Background: 22q11.2 deletion syndrome (22q11.2DS) is the most common chromosomal interstitial-deletion disorder, occurring in approximately 1 in 2000 to 6000 live births. Affected individuals exhibit variable clinical phenotypes that can include velopharyngeal anomalies, heart defects, T-cell-related immune deficits, dysmorphic facial features, neurodevelopmental disorders, including autism, early cognitive decline, schizophrenia, and other psychiatric disorders. Developing comprehensive treatments for 22q11.2DS requires an understanding of both the psychophysiological and neural mechanisms driving clinical outcomes. Our project probes the core psychophysiological abnormalities of 22q11.2DS in parallel with molecular studies of stem cell-derived neurons to unravel the basic mechanisms and pathophysiology of 22q11.2-related psychiatric disorders, with a primary focus on psychotic disorders. Our study is guided by the central hypothesis that abnormal neural processing associates with psychophysiological processing and underlies clinical diagnosis and symptomatology. Here, we present the scientific background and justification for our study, sharing details of our study design and human data collection protocol. Methods: Our study is recruiting individuals with 22q11.2DS and healthy comparison subjects between the ages of 16 and 60 years. We are employing an extensive psychophysiological assessment battery (e.g., EEG, evoked potential measures, and acoustic startle) to assess fundamental sensory detection, attention, and reactivity. To complement these unbiased measures of cognitive processing, we will develop stem-cell derived neurons and examine neuronal phenotypes relevant to neurotransmission. Clinical characterization of our 22q11.2DS and control participants relies on diagnostic and research domain criteria assessments, including standard Axis-I diagnostic and neurocognitive measures, following from the Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) and the North American Prodrome Longitudinal Study (NAPLS) batteries. We are also collecting measures of autism spectrum (ASD) and attention deficit/hyperactivity disorder (ADHD)-related symptoms. Discussion: Studying 22q11.2DS in adolescence and adulthood via deep phenotyping across multiple clinical and biological domains may significantly increase our knowledge of its core disease processes. Our manuscript describes our ongoing study’s protocol in detail. These paradigms could be adapted by clinical researchers studying 22q11.2DS, other CNV/single gene disorders, or idiopathic psychiatric syndromes, as well as by basic researchers who plan to incorporate biobehavioral outcome measures into their studies of 22q11.2DS.

Background Latency of the acoustic startle reflex is the time from presentation of the startling stimulus until the response, and provides an index of neural processing speed. Schizophrenia subjects exhibit slowed latency compared to healthy controls. One prior publication reported significant heritability of latency. The current study was undertaken to replicate and extend this solitary finding in a larger cohort. Methods Schizophrenia probands, their relatives, and control subjects from the Consortium on the Genetics of Schizophrenia (COGS-1) were tested in a paradigm to ascertain magnitude, latency, and prepulse inhibition of startle. Trial types in the paradigm were: pulse-alone, and trials with 30, 60, or 120ms between the prepulse and pulse. Comparisons of subject groups were conducted with ANCOVAs to assess startle latency and magnitude. Heritability of startle magnitude and latency was analyzed with a variance component method implemented in SOLAR v.4.3.1. Results 980 subjects had analyzable startle results: 199 schizophrenia probands, 456 of their relatives, and 325 controls. A mixed-design ANCOVA on startle latency in the four trial types was significant for subject group (F(2,973)=4.45, p=0.012) such that probands were slowest, relatives were intermediate and controls were fastest. Magnitude to pulse-alone trials differed significantly between groups by ANCOVA (F(2,974)=3.92, p=0.020) such that controls were lowest, probands highest, and relatives intermediate. Heritability was significant (p<0.0001), with heritability of 34–41% for latency and 45–59% for magnitude. Conclusion Both startle latency and magnitude are significantly heritable in the COGS-1 cohort. Startle latency is a strong candidate for being an endophenotype in schizophrenia.

