Thomas Schneider-Axmann

Hippocampal plasticity in response to exercise in schizophrenia.

CONTEXT Hippocampal volume is lower than expected in patients with schizophrenia; however, whether this represents a fixed deficit is uncertain. Exercise is a stimulus to hippocampal plasticity. OBJECTIVE To determine whether hippocampal volume would increase with exercise in humans and whether this effect would be related to improved aerobic fitness. DESIGN Randomized controlled study. SETTING Patients attending a day hospital program or an outpatient clinic. PATIENTS OR OTHER PARTICIPANTS Male patients with chronic schizophrenia and matched healthy subjects. INTERVENTIONS Aerobic exercise training (cycling) and playing table football (control group) for a period of 3 months. MAIN OUTCOME MEASURES Magnetic resonance imaging of the hippocampus. Secondary outcome measures were magnetic resonance spectroscopy, neuropsychological (Rey Auditory Verbal Learning Test, Corsi block-tapping test), and clinical (Positive and Negative Syndrome Scale) features. RESULTS Following exercise training, relative hippocampal volume increased significantly in patients (12%) and healthy subjects (16%), with no change in the nonexercise group of patients (-1%). Changes in hippocampal volume in the exercise group were correlated with improvements in aerobic fitness measured by change in maximum oxygen consumption (r = 0.71; P = .003). In the schizophrenia exercise group (but not the controls), change in hippocampal volume was associated with a 35% increase in the N-acetylaspartate to creatine ratio in the hippocampus. Finally, improvement in test scores for short-term memory in the combined exercise and nonexercise schizophrenia group was correlated with change in hippocampal volume (r = 0.51; P < .05). CONCLUSION These results indicate that in both healthy subjects and patients with schizophrenia hippocampal volume is plastic in response to aerobic exercise.

Dysfunctional long-term potentiation-like plasticity in schizophrenia revealed by transcranial direct current stimulation

Neural and cortical plasticity represent the ability of the brain to reorganize its function in response to a challenge. Plasticity involves changing synaptic activity and connectivity. Long-term-potentiation is one important mechanism underlying these synaptic changes. Disturbed neuronal plasticity is considered to be part of the pathophysiology of schizophrenia and has been linked to the different clinical features of this severe illness. The aim of the present study was to investigate nonfocal cortical plasticity and cortical excitability in recent-onset and multi-episode schizophrenia compared with healthy subjects. Nonfocal cortical plasticity can be induced in the motor cortex of healthy subjects with anodal transcranial direct current stimulation. Animal and human research indicates that this long-term-potentiation-like plasticity is glutamate-dependent and that these plasticity shifts can last for several hours. Transcranial direct current stimulation-induced plasticity was monitored by transcranial magnetic stimulation-generated motor evoked potentials. Well-characterized transcranial magnetic stimulation protocols were applied to determine the physiological basis of plasticity changes. Multi-episode schizophrenia patients showed significantly reduced long-term-potentiation-like plasticity compared to recent-onset schizophrenia patients and healthy controls. All schizophrenia patients demonstrated reduced cortical inhibition. Our results indicate that the long-term-potentiation-like plasticity deficit in schizophrenia patients is related to the disease course. Disturbances of N-methyl-d-aspartate, gamma-aminobutyric acid and dopamine receptors may account for this plasticity deficit. LTP-like plasticity deficits might be related to disturbed information processing in schizophrenia patients.

Stereologic investigation of the posterior part of the hippocampus in schizophrenia

Structural magnetic resonance imaging and postmortem studies showed volume loss in the hippocampus in schizophrenia. The noted tissue reduction in the posterior section suggests that some cellular subfractions within this structure might be reduced in schizophrenia. To address this, we investigated numbers and densities of neurons, oligodendrocytes and astrocytes in the posterior hippocampal subregions in postmortem brains from ten patients with schizophrenia and ten matched controls using design-based stereology performed on Nissl-stained sections. Compared to the controls, the patients with schizophrenia showed a significant decrease in the mean number of oligodendrocytes in the left and right CA4. This is the first finding of reduced numbers of oligodendrocytes in CA4 of the posterior part of the hippocampus in schizophrenia. Our results are in line with earlier findings in the literature concerning decreased numbers of oligodendrocytes in the prefrontal cortex in schizophrenia. Our results may indicate disturbed connectivity of the CA4 of the posterior part of the hippocampus in schizophrenia and, thus, contribute to the growing number of studies showing the involvement of posterior hippocampal pathology in the pathophysiology of schizophrenia.

