The Danish 22q11 research initiative

Background: Neurodevelopmental 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/design: The 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. Discussion: Identification 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

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

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.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.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. 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. Keywords: 22q11 deletion syndrome, Dynamic causal modelling, Posterior probability maps, EEG, Mismatch negativity, Repetition suppressio

Persistent gating deficit and increased sensitivity to NMDA receptor antagonism after puberty in a new mouse model of the human 22q11.2 micro-deletion syndrome – a study in male mice

Background: The hemizygous 22q11.2 micro-deletion is a common copy number variant in humans. The deletion confers high risk of neurodevelopmental disorders including autism and schizophrenia. Up to 41% of deletion carriers experience psychotic symptoms. Methods: We present a new mouse model (Df(h22q11)/+) of the deletion syndrome (22q11.2DS) and report on the most comprehensive study undertaken in 22q11.2DS models. The study was conducted in male mice. Results: We found elevated post-pubertal NMDA receptor antagonist induced hyper-locomotion, age-independent prepulse inhibition (PPI) deficits and increased acoustic startle response (ASR). The PPI deficit and increased ASR was resistant to antipsychotic treatment. The PPI deficit was not a consequence of impaired hearing measured by auditory brain stem responses. The Df(h22q11)/+ mice also displayed increased amplitude of loudness-dependent auditory evoked potentials. Prefrontal cortex and dorsal striatal (DStr) elevations of the dopamine metabolite DOPAC and increased DStr expression of the AMPA receptor subunit GluR1 was found. The Df(h22q11)/+ mice did not deviate from wild-type mice in a wide range of other behavioural and biochemical assays. Limitations: The 22q11.2 micro-deletion has incomplete penetrance in humans and the severity of disease depends on the complete genetic makeup in concert with environmental factors. In order to obtain more marked phenotypes reflecting the severe conditions related to 22q11.2DS it is suggested to expose the Df(h22q11)/+ mice to environmental stressors which may unmask latent psychopathology. Conclusion: The Df(h22q11)/+ model will be a valuable tool for increasing our understanding of the aetiology of schizophrenia and other psychiatric disorders associated with the 22q11DS.The research leading to these results was conducted as part of NEWMEDS and received support from the Innovative Medicine Initiative Joint Undertaking under grant agreement n° 115008 of which resources are composed of EFPIA in-kind contribution and financial contribution from the European Union’s Seventh Framework Programme (FP7/2007-2013). This work was further supported by grants from the Danish Advanced Technology Foundation (File no. 001-2009-2) and by the Instituto de Salud Carlos III, Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM)

22q11.2 deletion syndrome is associated with impaired auditory steady-state gamma response

Background: The 22q11.2 deletion syndrome confers a markedly increased risk for schizophrenia. 22q11.2 deletion carriers without manifest psychotic disorder offer the possibility to identify functional abnormalities that precede clinical onset. Since schizophrenia is associated with a reduced cortical gamma response to auditory stimulation at 40 Hz, we hypothesized that the 40 Hz auditory steady-state response (ASSR) may be attenuated in nonpsychotic individuals with a 22q11.2 deletion. Methods: Eighteen young nonpsychotic 22q11.2 deletion carriers and a control group of 27 noncarriers with comparable age range (12-25 years) and sex ratio underwent 128-channel EEG. We recorded the cortical ASSR to a 40 Hz train of clicks, given either at a regular inter-stimulus interval of 25 ms or at irregular intervals jittered between 11 and 37 ms. Results: Healthy noncarriers expressed a stable ASSR to regular but not in the irregular 40 Hz click stimulation. Both gamma power and inter-trial phase coherence of the ASSR were markedly reduced in the 22q11.2 deletion group. The ability to phase lock cortical gamma activity to regular auditory 40 Hz stimulation correlated with the individual expression of negative symptoms in deletion carriers (rho = -0.487, P = .041). Conclusions: Nonpsychotic 22q11.2 deletion carriers lack efficient phase locking of evoked gamma activity to regular 40 Hz auditory stimulation. This abnormality indicates a dysfunction of fast intracortical oscillatory processing in the gamma-band. Since ASSR was attenuated in nonpsychotic deletion carriers, ASSR deficiency may constitute a premorbid risk marker of schizophrenia