Biomedical subjects

Fritz A Henn

Publications and source records attributed to Fritz A Henn.

At least 19 recordsLinked to original sources

PubMed2007

Subcortical and medial temporal MR-detectable metabolite abnormalities in unipolar major depression.

The purpose of the present study was to determine whether MR-detectable alterations of choline-containing compounds in two key neural systems involved in major depression disorder namely the hippocampus and the basal ganglia can be detected. Multislice proton magnetic resonance spectroscopic imaging was applied in 11 patients with major depressive disorder (MDD) and ten matched healthy subjects. Voxels were selected from the left and right side of the hippocampus and the putamen. Significantly lower choline-containing compounds in the hippocampus and significantly higher choline-containing compounds in the putamen of patients with MDD compared to healthy subjects were found. No significant differences were found for the other metabolites in the two regions evaluated. Abnormal levels of choline-containing compounds most likely reflect altered membrane phospholipid metabolism. A reduced level in the hippocampus and an increased level in the putamen suggest regionally opponent membrane abnormalities.

Adult↗

PubMed2006

Neural correlates of working memory dysfunction in first-episode schizophrenia patients: an fMRI multi-center study.

Working memory dysfunction is a prominent impairment in patients with schizophrenia. Our aim was to determine cerebral dysfunctions by means of functional magnetic resonance imaging (fMRI) in a large sample of first-episode schizophrenia patients during a working memory task. 75 first-episode schizophrenia patients and 81 control subjects, recruited within a multi-center study, performed 2- and 0-back tasks while brain activation was measured with fMRI. In order to guarantee comparability between data quality from different scanners, we developed and adopted a standardized, fully automated quality assurance of scanner hard- and software as well as a measure for in vivo data quality. After these quality-control measures had been implemented, 48 patients and 57 controls were included in the final analysis. During attention-related processes, even when the performance between patients and controls was comparable, there was a recognizable emergence of cerebral dysfunctions with hypoactivations in the ventrolateral prefrontal cortex (VLPFC), in the superior temporal cortex and in the thalamus. During working memory performance, parietal hypoactivations, especially in the precuneus, were prominent and were accompanied by poorer performance in patients. A hyperfrontality emerged in the ventrolateral prefrontal cortex. Hence, results point to a dysfunctional ventrolateral prefrontal-parietal network during working memory in patients, suggesting impairments in basic functions such as retrieval, storage and maintenance. The brain activation pattern of this large and significant sample of first-episode schizophrenia patients indicates an imbalanced system failing to adjust the amount of brain activity required in the cerebral network involved in attention and working memory.

Adolescent↗

PubMed2006

D2 antidopaminergic modulation of frontal lobe function in healthy human subjects.

BACKGROUND: Although the major principles of dopamine (DA) signaling have been well described previously, its precise modulatory impact on the prefrontal cortex (PFC) in humans is poorly understood. Two major neurophysiological models propose segregated functional circuits on the systems level as well as D(1) and D(2) receptor-dependent processing states on the cellular level (two-state model). METHODS: We examined the predictive validity of these models in 10 healthy male volunteers with a haloperidol challenge (HLP). Cortico-striatal-thalamo-cortical (CSTC) motor loop functions were examined during functional magnetic resonance imaging (fMRI) with a sequential finger opposition task. Neuropsychological implications of the two-state model were evaluated with a test battery of D(1)- or D(2)-sensitive prefrontal measures. RESULTS: Analysis of fMRI data revealed a significant HLP-induced blood oxygen level dependent-signal decrease in the sensorimotor striatum and a lateralized activation loss of ipsilateral higher order motor cortices and contralateral cerebellum. Neuropsychological evaluation demonstrated a preferential impairment of D(2)-sensitive functions, whereas D(1) or non-dopaminergic domains were unaffected. CONCLUSIONS: Our data support the hypothesis that mesocortical D(1) and D(2) receptors exert differential influences in the PFC for cognitive function, but the nigrostriatal CSTC network model for the motor domain could not be confirmed.

Adult↗

PubMed2006

Alcohol consumption significantly influences the MR signal of frontal choline-containing compounds.

