Bernhard T. Baune

Evidence for a cytokine model of cognitive function

Aiming at a formulation of a cytokine model of cognitive function under immunologically unchallenged physiological conditions, this article reviews the cytokine biology in the central nervous system (CNS) and recent developments in normal cytokine functions within the CNS that subserve cognitive processes. Currently available evidence shows that the cytokines IL-1beta, IL-6 and TNF-alpha play a role in complex cognitive processes at the molecular level, such as synaptic plasticity, neurogenesis, as well as neuromodulation. Such findings provide evidence for a cytokine model of cognitive function, which shows that cytokines play an intimate role in the molecular and cellular mechanisms subserving learning, memory and cognition under physiological conditions. These cytokine-mediated cognitive processes have implications in the long-term development and pathogenesis of specific neuropsychiatric disorders such as major depression and dementia. The identification of this central role of cytokines in various brain activities during health provides greater insight into normal brain functions, especially synaptic plasticity, memory and cognition, and facilitates the understanding of specific biological mechanisms involved in neuropsychiatric diseases, such as dementia and depression. In order to extend the suggested cytokine model of cognitive function onto other members of the cytokine family, future research is required to investigate the physiological effects of other cytokines such as interferon-gamma (IFNgamma), alpha(1)-antichymotrypsin and IL-2 on cognitive function at the molecular level under immunologically unchallenged conditions.

Genome-wide association for major depressive disorder: a possible role for the presynaptic protein piccolo

Major depressive disorder (MDD) is a common complex trait with enormous public health significance. As part of the Genetic Association Information Network initiative of the US Foundation for the National Institutes of Health, we conducted a genome-wide association study of 435 291 single nucleotide polymorphisms (SNPs) genotyped in 1738 MDD cases and 1802 controls selected to be at low liability for MDD. Of the top 200, 11 signals localized to a 167 kb region overlapping the gene piccolo (PCLO, whose protein product localizes to the cytomatrix of the presynaptic active zone and is important in monoaminergic neurotransmission in the brain) with P-values of 7.7 × 10−7 for rs2715148 and 1.2 × 10−6 for rs2522833. We undertook replication of SNPs in this region in five independent samples (6079 MDD independent cases and 5893 controls) but no SNP exceeded the replication significance threshold when all replication samples were analyzed together. However, there was heterogeneity in the replication samples, and secondary analysis of the original sample with the sample of greatest similarity yielded P=6.4 × 10−8 for the nonsynonymous SNP rs2522833 that gives rise to a serine to alanine substitution near a C2 calcium-binding domain of the PCLO protein. With the integrated replication effort, we present a specific hypothesis for further studies.

The role of cognitive impairment in general functioning in major depression

The association between cognitive performance and general functioning in depression is controversial. The present study evaluated the association between cognitive dysfunction and major depressive disorder (MDD, N=70) as compared with age- and gender-matched healthy controls (n=206) and its relationship to general functioning (physical and mental health quality of life, activities of daily living, and employment status) in participants with current MDD (n=26) and those with previous MDD only (n=44). Participants were assessed clinically using the Mini International Neuropsychiatric Interview (M.I.N.I.) for the depression groups and the Diagnostic Interview for Psychoses (DIP-DM) for the control group. Measures to evaluate cognition and quality of lifes comprised the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS), the Short Form-36 Health Survey Questionnaire, and the Activities/Instrumental Activities of Daily Living (ADL/IADL); employment status was also assessed in MDD. The results showed that a) while individuals with current depression had worse cognitive performance in all domains than healthy controls, those individuals with previous depression had lasting cognitive impairments in the domains of immediate memory and attention as compared with healthy controls; b) individuals with current depression had lower scores in the visuospatial/constructional and attention domains and the total score than individuals with previous depression; c) individuals in the depression group as a whole who were currently unemployed had significantly lower scores in all domains (except attention) of cognitive function; d) cognitive function was not related to either physical or mental quality of life or impairments of activities of daily living (ADL, IADL); e) that unemployment in previous depression was related to poor cognitive function similar to those with current depression. The results indicate that MDD may have detrimental and lasting effects on cognitive performance partly related to poorer general functioning.

A psychoneuroimmunological review on cytokines involved in antidepressant treatment response

The literature exploring the role that cytokine functioning plays in the pathogenesis and treatment of depressive illness is reviewed. The review focuses on the influence of antidepressants on cytokines, and on how treatment response might be affected by genetic variants of cytokines.

