The development of neurocognitive biomarkers for schizophrenia (SCZ) has relied on lengthy test batteries that are infeasible to deploy in clinical settings. Using machine learning, we sought to identify a subset of neurocognitive domains that could distinguish between patients with SCZ and healthy comparison subjects (HCS). Leveraging data from 559 patients with SCZ or schizoaffective disorder and 745 HCS who completed 15 neurocognitive assessments spanning a diverse range of neurocognitive domains, we developed a machine learning model that could accurately separate SCZ from HCS (area under the receiver operating characteristic curve of 0.899), and was replicated in an independent cohort. Recursive feature elimination revealed that just two neurocognitive domains—verbal learning and emotion identification—were sufficient to achieve the same classification accuracy. These findings support a ‘less-is-more’ approach to efficient neurocognitive profiling across the schizophreniform spectrum and highlight what may be the most impaired neurocognitive domains in this debilitating disorder. This study identifies key neurocognitive domains that distinguish patients with schizophrenia from healthy individuals using machine learning. Analyzing data from 1,304 participants, it demonstrates that verbal learning and emotion identification effectively classify conditions, promoting efficient neurocognitive profiling strategies.

Background The hippocampus is smaller and functionally disrupted in individuals with 22q11.2 deletion syndrome (22q11DS), but the cause remains unclear. During gestational weeks 20 to 30, an inversion in the dentate gyrus and cornu ammonis occurs. This process can go awry, resulting in incomplete hippocampal inversion (IHI). In the general population, IHI is more common in the left hemisphere than the right hemisphere; however, its prevalence, severity, and functional impact in 22q11DS remain unexplored. Investigating IHI in 22q11DS could uncover morphological hippocampal abnormalities linked to neuropsychiatric and neurocognitive symptoms. Methods Using 3T structural magnetic resonance imaging data, the presence and severity of IHI were assessed in individuals with 22q11DS (n = 108) and healthy comparison participants (HCs) (n = 633). Total and subregional hippocampal volumes, psychopathology, and hippocampal-based memory were evaluated. Results IHI prevalence was significantly higher in individuals with 22q11DS compared with HCs in both the left (63% vs. 30%, p < .001) and right (29% vs. 8%, p < .001) hemispheres. IHI severity was also greater in participants with 22q11DS (p < .001) bilaterally. IHI influenced hippocampal volume differences, with left IHI primarily affecting the head (p < .01) and tail (p < .001) and right IHI affecting only the tail (p < .001). In exploratory analyses within participants with 22q11DS, left IHI presence was linked to poorer face memory (p < .05) but not to psychopathology. Conclusions These findings highlight a high prevalence of hippocampal morphological alterations in 22q11DS, which are associated with memory performance. Earlier developmental and longitudinal studies are needed to clarify the role of IHI in 22q11DS sequelae.

This article describes the rationale, aims, and methodology of the Accelerating Medicines Partnership® Schizophrenia (AMP® SCZ). This is the largest international collaboration to date that will develop algorithms to predict trajectories and outcomes of individuals at clinical high risk (CHR) for psychosis and to advance the development and use of novel pharmacological interventions for CHR individuals. We present a description of the participating research networks and the data processing analysis and coordination center, their processes for data harmonization across 43 sites from 13 participating countries (recruitment across North America, Australia, Europe, Asia, and South America), data flow and quality assessment processes, data analyses, and the transfer of data to the National Institute of Mental Health (NIMH) Data Archive (NDA) for use by the research community. In an expected sample of approximately 2000 CHR individuals and 640 matched healthy controls, AMP SCZ will collect clinical, environmental, and cognitive data along with multimodal biomarkers, including neuroimaging, electrophysiology, fluid biospecimens, speech and facial expression samples, novel measures derived from digital health technologies including smartphone-based daily surveys, and passive sensing as well as actigraphy. The study will investigate a range of clinical outcomes over a 2-year period, including transition to psychosis, remission or persistence of CHR status, attenuated positive symptoms, persistent negative symptoms, mood and anxiety symptoms, and psychosocial functioning. The global reach of AMP SCZ and its harmonized innovative methods promise to catalyze the development of new treatments to address critical unmet clinical and public health needs in CHR individuals.

