RESUMEN
We and others have observed reduced volumes of brain regions, including the nucleus accumbens, globus pallidus, hypothalamus, and habenula in opioid addiction. Notably, the insular cortex has been under increasing study in addiction, and a smaller anterior insula has been found in alcohol-addicted cases. Here, we have investigated whether similar effects occur in heroin addicts compared to healthy controls. Volumes of the anterior and posterior insula in heroin addicts (n = 14) and controls (n = 13) were assessed by morphometry of Nissl-myelin-stained serial whole-brain coronal sections. The mean relative volume of the anterior insular cortex was smaller than in non-addicted controls (3010 ± 614 *10-6 versus 3970 ± 1306 *10-6; p = 0.021). However, no significant differences in neuronal cell counts were observed. Therefore, the observed volume reduction appears to be a consequence of damaged connecting structures such as neuropil and glial cells. The findings were not confounded by age or duration of autolysis. Our results provide further evidence of structural deficits in key hubs of the addiction circuitry in heroin-dependent individuals and warrant further research in this area.
Asunto(s)
Dependencia de Heroína , Heroína , Humanos , Masculino , Corteza Insular , Encéfalo , Núcleo Accumbens , Imagen por Resonancia Magnética/métodos , Corteza Cerebral/diagnóstico por imagenRESUMEN
BACKGROUND: We recently reported increased levels of neutrophils, monocytes and C-reactive protein (CRP) correlated with symptom severity in acute schizophrenia. Here, we investigated if a similar pattern of innate immune system activation occurs in major depression (MD). METHODS: We assessed differential blood counts, CRP, depression symptoms (HAMD-21) and psychosocial functioning (GAF) in controls (n = 129) and patients with first (FEMD: n = 82) or recurrent (RMD: n = 47) disease episodes of MD at baseline (T0; hospital admission) and after 6-weeks treatment (T6). RESULTS: Considering smoking, BMI and gender as covariates, neutrophils (FEMD: p = 0.034, RMD: p = 0.034) and CRP (FEMD: p < 0.001, RMD: p = 0.021) were higher, and eosinophils (FEMD: p = 0.005, RMD: p = 0.004) lower in patients versus controls at T0. Baseline lymphocyte counts were elevated in RMD (p = 0.003) but not FEMD. Results were confirmed by analyses of nonsmokers. At follow-up, eosinophils rose significantly in FEMD (p = 0.011) but no significant changes were observed in RMD. Improvement in HAMD-21 correlated with T0-T6 changes of neutrophil counts in FEMD (r = 0.364, p = 0.024). Compared with our previous schizophrenia study, raised baseline neutrophil and reduced eosinophil counts in MD had smaller effect sizes and treatment had a weaker association with T0-T6 changes in neutrophils. In addition, lymphocytes were elevated at T0 in recurrent MD but not in schizophrenia patients. CONCLUSIONS: These findings suggest that innate immunity may be involved in early stages of MD, and adaptive immunity may be involved in chronic disease. Thus, further studies may lead to new disease stage-dependent MD treatment strategies targeting different aspects of immune system activation.
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Proteína C-Reactiva , Trastorno Depresivo Mayor , Proteína C-Reactiva/metabolismo , Depresión , Humanos , Inmunidad Innata , Leucocitos/metabolismo , Receptores InmunológicosRESUMEN
Although the expression of co-stimulatory molecules plays an important role in the immune system, only little is known about their regulation in dementias. Therefore, we determined the expression of CD28, ICOS (CD278) and CTLA-4 (CD152) by CD4 + and CD8 + T cells in the peripheral blood of patients with mild cognitive impairment (MCI; N = 19), Alzheimer's disease (AD; N = 51), vascular dementia (VD; N = 21) and frontotemporal dementia (FTD; N = 6) at the point in time of diagnosis compared to 19 non-demented elderly persons. The expression of CD28 and ICOS by CD4 + and CD8 + T cells was not changed in AD, FTD or VD patients. The expression of the negative regulator CTLA-4 was increased by CD4 + T cells from AD and FTD patients and by CD8 + T cells from VD patients. The classification of the AD patients according to the severity of the disorder showed stage-dependent alterations of CD28, ICOS and CTLA-4 expression. In AD patients, the correlation analysis showed an association between the decline in CD28 + T cells and the increase in CTLA-4 + T cells with cognitive decline, measured by the mini-mental state examination (MMSE), tau proteins and Amyloid-ß, important AD biomarkers in cerebrospinal fluid (CSF). In FTD patients, a positive association between Q Albumin, a marker for blood-CSF-barrier function, and CD28 and a negative correlation between Q Albumin and ICOS expression were determined. Our data suggest a dysregulated balance between the expression of negative and positive co-stimulatory molecules by T cells in AD patients, which might contribute to chronic inflammation observed in dementia.
