In 1874, Karl Kahlbaum described catatonia as an independent syndrome characterized by motor, affective, and behavioral anomalies. In the following years, various catatonia concepts were established ...with all sharing the prime focus on motor and behavioral symptoms while largely neglecting affective changes. In 21st century, catatonia is a well-characterized clinical syndrome. Yet, its neurobiological origin is still not clear because methodological shortcomings of hitherto studies had hampered this challenging effort. To fully capture the clinical picture of catatonia as emphasized by Karl Kahlbaum, 2 decades ago a new catatonia scale was developed (Northoff Catatonia Rating Scale NCRS). Since then, studies have used NCRS to allow for a more mechanistic insight of catatonia. Here, we undertook a systematic review searching for neuroimaging studies using motor/behavioral catatonia rating scales/criteria and NCRS published up to March 31, 2019. We included 19 neuroimaging studies. Studies using motor/behavioral catatonia rating scales/criteria depict cortical and subcortical motor regions mediated by dopamine as neuronal and biochemical substrates of catatonia. In contrast, studies relying on NCRS found rather aberrant higher-order frontoparietal networks which, biochemically, are insufficiently modulated by gamma-aminobutyric acid (GABA)-ergic and glutamatergic transmission. This is further supported by the high therapeutic efficacy of GABAergic agents in acute catatonia. In sum, this systematic review points out the difference between motor/behavioral and NCRS-based classification of catatonia on both neuronal and biochemical grounds. That highlights the importance of Kahlbaum's original truly psychomotor concept of catatonia for guiding both research and clinical diagnosis and therapy.
This paper reviews the body of evidence that not only tryptophan and consequent 5-HT depletion, but also induction of indoleamine 2,3-dioxygenase (IDO) and the detrimental effects of tryptophan ...catabolites (TRYCATs) play a role in the pathophysiology of depression. IDO is induced by interferon (IFN)γ, interleukin-6 and tumor necrosis factor-α, lipopolysaccharides and oxidative stress, factors that play a role in the pathophysiology of depression. TRYCATs, like kynurenine and quinolinic acid, are depressogenic and anxiogenic; activate oxidative pathways; cause mitochondrial dysfunctions; and have neuroexcitatory and neurotoxic effects that may lead to neurodegeneration. The TRYCAT pathway is also activated following induction of tryptophan 2,3-dioxygenase (TDO) by glucocorticoids, which are elevated in depression. There is evidence that activation of IDO reduces plasma tryptophan and increases TRYCAT synthesis in depressive states and that TDO activation may play a role as well. The development of depressive symptoms during IFNα-based immunotherapy is strongly associated with IDO activation, increased production of detrimental TRYCATs and lowered levels of tryptophan. Women show greater IDO activation and TRYCAT production following immune challenge than men. In the early puerperium, IDO activation and TRYCAT production are associated with the development of affective symptoms. Clinical depression is accompanied by lowered levels of neuroprotective TRYCATs or increased levels or neurotoxic TRYCATs, and lowered plasma tryptophan, which is associated with indices of immune activation and glucocorticoid hypersecretion. Lowered tryptophan and increased TRYCATs induce T cell unresponsiveness and therefore may exert a negative feedback on the primary inflammatory response in depression. It is concluded that activation of the TRYCAT pathway by IDO and TDO may be associated with the development of depressive symptoms through tryptophan depletion and the detrimental effects of TRYCATs. Therefore, the TRYCAT pathway should be a new drug target in depression. Direct inhibitors of IDO are less likely to be useful drugs than agents, such as kynurenine hydroxylase inhibitors; drugs which block the primary immune response; compounds that increase the protective effects of kynurenic acid; and specific antioxidants that target IDO activation, the immune and oxidative pathways, and 5-HT as well.