The aim of this work was to evaluate the relationship between the amount of alcohol consumption of a group of social drinkers and the magnetic resonance spectroscopy signal of choline-containing compounds (Cho) in the frontal lobe. Two independent long echo (TE = 135 ms) (1)H MRSI studies, the first comprising 24 subjects with very low alcohol consumption, the second 18 subjects with a more widespread alcohol consumption were conducted. Significant correlations of Cho measures from frontal white matter and from the anterior cingulate gyrus with alcohol consumption in the last 90 days prior to the MR examination were found. Age, gender, and smoking did not show significant effects on the metabolite measures. Partialling out the effect of the voxel white matter content did not change the correlation of choline measures with alcohol consumption. The main conclusion from the repeated finding of a positive correlation of alcohol consumption and frontal Cho signals is that monitoring for alcohol consumption is mandatory in MRS studies where pathology depended Cho changes are hypothesized.

Adult↗

PubMed2006

Correlation between MR-spectroscopic rat hippocampal choline levels and phospholipase A2.

Hippocampal choline-containing compounds (Cho) determined with 1H MR spectroscopy (MRS) are decreased in major depression episodes and return to baseline levels after antidepressive electroconvulsive therapy (ECT). A rise in hippocampal Cho has been observed in rats upon electroconvulsive shocks (ECS), an analogue of human ECT. Choline production involves the activity of various phospholipases. In order to investigate whether the increase of Cho correlates with an enhanced expression of phosphoslipase A2 (PLA2) we took rectangular tissue samples from the region of the MRS voxel for immunoblotting. Our data show a significant inverse correlation (p = 0.018) between PLA2 protein levels and MRS Cho/NAA levels suggesting a possible downregulation of PLA2 in compensation for an upregulation of other phospholipases.

Animals↗

PubMed2005

Antidepressants differentially affect expression of complexin I and II RNA in rat hippocampus.

Disturbance of synaptic transmission is currently viewed as an important pathophysiological mechanism and therapeutic target of mood disorders. Amongst other lines of evidence this theory is based on human post-mortem investigations showing differential expression of complexins. In order to discriminate between molecular correlates of the disease itself and effects of psychotropic drugs given to patients, we performed an animal trial using subchronic antidepressant treatment. Cohorts of adult male Sprague-Dawley rats were treated over a period of 14 days with intraperitoneal injections of either saline (0.9%, n=8), desipramine (15 mg/kg, n=7), fluoxetine (10 mg/kg, n=8), or tranylcypromine (10 mg/kg, n=5). Brain slices were used for in situ hybridizations with 35S labelled RNA probes of the genes complexin I, complexin II and syntaxin 1 A, the SNARE complex protein interacting with the complexins, and assessed semi-quantitatively for region-specific expression levels. Expression of complexin I was induced only in habenular nuclei after treatment with fluoxetine. In contrast, complexin II was significantly induced by desipramine and tranylcypromine, but not fluoxetine, in several brain regions. All treatment groups, but most significantly fluoxetine-treated animals, showed higher expression levels of syntaxin 1A. Antidepressants differentially affect expression levels of complexin I and more prominently complexin II and syntaxin 1A. The induction of complexin II and syntaxin 1A might strengthen the synaptic transmission at axo-dendritic or axo-axonal synapses. Previous post-mortem findings reporting on downregulation of complexins cannot be explained as mere effects of psychotropic drug treatment.

Adaptor Proteins, Vesicular Transport↗

PubMed2005

Mice with genetically altered glucocorticoid receptor expression show altered sensitivity for stress-induced depressive reactions.

Altered glucocorticoid receptor (GR) signaling is a postulated mechanism for the pathogenesis of major depression. To mimic the human situation of altered GR function claimed for depression, we generated mouse strains that underexpress or overexpress GR, but maintain the regulatory genetic context controlling the GR gene. To achieve this goal, we used the following: (1) GR-heterozygous mutant mice (GR+/-) with a 50% GR gene dose reduction, and (2) mice overexpressing GR by a yeast artificial chromosome resulting in a twofold gene dose elevation. GR+/- mice exhibit normal baseline behaviors but demonstrate increased helplessness after stress exposure, a behavioral correlate of depression in mice. Similar to depressed patients, GR+/- mice have a disinhibited hypothalamic-pituitary-adrenal (HPA) system and a pathological dexamethasone/corticotropin-releasing hormone test. Thus, they represent a murine depression model with good face and construct validity. Overexpression of GR in mice evokes reduced helplessness after stress exposure, and an enhanced HPA system feedback regulation. Therefore, they may represent a model for a stress-resistant strain. These mouse models can now be used to study biological changes underlying the pathogenesis of depressive disorders. As a first potential molecular correlate for such changes, we identified a downregulation of BDNF protein content in the hippocampus of GR+/- mice, which is in agreement with the so-called neurotrophin hypothesis of depression.