BackgroundMinor physical anomalies (MPAs) are congenital morphological abnormalities linked to disruptions of fetal development. MPAs are common in 22q11.2 deletion syndrome (22q11DS) and psychosis spectrum disorders (PS) and likely represent a disruption of early embryologic development that may help identify overlapping mechanisms linked to psychosis in these disorders.MethodsHere, 2D digital photographs were collected from 22q11DS (n = 150), PS (n = 55), and typically developing (TD; n = 93) individuals. Photographs were analyzed using two computer-vision techniques: (1) DeepGestalt algorithm (Face2Gene (F2G)) technology to identify the presence of genetically mediated facial disorders, and (2) Emotrics-a semi-automated machine learning technique that localizes and measures facial features.ResultsF2G reliably identified patients with 22q11DS; faces of PS patients were matched to several genetic conditions including FragileX and 22q11DS. PCA-derived factor loadings of all F2G scores indicated unique and overlapping facial patterns that were related to both 22q11DS and PS. Regional facial measurements of the eyes and nose were smaller in 22q11DS as compared to TD, while PS showed intermediate measurements.ConclusionsThe extent to which craniofacial dysmorphology 22q11DS and PS overlapping and evident before the impairment or distress of sub-psychotic symptoms may allow us to identify at-risk youths more reliably and at an earlier stage of development.

Back to table of contents Previous article Priority Data LetterNo AccessSensitivity of Schizophrenia Endophenotype Biomarkers to Anticholinergic Medication BurdenYash B. Joshi, M.D., Ph.D., Juan L. Molina, M.D., David L. Braff, M.D., Michael F. Green, Ph.D., Ruben C. Gur, Ph.D., Raquel E. Gur, M.D., Ph.D., Keith H. Nuechterlein, Ph.D., William S. Stone, Ph.D., Tiffany A. Greenwood, Ph.D., Laura C. Lazzeroni, Ph.D., Allen D. Radant, M.D., Jeremy M. Silverman, Ph.D., Joyce Sprock, B.A., Catherine A. Sugar, Ph.D., Debby W. Tsuang, M.D., Ph.D., Ming T. Tsuang, M.D., Ph.D., Bruce I. Turetsky, M.D., Neal R. Swerdlow, M.D., Ph.D., Gregory A. Light, Ph.D.Yash B. Joshi, M.D., Ph.D., Juan L. Molina, M.D., David L. Braff, M.D., Michael F. Green, Ph.D., Ruben C. Gur, Ph.D., Raquel E. Gur, M.D., Ph.D., Keith H. Nuechterlein, Ph.D., William S. Stone, Ph.D., Tiffany A. Greenwood, Ph.D., Laura C. Lazzeroni, Ph.D., Allen D. Radant, M.D., Jeremy M. Silverman, Ph.D., Joyce Sprock, B.A., Catherine A. Sugar, Ph.D., Debby W. Tsuang, M.D., Ph.D., Ming T. Tsuang, M.D., Ph.D., Bruce I. Turetsky, M.D., Neal R. Swerdlow, M.D., Ph.D., Gregory A. Light, Ph.D.Published Online:11 Apr 2023https://doi.org/10.1176/appi.ajp.20220649AboutSectionsView articleView Full TextPDF/EPUB ToolsAdd to favoritesDownload CitationsTrack Citations ShareShare onFacebookTwitterLinked InEmail View article Access content To read the fulltext, please use one of the options below to sign in or purchase access. Personal login Institutional Login Sign in via OpenAthens Register for access Purchase Save for later Item saved, go to cart PPV Articles - American Journal of Psychiatry $35.00 Add to cart PPV Articles - American Journal of Psychiatry Checkout Please login/register if you wish to pair your device and check access availability. Not a subscriber? Subscribe Now / Learn More PsychiatryOnline subscription options offer access to the DSM-5 library, books, journals, CME, and patient resources. This all-in-one virtual library provides psychiatrists and mental health professionals with key resources for diagnosis, treatment, research, and professional development. Need more help? PsychiatryOnline Customer Service may be reached by emailing [email protected] or by calling 800-368-5777 (in the U.S.) or 703-907-7322 (outside the U.S.). FiguresReferencesCited byDetailsCited byPoints that Need Attention in Early Auditory Information Processing Research in Schizophrenia: Response to Lin and HsiehYash Joshi, M.D., Ph.D., Neal Swerdlow, M.D., Ph.D., Gregory Light, Ph.D.1 November 2023 | American Journal of Psychiatry, Vol. 180, No. 11Points that Need Attention in Early Auditory Information Processing Research in SchizophreniaYi-Ting Lin, M.D. Ming H. Hsieh, M.D., Ph.D.1 November 2023 | American Journal of Psychiatry, Vol. 180, No. 11The Power of PotentialsSteven Siegel, M.D., Ph.D., Lindsey Crown, Ph.D., Robert Featherstone, Ph.D.1 July 2023 | American Journal of Psychiatry, Vol. 180, No. 7From Postmortem Molecular Studies to Social Determinants of Health Relevant to Racial and Ethnic DisparitiesNed H. Kalin, M.D.1 July 2023 | American Journal of Psychiatry, Vol. 180, No. 7 Volume 180Issue 7 July 01, 2023Pages 519-523 Metrics KeywordsSchizophrenia Spectrum and Other Psychotic DisordersCognition/Learning/MemoryPharmacotherapyPDF download History Received 27 July 2022 Revised 2 November 2022 Accepted 12 December 2022 Published online 11 April 2023 Published in print 1 July 2023

