Elvira Fischer

Effect of N-Acetyl Cysteine on Oxidative DNA Damage and the Frequency of DNA Deletions in Atm-Deficient Mice

Ataxia telangiectasia (AT) is a hereditary human disorder resulting in a wide variety of clinical manifestations, including progressive neurodegeneration, immunodeficiency, and high incidence of lymphoid tumors. Cells from patients with AT show genetic instability, hypersensitivity to radiation, and a continuous state of oxidative stress. Oxidative stress and genetic instability, including DNA deletions, are involved in carcinogenesis. We examined the effect of dietary supplementation with the thiol-containing antioxidant N-acetyl-l-cysteine (NAC) on levels of oxidative DNA damage and the frequency of DNA deletions in Atm-deficient (AT-mutated) mice. We confirmed that Atm-deficient mice display an increased frequency of DNA deletions (Bishop et al., Cancer Res 2000;60:395). Furthermore, we found that Atm-deficient mice have significantly increased levels of 8-OH deoxyguanosine, an indication of oxidative DNA damage. Dietary supplementation with NAC significantly reduced 8-OH deoxyguanosine level and the frequency of DNA deletions in Atm-deficient mice. These levels were similar to the levels in wild-type mice. Our findings demonstrate that NAC counteracts genetic instability and suggest that genetic instability may be a consequence of oxidative stress in Atm-deficient mice.

Visual Motion Responses in the Posterior Cingulate Sulcus: A Comparison to V5/MT and MST

Motion processing regions apart from V5+/MT+ are still relatively poorly understood. Here, we used functional magnetic resonance imaging to perform a detailed functional analysis of the recently described cingulate sulcus visual area (CSv) in the dorsal posterior cingulate cortex. We used distinct types of visual motion stimuli to compare CSv with V5/MT and MST, including a visual pursuit paradigm. Both V5/MT and MST preferred 3D flow over 2D planar motion, responded less yet substantially to random motion, had a strong preference for contralateral versus ipsilateral stimulation, and responded nearly equally to contralateral and to full-field stimuli. In contrast, CSv had a pronounced preference to 2D planar motion over 3D flow, did not respond to random motion, had a weak and nonsignificant lateralization that was significantly smaller than that of MST, and strongly preferred full-field over contralateral stimuli. In addition, CSv had a better capability to integrate eye movements with retinal motion compared with V5/MT and MST. CSv thus differs from V5+/MT+ by its unique preference to full-field, coherent, and planar motion cues. These results place CSv in a good position to process visual cues related to self-induced motion, in particular those associated to eye or lateral head movements.

Color and shape interactions in the recognition of natural scenes by human and monkey observers

Trichromatic color vision is a fundamental aspect of the visual system shared by humans and non-human primates. In human observers, color has been shown to facilitate object identification. However, little is known about the role that color plays in higher level vision of non-human primates. Here, we addressed this question and studied the interaction between luminance- and color-based structural information for the recognition of natural scenes. We present psychophysical data showing that both monkey and human observers equally profited from color when recognizing natural scenes, and they were equally impaired when scenes were manipulated using colored noise. This effect was most prominent for degraded image conditions. By using a specific procedure for stimulus degradation, we found that the improvement as well as the impairment in visual memory performance is due to contribution of image color independent of luminance-based object information. Our results demonstrate that humans as well as non-human primates exploit their sensory ability of color vision to achieve higher performance in visual recognition tasks especially when shape features are degraded.

Attention reorganizes connectivity across networks in a frequency specific manner

ABSTRACT Attention allows our brain to focus its limited resources on a given task. It does so by selective modulation of neural activity and of functional connectivity (FC) across brain‐wide networks. While there is extensive literature on activity changes, surprisingly few studies examined brain‐wide FC modulations that can be cleanly attributed to attention compared to matched visual processing. In contrast to prior approaches, we used an ultra‐long trial design that avoided transients from trial onsets, included slow fluctuations (<0.1 Hz) that carry important information on FC, and allowed for frequency‐segregated analyses. We found that FC derived from long blocks had a nearly two‐fold higher gain compared to FC derived from traditional (short) block designs. Second, attention enhanced intrinsic (negative or positive) correlations across networks, such as between the default‐mode network (DMN), the dorsal attention network (DAN), and the visual system (VIS). In contrast attention de‐correlated the intrinsically correlated visual regions. Third, the de‐correlation within VIS was driven primarily by high frequencies, whereas the increase in DAN‐VIS predominantly by low frequencies. These results pinpoint two fundamentally distinct effects of attention on connectivity. Information flow increases between distinct large‐scale networks, and de‐correlation within sensory cortex indicates decreased redundancy. HIGHLIGHTSAttention paradigm with ultra‐long trials of 2 min and matched vision control.Ultra‐long trials increased connectivity two‐fold compared to 20 s trials.Attention, compared to matched visual stimulation, de‐correlated visual cortex.Visual de‐correlation mediated by high frequencies, other connections by all bands.Results suggest reorganization of connections by attention is frequency specific.