► Induction of the tryptophan catabolite (TRYCAT) pathway is associated with the onset of depression. ► Activation of IDO and TDO may induce this pathway and increase the synthesis of detrimental TRYCATs. ► IDO is induced by proinflammatory cytokines, TDO by glucocorticoids, both increased in depression. ► Activation of IDO and TDO deplete plasma tryptophan and consequently brain 5-HT. ► The TRYCAT pathway is new drug target in depression.
•We investigate brain function and structure in persons with “smartphone addiction” (SPA).•Persons with SPA showed lower gray matter volume in insula and temporal cortex.•Persons with SPA showed ...reduced resting-state activity of the anterior cingulate cortex.•Anterior cingulate cortex volume and activity was associated with SPA-severity.•The data suggest aberrant neural integrity of the salience network.
Popularity and availability of smartphones have dramatically increased in the past years. This trend is accompanied by increased concerns regarding potentially adverse effects of excessive smartphone use, particularly with respect to physical and mental health. Recently, the term “smartphone addiction” (SPA) has been introduced to describe smartphone-related addictive behavior and associated physical and psychosocial impairment. Here, we used structural and functional magnetic resonance imaging (MRI) at 3 T to investigate gray matter volume (GMV) and intrinsic neural activity in individuals with SPA (n = 22) compared to a control group (n = 26). SPA was assessed using the Smartphone Addiction Inventory (SPAI), GMV was investigated by means of voxel-based morphometry, and intrinsic neural activity was measured by the amplitude of low frequency fluctuations (ALFF). Compared to controls, individuals with SPA showed lower GMV in left anterior insula, inferior temporal and parahippocampal cortex (p < 0.001, uncorrected for height, followed by correction for spatial extent). Lower intrinsic activity in SPA was found in the right anterior cingulate cortex (ACC). A significant negative association was found between SPAI and both ACC volume and activity. In addition, a significant negative association between SPAI scores and left orbitofrontal GMV was found. This study provides first evidence for distinct structural and functional correlates of behavioral addiction in individuals meeting psychometric criteria for SPA. Given their widespread use and increasing popularity, the present study questions the harmlessness of smartphones, at least in individuals that may be at increased risk for developing smartphone-related addictive behaviors.
•Motor dysfunction precedes the onset of manifest schizophrenia.•Motor deficits reflect vulnerability for developing schizophrenia.•Motor dysfunction is an intermediate phenotype candidate for ...schizophrenia.
Schizophrenia is a severe behavioral syndrome of neurodevelopmental nature marked by primary or genuine motor abnormalities (GMA), which refer to spontaneous and medication-independent motor phenomena. Since motor dysfunction thus might be a consequence of events occurring during early childhood and adolescence, GMA can be detected in the period preceding manifest schizophrenia. However, the question whether motor system dysfunction might be a promising motor intermediate phenotype for schizophrenia remains unanswered. In this review, we systematically evaluate the evidence on GMA in healthy persons, individuals with schizotypal personality traits, persons at ultra-high risk for psychosis, and unaffected first-degree relatives of schizophrenia patients. What becomes evident is a continuum of GMA expression, which appears to be linked to abnormalities of cerebello-thalamo-cortical, fronto-parietal, and cortico-subcortical motor circuits. According to current evidence, motor dysfunction is a key aspect of the neurodevelopmental risk factor model of schizophrenia. Insights provided by this research will help promoting the RDoC Motor System construct and expand the clinical relevance of the motor domain in the period preceding manifest schizophrenia.
