Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease of the central nervous system (CNS). It affects more than two million people worldwide, mainly young adults, and may lead to ...progressive neurological disability. Chemokines and their receptors have been shown to play critical roles in the pathogenesis of experimental autoimmune encephalomyelitis (EAE), a murine disease model induced by active immunization with myelin proteins or transfer of encephalitogenic CD4⁺ T cells that recapitulates clinical and neuropathological features of MS. Chemokine ligand-receptor interactions orchestrate leukocyte trafficking and influence multiple pathophysiological cellular processes, including antigen presentation and cytokine production by dendritic cells (DCs). The C-C class chemokines 17 (CCL17) and 22 (CCL22) and their C-C chemokine receptor 4 (CCR4) have been shown to play an important role in homeostasis and inflammatory responses. Here, we provide an overview of the involvement of CCR4 and its ligands in CNS autoimmunity. We review key clinical studies of MS together with experimental studies in animals that have demonstrated functional roles of CCR4, CCL17, and CCL22 in EAE pathogenesis. Finally, we discuss the therapeutic potential of newly developed CCR4 antagonists and a humanized anti-CCR4 antibody for treatment of MS.
We currently observe a disconcerting phenomenon in machine learning studies in psychiatry: While we would expect larger samples to yield better results due to the availability of more data, larger ...machine learning studies consistently show much weaker performance than the numerous small-scale studies. Here, we systematically investigated this effect focusing on one of the most heavily studied questions in the field, namely the classification of patients suffering from Major Depressive Disorder (MDD) and healthy controls based on neuroimaging data. Drawing upon structural MRI data from a balanced sample of N = 1868 MDD patients and healthy controls from our recent international Predictive Analytics Competition (PAC), we first trained and tested a classification model on the full dataset which yielded an accuracy of 61%. Next, we mimicked the process by which researchers would draw samples of various sizes (N = 4 to N = 150) from the population and showed a strong risk of misestimation. Specifically, for small sample sizes (N = 20), we observe accuracies of up to 95%. For medium sample sizes (N = 100) accuracies up to 75% were found. Importantly, further investigation showed that sufficiently large test sets effectively protect against performance misestimation whereas larger datasets per se do not. While these results question the validity of a substantial part of the current literature, we outline the relatively low-cost remedy of larger test sets, which is readily available in most cases.
Reduced hippocampal volumes are probably the most frequently reported structural neuroimaging finding associated with major depressive disorder (MDD). However, it remains unclear whether altered ...hippocampal structure represents a risk factor for or a consequence of MDD. Reduced hippocampal volumes were consistently reported in subjects affected by childhood maltreatment. As the prevalence of childhood maltreatment is highly elevated in MDD populations, previous morphometric findings regarding hippocampal atrophy in MDD therefore might have been confounded by maltreatment experiences. The aim of this study was to differentiate the impact of childhood maltreatment from the influence of MDD diagnosis on hippocampal morphometry. Depressed patients (85) as well as 85 age- and sex-matched healthy controls underwent structural MRI. The Childhood Trauma Questionnaire was administered to estimate experiences of childhood maltreatment. Hippocampal volume and surface structure was examined by the use of two independent methods, automated segmentation (FSL-FIRST) and voxel-based morphometry (VBM8). In line with existing studies, MDD patients showed reduced hippocampal volumes, and childhood maltreatment was consistently associated with hippocampal volume loss in both, patients and healthy controls. However, no analysis revealed significant morphological differences between patients and controls if maltreatment experience was regressed out. Our results suggest that hippocampal alterations in MDD patients may at least partly be traced back to higher occurrence of early-life adverse experiences. Regarding the strong morphometric impact of childhood maltreatment and its distinctly elevated prevalence in MDD populations, this study provides an alternative explanation for frequently observed limbic structural abnormalities in depressed patients.