Neuroplastic changes in depression: a role for the immune system.

Accumulating evidence suggests that there is a rich cross-talk between the neuroimmune system and neuroplasticity mechanisms under both physiological conditions and pathophysiological conditions in depression. Anti-neuroplastic changes which occur in depression include a decrease in proliferation of neural stem cells (NSCs), decreased survival of neuroblasts and immature neurons, impaired neurocircuitry (cortical-striatal-limbic circuits), reduced levels of neurotrophins, reduced spine density and dendritic retraction. Since both humoral and cellular immune factors have been implicated in neuroplastic processes, in this review we present a model suggesting that neuroplastic processes in depression are mediated through various neuroimmune mechanisms. The review puts forward a model in that both humoral and cellular neuroimmune factors are involved with impairing neuroplasticity under pathophysiological conditions such as depression. Specifically, neuroimmune factors including interleukin (IL)-1, IL-6, tumour necrosis factor (TNF)-α, CD4⁺CD25⁺T regulatory cells (T reg), self-specific CD4⁺T cells, monocyte-derived macrophages, microglia and astrocytes are shown to be vital to processes of neuroplasticity such as long-term potentiation (LTP), NSC survival, synaptic branching, neurotrophin regulation and neurogenesis. In rodent models of depression, IL-1, IL-6 and TNF are associated with reduced hippocampal neurogenesis; mechanisms which are associated with this include the stress-activated protein kinase (SAPK)/Janus Kinase (JNK) pathway, hypoxia-inducible factors (HIF)-1α, JAK-Signal Transducer and Activator of Transcription (STAT) pathway, mitogen-activated protein kinase (MAPK)/cAMP responsive element binding protein (CREB) pathway, Ras-MAPK, PI-3 kinase, IKK/nuclear factor (NF)-κB and TGFβ activated kinase-1 (TAK-1). Neuroimmunological mechanisms have an active role in the neuroplastic changes associated with depression. Since therapies in depression, including antidepressants (AD), omega-3 polyunsaturated fatty acids (PUFAs) and physical activity exert neuroplasticity-enhancing effects potentially mediated by neuroimmune mechanisms, the immune system might serve as a promising target for interventions in depression.

Reduced amygdala–prefrontal coupling in major depression: association with MAOA genotype and illness severity

The amygdala plays a pivotal role in a cortico-limbic circuitry implicated in emotion processing and regulation. In the present study, functional connectivity of the amygdala with prefrontal areas involved in emotion regulation was investigated during a facial expression processing task in a sample of 34 depressed inpatients and 31 healthy controls. All patients were genotyped for a common functional variable number tandem repeat (VNTR) polymorphism in the promoter region of the monoamine oxidase A gene (MAOA u-VNTR) which has been previously associated with major depression as well as reduced cortico-limbic connectivity in healthy subjects. In our control group, we observed tight coupling of the amygdala and dorsal prefrontal areas comprising the dorsolateral prefrontal cortex (DLPFC), dorsal parts of the anterior cingulate cortex (dACC), and lateral orbitofrontal cortex. Amygdala-prefrontal connectivity was significantly reduced in depressed patients and carriers of the higher active MAOA risk alleles (MAOA-H). Hence, depressed MAOA-H carriers showed the weakest amygdala-prefrontal coupling of the investigated subgroups. Furthermore, reduced coupling of this circuitry predicted more than 40% variance of clinical variables characterizing a longer and more severe course of disease. We conclude that genetic variation in the MAOA gene may affect the course of major depression by disrupting cortico-limbic connectivity.

5-HTTLPR Biases Amygdala Activity in Response to Masked Facial Expressions in Major Depression

The amygdala is a key structure in a limbic circuit involved in the rapid and unconscious processing of facial emotions. Increased amygdala reactivity has been discussed in the context of major depression. Recent studies reported that amygdala activity during conscious emotion processing is modulated by a functional polymorphism in the serotonin transporter gene (5-HTTLPR) in healthy subjects. In the present study, amygdala reactivity to displays of emotional faces was measured by means of fMRI at 3T in 35 patients with major depression and 32 healthy controls. Conscious awareness of the emotional stimuli was prevented via backward-masking to investigate automatic emotion processing. All subjects were genotyped for the 5-HTTLPR polymorphism. Risk allele carriers (S or LG) demonstrated increased amygdala reactivity to masked emotional faces, which in turn was significantly correlated with life-time psychiatric hospitalization as an index of chronicity. This might indicate that genetic variations of the serotonin transporter could increase the risk for depression chronification via altering limbic neural activity on a preattentive level of emotion processing.