Animals↗

PubMed2005

Increased serum S100B in elderly, chronic schizophrenic patients: negative correlation with deficit symptoms.

In schizophrenia, elevations of serum and CSF S100B levels have been reported and related to state of the disease and negative symptoms. In elderly chronic schizophrenic inpatients with stable medication, S100B may be increased and correlated to psychopathology and neuropsychological deficits. We have measured serum levels of S100B in 41 elderly, chronic schizophrenic patients and 23 age- and gender-matched controls using an immunoluminometric assay. In patients, we assessed detailed psychopathology and neuropsychological performance and determined serum levels of haloperidol, clozapine and its two main metabolites desmethylclozapine and clozapine metabolite N-oxid by HPLC. S100B levels were increased in elderly chronic schizophrenic patients compared to healthy controls. In patients, levels were negatively correlated with deficit symptoms and positively with age. There were no significant differences of S100B between medication groups and no correlation with serum levels of antipsychotics or neuropsychological scores. Elevations of S100B in elderly chronic schizophrenic patients may be related to an active disease process lasting until old-age. Correlations point to the impact of S100B in neuroplasticity and ageing. Post-mortem studies should clarify the presence of altered S100B function in the brain and its relationship to neuroplastic or neurodegenerative processes.

Aged↗

PubMed2005

Stress models of depression: forming genetically vulnerable strains.

Among the most useful models for depressive disorders are those, which involve a stress induced change in behaviour. Learned helplessness is one such model and is induced through exposure to uncontrollable and unpredictable aversive events. Learned helplessness as induced in rats using foot shock is well characterized and has good face validity and predictive validity as a model of depression, including alterations in HPA axis activity and REM sleep characteristic of depression. The data concerning the validity will be briefly reviewed. The model can also be used to look at the role of genetics through selective breeding. These studies will be reviewed and the utility of the genetic strains for understanding the interaction of stress and affect will be examined. A second model of depression using exposure to chronic stress also has high face and predictive validity. A new form of this approach, recently described, also is suitable for the examination of genetic factors leading to depressive like behaviour and this will be presented.

Animals↗

PubMed2005

[Continuation ECT].

A renaissance of electroconvulsive therapy in psychiatry can be observed in Germany. Here, ECT was named as a first line therapy for treating psychotic depression, depressive stupor, schizoaffective psychoses with severe depressive symptoms. Suprisingly, ECT is most commonly not used as a continuation therapy after achieving acute remission. With rare exceptions, antidepressive medication is chosen for this purpose. The use of continuation ECT (cECT) and subsequent maintenance ECT (mECT) is not (or just marginally) mentioned in practice guidelines. In our case report we report a successful cECT and mECT of a geriatric patient with severe comorbidity. This case is exemplified with respect to recent guidelines and study results. Particularly suggestions for interval duration, total duration of treatment, effects on cognition and memory, comorbidity and comedication, and reflections on quality of life and costs were discussed. We would therefore recommend a broader use of this proven treatment tool for keeping major depressions in remission.

Aged↗

PubMed2005

Lithium and ECT--concurrent use still demands attention: three case reports.

Bipolar disorders as well as recurrent major depressive episodes can be most effectively treated with electroconvulsive therapy (ECT). Since continuation/maintenance ECT is not well established, prophylactic therapy in recurrent illnesses is more commonly carried out using antidepressive medication alone or more often in combination with lithium. In case of relapse the clinically important question of discontinuation of lithium versus the concurrent use of ECT and lithium may arise. The safety of concurrent use has also to be balanced when lithium treatment is started within an ECT course. Since recent studies have reported no negative interactions with concurrent use, we here report three cases (one case of a prolonged seizure, a serotonin syndrome and a focal seizure) of severe lithium-induced side effects while patients underwent ECT without complications and lithium serum levels were still subtherapeutic. Clinical consequences are discussed and disturbances of the blood brain barrier system as a speculative cause are hypothesized taking previous studies, animal studies and an additional reported clinical case into account.

Adult↗

PubMed2005

Genotype-phenotype studies in bipolar disorder showing association between the DAOA/G30 locus and persecutory delusions: a first step toward a molecular genetic classification of psychiatric phenotypes.