Background Childhood maltreatment represents a strong risk factor for the development of depression and posttraumatic stress disorder (PTSD) in later life. In the present study, we investigated the ...neurobiological underpinnings of this association. Since both depression and PTSD have been associated with increased amygdala responsiveness to negative stimuli as well as reduced hippocampal gray matter volume, we speculated that childhood maltreatment results in similar functional and structural alterations in previously maltreated but healthy adults. Methods One hundred forty-eight healthy subjects were enrolled via public notices and newspaper announcements and were carefully screened for psychiatric disorders. Amygdala responsiveness was measured by means of functional magnetic resonance imaging and an emotional face-matching paradigm particularly designed to activate the amygdala in response to threat-related faces. Voxel-based morphometry was used to study morphological alterations. Childhood maltreatment was assessed by the 25-item Childhood Trauma Questionnaire (CTQ). Results We observed a strong association of CTQ scores with amygdala responsiveness to threat-related facial expressions. The morphometric analysis yielded reduced gray matter volumes in the hippocampus, insula, orbitofrontal cortex, anterior cingulate gyrus, and caudate in subjects with high CTQ scores. Both of these associations were not influenced by trait anxiety, depression level, age, intelligence, education, or more recent stressful life events. Conclusions Childhood maltreatment is associated with remarkable functional and structural changes even decades later in adulthood. These changes strongly resemble findings described in depression and PTSD. Therefore, the present results might suggest that limbic hyperresponsiveness and reduced hippocampal volumes could be mediators between the experiences of adversities during childhood and the development of emotional disorders.
Electroconvulsive therapy (ECT) is one of the most effective treatments for severe depression. However, biomarkers that accurately predict a response to ECT remain unidentified.
To investigate ...whether certain factors identified by structural magnetic resonance imaging (MRI) techniques are able to predict ECT response.
In this nonrandomized prospective study, gray matter structure was assessed twice at approximately 6 weeks apart using 3-T MRI and voxel-based morphometry. Patients were recruited through the inpatient service of the Department of Psychiatry, University of Muenster, from March 11, 2010, to March 27, 2015. Two patient groups with acute major depressive disorder were included. One group received an ECT series in addition to antidepressants (n = 24); a comparison sample was treated solely with antidepressants (n = 23). Both groups were compared with a sample of healthy control participants (n = 21).
Binary pattern classification was used to predict ECT response by structural MRI that was performed before treatment. In addition, univariate analysis was conducted to predict reduction of the Hamilton Depression Rating Scale score by pretreatment gray matter volumes and to investigate ECT-related structural changes.
One participant in the ECT sample was excluded from the analysis, leaving 67 participants (27 men and 40 women; mean SD age, 43.7 10.6 years). The binary pattern classification yielded a successful prediction of ECT response, with accuracy rates of 78.3% (18 of 23 patients in the ECT sample) and sensitivity rates of 100% (13 of 13 who responded to ECT). Furthermore, a support vector regression yielded a significant prediction of relative reduction in the Hamilton Depression Rating Scale score. The principal findings of the univariate model indicated a positive association between pretreatment subgenual cingulate volume and individual ECT response (Montreal Neurological Institute MNI coordinates x = 8, y = 21, z = -18; Z score, 4.00; P < .001; peak voxel r = 0.73). Furthermore, the analysis of treatment effects revealed a increase in hippocampal volume in the ECT sample (MNI coordinates x = -28, y = -9, z = -18; Z score, 7.81; P < .001) that was missing in the medication-only sample.
A relatively small degree of structural impairment in the subgenual cingulate cortex before therapy seems to be associated with successful treatment with ECT. In the future, neuroimaging techniques could prove to be promising tools for predicting the individual therapeutic effectiveness of ECT.