The Danish 22q11 research initiative.

BackgroundNeurodevelopmental brain disorders such as schizophrenia, autism and attention deficit hyperactivity disorder are complex disorders with heterogeneous etiologies. Schizophrenia and autism are difficult to treat and often cause major individual suffering largely owing to our limited understanding of the disease biology. Thus our understanding of the biological pathogenesis needs to be substantiated to enable development of more targeted treatment options with improved efficacy. Insights into the pre-morbid disease dynamics, the morbid condition and the underlying biological disease mechanisms may come from studies of subjects with homogenous etiologies. Breakthroughs in psychiatric genetics have shown that several genetic anomalies predispose for neurodevelopmental brain disorders. We have established a Danish research initiative to study the common microdeletion at chromosome 22q11.2, which is one of the genetic anomalies that confer high risk of schizophrenia, autism and attention deficit hyperactivity disorder.Methods/designThe study applies a “cause-to-outcome” strategy to identify pre-morbid pathogenesis and underlying biological disease mechanisms of psychosis and secondarily the morbid condition of autism and attention deficit hyperactivity disorder. We use a population based epidemiological design to inform on disease prevalence, environmental risk factors and familial disposition for mental health disorders and a case control study design to map the functional effects across behavioral and neurophysiological traits of the 22q11 deletion in a recruited sample of Danish individuals.DiscussionIdentification of predictive pre-morbid clinical, cognitive, functional and structural brain alterations in 22q11 deletion carriers may alter current clinical practice from symptomatic therapy of manifest mental illness into early intervention strategies, which may also be applicable to at risk subjects without known etiology. Hopefully new insights into the biological disease mechanisms, which are mandatory for novel drug developments, can improve the outcome of the pharmacological interventions in psychiatry.

Altered auditory processing and effective connectivity in 22q11.2 deletion syndrome

22q11.2 deletion syndrome (22q11.2DS) is one of the most common copy number variants and confers a markedly increased risk for schizophrenia. As such, 22q11.2DS is a homogeneous genetic liability model which enables studies to delineate functional abnormalities that may precede disease onset. Mismatch negativity (MMN), a brain marker of change detection, is reduced in people with schizophrenia compared to healthy controls. Using dynamic causal modelling (DCM), previous studies showed that top-down effective connectivity linking the frontal and temporal cortex is reduced in schizophrenia relative to healthy controls in MMN tasks. In the search for early risk-markers for schizophrenia we investigated the neural basis of change detection in a group with 22q11.2DS. We recorded high-density EEG from 19 young non-psychotic 22q11.2 deletion carriers, as well as from 27 healthy non-carriers with comparable age distribution and sex ratio, while they listened to a sequence of sounds arranged in a roving oddball paradigm. Despite finding no significant reduction in the MMN responses, whole-scalp spatiotemporal analysis of responses to the tones revealed a greater fronto-temporal N1 component in the 22q11.2 deletion carriers. DCM showed reduced intrinsic connection within right primary auditory cortex as well as in the top-down, connection from the right inferior frontal gyrus to right superior temporal gyrus for 22q11.2 deletion carriers although not surviving correction for multiple comparison. We discuss these findings in terms of reduced adaptation and a general increased sensitivity to tones in 22q11.2DS.

Individuals with 22q11.2 deletion syndrome show intact prediction but reduced adaptation in responses to repeated sounds: evidence from Bayesian mapping

Background One of the most common copy number variants, the 22q11.2 microdeletion, confers an increased risk for schizophrenia. Since schizophrenia has been associated with an aberrant neural response to repeated stimuli through both reduced adaptation and prediction, we here hypothesized that this may also be the case in nonpsychotic individuals with a 22q11.2 deletion. Methods We recorded high-density EEG from 19 individuals with 22q11.2 deletion syndrome (12-25 years), as well as 27 healthy volunteers with comparable age and sex distribution, while they listened to a sequence of sounds arranged in a roving oddball paradigm. Using posterior probability maps and dynamic causal modelling we tested three different models accounting for repetition dependent changes in cortical responses as well as in effective connectivity; namely an adaptation model, a prediction model, and a model including both adaptation and prediction. Results Repetition-dependent changes were parametrically modulated by a combination of adaptation and prediction and were apparent in both cortical responses and in the underlying effective connectivity. This effect was reduced in individuals with a 22q11.2 deletion and was negatively correlated with negative symptom severity. Follow-up analysis showed that the reduced effect of the combined adaptation and prediction model seen in individuals with 22q11.2 deletion was driven by reduced adaptation rather than prediction failure. Conclusions Our findings suggest that adaptation is reduced in individuals with a 22q11.2 deletion, which can be interpreted in light of the framework of predictive coding as a failure to suppress prediction errors.