P. Danos’s research while affiliated with University of Giessen and other places

Our sense of self is strongly colored by emotions although at the same time we are well able to distinguish affect and self. Using functional magnetic resonance imaging, we here tested for the differential effects of self-relatedness and emotion dimensions (valence, intensity) on parametric modulation of neural activity during perception of emotional stimuli. We observed opposite parametric modulation of self-relatedness and emotion dimensions in the dorsomedial prefrontal cortex and the ventral striatum/nucleus accumbens, whereas neural activity in subcortical regions (tectum, right amygdala, hypothalamus) was modulated by self-relatedness and emotion dimensions in the same direction. In sum, our results demonstrate that self-relatedness is closely linked to emotion dimensions of valence and intensity in many lower subcortical brain regions involved in basic emotional systems and, at the same time, distinct from them in higher cortical regions that mediate cognitive processes necessary for becoming aware of one's self, for example self-consciousness. Hum

Structural and functional pathology of limbic structures including the hippocampus are frequently replicated in schizophrenia. Although the fornix is the main afferent system of the hippocampus to the septal nuclei and the hypothalamus (especially the mammillary bodies), relatively few studies have investigated structural changes of the fornix in schizophrenia. We measured the volume of the fornix in post-mortem brains in 19 patients with schizophrenia, 9 patients with bipolar disorder, 7 patients with unipolar depression, and 14 control subjects by planimetry of serial sections. The volumes, the mean cross-sectional areas, and the anterior to posterior distances of the fornix did not differ among patients with schizophrenia, bipolar disorder, unipolar depression, and control subjects. No lateralization existed between the right and the left fornices in among patients in the diagnostic groups and the control subjects. The fornix does not show morphometrical abnormalities in patients with schizophrenia, bipolar disorder and unipolar depression compared with control subjects, which might indicate that the fornix is not a primary focus of structural changes in these diseases.

Suicide has a high prevalence in patients with schizophrenia and affective disorder. Our recent postmortem study [Steiner J, Mawrin C, Ziegeler A, Bielau H, Ullrich O, Bernstein HG, Bogerts B. Distribution of HLA-DR-positive microglia in schizophrenia reflects impaired cerebral lateralization. Acta Neuropathologica (Berl) 2006;112:305-16.] revealed increased microglial densities in two schizophrenic patients who had committed suicide. Therefore, the hypothesis of microglial activation during acute psychosis was proposed. Alternatively, "suicide" could be a diagnosis-independent factor leading to microgliosis. To clarify this question, microglial HLA-DR expression was analyzed by immunohistochemistry in the dorsolateral prefrontal cortex (DLPFC), anterior cingulate cortex (ACC), mediodorsal thalamus (MD) and hippocampus of 16 schizophrenics, 14 depressed patients with affective disorder and 10 matched controls. A subgroup of six schizophrenics and seven patients with affective disorder who committed suicide was included. ANOVA revealed no effect of diagnosis on microglial density (DLPFC: P=0.469; ACC: P=0.349; MD: P=0.569; hippocampus: P=0.497). However, significant microgliosis was observed in the DLPFC (P=0.004), ACC (P=0.012) and MD (P=0.004) of suicide patients. A similar trend was seen in the hippocampus (P=0.057). In conclusion, immunological factors may play a hitherto underestimated role in suicide. First, microglial activation might be interpreted as a consequence of presuicidal stress. Second, one might speculate a causal link between microglial activation and suicidal behaviour, such as neuroendocrine factors, cytokines, and nitric oxide, which are released from microglial cells and are known to modulate noradrenergic or serotonergic neurotransmission and thus may trigger suicidality.

Executive functions, which are neuroanatomically associated with the frontal lobe, are known to be impaired in schizophrenia. It is, however, still unclear whether the underlying functional disturbance is due to a hyper- or a hypoactivation of the dorsolateral prefrontal cortex (DLPFC) or neither. To address this question, we examined the brain activation of 21 schizophrenic patients on atypical antipsychotic medication and 21 healthy control subjects during a mental maze task by means of fMRI. We found no significant overall difference in cerebral activation between the groups, but differences in the change in DLPFC activation from the first to the second half of the experiment. In the maze compared to the control task, there was a decrease in activation in the DLPFC in the patients and an almost significant increase in the controls. The change in activation in the patient group correlated with a change in subjective sleepiness, while the increase in activation in the controls could be attributed to learning processes. We hypothesized that differential temporal influences on brain activation could lead to either hyper- or hypoactivation of the DLPFC in schizophrenia.

The mammillary bodies (MB) are important relay nuclei within limbic and extralimbic connections. They are known to play important roles in memory formation and are affected in alcoholism and vitamin B1 deficiency. Their strategic position linking temporo-limbic to cortico-thalamic brain structures make the MB a candidate brain structure for alterations in schizophrenia. We studied 15 postmortem brains of schizophrenics and 15 matched control brains. Brain sections were stained either with Heidenhain-Woelcke, glutamic acid decarboxylase (GAD), calretinin, or parvalbumin. We determined the volumes of the MB and performed cell countings using stereological principles and a computerized image analysis system. The volumes of MB do not differ between schizophrenics and controls. However, in schizophrenia the number of neurons as well as the resulting neuronal densities was significantly reduced on both sides (on left side by 38.9%, on right side by 22%). No changes were seen in the number of GAD-expressing or calretinin-containing neurons, whereas the number of parvalbumin-immunoreactive MB neurons was reduced by more than 50% in schizophrenia. This cell loss (as a result of developmental malformation and/or neurodegeneration) points to a prominent involvement of the MB in the pathomorphology of schizophrenia. Parvalbumin-immunoreactive GABAergic interneurons have been reported to be diminished in schizophrenia. However, in the MB parvalbumin labels a subpopulation of glutamate/aspartate-containing neurons projecting mainly to the anterior thalamus. Thus, our data provide new evidence for impaired limbic circuits in schizophrenia.

So-called Porteus mazes are used to investigate prefrontal cortex (PFC) functioning in normal subjects and patients with different neuropsychiatric disorders. Here we present data confirming the involvement of the PFC for the first time by means of functional magnetic resonance imaging (fMRI). To minimize motor-related activation, mental mazes were used. Mazes as well as pseudo-mazes without any bifurcations were presented to 49 healthy participants during fMRI scans. Both, mazes as well as pseudo-mazes, activated a large network from visual to parietal regions, reflecting the dorsal stream of visual information processing. Mazes but not pseudo-mazes also activated bilateral areas of the PFC indicating their special role in decision processes. In addition, although no motor response was required during maze performance, both tasks activated subcortical and cortical motor areas. These tasks are suitable for investigating and specifying PFC functioning and its impairment in psychiatric disorders such as schizophrenia. In addition, mental mazes might be a suitable task for the investigation of patients with motor disturbances.

Structural 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 mum whole brain serial paraffin sections. Comparisons between patients with bipolar disorder, major depressive disorder and controls showed a significant (Lambda = 0.35, F(20,56) = 1.93, P = 0.028) overall difference in volumes of all investigated regions with strong effect sizes ( f > 0.40) contributed by the hypothalamus, external pallidum, putamen and thalamus. As compared to controls, a strong effect size (f > 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.