Schizophrenia has a heritability of 60-80%1, much of which is attributable to common risk alleles. Here, in a two-stage genome-wide association study of up to 76,755 individuals with schizophrenia and 243,649 control individuals, we report common variant associations at 287 distinct genomic loci. Associations were concentrated in genes that are expressed in excitatory and inhibitory neurons of the central nervous system, but not in other tissues or cell types. Using fine-mapping and functional genomic data, we identify 120 genes (106 protein-coding) that are likely to underpin associations at some of these loci, including 16 genes with credible causal non-synonymous or untranslated region variation. We also implicate fundamental processes related to neuronal function, including synaptic organization, differentiation and transmission. Fine-mapped candidates were enriched for genes associated with rare disruptive coding variants in people with schizophrenia, including the glutamate receptor subunit GRIN2A and transcription factor SP4, and were also enriched for genes implicated by such variants in neurodevelopmental disorders. We identify biological processes relevant to schizophrenia pathophysiology; show convergence of common and rare variant associations in schizophrenia and neurodevelopmental disorders; and provide a resource of prioritized genes and variants to advance mechanistic studies.

Semantic processing abnormalities have been observed across the schizophrenia spectrum. However, it is unclear whether associations between semantic processing measures and schizotypal traits are stable over time. The current study aimed to explore the temporal stability of semantic processing measures and their correlations with schizotypal traits. In this study, we used the Schizotypal Personality Questionnaire (SPQ) to assess schizotypal traits and explored the association between schizotypal traits and semantic processing measures (i.e., N400- a large negativity with a broad scalp distribution, peaking around 400 ms after the presentation of any potentially meaningful stimulus) at baseline (Time 1; n = 63) and 3 months later (Time 2; n = 44). Repeated-measure ANOVA was conducted to examine the stability of the semantic processing measures; the intraclass correlation coefficient (ICC) was used to examine test-retest reliability; Pearson's r was calculated to explore associations between schizotypal traits and semantic processing measures. Results showed that both behavioral (reaction times) and N400 measures showed high reliability but low temporal stability. N400 latency for semantically unrelated stimuli was correlated with the cognitive-perceptual and the disorganized dimensions of schizotypal traits at Time 2. In conclusion, semantic processing measures generally showed good reliability. Schizotypal traits were correlated with N400 latencies in the current sample, but further studies are needed to examine whether this association is stable.