Differentiating bipolar disorders (BD) from unipolar depression (UD) remains a major clinical challenge. The identification of neurobiological markers may help to differentiate these disorders, ...particularly during depressive episodes. This cross-sectional study, including 33 patients with UD, 33 patients with BD, and 34 healthy controls, is one of the first to directly compare UD and BD with respect to reward processing. A card-guessing paradigm was employed and brain activity associated with reward processing was investigated by means of fMRI. A 3 (group) × 2 (condition: reward>control, loss>control) ANOVA was conducted using the nucleus accumbens (NAcc) as ROI. Furthermore, a whole-brain approach was applied. A functional connectivity analysis was performed to characterize diagnosis-related alterations in the functional coupling between the NAcc and other brain areas. The ANOVA revealed higher activity for healthy controls (HCs) than for BD and UD in the NAcc during reward processing. Moreover, UD showed a higher functional connectivity between the NAcc and the VTA than HC. The patients groups could be differentiated in that BD showed a decreased activation, in the reward condition, of the NAcc, caudate nucleus, thalamus, putamen, insula, and prefrontal areas compared with UD. These results may help to refine the understanding of neural correlates of reward processing in both disorders, and to understand the neural underpinnings of anhedonia, a core symptom of depressive episodes.
Fear conditioning and extinction are basic forms of associative learning that have gained considerable clinical relevance in enhancing our understanding of anxiety disorders and facilitating their ...treatment. Modern neuroimaging techniques have significantly aided the identification of anatomical structures and networks involved in fear conditioning. On closer inspection, there is considerable variation in methodology and results between studies. This systematic review provides an overview of the current neuroimaging literature on fear conditioning and extinction on healthy subjects, taking into account methodological issues such as the conditioning paradigm. A Pubmed search, as of December 2008, was performed and supplemented by manual searches of bibliographies of key articles. Two independent reviewers made the final study selection and data extraction. A total of 46 studies on cued fear conditioning and/or extinction on healthy volunteers using positron emission tomography or functional magnetic resonance imaging were reviewed. The influence of specific experimental factors, such as contingency and timing parameters, assessment of conditioned responses, and characteristics of conditioned and unconditioned stimuli, on cerebral activation patterns was examined. Results were summarized descriptively. A network consisting of fear-related brain areas, such as amygdala, insula, and anterior cingulate cortex, is activated independently of design parameters. However, some neuroimaging studies do not report these findings in the presence of methodological heterogeneities. Furthermore, other brain areas are differentially activated, depending on specific design parameters. These include stronger hippocampal activation in trace conditioning and tactile stimulation. Furthermore, tactile unconditioned stimuli enhance activation of pain related, motor, and somatosensory areas. Differences concerning experimental factors may partly explain the variance between neuroimaging investigations on human fear conditioning and extinction and should, therefore, be taken into serious consideration in the planning and the interpretation of research projects.
Low-grade inflammation plays a role not only in the pathogenesis of major depressive disorder (MDD) but probably also in the poor responsiveness to regular antidepressants. There are also indications ...that anti-inflammatory agents improve the outcomes of antidepressants.
To study whether the presence of low-grade inflammation predicts the outcome of antidepressants, anti-inflammatory agents, or combinations thereof.
We carried out a systematic review of the literature on the prediction capability of the serum levels of inflammatory compounds and/or the inflammatory state of circulating leukocytes for the outcome of antidepressant/anti-inflammatory treatment in MDD. We compared outcomes of the review with original data (collected in two limited trials carried out in the EU project MOODINFLAME) on the prediction capability of the inflammatory state of monocytes (as measured by inflammatory gene expression) for the outcome of venlafaxine, imipramine, or sertraline treatment, the latter with and without celecoxib added.
Collectively, the literature and original data showed that: 1) raised serum levels of pro-inflammatory compounds (in particular of CRP/IL-6) characterize an inflammatory form of MDD with poor responsiveness to predominately serotonergic agents, but a better responsiveness to antidepressant regimens with a) (add-on) noradrenergic, dopaminergic, or glutamatergic action or b) (add-on) anti-inflammatory agents such as infliximab, minocycline, or eicosapentaenoic acid, showing-next to anti-inflammatory-dopaminergic or lipid corrective action; 2) these successful anti-inflammatory (add-on) agents, when used in patients with low serum levels of CRP/IL-6, decreased response rates in comparison to placebo. Add-on aspirin, in contrast, improved responsiveness in such "non-inflammatory" patients; 3) patients with increased inflammatory gene expression in circulating leukocytes had a poor responsiveness to serotonergic/noradrenergic agents.
