Georg Winterer

Genes, dopamine and cortical signal-to-noise ratio in schizophrenia

A large body of phenomenological evidence implicates abnormal connectivity of brain macrocircuitry and microcircuitry in schizophrenia. Recent discoveries of susceptibility genes for schizophrenia have zeroed in on the synaptic signaling machinery of cortical microcircuits as fundamental to disease causation and have militated for further revision of the role of dopamine in this illness. Dopamine, long implicated in psychosis and in antipsychotic drug effects, is crucial in optimizing signal-to-noise ratio of local cortical microcircuits. This action of dopamine is achieved principally by D1- and D2-receptor-mediated effects on pyramidal and local circuit neurons, which mediate neuronal excitability and recurrent inhibition and thus contribute to the stability of cortical representations of external and internal stimuli. In schizophrenia, an abnormal cortical dopamine D1/D2 activation ratio - in concert with, and in part related to, altered GABA and glutamate transmission - appears to interfere crucially with this process.

Ultrastructural Hippocampal and White Matter Alterations in Mild Cognitive Impairment: A Diffusion Tensor Imaging Study

Mild cognitive impairment (MCI) is considered to be a transitional stage between normal aging and dementia. In Alzheimer’s disease (AD), white matter structural pathology is due to Wallerian degeneration and central angiopathy. However, in MCI patients, the presence and extent of white matter alterations as a possible correlate of impaired memory function and as predictor of subsequent progression to AD is not clarified yet. Diffusion tensor imaging (DTI) reveals the ultrastructural integrity of cerebral white matter tracts. Therefore, it could detect pathological processes that modify tissue integrity in patients with MCI. In our prospective study, conventional and diffusion tensor MR scans were obtained from 14 patients with MCI, 19 patients with AD, and 10 healthy controls. Mean diffusivity (MD) and fractional anisotropy (FA) were measured in temporal, frontal, parietal and occipital white matter regions as well as in the corpus callosum (genu and splenium) and the hippocampus. MCI patients showed higher MD values in the left centrum semiovale (p = 0.013; right: p = 0.026), in the left temporal (p = 0.006), the right temporal (p = 0.014) and the left hippocampal (p = 0.002) region as compared to the control group. FA values of MCI patients and controls did not differ significantly in any region. Compared to controls, AD patients had increased MD values in the left centrum semiovale (p = 0.012), the left parietal (p = 0.001), the right parietal (p = 0.028), the left temporal (p = 0.018), the right temporal (p = 0.011) and the left hippocampal region (p = 0.002). Decreased FA values were measured in the left temporal area (p = 0.017) and in the left hippocampus (p = 0.031) in AD patients compared to controls. FA and MD values did not differ significantly between AD and MCI patients. Elevated MD values indicating brain tissue alterations in MCI patients were found in regions that are typically involved in early changes due to AD, particularly the left hippocampus. The sensitivity of distinguishing MCI patients from controls was 71.4% (with a specificity set at 80%). Therefore, the DTI technique validates the MCI concept, and diffusion tensor MR measurement can be a helpful tool to quantify MCI pathology in vivo.

Computational models of schizophrenia and dopamine modulation in the prefrontal cortex

Computational neuroscience models can be used to understand the diminished stability and noisy neurodynamical behaviour of prefrontal cortex networks in schizophrenia. These neurodynamical properties can be captured by simulated neural networks with randomly spiking neurons that introduce noise into the system and produce trial-by-trial variation of postsynaptic potentials. Theoretical and experimental studies have aimed to understand schizophrenia in relation to noise and signal-to-noise ratio, which are promising concepts for understanding the symptoms that characterize this heterogeneous illness. Simulations of biologically realistic neural networks show how the functioning of NMDA (N-methyl-D-aspartate), GABA (g-aminobutyric acid) and dopamine receptors is connected to the concepts of noise and variability, and to related neurophysiological findings and clinical symptoms in schizophrenia.

Neurophysiological biomarkers for drug development in schizophrenia

Schizophrenia represents a pervasive deficit in brain function, leading to hallucinations and delusions, social withdrawal and a decline in cognitive performance. As the underlying genetic and neuronal abnormalities in schizophrenia are largely unknown, it is challenging to measure the severity of its symptoms objectively, or to design and evaluate psychotherapeutic interventions. Recent advances in neurophysiological techniques provide new opportunities to measure abnormal brain functions in patients with schizophrenia and to compare these with drug-induced alterations. Moreover, many of these neurophysiological processes are phylogenetically conserved and can be modelled in preclinical studies, offering unique opportunities for use as translational biomarkers in schizophrenia drug discovery.