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Enfermedad de Alzheimer , Demencia Frontotemporal , Anciano , Albúminas , Enfermedad de Alzheimer/diagnóstico , Péptidos beta-Amiloides/líquido cefalorraquídeo , Biomarcadores/líquido cefalorraquídeo , Antígenos CD28 , Antígeno CTLA-4 , Demencia Frontotemporal/líquido cefalorraquídeo , Demencia Frontotemporal/diagnóstico , Humanos , Fragmentos de Péptidos/líquido cefalorraquídeo , Proteínas tau/líquido cefalorraquídeoRESUMEN
The Habenula is increasingly being investigated in addiction. Reduced volumes of other relevant brain regions in addiction, such as nucleus accumbens, globus pallidus and hypothalamus have been reported. Reduced volumes of the habenula as well as reduced neuronal cell count in the habenula have also been reported in mood disorders and an overlap between mood disorders and addiction is clinically widely recognized. Thus, our aim was to investigate possible volume and neuronal cell count differences in heroin addicts compared to healthy controls. Volumes of the medial (MHB) and lateral habenula (LHB) in heroin addicts (n = 12) and healthy controls (n = 12) were assessed by morphometry of 20 µm serial whole brain sections. Total brain volume was larger in the heroin group (mean 1466.6 ± 58.5 cm3 vs. mean 1331.5 ± 98.8 cm3), possibly because the heroin group was about 15 years younger (p = 0.001). Despite larger mean whole brain volume, the mean relative volume of the MHB was smaller than in healthy non-addicted controls (6.94 ± 2.38 × 10-6 vs.10.64 ± 3.22 × 10-6; p = 0.004). A similar finding was observed regarding relative volumes of the LHB (46.62 ± 10.90 × 10-6 vs. 63.05 ± 16.42 × 10-6 p = 0.009). In parallel, neuronal cell numbers were reduced in the MHB of heroin-addicted subjects (395,966 ± 184,178 vs. 644,149 ± 131,140; p < 0.001). These findings were not significantly confounded by age and duration of autolysis. Our results provide further evidence for brain-structural deficits in heroin addiction.
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Habénula , Dependencia de Heroína , Neuronas , Autopsia , Estudios de Casos y Controles , Recuento de Células , Habénula/patología , Dependencia de Heroína/patología , Humanos , Masculino , Neuronas/patología , Tamaño de los ÓrganosRESUMEN
An increasing number of clinical, epidemiological and genetic studies as well as investigations of CSF and blood suggests that neuroinflammation plays an essential role in the etiology of schizophrenia and mood disorders. However, direct neuropathological evidence of inflammation within the brain tissue remains sparse and the regional distribution of lymphocytes as surrogate markers of blood-brain barrier (BBB) impairment has not yet been investigated in this context. Densities of T and B lymphocytes were assessed in coronal whole brain sections of 22 patients with schizophrenia and 20 patients suffering from major depression or bipolar disorder, compared to 20 individuals without neuropsychiatric disorders from the Magdeburg Brain Collection. Cell densities were determined by immunohistochemical staining (anti-CD3 for T cells, anti-CD20 for B cells), followed by automated microscopic image acquisition and analysis. Hierarchical clustering and detailed cluster analysis were performed to detect possible subgroups of patients. Regional distribution was assessed by analysis of color coded mappings based on microsopic scans. Elevated lymphocyte density was found in 7 out of 20 mood disorder patients (adj. p = 0.022; Fisher's exact test, FET), 9 out of 22 schizophrenic patients (adj. p = 0.014; FET) and in 1 of 20 controls (p < 0.005; FET). Several cases showed different patterns of infiltration affecting cortical regions or subcortical white matter, while some presented diffuse infiltration. In two thirds of patients, no increased lymphocyte density could be found. The current findings indicate that lymphocyte infiltration occurs in a greater proportion of schizophrenia and mood disorder patients as compared to healthy controls. Under healthy conditions lymphocytes rarely cross the BBB. Thus, higher densities are considered indicators of neuroinflammation associated with an impairment of the BBB.
