Kurt Trübner

Volume deficits of subcortical nuclei in mood disorders A postmortem study.

AbstractStructural changes in subcortical nuclei may underlie clinical symptoms of mood disorders. The goal was to determine whether macrostructural changes exist in brain areas assumed to be involved in regulation of mood and whether such changes differ between major depressive disorder and bipolar disorder. A case–control design was used to compare volumes of all major subcortical nuclei. Brains of patients with major depressive disorder (n = 9) or bipolar disorder (n = 11) or of individuals without a neuropsychiatric disorder (n = 22) were included. Exclusion criteria were a history of substance abuse or histological signs of neurodegenerative disorders.Volumes of the striato–pallidal nuclei, of the hypothalamus, thalamus, amygdala, hippocampus and basal limbic forebrain were determined in the right and left hemisphere by planimetry of 20 μm whole brain serial paraffin sections. Comparisons between patients with bipolar disorder, major depressive disorder and controls showed a significant (Λ = 0.35, F20,56 = 1.93, P = 0.028) overall difference in volumes of all investigated regions with strong effect sizes ( ƒ > 0.40) contributed by the hypothalamus, external pallidum, putamen and thalamus. As compared to controls, a strong effect size (ƒ > 0.40) was found in the bipolar group for smaller volumes of the hypothalamus, external pallidum, putamen and thalamus,whereas in patients with major depressive disorder a strong effect size was only found for a smaller volume of the external pallidum. In conclusion our data suggest that pathways presumably involved in mood regulation have structural pathology in affective disorders with more pronounced abnormalities in bipolar disorder.

Tyrosine hydroxylase immunoreactivity in the locus coeruleus is elevated in violent suicidal depressive patients

Our postmortem study aimed to determine the impact of suicide on the number of noradrenergic neurons of the locus coeruleus (LC) in suicidal depressive patients. Noradrenergic neurons were shown by immunostaining tyrosine hydroxylase in the LC of 22 non-elderly patients with mood disorders compared to 21 age- and sex-matched normal controls. Eleven patients were suicide victims and the other eleven died of natural causes. Seven violent suicide victims revealed an increased number of tyrosine hydroxylase immunoreactive (TH-ir) neurons compared with non-violent suicide victims and controls. No difference was found between the number of TH-ir neurons in all suicidal patients and controls and between non-suicidal patients and controls. The differences of TH-immunoreactivity could neither be attributed to medication nor to the polarity of depressive disorder (unipolar/bipolar). The numbers of TH-ir neurons in suicidal patients correlated negatively with the mean doses of antidepressants. The study suggested a presynaptic noradrenergic dysregulation in the LC related to the level of self-aggression. Traditional antidepressants may, therefore, regulate noradrenergic activity of the LC in suicide patients, however, without demonstrating the suicide-preventing effect.

Demonstration of disturbed activity of the lateral amygdaloid nucleus projection neurons in depressed patients by the AgNOR staining method

BACKGROUND The aim to find a morphological biomarker of disturbed activity of the lateral amygdaloid nucleus in depression was approached by a karyometric analysis of projection neurons. METHODS The study was performed on paraffin-embedded brains from 19 depressed patients from both the major depressive disorder (MDD) and the bipolar disorder (BD) diagnostic groups, including 10 suicides, and 24 matched controls. The karyometric parameters of the lateral amygdaloid nucleus (La) projection neurons bilaterally were evaluated by the argyrophilic nucleolar organiser region (AgNOR) silver staining method. RESULTS An increased AgNOR number was found in the right La in suicides compared to controls. The intra-group comparisons between the hemispheres suggest a disturbed amygdaloid lateralisation in depressed patients. The effects were independent from psychotropic medication. There was a strong positive correlation between the nuclear area in La projection neurons and prefrontal limbic areas pyramidal neurons in the right hemisphere specific for suicide and MDD. LIMITATIONS A major limitation of this study is the relatively small number of cases. A further limitation is given by the lack of data on drug exposure across the entire lifespan. CONCLUSION The results suggest that depressed patients from both the MDD and BD diagnostic groups exhibit an increased activity of the La output neurons specific for suicidal patients. The distinctness of the diagnostic groups of mood disorders was accentuated in the correlation analysis. This putative hyperactivity was specific for the right hemisphere and psychotropic medication most likely did not counteract it.

The changes of AgNOR parameters of anterior cingulate pyramidal neurons are region-specific in suicidal and non-suicidal depressive patients

The anterior cingulate cortex (AC) is consistently implicated in the pathophysiology of depression. While suicide has been shown in previous reports to be closely related to depression, it is still a distinct phenomenon. The aim to differentiate between depression and suicide was approached by the karyometric analysis of AC pyramidal neurons. The study was performed on paraffin-embedded brains from 20 depressive patients (10 of whom had committed suicide) and 24 matched controls. The karyometric parameters of the layer III and V pyramidal neurons of the dorsal and ventral AC were evaluated bilaterally by Argyrophilic Nucleolar Organiser (AgNOR) silver staining method. Control-specific was the increased nuclear area in ontogenetically younger pyramidal neurons layer III in the left dorsal compared with ventral AC (Wilcoxon test, P<0.01). The decreased AgNOR number per nucleus in these cells in the right ventral AC was depression-specific compared with controls (t-test, P=0.047). On the other hand, the diffuse decrease in AgNOR ratio throughout pyramidal neurons on the left side was specific for suicidal depressive patients compared with non-suicidal patients and controls (ANOVA, P=0.028). The results suggest that regionally differentiated depression- and suicide-specific disturbed function of the most important AC output cells exists in depressive patients.