Schizophrenia (SCZ) is an etiologically heterogeneous disease with genetic and environmental risk factors (e.g., Toxoplasma gondii infection) differing among affected individuals. Distinguishing such risk factors may point to differences in pathophysiological pathways and facilitate the discovery of individualized treatments. Toxoplasma gondii (TOXO) has been implicated in increasing the risk of schizophrenia. To determine whether TOXO-positive individuals with SCZ have a different polygenic risk burden than uninfected people, we applied the SCZ polygenic risk score (SCZ-PRS) derived from the Psychiatric GWAS Consortium separately to the TOXO-positive and TOXO-negative subjects with the diagnosis of SCZ as the outcome variable. The SCZ-PRS does not include variants in the major histocompatibility complex. Of 790 subjects assessed for TOXO, the 662 TOXO-negative subjects (50.8% with SCZ) reached a Bonferroni corrected significant association (p = 0.00017, R2 = 0.023). In contrast, the 128 TOXO-positive individuals (53.1% with SCZ) showed no significant association (p = 0.354) for SCZ-PRS and had a much lower R2 (R2 = 0.007). To account for Type-2 error in the TOXO-positive dataset, we performed a random sampling of the TOXO-negative subpopulation (n = 130, repeated 100 times) to simulate equivalent power between groups: the p-value was <0.05 for SCZ-PRS 55% of the time but was rarely (6% of the time) comparable to the high p-value of the seropositive group at p > 0.354. We found intriguing evidence that the SCZ-PRS predicts SCZ in TOXO-negative subjects, as expected, but not in the TOXO-positive individuals. This result highlights the importance of considering environmental risk factors to distinguish a subgroup with independent or different genetic components involved in the development of SCZ.

Background: The auditory N100 is an event related potential (ERP) that is reduced in schizophrenia, but its status in individuals at clinical high risk for psychosis (CHR) and its ability to predict conversion to psychosis remains unclear. We examined whether N100 amplitudes are reduced in CHR subjects relative to healthy controls (HC), and this reduction predicts conversion to psychosis in CHR. Methods: Subjects included CHR individuals (n = 552) and demographically similar HC subjects (n = 236) from the North American Prodrome Longitudinal Study. Follow-up assessments identified CHR individuals who converted to psychosis (CHR[sbnd]C; n = 73) and those who did not (CHR-NC; n = 225) over 24 months. Electroencephalography data were collected during an auditory oddball task containing Standard, Novel, and Target stimuli. N100 peak amplitudes following each stimulus were measured at electrodes Cz and Fz. Results: The CHR subjects had smaller N100 absolute amplitudes than HC subjects at Fz (F(1,786) = 4.00, p 0.046). A model comparing three groups (CHR[sbnd]C, CHR-NC, HC) was significant for Group at the Cz electrode (F(2,531) = 3.58, p = 0.029). Both Standard (p = 0.019) and Novel (p = 0.017) stimuli showed N100 absolute amplitude reductions in CHR-C relative to HC. A smaller N100 amplitude at Cz predicted conversion to psychosis in the CHR cohort (Standard: p = 0.009; Novel: p = 0.001) and predicted shorter time to conversion (Standard: p = 0.013; Novel: p = 0.001). Conclusion: N100 amplitudes are reduced in CHR individuals which precedes the onset of psychosis. N100 deficits in CHR individuals predict a greater likelihood of conversion to psychosis. Our results highlight N100's utility as a biomarker of psychosis risk.

The prevalence of Toxoplasma gondii (TOXO) infection in schizophrenia (SCZ) is elevated compared to controls (odds ratio = 2.73). TOXO infection is associated with psychomotor slowing in rodents and non-psychiatric humans. Latency of the acoustic startle response, an index of neural processing speed, is the time it takes for a startling stimulus to elicit the reflexive response through a three-synapse subcortical circuit. We report a significant slowing of latency in TOXO seropositive SCZ vs. seronegative SCZ, and in TOXO seropositive controls vs. seronegative controls. Latency was likewise slower in SCZ subjects than in controls. These findings indicate a slowing of neural processing speed with chronic TOXO infection; the slowest startle latency was seen in the TOXO seropositive SCZ group.

Background Pharmacologic treatment options for posttraumatic stress disorder (PTSD) are limited in number and effectiveness. Medications currently in use to treat PTSD were originally approved based on their efficacy in other disorders, such as major depression. Substantial research in PTSD suggests that increased activity of corticotropin releasing hormone (CRH)-containing circuits are involved in the pathophysiology of the disease. This Phase II trial aims to evaluate the efficacy of a CRH type 1 receptor (CRHR1) antagonist in the treatment of PTSD. Methods/design Currently untreated adult women, ages 18 to 65 years, with a primary psychiatric diagnosis of PTSD of at least 3 months’ duration, are being enrolled in a parallel-group, double-blind, placebo-controlled, randomized clinical trial evaluating the efficacy and safety of GSK561679, a novel CRHR1 receptor antagonist. GSK561679 (or matching placebo) is prescribed at a fixed dose of 350 mg nightly for six weeks. The primary trial hypothesis is that GSK561679 will reduce symptoms of PTSD, as measured by the Clinician-Administered PTSD Scale (CAPS), significantly more than placebo after six weeks of treatment. Putative biological markers of PTSD which may influence treatment response are measured prior to randomization and after five weeks’ exposure to the study medication, including: fear conditioning and extinction using psychophysiological measures; variants of stress-related genes and gene expression profiles; and indices of HPA axis reactivity. In addition, the impact of PTSD and treatment on neuropsychological performance and functional capacity are assessed at baseline and after the fifth week of study medication. After completion of the six-week double blind treatment period, subjects enter a one-month follow-up period to monitor for sustained response and resolution of any adverse effects. Discussion Considerable preclinical and human research supports the hypothesis that alterations in central nervous system CRH neuronal activity are a potential mediator of PTSD symptoms. This study is the first to assess the efficacy of a specific antagonist of a CRH receptor in the treatment of PTSD. Furthermore, the biological and neuropsychological measures included in this trial will substantially inform our understanding of the mechanisms of PTSD.