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Linfocitos B , Trastorno Bipolar , Esquizofrenia , Linfocitos T , Encéfalo , Humanos , Trastornos del HumorRESUMEN
In schizophrenia, decreased hippocampal volume, reduced oligodendrocyte numbers in hippocampal cornu ammonis (CA) subregions and reduced neuron number in the dentate gyrus have been reported; reduced oligodendrocyte numbers were significantly related to cognitive deficits. The hippocampus is involved in cognitive functions and connected to the hypothalamus, anterior thalamus, and cingulate cortex, forming the Papez circuit, and to the mediodorsal thalamus. The relationship between the volume of these interconnected regions and oligodendrocyte and neuron numbers in schizophrenia is unknown. Therefore, we used stepwise logistic regression with subsequent multivariate stepwise linear regression and bivariate correlation to analyze oligodendrocyte and neuron numbers in the posterior hippocampal subregions CA1, CA2/3, CA4, dentate gyrus, and subiculum and volumes of the hippocampal CA region, cingulum, anterior and mediodorsal thalamus and hypothalamus in postmortem brains of 10 schizophrenia patients and 11 age- and gender-matched healthy controls. Stepwise logistic regression identified the following predictors for diagnosis, in order of inclusion: (1) oligodendrocyte number in CA4, (2) hypothalamus volume, (3) oligodendrocyte number in CA2/3, and (4) mediodorsal thalamus volume. Subsequent stepwise linear regression analyses identified the following predictors: (1) for oligodendrocyte number in CA4: (a) oligodendrocyte number in CA2/3, (b) diagnostic group, (c) hypothalamus volume, and (d) neurons in posterior subiculum; (2) for hypothalamus volume: (a) mediodorsal thalamus volume; (3) for oligodendrocyte number in CA2/3: oligodendrocyte number (a) in posterior CA4 and (b) in posterior subiculum; (4) for mediodorsal thalamus volume: volumes of (a) anterior thalamus and (b) hippocampal CA. In conclusion, we found a positive relationship between hippocampal oligodendrocyte number and the volume of the hypothalamus, a brain region connected to the hippocampus, which is important for cognition.
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Hipocampo/patología , Hipotálamo/patología , Red Nerviosa/patología , Oligodendroglía/citología , Esquizofrenia/patología , Tálamo/patología , Adulto , Autopsia , Femenino , Hipocampo/citología , Humanos , Hipotálamo/citología , Masculino , Persona de Mediana Edad , Esquizofrenia/diagnósticoRESUMEN
The past decades have witnessed an explosion of knowledge on brain structural abnormalities in schizophrenia and depression. Focusing on the hypothalamus, we try to show how postmortem brain microscopy has contributed to our understanding of mental disease-related pathologic alterations of this brain region. Gross anatomical abnormalities (volume changes of the third ventricle, the hypothalamus, and its nuclei) and alterations at the cellular level (loss of neurons, increased or decreased expression of hypothalamic peptides such as oxytocin, vasopressin, corticotropin-releasing hormone, and other regulatory factors as well as of enzymes involved in neurotransmitter and neuropeptide metabolism) have been reported in schizophrenia and/or depression. While histologic research has mainly concentrated on neurons, little is currently known about the impact of non-neuronal cells for hypothalamus pathology in mental disorders. Their study would be a rewarding task for the future.
