivity between the amygdala and the ACC.[47] Reduced amygdala connectivity with the dlPFC and the motor cortex, whereas stronger connectivity with the amygdala and insular cortex and cerebellum was noted in a study.[47] In another fMRI study, Sandström et al.[48] found patients on work-related long-term sick leave tended to under-recruit prefrontal cortical areas during performance of tasks involving executive function and memory compared to healthy controls and a depressed group.

In a study comparing well-being measures of emotional exhaustion, depersonalization, and overall burnout revealed no significant correlation with between the degree of burnout and activity in cognitive control regions was noted.[49]

Resting-state electroencephalography analysis

The burnout group observed to have significantly lower alpha power in the eyes-open condition compared to the controls.[50] This suggests cortical hyperactivity and greater mental effort suggestive of the possible development of compensatory mechanisms by burnout subjects.[50]

Neurotrophic factors

Sertoz et al. identified quantified lower serum BDNF levels in a clinical burnout versus a control group.[31] Several studies replicated similar findings in depressed patients which were reversed by antidepressants.[50],[51]

Changes in cognition

Tavella et al. concluded cognitive changes as appear integral to the burnout syndrome.[52] In a study done by Sandström et al. found deficits in nonverbal memory, visual and auditory attention.[53] McEwen et al. noted that hippocampal function can be impacted by chronic stress leading to deficits in visuospatial and memory domains.[54] Sandström et al.[45] in their study comparing stress related exhaustion found deficits in attention, response control and visuospatial memory. Selective deficits in executive functioning were observed in a study done by Ohman et al.[55] Olsson et al.[56] reported that patients with burnout had less reaction time with higher number of errors. Oosterholt et al.[57] also found reduced reaction time without any difference in executive function compared to nonclinical and healthy control groups. Cognitive performance was examined by Osterberg et al. in a group of patients with burnout versus nonclinical controls.[58] The patients demonstrated impaired performance in attention and reaction times, but better performance was noted on Wechsler Adult Intelligence Scale-Revised (WAIS-R) digit symbol. Studies concluded complex etiology of cognitive deficits as reduced hippocampal volumes, HPA axis functioning, and increased pro-inflammatory cytokine levels.[59],[60]


Armon et al. observed bidirectional, reciprocal association between sleep and burnout.[61] Positive correlation with nonrestorative sleep, reduced sleep quality, feeling unrefreshed, and sleepiness/fatigue during the day and burnout in a study which measured sleep problems using Self-report measures.[62] Greater sleep fragmentation, more arousals, less slow wave, and reduced rapid eye movement sleep were observed in objective studies done with an aid of polysomnography.[10] Brand et al.[63] reported relation of burnout symptoms of physical and emotional exhaustion to sleep problems. In a study done by Soderstr€om et al. reported that polysomnography of individuals with high burnout scores has increased arousal periods and more diurnal sleepiness.[64] Canazei et al. concluded a possible therapeutic efficacy of light therapy as it is found to have its positive effect on quality of nighttime sleep.[65]

DNA methylation

Bakusic et al. in their systematic review of 25 articles examining DNA found showed differential methylation patterns of the glucocorticoid receptor gene (NR3C1), the serotonin transporter gene (SLC6A4), and the brain derived neurotrophic factor gene in burnout, chronic stress and depression.[66] a genotype-independent hypermethylation of SLC6A4 associated with work stress and burnout was found in a study done by Alasaari et al.,[67] whereas Philibert et al.[68] observed association of the S allele of the 5-HTTLPR gene with decreased SLC6A4 expression in patients with major depressive disorder.

Accelerated aging

Zanaty et al. in their study comparing anesthetists with doctors in less stressful roles found that anesthetist had greater skin aging, increased free radicals, and a shortening of telomere length.[69] Shorter leukocyte telomere lengths were noted in a study population with severe burnout compared to those with no exhaustion.[5]


A 10-year prospective population study of burnout was carried out by Ahola et al.[5] found which concluded that in participants younger than 45 years of age at the time of entry in the study overall burnout and exhaustion were related to all-cause mortality.

Cardiovascular disease

It is thought that metabolic, immune and inflammatory mechanisms contribute to cardiovascular disease (CVD). In a study done by Shirom et al.[70] it was observed that emotional burnout was associated with increased levels of cholesterol and triglycerides. Toker et al. conducted a longitudinal study of 8838 apparently healthy employees where baseline burnout levels were found to be associated with an increased risk of coronary heart disease.[62] Gerber et al.[71] in a nonclinical sample, found cardiovascular fitness was associated with decreased symptoms of burnout.

Type II diabetes mellitus

A 4.3-fold increased risk of developing type II diabetes was observed in a longitudinal study of healthy individuals.[6] It is hypothesized release corticosteroid and catecholamine due to stress induces acute phase reactants which stimulates insulin resistance and type II diabetes.