Reduced oscillatory gamma-band responses in unmedicated schizophrenic patients indicate impaired frontal network processing

OBJECTIVE Integration of sensory information by cortical network binding appears to be crucially involved in target detection. Studies in schizophrenia using functional and diffusion tensor neuroimaging, event-related potentials and EEG coherence indicate an impairment of cortical network coupling in this disorder. Previous electrophysiological investigations in animals and humans suggested that gamma activity (oscillations at around 40 Hz) is essential for cortical network binding. Studies in medicated schizophrenia provide evidence for a reduced gamma activity in the context of auditory stimulus processing. This is the first investigation of oscillatory activations in the gamma-band in an auditory oddball paradigm in unmedicated schizophrenic patients. METHODS EEG gamma-band responses (GBRs) of 15 drug-free schizophrenic patients and 15 age- and gender-matched healthy controls were compared. A wavelet transform based on Morlet wavelets was employed for the calculation of oscillatory GBRs. RESULTS In response to standard stimuli, early evoked GBRs (20-100 ms), which are supposed to reflect auditory cortex activation, did not show significant group differences. However, schizophrenic patients showed reduced evoked GBRs in a late latency range (220-350 ms), particularly after target stimuli. This deficit occurred over right frontal scalp regions. Furthermore, significant correlations were observed between oscillatory GBRs and clinical parameters in schizophrenic patients. CONCLUSIONS The results are consistent with a relative preserved stimulus processing in the auditory cortex as reflected by the early GBR. The reduced late GBR is compatible with an abnormal interaction within a frontal lobe network, as was postulated by previous neuroimaging studies. SIGNIFICANCE The present study provides evidence for disturbed processing within frontal cortical regions in unmedicated schizophrenic patients as indicated by reduced evoked EEG GBRs.

Association of a regulatory polymorphism in the promoter region of the monoamine oxidase A gene with antisocial alcoholism

We analyzed a novel functional 30-bp repeat polymorphism in the promoter region of the X-chromosomal monoamine oxidase A gene (MAOA) to test whether length variation of the repeat polymorphism contributes to variation in the individual vulnerability to antisocial behavior and liability to alcohol dependence. The repeat number (3-5) of the MAOA polymorphism was assessed in 488 male subjects of German descent, a sample comprising 185 psychiatrically screened control subjects and 303 alcohol-dependent subjects including 59 alcoholics with antisocial personality disorder. The frequency of the low-activity 3-repeat allele was significantly increased in 59 antisocial alcoholics compared to 185 control subjects (51 vs. 35%; P = 0.031) and to 244 alcoholics without antisocial personality disorder (51 vs. 32%; P = 0.008), respectively. We found no significant difference in the frequency of the 3-repeat allele between 244 alcoholics without an antisocial personality disorder and the control subjects. Our findings suggest that the low-activity 3-repeat allele of the MAOA promoter polymorphism confers increased susceptibility to antisocial behavior rather than alcohol dependence per se in alcohol-dependent males.

Association of the G1947A COMT (Val108/158Met) gene polymorphism with prefrontal P300 during information processing

BACKGROUND A common functional polymorphism, G1947A, of the catechol-O-methyltransferase (COMT) enzyme has gained interest in schizophrenia research because of its critical involvement in cortical dopamine catabolism and frontal lobe function. An assumed mechanism of dopamine is the reduction of noise in prefrontal neural networks during information processing. Therefore, the hypothesis was tested whether a variation of the COMT genotype is associated with prefrontal noise, which is in part reflected by the frontal P300 amplitude. It was predicted that homozygous Met allele carriers have a lower frontal P300 amplitude. METHODS The P300 component (auditory oddball) was recorded in 49 schizophrenic patients and 170 healthy control subjects. Three single nucleotide polymorphisms (SNPs) of the COMT gene (G1947A, C1883G, and G1243A) were investigated. RESULTS We observed a significant effect of G1947A COMT genotype on frontal P300 amplitude, with evidence for a genotype x diagnosis interaction. Lower frontal P300 amplitudes occurred in homozygous carriers of the Met allele, particularly in schizophrenic patients. CONCLUSIONS The association of the frontal P300 amplitude with the G1947A COMT genotype further emphasizes the functional role of this SNP. As the finding was mainly observed in schizophrenic patients, this may indicate that additional factors are required to interact with COMT genotype to affect prefrontal function. The smaller frontal P300 amplitude in Met carriers suggests that the amount of noise in prefrontal neural networks during information processing might be in part under genetic control, which is mediated by dopamine.