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Hormona Liberadora de Corticotropina/metabolismo , Hipotálamo/metabolismo , Microscopía , Neuronas/metabolismo , Neurotransmisores/metabolismo , Animales , Humanos , Oxitocina/metabolismoRESUMEN
Deep brain stimulation (DBS) of the globus pallidus internus was recently proposed as a potential new treatment target for opioid addiction. DBS requires computer-assisted-3D planning to implant the stimulation electrode precisely. As volumes of brain regions may differ in addiction compared to healthy controls, our aim was to investigate possible volume differences in addicts compared to healthy controls. Volumes of the globus pallidus externus (PE) and internus (PI) in heroin addicts (n = 14) and healthy controls (n = 12) were assessed using morphometry of serial whole-brain sections. Total brain volume was larger in the heroin group (mean 1479 ± 62 cm3 vs. mean 1352 ± 103 cm3), as the heroin group was more than 10 years younger (p = 0.001). Despite larger mean whole brain volume, the mean relative volume of the PE and PI was smaller in addicted subjects compared to healthy controls (PE 0.658 ± 0.183 × 10-3 vs. 0.901 ± 0.284 × 10-3; ANOVA F(1, 24) = 6.945, p = 0.014, η2 = 0.224; PI 0.253 ± 0.095 × 10-3 vs. 0.345 ± 0.107 × 10-3; ANOVA F(1, 24) = 5.374, p = 0.029, η2 = 0.183). These findings were not significantly confounded by age, duration of autolysis, and fixation time. Our results provide further evidence for structural and not only functional deficits of the globus pallidus in addiction. In the context of previous studies, our findings support the idea of shared pathophysiological processes between comorbid depression and impulsivity in opioid addiction.
Asunto(s)
Globo Pálido/patología , Dependencia de Heroína/patología , Adulto , Autopsia , Humanos , Masculino , Persona de Mediana Edad , Adulto JovenRESUMEN
A large proportion of the persons who join terrorist groups as well as lone-acting terrorists have a history of violent behavior or mental disorder that predated their becoming terrorists. This suggests that brain alterations found to occur in violent perpetrators may also be present in a significant percentage of terrorists. After a short delineation of phylogenetically old neuronal networks that are important for the generation of aggressive behavior in inconspicuous brains, this review summarizes structural and functional brain-imaging studies in violent offenders published over the last 10 years. Depending on the subtype of violence (impulsive or instrumental), deviations in structure or function were mainly found in the prefrontal, orbitofrontal, and insular cortex, as well as in temporolimbic structures (e.g., the amygdala, hippocampus, and parahippocampus). These brain areas are essentially responsible for the control of the archaic neuronal generators of aggression located in the hypothalamus and limbic system. This regional distribution of brain alterations also shows a remarkable overlap with those brain regions that are crucial for such prosocial traits as empathy and compassion. Feelings of superiority, dominance, and satisfaction gained by performing violent and terroristic attacks suggest that a hedonistic component via an activation of brain reward systems plays an additional role. In our current debate about the causes of terrorism, aspects of brain dysfunction should receive more attention.
Asunto(s)
Agresión/fisiología , Encéfalo/fisiología , Terrorismo/psicología , Encéfalo/diagnóstico por imagen , Encéfalo/fisiopatología , Conectoma , HumanosRESUMEN
The role of the thalamus in schizophrenia has increasingly been studied in recent years. Deficits in the ventral thalamus have been described in only few postmortem and neuroimaging studies. We utilised our previously introduced neurodevelopmental animal model, the neonatal excitotoxic lesion of the ventral thalamus of Sprague-Dawley rats (Wolf et al., Pharmacopsychiatry 43:99-109, 22). At postnatal day (PD7), male pubs received bilateral thalamic infusions with ibotenic acid (IBA) or artificial cerebrospinal fluid (control). In adulthood, social interaction of two animals not familiar to each other was studied by a computerised video tracking system. This study displays clear lesion effects on social interaction of adult male rats. The significant reduction of total contact time and the significant increase in distance between the animals in the IBA group compared to controls can be interpreted as social withdrawal modelling a negative symptom of schizophrenia. The significant increase of total distance travelled in the IBA group can be hypothesised as agitation modelling a positive symptom of schizophrenia. Using a triple concept of social interaction, the percentage of no social interaction (Non-SI%) was significantly larger, and inversely, the percentage of passive social interaction (SI-passive%) was significantly smaller in the IBA group when compared to controls. In conclusion, on the background of findings in schizophrenic patients, the effects of neonatal ventral thalamic IBA lesions in adult male rats support the hypothesis of face and construct validity as animal model of schizophrenia.
