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. 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. 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 schizophrenia or bipolar disorder have attenuated auditory mismatch negativity (MMN) responses, indicating impaired sensory information processing. Computational models of effective connectivity between brain areas underlying MMN responses show reduced connectivity between fronto-temporal areas in individuals with schizophrenia. Here we ask whether children at familial high risk (FHR) of developing a serious mental disorder show similar alterations.We recruited 67 children at FHR for schizophrenia, 47 children at FHR for bipolar disorder as well as 59 matched population-based controls from the Danish High Risk and Resilience study. The 11-12-year-old participants engaged in a classical auditory MMN paradigm with deviations in frequency, duration, or frequency and duration, while we recorded their EEG. We used dynamic causal modeling (DCM) to infer on the effective connectivity between brain areas underlying MMN.DCM yielded strong evidence for differences in effective connectivity among groups in connections from right inferior frontal gyrus (IFG) to right superior temporal gyrus (STG), along with differences in intrinsic connectivity within primary auditory cortex (A1). Critically, the 2 high-risk groups differed in intrinsic connectivity in left STG and IFG as well as effective connectivity from right A1 to right STG. Results persisted even when controlling for past or present psychiatric diagnoses.We provide novel evidence that connectivity underlying MMN responses in children at FHR for schizophrenia and bipolar disorder is altered at the age of 11-12, echoing findings that have been found in individuals with manifest schizophrenia.
Patients with obsessive compulsive disorder (OCD) often show deficits in inhibitory control, which may underlie poor control over obsessions and compulsions. Several functional magnetic resonance imaging (fMRI) experiments utilizing a variety of tasks have investigated the neural correlates of inhibitory control in OCD. Evidence from existing meta-analyses suggests aberrant activation of regions in fronto-striatal circuits during inhibitory control. However, new fMRI articles have since been published, and a more rigorous methodology for neuroimaging meta-analyses is now available. First, to reevaluate the evidence for abnormal brain activation during performance of inhibitory control tasks in OCD while adhering to current best practices for meta-analyses, and second, to extend previous findings by separately assessing different subprocesses of inhibitory control. We systematically searched Web of Knowledge, ScienceDirect, Scopus, PubMed and the functional BrainMap database for fMRI articles that compared activation during performance of inhibitory control tasks in patients with OCD and healthy control (HC) subjects. Thirty-five experiments from 21 articles met our criteria for inclusion. We first performed activation-likelihood-estimation meta-analyses to elucidate brain areas in which case-control activation differences converged across articles and tasks. We then aimed to extend previous work by separately evaluating experiments requiring inhibition of a prepotent response without execution of an alternative response (i.e., response inhibition) and experiments requiring inhibition of a prepotent response and execution of an alternative response (i.e., cognitive inhibition). The 35 experiments included a total of 394 patients and 410 controls. We did not find evidence of abnormal brain activation in OCD during inhibitory control when pooling data from all experiments. Analysis restricted to cognitive inhibition experiments showed abnormal activation of the dorsal anterior cingulate cortex (dACC; P = .04, cluster-level familywise error-corrected, cluster volume of 824 mm3). We did not have sufficient data to evaluate response inhibition experiments separately. Findings of abnormal brain activation in OCD from different inhibitory control tasks do not appear to converge on the same brain regions, but the dACC may be implicated in abnormal cognitive inhibition. Our findings highlight a need for experiments that specifically target subprocesses of inhibitory control to achieve a more differentiated understanding of the neural correlates for impaired inhibitory control in OCD.
Abstract 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.
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.
Aim: Studying children of parents with schizophrenia or bipolar disorder, i.e. who are at familial high-risk of developing similar disorders, offers the possibility to identify abnormalities preceding the emergence of mental health disorders during adolescence. This paper reports the rationale and methodology of a single-site electroencephalography-study of the register-based Danish High Risk and Resilience Study–VIA 11. Focusing on event-related electroencephalographic read-outs that have previously been proposed as endophenotypes for schizophrenia, we set out to retrieve these endophenotypes in children at familial high-risk. Method: Event-related cortical responses to repetitive auditory stimuli or visuospatial flanker stimuli will be recorded with 128-channel electroencephalography in eleven-year-old children with one or two parents diagnosed with schizophrenia spectrum psychosis (n>40) or bipolar disorder (n>40) and control children without familial high-risk (n>40). We will test for between-group differences in auditory processing, focusing on the auditory steady-state response and mismatch negativity. We will also assess between-group differences in visually evoked cortical activity implicated in the resolution of a visuomotor response conflict such as P3b potential and lateralized readiness potential. We will further examine whether the individual expression of these electroencephalographic read-outs scale with clinical characteristics.Conclusions: The study will clarify whether the electroencephalographic-derived endophenotypes are only expressed in children of parents with schizophrenia or will also be present in children of parents with bipolar disorder. The multiple electrophysiological-based read-outs of brain reactivity will enable additional exploratory analyses. Together, the study will contribute to current attempts to validate and identify electroencephalographic-based endophenotypes of vulnerability for mental health disorders.
The ability to rapidly adjust our actions to changes in the environment is a key function of human motor control. Previous work implicated the dorsal premotor cortex (dPMC) in the up-dating of action plans based on environmental cues. Here we used electroencephalography (EEG) to identify neural signatures of up-dating cue-action relationships in the dPMC and connected frontoparietal areas. Ten healthy subjects performed a pre-cued alternate choice task. Simple geometric shapes cued button presses with the right or left index finger. The shapes of the pre-cue and go-cue differed in two third of trials. In these incongruent trials, the go-cue prompted a re-evaluation of the pre-cued action plan, slowing response time relative to trials with identical cues. This re-evaluation selectively increased theta band activity without modifying activity in alpha and beta band. Source-based analysis revealed a widespread theta increase in dorsal and mesial frontoparietal areas, including dPMC, supplementary motor area (SMA), primary motor and posterior parietal cortices (PPC). Theta activity scaled positively with response slowing and increased more strongly when the pre-cue was invalid and required subjects to select the alternate response. Together, the results indicate that theta activity in dPMC and connected frontoparietal areas is involved in the re-adjustment of cue-induced action tendencies.