The mismatch negativity (MMN) event-related potential (ERP) component is increasingly viewed as a prediction error signal elicited when a deviant sound violates the prediction that a frequent "standard" sound will repeat. Support for this predictive coding framework emerged with the identification of the repetition positivity (RP), a standard stimulus ERP component that increases with standard repetition and is thought to reflect strengthening of the standard's memory trace and associated predictive code. Using electroencephalographic recordings, we examined the RP elicited by repeating standard tones presented during a traditional "constant standard" MMN paradigm in individuals with the psychosis risk syndrome (PRS; n = 579) and healthy controls (HC; n = 241). Clinical follow-up assessments identified PRS participants who converted to a psychotic disorder (n = 77) and PRS nonconverters who were followed for the entire 24-month clinical follow-up period and either remained symptomatic (n = 144) or remitted from the PRS (n = 94). In HC, RP linearly increased from early-to late-appearing standards within local trains of repeating standards (p <.0001), consistent with auditory predictive code/memory trace strengthening. Relative to HC, PRS participants showed a reduced RP across standards (p =.0056). PRS converters showed a relatively small RP deficit for early appearing standards relative to HC (p =.0.0107) and a more prominent deficit for late-appearing standards (p =.0006) relative to both HC and PRS-remitted groups. Moreover, greater RP deficits predicted shorter time to conversion in a subsample of unmedicated PRS individuals (p=.02). Thus, auditory predictive coding/memory trace deficits precede psychosis onset and predict future psychosis risk in PRS individuals.

Finding biological predictors and novel mechanisms underlying negative symptoms of schizophrenia is of significant importance given the lack of effective treatments. Increasing data support a role for metabolic dysfunction and inflammation in reward processing deficits in psychiatric illness. Herein, we found an interaction between lipids and inflammation as a predictor of worse negative symptom severity in individuals with schizophrenia. Future studies may seek to further elucidate this relationship and thereby reveal novel treatment targets for negative symptoms.

BACKGROUND: Schizophrenia (SCZ) is a neurodevelopmental disorder that leads to poor social function. Oxytocin (OXT), a neuropeptide involved in social cognition, is a potential therapeutic agent for alleviating social dysfunction. Therefore, we investigated the effects of intranasal oxytocin (IN-OXT) on emotional processes in experimental interactive social contexts in individuals with SCZ. METHODS: In a male-only parallel randomized placebo-controlled double-blind trial, we investigated the effects of IN-OXT (24 IU) on visual fixation on pictures of faces and emotion recognition in an interactive ball-tossing game that probed processing of social and nonsocial stimuli. RESULTS: Intranasal oxytocin enhanced the recognition of emotions during an emotion-based ball-tossing game. This improvement was specific to the game that included social cue processing. Intranasal oxytocin did not affect eye gaze duration or gaze dwell time on faces in these patients. CONCLUSIONS: An acute low dose of IN-OXT had a modest effect on social cue processing and was limited to emotion recognition. Higher doses and long-term trials targeting emotional processing in SCZ may lead to improved social function.

Fear-potentiated startle is defined as an increase in the magnitude of the startle reflex in the presence of a stimulus that was previously paired with an aversive event. It has been proposed that a subject’s awareness of the contingencies in the experiment may affect fear-potentiated startle. The authors adapted a conditional discrimination procedure (AX+/BX−), previously validated in animals, to a human fear-potentiated startle paradigm in 50 healthy volunteers. This paradigm allows for an assessment of fear-potentiated startle during threat conditions as well as inhibition of fear-potentiated startle during safety conditions. A response keypad was used to assess contingency awareness on a trial-by-trial basis. Both aware and unaware subjects showed fear-potentiated startle. However, awareness was related to stimulus discrimination and fear inhibition.