Asunto(s)
Conducta Animal/efectos de los fármacos , Agonistas de Aminoácidos Excitadores/toxicidad , Ácido Iboténico/toxicidad , Conducta Social , Núcleos Talámicos Ventrales/efectos de los fármacos , Animales , Animales Recién Nacidos , Masculino , Actividad Motora/efectos de los fármacos , Ratas , Ratas Sprague-DawleyRESUMEN
The role of monocytes and macrophages in the pathogenesis of neurodegenerative disorders such as Alzheimer's disease (AD) is poorly understood. Recently, we have shown that the number of CD14+ monocytes remained constant during healthy aging and in AD patients. Although only little is known about the function of activated macrophages and microglia in AD, one important mechanism involves the expression of quinolinic acid (QUIN), an endogenous N-methyl-D-aspartate glutamate receptor (NMDA-R) agonist which mediates excitotoxicity especially in the hippocampus. We used immunofluorescence stainings of PBMCs to determine the expression of quinolinic acid (QUIN) and the MHC class II molecule HLA-DR in peripheral monocytic cells in 51 healthy volunteers aged 22-87 years and 43 patients with AD at diagnosis (0 weeks) and during the course of rivastigmine treatment at 0.25 year (12 weeks), 0.5 year (30 weeks), 1 year, and 1.5 years. The number of QUIN+ HLA-DR+ cells rises in healthy persons aged 30-40 years compared to persons aged 60-70 years, indicating that this cell population increases with aging. AD patients at diagnosis had an increased frequency of QUIN+, QUIN+ HLA-DR+, and QUIN+ HLA-DR+/HLA-DR+ cells compared to aged-matched controls. These cell populations remained increased in AD for up to one year after initiation of treatment with rivastigmine; no alterations were detected in aged healthy persons. We conclude that the expression of the neurotoxic agent QUIN is increased in peripheral monocytes from AD patients. These cells could enter the brain and contribute to excitotoxicity.
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Enfermedad de Alzheimer/metabolismo , Leucocitos Mononucleares/metabolismo , Ácido Quinolínico/metabolismo , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Masculino , Persona de Mediana Edad , Adulto JovenRESUMEN
N-Methyl-D-aspartate glutamate receptor (NMDA-R) antibodies (Abs) could play a role in neurodegenerative disorders. Since, in these diseases, NMDA-R Abs were detected in serum, but only sporadic in cerebrospinal fluid (CSF), the origin and impact of the Abs are still unresolved. We examined the presence of NMDA-R Abs in serum and CSF using a cell-based immunofluorescence assay as well as the function of the blood-CSF-barrier (B-CSF-B) by determination of Q albumin (ratio of albumin in CSF and serum) in patients with mild cognitive impairment (MCI; N = 59) and different types of dementia, Alzheimer's disease (AD; N = 156), subcortical ischemic vascular dementia (SIVD; N = 61), and frontotemporal dementia (FTD; N = 34). Serum IgA/IgM NMDA-R Abs and/or a disturbed B-CSF-B were sporadically present in all investigated patients' groups. In AD, these Abs often developed during the disease course. Patients with either no hippocampal atrophy and/or no AD-related characteristic changes in CSF, referred to "non-classical" AD, were characterized by seropositivity at diagnosis and loss of function of the B-CSF-B showed a progressive decline in cognitive functions and a poor prognosis. Our data indicate that NMDA-R Abs are present in different types of dementia and elderly healthy individuals. In combination with disturbed B-CSF-B integrity, they seem to promote their pathological potential on cognitive decline, and thus, a subgroup of dementia patients with these unique characteristics might inform clinicians.