OBJECTIVE:Many psychotropic medications used to treat schizophrenia have significant anticholinergic properties, which are linked to cognitive impairment and dementia risk in healthy subjects. Clarifying the impact of cognitive impairment attributable to anticholinergic medication burden may help optimize cognitive outcomes in schizophrenia. The aim of this study was to comprehensively characterize how this burden affects functioning across multiple cognitive domains in schizophrenia outpatients.METHODS:Cross-sectional data were analyzed using inferential statistics and exploratory structural equation modeling to determine the relationship between anticholinergic medication burden and cognition. Patients with a diagnosis of schizophrenia or schizoaffective disorder (N=1,120) were recruited from the community at five U.S. universities as part of the Consortium on the Genetics of Schizophrenia-2. For each participant, prescribed medications were rated and summed according to a modified Anticholinergic Cognitive Burden (ACB) scale. Cognitive functioning was assessed by performance on domains of the Penn Computerized Neurocognitive Battery (PCNB).RESULTS:ACB score was significantly associated with cognitive performance, with higher ACB groups scoring worse than lower ACB groups on all domains tested on the PCNB. Similar effects were seen on other cognitive tests. Effects remained significant after controlling for demographic characteristics and potential proxies of illness severity, including clinical symptoms and chlorpromazine-equivalent antipsychotic dosage.CONCLUSIONS:Anticholinergic medication burden in schizophrenia is substantial, common, conferred by multiple medication classes, and associated with cognitive impairments across all cognitive domains. Anticholinergic medication burden from all medication classes-including psychotropics used in usual care-should be considered in treatment decisions and accounted for in studies of cognitive functioning in schizophrenia.

Negative symptoms and cognitive deficits contribute strongly to disability in schizophrenia, and are resistant to existing medications. Recent drug development has targeted enhanced NMDA function by increasing mGluR2/3 signaling. However, the clinical utility of such agents remains uncertain, and markers of brain circuit function are critical for clarifying mechanisms and understanding individual differences in efficacy. We conducted a double-blind, placebo-controlled, randomized cross-over (14 day washout) pilot study evaluating adjunctive use of the mGluR2 positive allosteric modulator AZD8529 (80 mg daily for 3 days), in chronic stable patients with schizophrenia (n = 26 analyzed). We focused on 3 T fMRI response in frontostriatal regions during an n-back working memory task, testing the hypothesis that AZD8529 produces fMRI changes that correlate with improvement in negative symptoms and cognition. We found that AZD8529 did not produce significant group-average effects on symptoms or cognitive accuracy. However, AZD8529 did increase n-back fMRI activation in striatum (p < 0.0001) and anterior cingulate/paracingulate (p = 0.002). Greater drug-versus-placebo effects on caudate activation significantly correlated with greater reductions in PANSS negative symptom scores (r = −0.42, p = 0.031), and exploratory correlations suggested broader effects across multiple symptom domains and regions of interest. These findings demonstrate that fMRI responses to mGluR2 positive modulation relate to individual differences in symptom reduction, and could be pursued for future biomarker development. Negative clinical results at the group level should not lead to premature termination of investigation of this mechanism, which may benefit an important subset of individuals with schizophrenia. Imaging biomarkers may reveal therapeutic mechanisms, and help guide treatment toward specific populations.

For individuals at risk for psychosis, mood disturbances, such as depression, are thought to exacerbate psychosis symptoms, increase the risk of transitioning from prodrome to psychosis, and may lead to poorer prognosis and global functioning. Thus, understanding specific relations among mood and different psychosis spectrum symptoms is important. The present investigation aims to determine whether, 1) particular psychosis spectrum symptoms are associated with greater mood disturbance, and 2) differential effects of current mood state versus lifetime mood disorder diagnoses exist.

A quantitative review of literature concerning olfactory function in 22q11.2 deletion syndrome (22q11DS) patients was performed detailing the scope/magnitude of deficits and probing possible moderators. We searched MEDLINE, EMBASE and PubMed to identify studies for inclusion. Effect sizes were based on differences in psychophysical olfactory tests between 22q11DS patients (n = 194) and typically developing comparison subjects (n = 466). 22q11DS patients exhibited marked olfactory dysfunction (d=-1.11, 95% CI=-1.29<δ<-0.92) that was homogeneous (p = 0.86). Diffuse olfactory deficits were seen which were not moderated by age or sex. 22q11DS patients exhibit large/diffuse deficits in olfactory function that are of a similar magnitude to observed neuropsychological impairments.