Differential regional and cellular distribution of TFF3 peptide in the human brain

TFF3 is a member of the trefoil factor family (TFF) predominantly secreted by mucous epithelia. Minute amounts are also expressed in the immune system and the brain. In the latter, particularly the hypothalamo-pituitary axis has been investigated in detail in the past. Functionally, cerebral TFF3 has been reported to be involved in several processes such as fear, depression, learning and object recognition, and opiate addiction. Furthermore, TFF3 has been linked with neurodegenerative and neuropsychiatric disorders (e.g., Alzheimer’s disease, schizophrenia, and alcoholism). Here, using immunohistochemistry, a systematic survey of the TFF3 localization in the adult human brain is presented focusing on extrahypothalamic brain areas. In addition, the distribution of TFF3 in the developing human brain is described. Taken together, neurons were identified as the predominant cell type to express TFF3, but to different extent; TFF3 was particularly enriched in various midbrain and brain stem nuclei. Besides, TFF3 immunostaining staining was observed in oligodendroglia and the choroid plexus epithelium. The wide cerebral distribution should help to explain its multiple effects in the CNS.

Demonstration of disturbed activity of external globus pallidus projecting neurons in depressed patients by the AgNOR staining method.

BACKGROUND The external globus pallidus (EGP) is thought to play the most important integrating and conveying role in the striatopallidal system involved in the transfer from motivation to action. The aim to find a morphological biomarker of disturbed EGP activity in depression was approached by the karyometric analysis of large projecting neurons. METHODS The study was performed on paraffin-embedded brains from 19 depressed patients from both the major depressive disorder (MDD) and the bipolar disorder (BD) diagnostic groups encompassing 10 suicides and from 24 controls. The karyometric parameters of EGP neurons bilaterally were evaluated by argyrophilic nucleolar organiser (AgNOR) silver staining method. RESULTS A significantly decreased AgNOR area was found in the left EGP neurons in depressed patients compared to controls. The distinctness of the diagnostic groups and suicidal vs non-suicidal patients was not shown in the statistical comparisons. The AgNOR parameter which was decreased correlated positively with the mean dose of benzodiazepines in non-suicidal patients. LIMITATIONS A major limitation of this study is the relatively small number of cases. A further limitation is given by the lack of data on drug exposure across the whole lifespan of patients. CONCLUSION The results suggest disturbed, most likely decreased, activity of the left EGP projecting neurons in depressed patients, a disturbed activity that should hypothetically be counteracted by the applied pharmacotherapy in non-suicidal patients.

Demonstration of disturbed activity of orbitofrontal pyramidal neurons in depressed patients by the AgNOR staining method

BACKGROUND The aim to find the morphological biomarker of disturbed activity of the orbitofrontal cortex (OFC) in depression was approached by the karyometric analysis of pyramidal neurons. METHODS The study was performed on paraffin-embedded brains from 19 depressed patients from both major depressive disorder (MDD) and bipolar disorder (BD) diagnostic groups, including 9 suicides, and 24 matched controls. The karyometric parameters of medial OFC layer III and V pyramidal neurons bilaterally were evaluated by argyrophilic nucleolar organiser region (AgNOR) silver staining method. RESULTS The enlarged nuclear area was found in layer V pyramidal neurons in the right OFC in non-suicides compared to suicides and controls, which was most likely the effect of neuroleptics. The intra-group comparisons between the hemispheres suggest the disturbed orbitofrontal lateralisation in depressed patients (predominantly in suicides) with moderate distinctness of the MDD and the BD diagnostic groups. LIMITATIONS A major limitation of this study is a relatively small number of cases. A further limitation is given by the lack of data on drug exposure across the whole lifespan. CONCLUSION The results suggest disturbed activity of OFC pyramidal neurons in depression, distinct in suicide and the diagnostic groups of mood disorders. The non-suicidal patients seem to benefit from neuroleptics, which most likely increase the activity of the subpopulation of OFC pyramidal neurons.

Suicidal ligature strangulation using gymnastics bands

Suicidal ligature strangulation is a rare event. The most important issue to solve in the investigation is whether it is a case of homicide or suicide. The characteristics of suicidal ligature strangulation are summarized by Koops and Brinkmann with the emphasis on the nature of the ligature instrument(s). In this article, we present two cases of self-strangulation with an almost identical modus operandi using gymnastics bands. The autopsy findings and the nature of the ligature in these cases are depicted and in good accordance with the described typical observations in suicidal cases. The importance of a broad medico-legal investigation is demonstrated.

Insulin-regulated aminopeptidase immunoreactivity is abundantly present in human hypothalamus and posterior pituitary gland, with reduced expression in paraventricular and suprachiasmatic neurons in chronic schizophrenia

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.

Genital findings in boys suspected for sexual abuse

Injuries in the genital region of boys are mostly caused by accidents. In this study, three cases of child abuse and one case suspicious for child abuse but explainable by a congenital undiscovered malformation are presented. Injuries or findings in the genital region are especially suspicious for child abuse, including sexual abuse. Because of the possible misinterpretation and the consequences of a false confirmation of a child abuse, an interdisciplinary cooperation between pediatrics, forensic experts, and pediatric urologist should be carried out in doubtful cases.