Reduced cortical inhibition in first-episode schizophrenia

Disturbances in cortico-cortical and cortico-subcortical circuits in schizophrenia have been described by previous neuroimaging and electrophysiological studies. Transcranial magnetic stimulation (TMS) provides a neurophysiological technique for the measurement of cortical excitability, especially of the motoneural system. Previous studies using paired-pulse TMS to investigate short-interval cortical inhibition (SICI) and intracortical facilitation (ICF), mainly involving chronic schizophrenia patients, have been inconsistent and only one study in first-episode patients has been conducted so far. We assessed SICI (interstimulus interval, ISI, 3 milliseconds, ms) and ICF (ISI 7 ms) in 29 first-episode schizophrenia patients (FE-SZ) with limited exposure to antipsychotic treatment against measures of 28 healthy controls (HC). Amplitudes of motor evoked potentials (MEPs) were measured from the left and right first dorsal interosseus muscle (FDI). The conditioning stimulus was set at 80% intensity of resting motor threshold (RMT) and the test stimulus (TS) was set at an intensity that produced an MEP amplitude of about 1 mV. For SICI conditions, FE-SZ demonstrated significantly higher MEP amplitudes from left motor cortex (right FDI) compared to HC, and for MEPs from right motor cortex (left FDI) a similar trend was observable (FE-SZ 41% vs. HC 21% of TS, p=0.017 for left motor cortex, and FE-SZ 59% vs. HC 31% of TS, p=0.059 for right motor cortex; Mann-Whitney U-test). No significant difference in MEPs could be detected for ICF on either hemisphere. In addition, there was no difference in left and right RMT comparing patients and control subjects. Our result of a reduced SICI in a large sample of well characterized first-episode schizophrenia patients suggests that a GABAergic deficit may be involved in schizophrenic pathophysiology, already early in the disease course, supporting the intracortical dysconnectivity hypothesis.

Cognitive impairment of executive function as a core symptom of schizophrenia

Cognitive dysfunction is a common finding in schizophrenia. Nevertheless the specific pattern of neuropsychological impairment in schizophrenia compared to other severe mental illnesses has not been intensively studied. Twenty-four patients with schizophrenia belonging to different stages of the disease (11 first-episode patients, 13 patients with multiple episodes), 18 patients with bipolar disorder and 23 healthy control subjects underwent standardized neuropsychological assessment. Statistical analysis of covariance (ANCOVA) demonstrated that, compared to control subjects, patients with schizophrenia performed significantly worse in the trail-making test (P = 0.012), verbal fluency (category letter, P = 0.004), verbal learning/memory (P = 0.005), and the Wisconsin Card Sorting Test (WCST) (P = 0.004 for administered trials; P = 0.025 for perseverative responses, T value) indicating significant deficits in attention and psychomotor performance, and in particular in verbal working memory and cognitive flexibility for schizophrenic patients. A significant difference between schizophrenic and bipolar patients was found only in the WCST. Schizophrenic patients made significantly more perseverative responses (P = 0.002, ANCOVA), indicating a more pronounced and specific deficit in cognitive flexibility and frontally based executive function. In conclusion, these results may suggest a cognitive endophenotype in schizophrenia and underline the role of the prefrontal cortex in schizophrenic pathophysiology.

Sex-specific proteome differences in the anterior cingulate cortex of schizophrenia

Molecular knowledge about schizophrenia--a psychotic, multifactorial mental disorder that affects about 1% of the population worldwide--is limited and no diagnostic biomarkers are available. The comparative proteome analysis of human brain tissue from patients with schizophrenia and healthy controls may supply useful information on both the disorder and potential biomarkers candidates. Here, we present the results of our investigation of anterior cingulate cortex samples from 11 patients and 8 controls. We used two-dimensional gel electrophoresis combined with mass spectrometry, the most traditional approach to studying the proteome, to reveal the differentially expressed proteins in schizophrenia, and western blot to validate some interesting potential biomarker candidates such as dihydropyrimidinase-like 2 and alpha-crystallin, involved in a number of processes such as cytoskeleton arrangement. Most interesting is that our additional sex-specific proteome comparison showed that male and female schizophrenia patients present different patterns of proteome regulation, for instance for the proteins aldolase C, an enzyme of glycolysis, and glutamine synthetase that synthesizes glutamine, responsible for maintain glutamate levels. Our findings not only support previous findings but also indicate areas that warrant further study in schizophrenia.

Regulation of immune-modulatory genes in left superior temporal cortex of schizophrenia patients: a genome-wide microarray study

Abstract Objectives. The role of neuroinflammation in schizophrenia has been an issue for long time. There are reports supporting the hypothesis of ongoing inflammation and others denying it. This may be partly ascribed to the origin of the materials (CSF, blood, brain tissue) or to the genes selected for the respective studies. Moreover, in some locations, inflammatory genes may be up-regulated, others may be down-regulated. Methods. Genome-wide microarrays have been used for expression profiling in post-mortem brains of schizophrenia patients. Array data have been analyzed by gene set enrichment analysis (GSEA) and further confirmed with selected genes by real-time PCR. Results. In Brodman Area 22 of left superior temporal cortex, at least 70 genes (19%) out of 369 down-regulated genes (P < 0.05) belonged to the immune system. 23 from those 70 genes were randomly selected for real-time PCR. Six reached significance level at P < 0.05. Conclusions. The present data support a brain-specific view of the role immune-modulatory genes may play in the left superior temporal cortex in schizophrenia, because immune functions in the patients are not disturbed. In keeping with comparable, previous studies supporting the notion that schizophrenia is a disease of the synapse, we hypothesize that dysregulation of immune-related genes modifies synaptic functions and stability in this region.