Allergic contact dermatitis (ACD) is a T cell-mediated type of skin inflammation resulting from contact hypersensitivity (CHS) to antigens. There is strong comorbidity between ACD and major ...depression. Keratinocytes release immunomodulatory mediators including pro-inflammatory cytokines and chemokines, which modulate skin inflammation and are crucial cell type for the development of CHS. Our previous studies showed that fluoxetine and desipramine were effective in suppressing CHS in different mouse strains. However, the immune and molecular mechanisms underlying this effect remain to be explored. The aim of the current study was to determine the immune and molecular mechanisms of action of antidepressant drugs engaged in the inhibition of CHS response in the stimulated keratinocyte HaCaT cell line. The results show that LPS, TNF-α/IFN-γ, and DNFB stimulate HaCaT cells to produce large amounts of pro-inflammatory factors including IL-1β, IL-6, CCL2, and CXCL8. HaCaT stimulation was associated with increased expression of ICAM-1, a cell adhesion molecule, and decreased expression of E-cadherin. Imipramine, desipramine, and fluoxetine suppress the production of IL-1β, CCL2, as well as the expression of ICAM-1. LPS and TNF-α/IFN-γ activate p-38 kinase, but antidepressants do not regulate this pathway. LPS decreases E-cadherin protein expression and fluoxetine normalizes these effects. In summary, the antidepressant drugs examined in this study attenuate the stimulated secretion of pro-inflammatory cytokines, chemokines, and modulate adhesion molecule expression by the HaCaT cell line. Therefore, antidepressants may have some clinical efficacy in patients with ACD and patients with comorbid depression and contact allergy.
Extending beyond the motor domain, the cerebellum is involved in various aspects of cognition and affect. Multidisciplinary evidence has demonstrated topographic organization of higher-order ...cognitive functions within the cerebellum. We here review recent neuroimaging research that indicates cerebellar contributions to major depressive disorder (MDD). At the structural level, increased volume of lobule IX has been demonstrated in MDD patients, independent of acute or remitted disease state. Successful treatment with electroconvulsive therapy has been associated with increased lobule VIIA volume in depressed patients. At the functional level, connectivity analyses have shown reduced cerebro-cerebellar coupling of lobules VI and VIIA/B with prefrontal, posterior parietal, and limbic regions in patients with MDD. As a limitation, most of this evidence is based on smaller patient samples with incomplete phenotypic and neuropsychological characterization and with heterogenous medication. Some studies did not apply cerebellum-optimized data analysis protocols. Taken together, MDD pathophysiology affects distinct subregions of the cerebellum that communicate with cortical networks subserving cognitive and self-referential processing. This mini-review synthesizes research evidence from cerebellar structural and functional neuroimaging in depression, and provides future perspectives for neuroimaging of cerebellar contributions to MDD.
Catatonia is characterized by motor, affective and behavioral abnormalities. To date, the specific role of white matter (WM) abnormalities in schizophrenia spectrum disorders (SSD) patients with ...catatonia is largely unknown. In this study, diffusion magnetic resonance imaging (dMRI) data were collected from 111 right-handed SSD patients and 28 healthy controls. Catatonic symptoms were examined on the Northoff Catatonia Rating Scale (NCRS). We used whole-brain tract-based spatial statistics (TBSS), tractometry (along tract statistics using TractSeg) and graph analytics (clustering coefficient-CCO, local betweenness centrality-BC) to provide a framework of specific WM microstructural abnormalities underlying catatonia in SSD. Following a categorical approach, post hoc analyses showed differences in fractional anisotrophy (FA) measured via tractometry in the corpus callosum, corticospinal tract and thalamo-premotor tract as well as increased CCO as derived by graph analytics of the right superior parietal cortex (SPC) and left caudate nucleus in catatonic patients (NCRS total score ≥ 3; n = 30) when compared to non-catatonic patients (NCRS total score = 0; n = 29). In catatonic patients according to DSM-IV-TR (n = 43), catatonic symptoms were associated with FA variations (tractometry) of the left corticospinal tract and CCO of the left orbitofrontal cortex, primary motor cortex, supplementary motor area and putamen. This study supports the notion that structural reorganization of WM bundles connecting orbitofrontal/parietal, thalamic and striatal regions contribute to catatonia in SSD patients.