Inflammasomes in neuroinflammation and changes in brain function: a focused review

Recent literature has pointed to the existence of inflammasome-mediated inflammatory pathways in central nervous system (CNS) disorders and associated changes in behavior. Neuroinflammation, which is an innate immune response in the CNS against harmful and irritable stimuli such as pathogens and metabolic toxic waste, as well as to chronic mild stress, is mediated by protein complexes known as inflammasomes. Inflammasomes activate pro-inflammatory caspases 1 and 5, which then cleave the precursor forms of pro-inflammatory cytokines IL-1β, IL-18, and IL-33 into their active forms. These pro-inflammatory cytokines have been shown to promote a variety of innate immune processes associated with infection, inflammation, and autoimmunity, and thereby play an instrumental role in the instigation of neuroinflammation during old age and subsequent occurrence of neurodegenerative diseases, cognitive impairment, and dementia. In particular, NLRP inflammasomes may also have a role in the etiologies of depression, Alzheimers disease (AD) and in metabolic disorders, such as Type II diabetes, obesity and cardiovascular diseases that have been shown to be co-morbid with psychiatric illnesses. It has been reported that while these inflammasomes may be activated through TNF-α dependent pathways, other cytokines, like IFN-γ, may assist in inhibiting their activation and thus delay disease progression. Furthermore, some other cytokines, including IL-6, may not have a direct role in inflammasome-mediated diseases. An array of recent research suggests that NLRP inflammasomes targeted therapies could be used for alleviating neuroinflammation and for treatment of associated psychiatric illnesses, although this still remains a challenge and necessitates further extensive research. This review examines the complex inflammatory signaling pathways involved in the activation of NLRP inflammasomes and the role they play in promoting neuroinflammation and subsequent behavioral changes.

Depression and type 2 diabetes: Inflammatory mechanisms of a psychoneuroendocrine co-morbidity

Unipolar depression and diabetes mellitus each account for a significant proportion of the global burden of disease. Epidemiological literature suggests a bi-directional relationship between these two common disorders, and evidence from the molecular sciences supports a role for inflammation in the pathogenesis and pathophysiology of each disorder individually. Recent advances in understanding the neurobiology of depression have implicated dysfunction of the hypothalamus-pituitary-adrenal axis, neurotrophins, and inflammatory mediators in the development of this disorder. Similarly, dysregulated facets of both the innate and adaptive immune system have been implicated in the onset of insulin resistance and type 2 diabetes. This review draws upon an emerging body of epidemiological and mechanistic evidence to support the hypothesis that shared inflammatory mechanisms may represent a key biological link in this co-morbidity. Given the shared mechanisms of this co-morbidity, these patients may be excellent candidates for novel immune targeted pharmacotherapy.

Association of the COMT val158met Variant with Antidepressant Treatment Response in Major Depression

In several previous biochemical, pharmacological, and genetic studies, the catechol-O-methyltransferase (COMT) has been suggested to be involved in the pathogenesis as well as the pharmacological treatment of affective disorders. In the present study, 256 patients with major depression (DSM-IV) of Caucasian descent were genotyped for the functional COMT val158met polymorphism and characterized for clinical response to antidepressive pharmacological treatment as measured by intra-individual changes of Hamilton Depression (HAM-D-21) scores over 6 weeks. The COMT 158val/val genotype conferred a significant risk of worse response after 4–6 weeks of antidepressant treatment in patients with major depression (week 4: p=0.003; week 5: p<0.0001; week 6: p<0.0001) after Bonferroni correction for multiple comparisons. The present results strongly point toward a negative influence of the higher activity COMT 158val/val genotype on antidepressant treatment response during the first 6 weeks of pharmacological treatment in major depression, possibly conferred by consecutively decreased dopamine availability. This finding suggests a potentially beneficial effect of an antidepressive add-on therapy with substances increasing dopamine availability individually tailored according to COMT val158met genotype.