Accumulation of intraneuronal Aβ correlates with ApoE4 genotype

In contrast to extracellular plaque and intracellular tangle pathology, the presence and relevance of intraneuronal Aβ in Alzheimer’s disease (AD) is still a matter of debate. Human brain tissue offers technical challenges such as post-mortem delay and uneven or prolonged tissue fixation that might affect immunohistochemical staining. In addition, previous studies on intracellular Aβ accumulation in human brain often used antibodies targeting the C-terminus of Aβ and differed strongly in the pretreatments used. To overcome these inconsistencies, we performed extensive parametrical testing using a highly specific N-terminal Aβ antibody detecting the aspartate at position 1, before developing an optimal staining protocol for intraneuronal Aβ detection in paraffin-embedded sections from AD patients. To rule out that this antibody also detects the β-cleaved APP C-terminal fragment (β-CTF, C99) bearing the same epitope, paraffin-sections of transgenic mice overexpressing the C99-fragment were stained without any evidence for cross-reactivity in our staining protocol. The staining intensity of intraneuronal Aβ in cortex and hippocampal tissue of 10 controls and 20 sporadic AD cases was then correlated to patient data including sex, Braak stage, plaque load, and apolipoprotein E (ApoE) genotype. In particular, the presence of one or two ApoE4 alleles strongly correlated with an increased accumulation of intraneuronal Aβ peptides. Given that ApoE4 is a major genetic risk factor for AD and is involved in neuronal cholesterol transport, it is tempting to speculate that perturbed intracellular trafficking is involved in the increased intraneuronal Aβ aggregation in AD.

Deficient Inhibitory Cortical Networks in Antipsychotic-Naive Subjects at Risk of Developing First-Episode Psychosis and First-Episode Schizophrenia Patients: A Cross-Sectional Study

BACKGROUND Impaired cortical inhibition is a well-established finding in schizophrenia patients and has been linked to dysfunctional gamma-aminobutyric acid (GABA)ergic transmission. However, there have been no previous studies investigating cortical excitability with particular regard to intracortical inhibitory networks in antipsychotic-naive subjects at risk of developing first-episode psychosis. METHODS A total of 18 subjects at risk, 18 first-episode schizophrenia patients, and 18 healthy control subjects were included in this study. Transcranial magnetic stimulation over the left primary motor cortex was used to determine short-latency intracortical inhibition, intracortical facilitation, and the contralateral silent period (CSP). Short-latency intracortical inhibition can be considered as a parameter of GABA type A (GABA(A))-mediated inhibition and it has been proposed that CSP can test GABA type B (GABA(B))-mediated inhibitory intracortical networks. RESULTS Subjects at risk and first-episode patients showed a reduced short-latency intracortical inhibition compared with healthy control subjects, suggesting reduced GABA(A)-mediated inhibition. First-episode patients had a prolonged CSP duration compared with the other two groups, implying a GABA(B) imbalance only in patients with full-blown psychosis. Analyses did not reveal group differences for intracortical facilitation. CONCLUSIONS These results indicate specific alterations in inhibitory cortical networks in subjects at risk and in first-episode patients. It appears that there is already a cortical inhibitory deficit in at-risk individuals. These results suggest a possible GABA(A) dysfunction early in the disease course, whereas alterations in GABA(B) functionality seem to occur later in the diseases progression. Future longitudinal studies will be needed to clarify this inhibitory deficit and its relation to the transition to psychosis.

Neuregulin-1 haplotype HAPICE is associated with lower hippocampal volumes in schizophrenic patients and in non-affected family members

The neuregulin-1 (NRG1) gene on chromosome 8p has been suggested as a potential susceptibility gene for schizophrenia. The exact way in which genetic variation in NRG1 might impact on this susceptibility for the disorder is a focus of current research. The present study aimed at investigating the possible relationship between a putative NRG1 at-risk haplotype (HAP(ICE)) and hippocampal volumes in schizophrenic patients and their healthy first-degree relatives. We genotyped 30 schizophrenic patients and 52 non-affected family members with regard to the presence or absence of the NRG1 haplotype HAP(ICE). Structural magnetic resonance imaging was used to determine hippocampal brain volumes in the same subjects. Patients and relatives carrying haplotype HAP(ICE) both had smaller relative hippocampal volumes as compared to patients or relatives who did not carry this haplotype. These findings provide first direct evidence for a link between NRG1 genetic variation and hippocampal volume reductions in schizophrenic patients and non-affected relatives. This preliminary evidence may help to guide further research into the pathophysiological pathways that underlie this genetic susceptibility for schizophrenia.