The rapidly evolving field of sensorimotor neuroscience reflects the scientific and clinical relevance of sensorimotor abnormalities as an intrinsic component of the disease process, e.g., in ...patients with schizophrenia spectrum disorders (SSD). Despite previous efforts, however, prevalence rates and relationships between different categories of sensorimotor abnormalities in SSD patients are still subject of ongoing debate. In this study, we examined five different categories of the sensorimotor domain (Neurological soft signs (NSS), parkinsonism, catatonia, akathisia, and tardive dyskinesia) according to well-established clinical ratings scales and the respective cut-off criteria in a sample of 131 SSD patients. We used a collection of statistical methods to better understand prevalence, overlap and heterogeneity, as well as psychopathological and cognitive correlates of sensorimotor abnormalities. 97.7% of the SSD patients considered by this study exhibited at least one categorically defined sensorimotor abnormality that tended to co-vary within three different sensorimotor subgroups (moderate, hyperkinetic and hypokinetic). Finally, hyperkinetic and hypokinetic groups differed significantly in their neurocognitive performance compared with the moderate group. The results suggest different patterns of clinical overlap, highlight the relationship between sensorimotor and cognitive domain and provide clues for further neurobiological studies.
Maes M, Kubera M, Leunis J‐C, Berk M, Geffard M, Bosmans E. In depression, bacterial translocation may drive inflammatory responses, oxidative and nitrosative stress (O&NS), and autoimmune responses ...directed against O&NS‐damaged neoepitopes.
Objective: Depression is accompanied by activation of immuno‐inflammatory and oxidative and nitrosative stress (IO&NS) pathways, and increased IgM/IgA responses to lipopolysaccharide (LPS) of gram‐negative commensal bacteria. The latter suggests that bacterial translocation has caused IgM/IgA responses directed against LPS. Bacterial translocation may drive IO&NS responses.
Method: To examine the associations between IgM/IgA responses to LPS and IO&NS measurements, including plasma/serum interleukin‐1 (IL‐1), tumor necrosis factor (TNF)α, neopterin, lysozyme, oxidized LDL (oxLDL) antibodies, peroxides, and IgM (auto)immune responses against malondialdehyde (MDA), azelaic acid, phophatidyl inositol (Pi), NO‐tryptophan and NO‐tyrosine in depressed patients and controls.
Results: We found significant positive associations between IgM/IgA responses to LPS and oxLDL antibodies, IgM responses against MDA, azelaic acid, Pi, NO‐tryptophan, and NO‐tyrosine. The IgA responses to LPS were correlated with lysozyme. There were no significant positive correlations between the IgM/IgA responses to LPS and IL‐1 and neopterin.
Conclusion: The findings show that in depression there is an association between increased bacterial translocation and lysozyme production, an antibacterial compound, O&NS processes, and autoimmune responses directed against O&NS generated neoantigenic determinants. It is suggested that bacterial translocation may drive IO&NS pathways in depression and thus play a role in its pathophysiology.
Excessive smartphone use (ESU), that is, a pattern of smartphone use that shows specific features of addictive behavior, has increasingly attracted societal and scientific interest in the past years. ...On the neurobiological level, ESU has recently been related to structural and functional variation in reward and salience processing networks, as shown by, for example, aberrant patterns of neural activity elicited by specific smartphone cues.
Expanding on these findings, using cross-modal correlations of magnetic resonance imaging (MRI)-based measures with nuclear imaging-derived estimates, we aimed at identifying neurochemical pathways that are related to ESU.
Cross-modal correlations between functional MRI data derived from a cue-reactivity task administered in persons with and without ESU and specific PET/SPECT receptor probability maps.
The endogenous mu-opioid receptor (MOR) system was found to be significantly (FDR-corrected) correlated with fMRI data, and z-transformed correlation coefficients showed an association (albeit nonsignificant after FDR-correction) between MOR and the Smartphone Addiction Inventory "withdrawal" dimension.
We could identify the MOR system as a neurochemical pathway associated with ESU. The MOR system is closely linked to the reward system, which has been recognized as a key player in addictive disorders. Together with its potential link to withdrawal, the MOR system hints toward a biologically highly relevant marker, which should be taken into consideration in the ongoing scientific discussion on technology-related addictive behaviors.
PDF