Recently emerging evidence indicates accelerated age-related changes in the structure and function of the brain in schizophrenia, raising a question about its potential consequences on cognitive function. Using a large sample of schizophrenia patients and controls and a battery of tasks across multiple cognitive domains, we examined whether patients show accelerated age-related decline in cognition and whether an age-related effect differ between females and males. We utilized data of 1,415 schizophrenia patients and 1,062 healthy community collected by the second phase of the Consortium on the Genetics of Schizophrenia (COGS-2). A battery of cognitive tasks included the Letter-Number Span Task, two forms of the Continuous Performance Test, the California Verbal Learning Test, Second Edition, the Penn Emotion Identification Test and the Penn Facial Memory Test. The effect of age and gender on cognitive performance was examined with a general linear model. We observed age-related changes on most cognitive measures, which was similar between males and females. Compared to controls, patients showed greater deterioration in performance on attention/vigilance and greater slowness of processing social information with increasing age. However, controls showed greater age-related changes in working memory and verbal memory compared to patients. Age-related changes (η2p of 0.001 to .008) were much smaller than between-group differences (η2p of 0.005 to .037). This study found that patients showed continued decline of cognition on some domains but stable impairment or even less decline on other domains with increasing age. These findings indicate that age-related changes in cognition in schizophrenia are subtle and not uniform across multiple cognitive domains.

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 120 ms 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. Published by Elsevier B.V.y

Background: Traumatic experiences are associated with neumfunctional dysregulations in key regions of the emotion regulation circuits. In particular, amygdala responsivity to negative stimuli is exaggerated while engagement of prefrontal regulatory control regions is attenuated. Successful application of emotion regulation (ER) strategies may counteract this disbalance, however, application of learned strategies in daily life is hampered in individuals afflicted by posttraumatic stress disorder (PTSD). We hypothesized that a single session of real-time fMRI (rtfMRI) guided upregulation of prefrontal regions during an emotion regulation task enhances self-control during exposure to negative stimuli and facilitates transfer of the learned ER skills to daily life. Methods: In a cross-over design, individuals with a PTSD diagnosis after a single traumatic event (n = 20) according to DSM-IV-TR criteria and individuals without a formal psychiatric diagnosis (n = 21) underwent a cognitive reappraisal training. In randomized order, all participants completed two rtfMRI neumfeedback (NF) runs targeting the left lateral prefrontal cortex (1PFC) and two control runs without NF (NoNF) while using cognitive reappraisal to reduce their emotional response to negative scenes. During the NoNF runs, two %%-signs were displayed instead of the two-digit feedback (FB) to achieve a comparable visual stimulation. The project aimed at defining the clinical potential of the training according to three success markers: (1) NF induced changes in left lateral prefrontal cortex and bilateral amygdala activity during the regulation of aversive scenes compared to cognitive reappraisal alone (primary registered outcome), (2) associated changes on the symptomatic and behavioral level such as indicated by PTSD symptom severity and affect ratings, (3) clinical utility such as indicated by perceived efficacy, acceptance, and transfer to daily life measured four weeks after the training. Results: In comparison to the reappraisal without feedback, a neurofeedback-specific decrease in the left lateral PFC (d = 0.54) alongside an attenuation of amygdala responses (d = 0.33) emerged. Reduced amygdala responses during NF were associated with symptom improvement (r = 0.42) and less negative affect (r = 0.63) at followup. The difference in symptom scores exceeds requirements for a minimal clinically important difference and corresponds to a medium effect size (d= 0.64). Importantly, 75% of individuals with PTSD used the strategies in daily life during a one-month follow-up period and perceived the training as efficient. Conclusion: Our findings suggest beneficial effects of the NF training indicated by reduced amygdala responses that were associated with improved symptom severity and affective state four weeks after the NF training as well as patient-centered perceived control during the training, helpfulness and application of strategies in daily life. However, reduced prefrontal involvement was unexpected. The study suggests good tolerability of the training protocol and potential for clinical use in the treatment of PTSD.