Reduced Event-Related Current Density in the Anterior Cingulate Cortex in Schizophrenia

There is good evidence from neuroanatomic postmortem and functional imaging studies that dysfunction of the anterior cingulate cortex plays a prominent role in the pathophysiology of schizophrenia. So far, no electrophysiological localization study has been performed to investigate this deficit. We investigated 18 drug-free schizophrenic patients and 25 normal subjects with an auditory choice reaction task and measured event-related activity with 19 electrodes. Estimation of the current source density distribution in Talairach space was performed with low-resolution electromagnetic tomography (LORETA). In normals, we could differentiate between an early event-related potential peak of the N1 (90-100 ms) and a later N1 peak (120-130 ms). Subsequent current-density LORETA analysis in Talairach space showed increased activity in the auditory cortex area during the first N1 peak and increased activity in the anterior cingulate gyrus during the second N1 peak. No activation difference was observed in the auditory cortex between normals and patients with schizophrenia. However, schizophrenics showed significantly less anterior cingulate gyrus activation and slowed reaction times. Our results confirm previous findings of an electrical source in the anterior cingulate and an anterior cingulate dysfunction in schizophrenics. Our data also suggest that anterior cingulate function in schizophrenics is disturbed at a relatively early time point in the information-processing stream (100-140 ms poststimulus).

Schizophrenia: reduced signal-to-noise ratio and impaired phase-locking during information processing.

OBJECTIVE This study was performed in order to clarify the mechanisms which underlie the reduced signal-to-noise of event-related potentials in schizophrenic patients. Specifically, we wanted to find out, whether it is reduced activation and/or synchronization (phase-locking) in specific frequency bands of the ongoing EEG which is related to the decreased signal amplitude and signal-to-noise ratio in schizophrenics. METHODS We investigated 41 unmedicated schizophrenics (10 of them drug-naïve) and compared them with healthy control subjects (n = 233) as well as unmedicated subjects with schizotypal personality (n = 21), who were considered to be high-risk subjects for schizophrenia, and unmedicated depressive patients (n = 71). We measured event-related activity during an acoustical choice reaction paradigm and calculated the signal-to-noise ratio, signal power and noise for a time interval of 50-200 ms after stimulus presentation. Signal-to-noise ratio was calculated from the power of the averaged trials (signal power) divided by the mean power of the single trials minus the power of the average (noise power). Also, we performed a frequency analysis of the pre- and poststimulus EEG based on a factor analytical approach. Group comparisons were performed with ANCOVA. RESULTS As expected, a decreased signal-to-noise ratio of evoked activity was found in the schizophrenic and a non-significant trend in the schizotypal subjects and the depressive patients. We were able to show that the observed decrease is due to a reduced signal power and an increase of absolute noise power. Frequency analysis of the evoked activity revealed that normals, schizophrenics schizotypal subjects and depressive patients increased theta/delta activity between pre- and poststimulus interval to a similar extend. However, this theta/delta-augmentation does not correlate with signal power in schizophrenics. Also, normals and depressive subjects augment coherence between both temporal lobes during information processing, which is not found in schizophrenics and schizotypal subjects. In contrast, these two groups augment frontal lobe coherence, which goes along with an increase of noise. CONCLUSIONS Reduced stimulus-induced phase-locking and bitemporal coherence of cortically evoked activity but not a failure to activate the cortex may be responsible for the observed low signal-to-noise ratio during information processing in schizophrenics. Accordingly, schizophrenics increase noise after stimulus presentation instead of building up a signal. This is discussed in the framework of the theory of stochastic resonance.

Smoking, quitting, and psychiatric disease: a review.

Tobacco smoking among patients with psychiatric disease is more common than in the general population, due to complex neurobiological, psychological, and pharmacotherapeutic mechanisms. Nicotine dependence exposes smokers with co-occurring mental illness to increased risks of smoking-related morbidity, mortality, and to detrimental impacts on their quality of life. The neurobiological and psychosocial links to smoking appear stronger in certain comorbidities, notably depression and schizophrenia. Through its action on the cholinergic system, nicotine may have certain beneficial effects across a range of mental health domains in these patients, including improved concentration and cognition, relief of stress and depressive affect, and feeling pleasurable sensations. Despite the availability of effective smoking cessation pharmacotherapies and psychosocial interventions, as well as increasing evidence that individuals with psychiatric disorders are motivated to quit, nicotine dependence remains an undertreated and under-recognized problem within this patient population. Evidence suggests that provision of flexible and individualized treatment programs may be successful. Furthermore, the complicated relationship observed between nicotine dependence, nicotine withdrawal symptoms, and mental illness necessitates integration of close monitoring in any successful smoking cessation program.