OBJECTIVE: The authors previously reported an association between the D-amino acid oxidase activator (DAOA)/G30 locus and both schizophrenia and bipolar affective disorder. Given the presumed role of DAOA/G30 in the neurochemistry of psychosis and its localization in a schizophrenia and bipolar affective disorder linkage region (13q34), it was hypothesized that the bipolar affective disorder finding would be mainly due to an association with psychotic features. METHOD: The marker/haplotype associations obtained in a subset of 173 bipolar affective disorder patients with psychotic features were similar to those in the overall patient group, suggesting that stratification on the basis of psychotic features in general might be too crude a procedure. The authors therefore tested whether confining caseness to specific psychotic features would improve detection of genotype-phenotype correlations. RESULTS: In a logistic regression, "persecutory delusions" were found to be the only significant explanatory variable for the DAOA/G30 risk genotype among 21 OPCRIT symptoms of psychosis. The authors therefore tested for association between DAOA/G30 and bipolar affective disorder in the 90 cases with a history of persecutory delusions. Whereas this subset showed strong association (odds ratio=1.83 for the best marker), the remaining larger sample of 165 patients with no such history did not differ from comparison subjects, suggesting that the association between DAOA/G30 and bipolar affective disorder is due to persecutory delusions. This was confirmed in an independent study of 294 bipolar affective disorder patients and 311 comparison subjects from Poland, in which an association between bipolar affective disorder and DAOA/G30 was only seen when case definition was restricted to cases with persecutory delusions. CONCLUSIONS: These data suggest that bipolar affective disorder with persecutory delusions constitutes a distinct subgroup of bipolar affective disorder that overlaps with schizophrenia.

Adult↗

PubMed2005

Further evidence for altered cerebellar neuronal integrity in schizophrenia.

OBJECTIVE: The authors' goal was to investigate the distribution of metabolites and voxel composition in the pons and three cerebellar subregions and compare metabolite integral values and differences in voxel composition between patients with schizophrenia and healthy subjects. METHOD: Proton magnetic resonance spectroscopic imaging was used to study the cerebellum and pons of 14 patients with schizophrenia and 14 healthy comparison subjects. RESULTS: The voxel composition was not significantly different between the groups, but the patients with schizophrenia had significantly lower N-acetylaspartate levels in the cerebellar cortex and vermis. CONCLUSIONS: The lower integral value of N-acetylaspartate in the cerebellar cortex and the vermis of patients with schizophrenia supports the theory of a dysfunctional corticocerebellar-thalamic-cortical circuit in schizophrenia.

Adult↗

PubMed2004

Voluntary alcohol intake in two rat lines selectively bred for learned helpless and non-helpless behavior.

RATIONALE: A high comorbidity between depression and alcoholism has been reported in several studies, but the mechanisms underlying this relationship remain unknown. OBJECTIVES: We tested whether learned helplessness in rats as a model for depression is associated with enhanced alcohol intake and relapse behavior. METHODS: Congenital learned helplessness (cLH) and congenital non-learned helplessness (cNLH) rats were selectively bred for differences in an escape paradigm. Sucrose preference was tested at the first hour of the dark phase. In order to study an association with alcohol drinking behavior, rats underwent a free-choice procedure with access to water, and 5% and 20% alcohol solutions for 6 weeks. After acquisition of alcohol drinking behavior, the alcohol deprivation effect (ADE) was assessed. Sensitivity to the sedative-hypnotic effect of alcohol was measured by loss of the righting reflex. RESULTS: cLH rats showed significantly lower preference for sucrose solutions during the second half hour of the dark phase than cNLH rats. Alcohol intake of male cLH rats was not significantly different from that of male cNLH rats. In contrast, cLH female rats consumed higher amounts of alcohol than female cNLH rats. The ADE was more pronounced in female animals, although the magnitude of the ADE was similar in both cNLH and cLH female rats. The time to regain the righting reflex was significantly higher in both male and female cLH rats than in cNLH rats. CONCLUSIONS: In summary, these data suggest that an inborn depressive-like behavior in female rats is associated with enhanced alcohol intake.

Alcohol Drinking↗

PubMed2004

Gene-environment interaction in hyperkinetic conduct disorder (HD + CD) as indicated by season of birth variations in dopamine receptor (DRD4) gene polymorphism.