Brain iron is vital to multiple aspects of brain function, including oxidative metabolism, myelination, and neurotransmitter synthesis. Atypical iron concentration in the basal ganglia is associated with neurodegenerative disorders in aging and cognitive deficits. However, the normative development of brain iron concentration in adolescence and its relationship to cognition are less well understood. Here, we address this gap in a longitudinal sample of 922 humans aged 8–26 years at the first visit (M = 15.1, SD = 3.72; 336 males, 486 females) with up to four multiecho T2* scans each. Using this sample of 1236 imaging sessions, we assessed the longitudinal developmental trajectories of tissue iron in the basal ganglia. We quantified tissue iron concentration using R2* relaxometry within four basal ganglia regions, including the caudate, putamen, nucleus accumbens, and globus pallidus. The longitudinal development of R2* was modeled using generalized additive mixed models (GAMMs) with splines to capture linear and nonlinear developmental processes. We observed significant increases in R2* across all regions, with the greatest and most prolonged increases occurring in the globus pallidus and putamen. Further, we found that the developmental trajectory of R2* in the putamen is significantly related to individual differences in cognitive ability, such that greater cognitive ability is increasingly associated with greater iron concentration through late adolescence and young-adulthood. Together, our results suggest a prolonged period of basal ganglia iron enrichment that extends into the mid-twenties, with diminished iron concentration associated with poorer cognitive ability during late adolescence. SIGNIFICANCE STATEMENT Brain tissue iron is essential to healthy brain function. Atypical basal ganglia tissue iron levels have been linked to impaired cognition in iron deficient children and adults with neurodegenerative disorders. However, the normative developmental trajectory of basal ganglia iron concentration during adolescence and its association with cognition are less well understood. In the largest study of tissue iron development yet reported, we characterize the developmental trajectory of tissue iron concentration across the basal ganglia during adolescence and provide evidence that diminished iron content is associated with poorer cognitive performance even in healthy youth. These results highlight the transition from adolescence to adulthood as a period of dynamic maturation of tissue iron concentration in the basal ganglia.

Natural systems, including the brain, often seem chaotic, since they are typically driven by complex nonlinear dynamical processes. Disruption in the fluid coordination of multiple brain regions contributes to impairments in information processing and the constellation of symptoms observed in neuropsychiatric disorders. Schizophrenia (SZ), one of the most debilitating mental illnesses, is thought to arise, in part, from such a network dysfunction, leading to impaired auditory information processing as well as cognitive and psychosocial deficits. Current approaches to neurophysiologic biomarker analyses predominantly rely on linear methods and may, therefore, fail to capture the wealth of information contained in whole EEG signals, including nonlinear dynamics. In this study, delay differential analysis (DDA), a nonlinear method based on embedding theory from theoretical physics, was applied to EEG recordings from 877 SZ patients and 753 nonpsychiatric comparison subjects (NCSs) who underwent mismatch negativity (MMN) testing via their participation in the Consortium on the Genetics of Schizophrenia (COGS-2) study. DDA revealed significant nonlinear dynamical architecture related to auditory information processing in both groups. Importantly, significant DDA changes preceded those observed with traditional linear methods. Marked abnormalities in both linear and nonlinear features were detected in SZ patients. These results illustrate the benefits of nonlinear analysis of brain signals and underscore the need for future studies to investigate the relationship between DDA features and pathophysiology of information processing.

The mismatch negativity is a cortical response to auditory changes and its reduction is a consistent finding in schizophrenia. Recent evidence revealed that the human brain detects auditory changes already at subcortical stages of the auditory pathway. This finding, however, raises the question where in the auditory hierarchy the schizophrenic deficit first evolves and whether the well-known cortical deficit may be a consequence of dysfunction at lower hierarchical levels. Finally, it should be resolved whether mismatch profiles differ between schizophrenia and affective disorders which exhibit auditory processing deficits as well. We used functional magnetic resonance imaging to assess auditory mismatch processing in 29 patients with schizophrenia, 27 patients with major depression, and 31 healthy control subjects. Analysis included whole-brain activation, region of interest, path and connectivity analysis. In schizophrenia, mismatch deficits emerged at all stages of the auditory pathway including the inferior colliculus, thalamus, auditory, and prefrontal cortex. In depression, deficits were observed in the prefrontal cortex only. Path analysis revealed that activation deficits propagated from subcortical to cortical nodes in a feed-forward mechanism. Finally, both patient groups exhibited reduced connectivity along this processing stream. Auditory mismatch impairments in schizophrenia already manifest at the subcortical level. Moreover, subcortical deficits contribute to the well-known cortical deficits and show specificity for schizophrenia. In contrast, depression is associated with cortical dysfunction only. Hence, schizophrenia and major depression exhibit different neural profiles of sensory processing deficits. Our findings add to a converging body of evidence for brainstem and thalamic dysfunction as a hallmark of schizophrenia.

We have previously reported our efforts to characterize the genetic architecture of 12 heritable endophenotypes for schizophrenia in the COGS-1 family sample. Candidate gene association and genome-wide linkage results converge on a single network related to glutamate signaling. We now report genome-wide association results for these endophenotypes in an independent cohort of schizophrenia cases and controls.