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Enfermedad de Alzheimer/diagnóstico , Autoanticuerpos/líquido cefalorraquídeo , Barrera Hematoencefálica/patología , Demencia/patología , Receptores de N-Metil-D-Aspartato/inmunología , Anciano , Anciano de 80 o más Años , Enfermedad de Alzheimer/líquido cefalorraquídeo , Enfermedad de Alzheimer/inmunología , Enfermedad de Alzheimer/patología , Demencia/líquido cefalorraquídeo , Demencia/inmunología , Femenino , Humanos , Masculino , Persona de Mediana EdadRESUMEN
The hypothalamus is at the core of the stress responses systems of the brain. Most interestingly, even though changes of HPA-function have been observed in opiate addiction not much is known about structural changes of the hypothalamus. Volumes of hypothalamus in heroin addicts (n = 14) and healthy controls (n = 12) were assessed by using morphometry of serial whole-brain sections. Total brain volume was larger in the heroin group (mean 1478.85 ± 62.34 cm3 vs. mean 1352.38 ± 103.24 cm3), as the heroin group was more than 10 years younger (p = 0.001). Thus, diagnosis-related effects in the hypothalamus were assessed using the hypothalamus volume relative to whole brain volume showing reduced volumes of the hypothalamus in the heroin group (0.201 ± 0.074 × 10-3 vs. 0.267 ± 0.048 × 10-3; ANOVA: F(1,23) = 6.211, p = 0.020) with a strong hemispheric effect (left side: about 20% reduction 0.209 ± 0.080 × 10-3 vs. 0.264 ± 0.049 × 10-3; F = 4.109; p = 0.054; right side: about 27% reduction, 0.198 ± 0.069 × 10-3 vs. 0.271 ± 0.050 × 10-3; F = -8.800; p = 0.007). Our results provide further evidence for structural and not only functional deficits of the hypothalamus in addiction.
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Diagnóstico , Dependencia de Heroína/patología , Hipotálamo/patología , Adulto , Autopsia , Estudios de Seguimiento , Lateralidad Funcional , Humanos , Masculino , Persona de Mediana Edad , Estadísticas no Paramétricas , Adulto JovenRESUMEN
The vasopressin- and oxytocin-degrading enzyme insulin-regulated aminopeptidase (IRAP) is expressed in various organs including the brain. However, knowledge about its presence in human hypothalamus is fragmentary. Functionally, for a number of reasons (genetic linkage, hydrolysis of oxytocin and vasopressin, its role as angiotensin IV receptor in learning and memory and others) IRAP might play a role in schizophrenia. We studied the regional and cellular localization of IRAP in normal human brain with special emphasis on the hypothalamus and determined numerical densities of IRAP-expressing cells in the paraventricular, supraoptic and suprachiasmatic nuclei in schizophrenia patients and controls. By using immunohistochemistry and Western blot analysis, IRAP was immunolocalized in postmortem human brains. Cell countings were performed to estimate numbers and numerical densities of IRAP immunoreactive hypothalamic neurons in schizophrenia patients and control cases. Shape, size and regional distribution of IRAP-expressing cells, as well the lack of co-localization with the glia marker glutamine synthetase, show that IRAP is expressed in neurons. IRAP immunoreactive cells were observed in the hippocampal formation, cerebral cortex, thalamus, amygdala and, abundantly, hypothalamus. Double labeling experiments (IRAP and oxytocin/neurophysin 1, IRAP with vasopressin/neurophysin 2) revealed that IRAP is present in oxytocinergic and in vasopressinergic neurons. In schizophrenia patients, the numerical density of IRAP-expressing neurons in the paraventricular and the suprachiasmatic nuclei is significantly reduced, which might be associated with the reduction in neurophysin-containing neurons in these nuclei in schizophrenia. The pathophysiological role of lowered hypothalamic IRAP expression in schizophrenia remains to be established.
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Cistinil Aminopeptidasa/metabolismo , Hipotálamo/enzimología , Hipotálamo/patología , Neuronas/enzimología , Neurohipófisis/metabolismo , Esquizofrenia/patología , Anciano , Autopsia , Enfermedad Crónica , Femenino , Glutamato-Amoníaco Ligasa/metabolismo , Humanos , Masculino , Persona de Mediana Edad , Neurofisinas/metabolismo , Oxitocina/metabolismo , Núcleo Hipotalámico Paraventricular/patología , Núcleo Supraquiasmático/patología , Vasopresinas/metabolismoRESUMEN
Resting-state fMRI studies have gained widespread use in exploratory studies of neuropsychiatric disorders. Graph metrics derived from whole brain functional connectivity studies have been used to reveal disease-related variations in many neuropsychiatric disorders including major depression (MDD). These techniques show promise in developing diagnostics for these often difficult to identify disorders. However, the analysis of resting-state datasets is increasingly beset by a myriad of approaches and methods, each with underlying assumptions. Choosing the most appropriate preprocessing parameters a priori is difficult. Nevertheless, the specific methodological choice influences graph-theoretical network topologies as well as regional metrics. The aim of this study was to systematically compare different preprocessing strategies by evaluating their influence on group differences between healthy participants (HC) and depressive patients. We thus investigated the effects of common preprocessing variants, including global mean-signal regression (GMR), temporal filtering, detrending, and network sparsity on group differences between brain networks of HC and MDD patients measured by global and nodal graph theoretical metrics. Occurrence of group differences in global metrics was absent in the majority of tested preprocessing variants, but in local graph metrics it is sparse, variable, and highly dependent on the combination of preprocessing variant and sparsity threshold. Sparsity thresholds between 16 and 22% were shown to have the greatest potential to reveal differences between HC and MDD patients in global and local network metrics. Our study offers an overview of consequences of methodological decisions and which neurobiological characteristics of MDD they implicate, adding further caution to this rapidly growing field.