Kitaoka-Higashiguchi et al.[72] found increased body mass index (BMI) levels in a burnout versus a non-burnout group of Japanese managers. By contrast, in a study done by Armon et al. in healthy employees could not establish that obesity predicted burnout but rather they concluded that obesity predicted reductions in subsequent burnout levels.[13]

Diet and exercise

Health-impairing behaviors thought to arise as coping strategies secondary to stress as per a European study of healthy doctors and nurses. Alexandrova-Karamanova et al. found positive association between fast food consumption, infrequent exercise, alcohol consumption and levels of burnout, potentially contributing to the syndrome.[73]

Allostatic load

Homeostasis refers to processes that maintain body systems essential for life within narrow operating ranges.[74] (McEwen and Wingfield 2003). Allostasis refers to the short-term bodily adaptation processes to environmental changes, through activation of neural, endocrine, and immune mechanisms, and thus supports homeostasis.[75] “Allostatic load” is an operationalized measure of biological parameters thought to indicate long-term maladaptive load on the body secondary to repeated or chronic stress.[76],[77] Components of allostatic load (AL) include blood pressure, lipids, glucose, insulin, C-reactive protein (CRP), BMI, waist circumference etc. Kitaoka Higashiguchi et al. in their study of “middle managers” in Japan found that changes in body weight, waist circumference, and BMI were greater in managers with burnout versus nonclinical controls.[71] In a Finnish population study[75] reported association of higher scores on burnout with increased AL. However, it is difficult to explain whether such changes were due to burnout or to depression as 60% of the association was found with depression. Juster et al.[76] reported that that increased AL was associated with chronic stress and burnout no difference in AL (based on BMI, BP, CRP, high-density lipoprotein, cholesterol, HbA1C, and glucose) was observed in a study done by Langelaan et al.[36] which compared managers with burnout versus nonclinical controls. A limitation of this study was that all managers were still working which may have been indicative of an “allostatic state” versus an “allostatic load” or “overload” phase.[78]

Immune function and burnout

C-reactive protein

It has been proposed that chronic low-grade inflammation is associated with chronic stress.[79] CRP is commonly used as a marker of general inflammation and hence chronic low grade inflammation associated with chronic stress can be picked up as slightly to moderately increased CRP levels. However, variation as per gender differences is unclear. Some studies observed no differences between burnout and nonburnout subjects[34],[35] whereas some studies reported increased CRP levels related to burnout.[80],[81] a positive association between CRP levels and higher burnout scores in women but not in men was observed by Toker et al.[82]

Leukocyte count

Metlaine et al.[81] in their study of burnout in white collar workers found higher mean leukocyte, neutrophil, and monocyte numbers in them as compared with healthy controls, whereas other studies fail to establish any association between different lymphocytes subsets and burnout.[21],[83],[84]

NK cell numbers or activity

Emotional stress has been reported to be associated with decreased NK cell activity.[85],[86] While Bargellini et al.[21] and Mommersteeg et al.[83] found no relation between absolute NK cell numbers and burnout, an association between high burnout depersonalization subscale score and decreased NK cell activity in male office workers was observed by Nakamura et al.[87]


Various studies have evaluated levels of individual cytokines as well as ratios between pro-and anti-inflammatory cytokines in relation to burnout. Grossi et al. reported direct association between tumor necrosis factor α (TNFα) levels in plasma and burnout score.[34] However, they found no relation between burnout score and transforming growth factor beta.[34] In their study, measuring 17 different cytokines Gajewski et al. found no relation between any of the cytokines and emotional exhaustion or depression. However, positive correlation was observed between the plasma concentrations of the pro-inflammatory cytokines interleukin-6 (IL-6) and IL-12 with the extent of emotional exhaustion in men but not in women.[84] Jonhdottir et al. observed no significant differences for any of the cytokines between women with exhaustion due to prolonged psychosocial stress and healthy controls.[80] Increased levels of MCP1, EGF and VEGF with no changes in cytokines levels in women exposed to prolonged psychosocial stress was reported by Åsberg et al.[87] Higher plasma TNFα levels, lower IL-4 levels, and a higher TNFα/IL-4 ratio were found to be associated with higher total burnout scores in a study in working school teachers.[88] No association was found between IL-10 levels or TNFα/IL-10 ratios and burnout scores.[88] Mommersteeg et al. observed increased levels of IL-10, but not TNFα, release in response to LPS stimulation in burnout than in healthy controls but no difference in IL-10 or interferon gamma after PHA (T-cell stimulator) was noted.[21]

Infectious diseases

Mohren et al.[89] examined burnout as a risk factor for such illnesses (including the common cold, gastroenteritis, and flu-like illnesses) in a large prospective sample. A possible causal association was found between the same which might be due to HPA axis suppression of the immune system in burnout with exhaustion being the strongest predictor of infection.

  Conclusion Top

Burnout syndrome arises from underlying chronic psychological stress. This leads to changes in autonomic nervous system, endocrine, and immune processes. Systemic inflammation, immune suppression, metabolic syndrome and CVD can be consequences of burnout in addition to the psychological effects and fatigue. Future research with more homogeneous clinical samples, prospective experimental designs and challenge tests will help to delineating the underlying biological mechanisms of burnout. This will help to point to potential treatment targets.

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Conflicts of interest

There are no conflicts of interest.

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