The presence of inflammation in patients with MDD heralds a poor outcome of first-line antidepressant therapies. Immediate step-ups to dopaminergic or glutamatergic regimens or to (add-on) anti-inflammatory agents are most likely indicated. However, at present, insufficient data exist to design protocols with reliable inflammation parameter cutoff points to guide such therapies, the more since detrimental outcomes are possible of anti-inflammatory agents in "non-inflamed" patients.
Major depressive disorder (MDD) is a severe mood disorder and frequently associated with alterations of the immune system characterized by enhanced levels of circulating pro-inflammatory cytokines ...and microglia activation in the brain. Increasing evidence suggests that dysfunction of mitochondria may play a key role in the pathogenesis of MDD. Mitochondria are regulators of numerous cellular functions including energy metabolism, maintenance of redox and calcium homeostasis, and cell death and therefore modulate many facets of the innate immune response. In depression-like behavior of rodents, mitochondrial perturbation and release of mitochondrial components have been shown to boost cytokine production and neuroinflammation. On the other hand, pro-inflammatory cytokines may influence mitochondrial functions such as oxidative phosphorylation, production of adenosine triphosphate, and reactive oxygen species, thereby aggravating inflammation. There is strong interest in a better understanding of immunometabolic pathways in MDD that may serve as diagnostic markers and therapeutic targets. Here, we review the interaction between mitochondrial metabolism and innate immunity in the pathophysiology of MDD. We specifically focus on immunometabolic processes that govern microglial and peripheral myeloid cell functions, both cellular components involved in neuroinflammation in depression-like behavior. We finally discuss microglial polarization and associated metabolic states in depression-associated behavior and in MDD.
Primary schizophreniform psychoses are thought to be caused by complex gene–environment interactions. Secondary forms are based on a clearly identifiable organic cause, in terms of either an ...etiological or a relevant pathogenetic factor. The secondary or “symptomatic” forms of psychosis have reentered the focus stimulated by the discovery of autoantibody (Ab)-associated autoimmune encephalitides (AEs), such as anti-NMDA-R encephalitis, which can at least initially mimic variants of primary psychosis. These newly described secondary, immune-mediated schizophreniform psychoses typically present with the acute onset of polymorphic psychotic symptoms. Over the course of the disease, other neurological phenomena, such as epileptic seizures, movement disorders, or reduced levels of consciousness, usually arise. Typical clinical signs for AEs are the acute onset of paranoid hallucinatory symptoms, atypical polymorphic presentation, psychotic episodes in the context of previous AE, and additional neurological and medical symptoms such as catatonia, seizure, dyskinesia, and autonomic instability. Predominant psychotic courses of AEs have also been described casuistically. The term autoimmune psychosis (AP) was recently suggested for these patients. Paraclinical alterations that can be observed in patients with AE/AP are inflammatory cerebrospinal fluid (CSF) pathologies, focal or generalized electroencephalographic slowing or epileptic activity, and/or suspicious “encephalitic” imaging findings. The antibody analyses in these patients include the testing of the most frequently found Abs against cell surface antigens (NMDA-R, CASPR2, LGI1, AMPA-R, GABA
B
-R), intracellular antigens (Hu, Ri, Yo, CV2/CRMP5, Ma2 Ta, amphiphysin, GAD65), thyroid antigens (TG, TPO), and antinuclear Abs (ANA). Less frequent antineuronal Abs (e.g., against DPPX, GABA
A
-R, glycine-R, IgLON5) can be investigated in the second step when first step screening is negative and/or some specific clinical factors prevail. Beyond, tissue-based assays on brain slices of rodents may detect previously unknown antineuronal Abs in some cases. The detection of clinical and/or paraclinical pathologies (e.g., pleocytosis in CSF) in combination with antineuronal Abs and the exclusion of alternative causes may lead to the diagnosis of AE/AP and enable more causal therapeutic immunomodulatory opportunities.
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