Asunto(s)
Trastorno Depresivo Mayor/diagnóstico por imagen , Trastorno Depresivo Mayor/fisiopatología , Imagen por Resonancia Magnética/métodos , Red Nerviosa/diagnóstico por imagen , Red Nerviosa/fisiopatología , Adulto , Femenino , Humanos , MasculinoRESUMEN
This study aimed to assess whether brain pathology might be more abundant in forensic inpatients in a high-security setting than in non-criminal individuals. By using a previously used reliable approach, we explored the frequency and extent of brain pathology in a large group of institutionalized offenders who had not previously been considered to be suffering from structural brain damage and compare it to healthy, non-offending subjects. MRI and CT brain scans from 148 male inpatients of a high-security mental health institution (offense type: 51 sex, 80 violent, 9 arson, and 8 nonviolent) that were obtained due to headache, vertigo, or psychological complaints during imprisonment were assessed and compared to 52 non-criminal healthy controls. Brain scans were assessed qualitatively with respect to evidence of structural brain damage. Each case received a semiquantitative rating of "normal" (=0), "questionably abnormal" (=1), or "definitely abnormal" (=2) for the lateral ventricles, frontal/parietal cortex, and medial temporal structures bilaterally as well as third ventricle. Forensic inpatients displayed signs of brain damage to a significantly higher degree than healthy controls (p < 0.001). Even after adjustment for age, in the patients, being younger than the controls (p < 0.05), every offender type group displayed a higher proportion of subjects with brain regions categorized as definitely abnormal than the non-criminal controls. Within the forensic inpatients, offense type groups did not significantly differ in brain pathology. The astonishingly high prevalence of brain pathology in institutionalized inmates of a high-security mental health institution who previously had not been considered to be suffering from an organic brain syndrome raises questions on whether such neuroradiological assessment might be considered as a routine procedure in newly admitted patients. Furthermore, it highlights that organic changes, detectable under clinical routine conditions, may play a role in the development of legally relevant behavioral disturbances which might be underestimated.
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Encéfalo/diagnóstico por imagen , Angiografía por Tomografía Computarizada/métodos , Patologia Forense , Imagen por Resonancia Magnética/métodos , Trastornos Psicóticos/patología , Adulto , Análisis de Varianza , Femenino , Humanos , Procesamiento de Imagen Asistido por Computador , Estudios Longitudinales , Masculino , Persona de Mediana Edad , Prisioneros , Estudios Retrospectivos , Adulto JovenRESUMEN
Profound white matter abnormalities have repeatedly been described in schizophrenia, which involve the altered expression of numerous oligodendrocyte-associated genes. Transcripts of the disrupted-in-schizophrenia 1 (DISC1) gene, a key susceptibility factor in schizophrenia, have recently been shown to be expressed by oligodendroglial cells and to negatively regulate oligodendrocyte differentiation and maturation. To learn more about the putative role(s) of oligodendroglia-associated DISC1 in schizophrenia, we analyzed the density of DISC1-immunoreactive oligodendrocytes in the fronto-parietal white matter in postmortem brains of patients with schizophrenia. Compared with controls (N = 12) and cases with undifferentiated/residual schizophrenia (N = 6), there was a significantly increased density of DISC1-expressing glial cells in paranoid schizophrenia (N = 12), which unlikely resulted from neuroleptic treatment. Pathophysiologically, over-expression of DISC1 protein(s) in white matter oligodendrocytes might add to the reduced levels of two myelin markers, 2',3'-cyclic-nucleotide 3'-phosphodiesterase and myelin basic protein in schizophrenia. Moreover, it might significantly contribute to cell cycle abnormalities as well as to deficits in oligodendroglial cell differentiation and maturation found in schizophrenia.