Recently, an interaction between season of birth and the expression of candidate genes has been suggested. Season of birth variations in tryptophan hydroxylase (TPH), the serotonin transporter (5-HTTLPR) and the dopamine D4 receptor (DRD4) gene polymorphisms are different for affective disorders and schizophrenia. The DRD4 gene has been postulated as a candidate gene for attention-deficit-hyperactivity disorder (ADHD), equivalent to hyperkinetic disorder (HD). The seven-repeat long variant of this gene (DRD4*7) in comparison to the short repeat variants of the DRD4 gene polymorphism, has been found to be associated with ADHD. A seasonal pattern of birth has also been proposed for different subtypes of ADHD. Therefore, in a subgroup of children with HD and conduct disorder (CD) and in healthy controls, we investigated a possible association between the DRD4*7 allele and HD + CD in association with the season of birth. Supporting this hypothesis, we found an interaction between the seasons of birth and the expression of the DRD4 candidate gene in children with HD + CD as well as in controls, which differ significantly from each other. Depending on the season of birth, children carrying the DRD4*7R allele showed different relative risks for developing HD + CD.

Adolescent↗

PubMed2004

Neurogenesis and depression: etiology or epiphenomenon?

The concept that decreased neurogenesis might be the cause of depression is supported by the effects of stress on neurogenesis and the demonstration that neurogenesis seems to be necessary for antidepressant action. Data from the animal models tested to date show that decreasing the rate of neurogenesis does not lead to depressive behavior. Furthermore, evidence shows that an effective treatment for depression, transcranial magnetic stimulation, does not alter rates of neurogenesis. On the basis of these findings, it is suggested that neurogenesis might play a subtle role in depression but that it is not the primary factor in the final common pathway leading to depression.

Animals↗

PubMed2004

Reduced expression of brain-derived neurotrophic factor in mice deficient for pituitary adenylate cyclase activating polypeptide type-I-receptor.

In vitro pituitary adenylate cyclase activating polypeptide (PACAP) induces the expression of brain-derived neurotrophic factor (BDNF) via its specific receptor PAC1. Since BDNF has been implicated in learning paradigms and mice lacking functional PAC1 have deficits in hippocampus-dependent associative learning, we investigated whether PAC1 mutants show alterations in hippocampal expression of BDNF and its receptor TrkB. Semi-quantitative in situ-hybridization using exon-specific BDNF-probes revealed significantly reduced expression of the exon-III and exon-V-specific transcripts within the hippocampal CA3 region in PAC1-deficient mice. A similar trend was observed for the exon-I-specific transcript. The expression of the exon-III-specific transcript was also reduced within the dentate gyrus, while Trk B-expression did not differ between genotypes. Our data demonstrate that even in vivo PAC1-mediated signaling seems to play a pivotal role for the transcriptional regulation of BDNF.

Animals↗

PubMed2004

Mice with reduced brain-derived neurotrophic factor expression show decreased choline acetyltransferase activity, but regular brain monoamine levels and unaltered emotional behavior.

The "neurotrophin hypothesis" of depression predicts that depressive disorders in humans coincide with a decreased activity and/or expression of brain-derived neurotrophic factor (BDNF) in the brain. Therefore, we investigated whether mice with a reduced BDNF expression due to heterozygous gene disruption demonstrate depression-like neurochemical changes or behavioral symptoms. BNDF protein levels of adult BDNF(+/-) mice were reduced to about 60% in several brain areas investigated, including the hippocampus, frontal cortex, striatum, and hypothalamus. The content of monoamines (serotonin, norepinephrine, and dopamine) as well as of serotonin and dopamine degradation products was unchanged in these brain regions. By contrast, choline acetyltransferase activity was significantly reduced by 19% in the hippocampus of BDNF(+/-) mice, indicating that the cholinergic system of the basal forebrain is critically dependent on sufficient endogenous BDNF levels in adulthood. Moreover, BDNF(+/-) mice exhibited normal corticosterone and adrenocorticotropic hormone (ACTH) serum levels under baseline conditions and following immobilization stress. In a panel of behavioral tests investigating locomotor activity, exploration, anxiety, fear-associated learning, and behavioral despair, BDNF(+/-) mice were indistinguishable from wild-type littermates. Thus, a chronic reduction of BDNF protein content in adult mice is not sufficient to induce neurochemical or behavioral alterations that are reminiscent of depressive symptoms in humans.

Adrenocorticotropic Hormone↗