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Lóbulo Frontal/patología , Regulación de la Expresión Génica/fisiología , Proteínas del Tejido Nervioso/metabolismo , Oligodendroglía/metabolismo , Lóbulo Parietal/patología , Esquizofrenia Paranoide/patología , Sustancia Blanca/patología , 2',3'-Nucleótido Cíclico Fosfodiesterasas/metabolismo , Adulto , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , Proteína Básica de Mielina/metabolismo , Estadísticas no ParamétricasRESUMEN
Multiple brain structural abnormalities have been reported in schizophrenia and major depressive disorder. A majority of disease-affected brain regions act as relay nodes within neural networks, which are known to be impaired in neuropsychiatric diseases. One of these regions is the claustrum, which has the highest connectivity in the human brain by regional volume. Its possible involvement in disturbed connectivity is yet incompletely explored, however. The present study aimed at searching for possible structural deviations of the claustrum in neuropsychiatric disorders. We found bilaterally reduced claustral volumes both in schizophrenia and in major depressive disorder. These structural impairments may have different, disease-related consequences: In patients with schizophrenia, they may contribute to sensory processing impairments, and in patients with major depressive disorder to disturbances in salience.
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Ganglios Basales/patología , Trastorno Depresivo Mayor/patología , Esquizofrenia/patología , Adulto , Análisis de Varianza , Estudios de Casos y Controles , Femenino , Lateralidad Funcional , Humanos , Masculino , Persona de Mediana Edad , Cambios Post Mortem , Caracteres SexualesRESUMEN
Major depressive disorder is characterized by abnormal brain connectivity at rest. Currently, most studies investigating resting-state activity rely on a priori restrictions on specific networks or seed regions, which may bias observations. We hence sought to elicit functional alterations in a hypothesis-free approach. We applied functional connectivity density (FCD) to identify abnormal connectivity for each voxel in the whole brain separately. Comparing resting-state fMRI in 21 MDD patients and 23 matched healthy controls, we identified atypical connections for regions exhibiting abnormal FCD and compared our results to those of an independent component analysis (ICA) on networks previously investigated in MDD. Patients showed reduced FCD in mid-cingulate cortex (MCC) and increased FCD in occipital cortex (OCC). These changes in global FCD were driven by abnormal local connectivity changes and reduced functional connectivity (FC) toward the left amygdala for MCC, and increased FC toward the right supplementary motor area for OCC. The altered connectivity was not reflected in ICA comparison of the salience and visual networks. Abnormal FC in MDD is present in cingulate and OCC in terms of global FCD. This converges with previous structural and metabolic findings; however, these particular changes in connectivity would not have been identified using canonical seed regions or networks. This implies the importance of FC measures in the investigation of brain pathophysiology in depression.
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Trastorno Depresivo Mayor/fisiopatología , Vías Nerviosas/fisiopatología , Adulto , Encéfalo/diagnóstico por imagen , Encéfalo/fisiopatología , Estudios de Casos y Controles , Trastorno Depresivo Mayor/diagnóstico por imagen , Femenino , Neuroimagen Funcional , Humanos , Imagen por Resonancia Magnética , Masculino , Descanso/fisiologíaRESUMEN
The human diagonal band of Broca is connected to other parts of the limbic system, such as the hippocampus, that are involved in the pathology of schizophrenia. This study aimed to characterize the volume and anterior-to-posterior distance of the human diagonal band of Broca (vertical limb) from post-mortem brains obtained from three groups: healthy control subjects (N = 17), patients with schizophrenia (N = 26), and patients with affective disorders (N = 12). There were no significant differences in the volume or anterior-to-posterior distance in the patients with schizophrenia or affective disorders compared with the healthy control subjects. To date, this is the first post-mortem investigation measuring the volume and the anterior-to-posterior distance of the diagonal band of Broca (vertical limb) in patients with schizophrenia or affective disorders compared with healthy control subjects.